Wellness and Prevention
Preface
Vincent Morelli, MD Roger Zoorob, MD, MPH Guest Editors
Research in the fields of wellness and prevention has increased dramatically in the last decade, and, as a result, the public’s awareness and interest in these realms has also been heightened. Today, more than ever, our patients seem to be looking to us as ‘‘information analysts’’ to help them wade through the ever-rising sea of health information and misinformation that is widely distributed on the Internet and in other publications. This issue of Primary Care: Clinics in Office Practice will be divided into two parts. First we will examine the latest data in the prevention of our most noted killers: cardiovascular disease, diabetes, obesity, and cancer. The second part will examine the plethora of information surrounding wellness—our relatively new concept of health maximization. We will examine the current hard data, as well as the hopes and theoretical claims of manufacturers and alternative practitioners. Much scientific work has been done in these domains in recent years, but more remains to be done. Our aim is to separate fact from fiction, the known from the hoped for, and to delineate the strengths, weaknesses, and limits of current medical research. We hope that primary care providers and medical students will find our work well written, well researched, and clinically relevant. We are pleased and honored to serve as Guest Editors for this issue, and we feel privileged to have worked with such a distinguished group of collaborators. Many thanks to the contributing authors who have worked painstakingly to make their articles scholarly and relevant in the clinical setting. We also thank the Department of Family and Community Medicine at Meharry Medical College and the Family Medicine Program at Vanderbilt University for providing us with the support needed to complete this project. Thanks also to Elissa Clapp for her creative contributions and to The New
Prim Care Clin Office Pract 35 (2008) xiii–xiv doi:10.1016/j.pop.2008.07.016 primarycare.theclinics.com 0095-4543/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.
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Orleans Healing Center for their inspiration and direction. Finally, our sincere thanks to our editor at Elsevier, Barbara Cohen-Kligerman, without whose help this project would never have been accomplished. Vincent Morelli, MD Family and Community Medicine Meharry Medical College 1005 Dr. DB Todd Boulevard Nashville, TN 37208 Roger Zoorob, MD, MPH Family and Community Medicine Meharry Medical College Family Medicine Residency 1005 Dr. DB Todd Boulevard Nashville, TN 37208 E-mail addresses:
[email protected] (V. Morelli)
[email protected] (R. Zoorob)
Preventing Hear t Dis eas e : Who Ne e ds to b e Concerne d a nd What to Do Mohamad Sidani, MD, MS*, Carol Ziegler, MS, RD, FNP KEYWORDS Antioxidants Vitamin E Vitamin B12 Vitamin C Folic acid Exercise
Cardiovascular disease (CVD) is the most prevalent health challenge to the global health care industry.1 Mortality from CVD accounted for 30% all mortality in the world during 2005. There were 7.2 million deaths from ischemic heart disease, 5.5 million deaths from cerebrovascular disease, and 3.9 million deaths from hypertension.1 It is projected that by the year 2010 CVD will be the leading cause of death in the developing world.2 For the past 80 years, CVD has been the leading cause of death in the United States and heavily burdens the economy at a cost of $314.1 billion in 2007.3 Although in the United States rates of CVD are elevated in rural compared with urban areas,4 these trends are reversed in nonindustrialized nations.5,6 Numerous epidemiologic studies link worldwide urbanization with adoption of adverse lifestyle changes and resultant increases in CVD.7 This effect may be attributable to decreases in physical activity and dietary fiber coupled with simultaneous increases in dietary fat and total calories consumed.8 Increased incidence of CVD is observed in immigrants who migrate to the United States when compared with those who have not expatriated. This same trend is seen in developing countries when citizens relocate from rural to urban areas.9–12 We could find no studies examining CVD when moving from third world cities where CVD risk is elevated, to United States cities where CVD is less prevalent than rural areas. The INTERHEART study identified risk factors associated with first myocardial infarction (MI). These risk factors include: family or personal history of previous MI, smoking, hypertension, specifically elevated systolic pressure, energy-dense/nutrient-poor diet, dyslipidemia, specifically elevated low density lipoprotein (LDL), physical inactivity, obesity, hyperglycemia, and type A personality.13 Many risk factors,
Meharry Medical College, School of Medicine, Department of Family and Community Medicine, 1005 Door, DB Todd Boulevard, Nashville, TN 37208, USA * Corresponding author. E-mail address:
[email protected] (M. Sidani). Prim Care Clin Office Pract 35 (2008) 589–607 doi:10.1016/j.pop.2008.07.007 primarycare.theclinics.com 0095-4543/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.
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such as personal history of MI, hypertension, hyperglycemia, obesity, and dyslipidemia, are identified late in disease progression and 50% of men and 63% of women who die suddenly from MI have no prior symptoms or known risk.14 The goal of prevention is compression of morbidity and enhancement of quality of life through modification of lifestyle and environmental risk factors. Treatment of established cardiovascular disease is expensive and inefficient relative to disease prevention. Early implementation of preventive measures aimed at decreasing risks for hypertension, elevated lipids, obesity, and smoking may decrease death and disability from CVD by 50%.2 Several randomized controlled trials have examined the effect of various lifestyle changes on the reduction of established CVD. The Lifestyle Heart Trial examined the effect of intensive lifestyle changes (10% fat, whole food vegetarian diet, aerobic exercise, stress management training, smoking cessation, and group psychosocial support) on 5-year CVD risk and reported CVD regression and decreased incidence of MI in the experimental group compared with CVD progression and increased incidence of MI in the control group.15 Although such regimented lifestyle changes are difficult to maintain in ‘‘real life,’’ some effective dietary and lifestyle interventions are addressed. This article discusses some of the more common nonpharmacologic methods of preventing heart disease. Primary versus secondary prevention is discussed if applicable. SMOKING
It is well established that smoking increases risk for heart disease and death from MI.16–18 Encouraging patients not to start smoking and assisting current smokers by way of smoking cessation interventions are crucial in the prevention of heart disease. Secondhand smoke exposure is an independent risk factor in CVD and constant exposure to secondhand smoke doubles the risk for MI.19 The establishment of this public health risk has lead to the enactment of legislation banning smoking in many public areas and launched research over the concern of links between environmental air pollution and CVD. AIR POLLUTION
Concerns over environmental exposure to pro-atherogenic matter may have farreaching effects for global health policy. Epidemiologic research suggests that particulate matter smaller than 2.5 mm in diameter (PM2.5) may injure cardiovascular tissue and promote atherosclerosis. (PM2.5 is generally emitted from activities such as industrial and residential combustion and from vehicle exhaust.) In 2007 the worst three cities in the United States for exposure to this matter were Los Angeles, California; Pittsburgh, Pennsylvania; and Fresno, California. (A ranking of cities by annual PM2.5 exposure levels may be found at the American Lung Association Web site http://lungaction.org/reports/sota07_cities.html). Air pollution has in fact been linked to increased rates of heart disease and triggering MI,20 and surprisingly seems to have a more deleterious effect on cardiovascular than pulmonary tissues.21 The Women’s Health Initiative Study showed a 24% increase in CVD and a 76% increase in CV mortality per 10 mg/m3 increase in annual average PM2.5 level,22 establishing a strong link between environmental exposure to small particulate atmospheric matter and CVD mortality. Another cross-sectional exposure study found that for every 10 mg/m3 increase in PM2.5 levels, carotid intima-medial thickness increased 5.9%23 (for reference the EPA sets the United States standard of safety at an average of 15 mg/m3; Beijing, Cairo,
Preventing Heart Disease
and Delhi all have PM2.5 levels greater than 150 mg/m3). The impact of air quality on cardiovascular health needs to be investigated further, but people living in areas where there is a relatively significant level of exposure to small particulate matter shoulder an increased risk for CVD mortality and efforts aimed at reduction of exposure would be prudent in disease prevention. THE ROLE OF DIET IN CARDIOVASCULAR DISEASE PREVENTION
Calorie-dense/nutrient-poor diet is a well-established contributor to CVD risk.24,25 Recent research links the western diet with type 2 diabetes and CVD risk.26 Dietary modification is a primary intervention in treating established CVD and has traditionally focused on decreasing dietary fat. Several long-term studies, including the Lyon Heart study27 and Seven Countries study,28 demonstrate that the lipid-lowering effects of diet rival the effects of statins. The Seven Countries study revealed that people living on the island of Crete had low rates of CVD despite a moderate-fat diet.28 Out of this study emerged the concept of the Mediterranean diet as preventive for heart disease. THE MEDITERRANEAN DIET
The Mediterranean diet is characterized by high intakes of fish, fruits and vegetables, whole grains, olive and canola oils, and relatively lower intakes of meat and refined flours. The primary fat is olive oil, primary dairy foods are yogurt and cheeses, and intakes of red meat and poultry are limited. The diet is also punctuated by moderate consumption of wine. When compared with other CVD interventions, the Mediterranean diet is impressive as a tool for CVD prevention. In the Lyon Diet Heart Study,27 605 people who had similar CVD risk panels who had survived their first MI were randomized to follow the Mediterranean diet (n 5 302) or the American Heart Association (AHA) prudent diet (n 5 303). The trial was stopped after 1 year because of the remarkable beneficial effects observed in the experimental group in which Mediterranean diet decreased CVD risk by 72%, independent of serum lipid levels. A later single-blind, randomized trial of patients who had established CVD or risk factors for CVD demonstrated decreased risk for cardiac events in people on an Indo-Mediterranean diet (consisting of whole grains, legumes, fruits, vegetables, nuts, and soybean or mustard oil) compared with the National Cholesterol Education Program Step I prudent diet.29 Additionally a dose-dependent effect is observed with respect to adherence to the diet. The National Institutes of Health–AARP Diet and Health study examined high versus low adherence to the Mediterranean diet over 5 years and found increased adherence to the diet results in increased (22%) reduction in death from heart disease compared with low adherence.30 In another study of 180 men and women followed for 2 years, the diet resulted in decreased body weight, blood pressure, blood glucose, insulin levels, triglycerides, and total cholesterol, increased high density lipoprotein (HDL) cholesterol, and it actually reversed the metabolic syndrome in 56% of participants versus 13% on the AHA prudent diet.31 In this author’s opinion, based on current research, advising patients to follow a Mediterranean-style diet is a leading strategy in preventing CVD. DIETARY APPROACHES TO STOP HYPERTENSION DIET
The Dietary Approaches to Stop Hypertension (DASH) trial was an outpatient controlled feeding study that tested the effects on blood pressure of two experimental dietary patterns compared with a control dietary pattern similar to what many Americans eat. Both diets differed from the control diet in the type of carbohydrates they
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contained. Relative to the control diet, each experimental diet contained less refined grains and sweets and more whole grains, fruit, and vegetables. Results showed that the DASH diet did indeed reduce systolic and diastolic blood pressure in normotensives (by 6 and 3 points, respectively) and in hypertensives (11 and 6 points respectively). DASH also reduced total cholesterol, including LDL and HDL.25 Authors of the study postulated that the effect was attributable to increased vegetable and fiber consumption, subsequent increased mineral intake, and decreased intake of saturated fat and sodium. An inverse relationship has been established between fruit and vegetable consumption and cardiovascular disease risk.32,33 Vegetarian diets have been shown to decrease risk for dying of heart disease by 24% in epidemiologic studies.34 CALORIC RESTRICTION
Caloric restriction is believed to prolong life expectancy and reduce incidence of chronic disease in humans and involves a reduction in total calories while maintaining nutritional adequacy by eating predominantly nutrient-dense foods. One small study compared 18 people currently following caloric restriction (<1500 or <2000 calories daily for women and men, respectively) with 18 age- and sex-matched people eating the typical American diet.35 The study reports average blood pressure in the experimental group of 100/60 versus 130/80 in the control group. Significantly lower body mass index and cholesterol were also observed in the experimental group and total reductions in CVD risk were reported to be attributable to significant reductions in carotid intima-media thickness and atherosclerotic lesions. A randomized controlled trial showed increases in glucose tolerance and insulin activity with implementation of caloric restriction compared with the typical western diet.36 Obvious benefits of caloric restriction include weight loss and decreased intake of saturated fat, both independently shown to decrease CVD risk. More research is needed on the long-term effects of caloric restriction and to elucidate possible other mechanisms for its efficacy in relation to CVD prevention. LOW-CARBOHYDRATE DIET
In part, cardiovascular disease results from inflammation in the arterial lining. Meals with high glycemic load have been shown to increase inflammation through insulin release and subsequent activation of the insulin-signaling pathway and release of proinflammatory mediators.37 Insulin has been theorized not only as a culprit in causing obesity and but also in chronic CVD.38 Such research has helped give a theoretic basis for the popular high protein/low carbohydrate diets, though the anti-inflammatory benefits of high protein/low carbohydrate diets has not been substantiated in clinical studies. A review of five studies examining the efficacy of the Atkins diet concluded that short-term weight loss and associated benefits may be observed, but long-term efficacy and safety studies are not available at this time, nor are any studies substantiating a long-term beneficial effect on CVD risk factors.39 Many people following the Atkins-type diet end up with a nutritionally imbalanced diet, concentrating on eating meats and fats and eliminating most plant sources of fiber, vitamins, and minerals.40 LOW-FAT AMERICAN HEART ASSOCIATION PRUDENT DIET AND DIETARY FATS
Diets that are low in saturated fat have been shown to protect against CVD and result in decreased caloric consumption and weight loss.41 The American Heart Association
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recommends a low-fat diet for people at risk for heart disease. One randomized controlled trial examined CVD risk in patients following a low-fat/high-fruit, -vegetable, and -grain diet for 8.1 years and reported no change in risk for coronary heart disease (CHD), stroke, or CVD in postmenopausal women.42 A simple reduction in dietary fat may not be the answer in dietary modification of CVD risk factors. With this in mind a meta-analysis of 50 studies on dietary fat and plasma lipids was conducted to delineate which specific fats were problematic in CVD. The study concluded that saturated fat was hypercholesterolemic, contributing significantly to CVD. The most remarkable increases in serum lipids were observed with higher intakes of saturated fats, such as myristic acid (a component of palm oil and butter fat) and palmitic acid (also found in palm oil and butter).43 Monounsaturated fats (olive oil, nuts, avocado, peanut oil, flaxseed oil, sesame oil, corn oil, whole-grain wheat, cereal, oatmeal, safflower oil, sunflower oil, tea-oil Camellia) were found to be hypocholesterolemic here and in prospective randomized trials.44 Polyunsaturated fatty acids (PUFAs, found in high concentrations in sunflower, corn, soybean, and flaxseed oils, and also in foods such as walnuts, flax seeds, and fish) were also been found to be hypocholesteremic, especially when replacing saturated fats or carbohydrates in high-carbohydrate diets. Interestingly, the analysis revealed that stearic acid, a saturated fatty acid found mostly in animal products, lowers plasma LDL when substituted for other saturated fatty acids (myristic and palmitic acids). Recent attention has been placed on the elimination of trans-fatty acids in CVD prevention. Trans fats are made by heating and hydrogenating liquid vegetable oils. The process makes them more stable, gives them a longer shelf life, and makes them more suitable for repeated heating without degradation, thus making them ideal for frying fast foods. Common dietary sources include margarines, processed foods, and fried fast foods. The trans isomer has been implicated in the atherosclerotic process45 and is associated with increased risk for CVD development.46 Analysis of data from the Nurse’s Health Study revealed a 50% decrease in CVD risk with replacement of just 2% of dietary trans fat with its cis isomer.42,47 Mechanistic links between CVD and trans-fatty acids center around increases in LDL and increases in inflammatory processes. In conclusion, evidence indicates that total fat intake may be less important than type of fat consumed when discussing CVD prevention. Doubt that the AHA prudent diet is the answer is evidenced by the relatively high-fat Mediterranean diet (30% fat, 8% saturated fat) being more effective in CVD prevention than the AHA prudent diet.27 DIETARY FAT: A CLOSER LOOK AT PREVENTION
Of the two major families of PUFA, n-3 and n-6, the n-6 fatty acids have been implicated in various inflammatory-related disease processes, whereas the n-3 family has been attributed with multiple cardioprotective effects.48,49 Establishing a favorable ratio of dietary n-3 to n-6 fatty acids is important in CVD prevention. With current intakes in the United States skewed in favor of the n-6 PUFA consumption, it is clear that the American diet favors this proinflammatory cascade.50 To close this gap, a combination of decreasing consumption of n-6 fatty acids (found in animal products, egg yolks, and most importantly soybean oil) and increasing consumption of n-3 fatty acids (found in fish oil, flaxseed oil, walnuts, and so forth) is beneficial.51 Grass-fed cattle have higher n-3 to n-6 fatty acid ratios than grain-fed herds. Epidemiologic evidence tells us that the higher the level of n-6 relative to n-3 in the diet, the higher the incidence of CVD. For example, in western societies, the ratio
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is w9:1, in Japanese 3:1, and in hunter-gatherer societies 1:1.52 More clinical trials are needed to elucidate the role of n-3 PUFAs in heart disease prevention. A recent review by the Cochrane Collaboration suggested that at this time there is insufficient evidence to suggest the use of n-3 PUFA as a clinical agent in CVD prevention.53 The AHA recommends people who have established coronary artery disease (CAD) take supplemental n-3 PUFA based on a study that revealed a 50% decrease in CAD mortality from MI in people eating fish twice per week.54 One cause for concern in recommending increased fish intake is that because of environmental pollution, much of the cold-water fish containing high levels of cardioprotective n-3 fatty acids may also contain high levels of methyl mercury, which can cause increased lipid peroxidation and CVD risk.55,56 MINERALS
Minerals are elements occurring naturally in the soil and water and alterations in levels of certain minerals (sodium, potassium, calcium, magnesium, selenium) are hypothesized to contribute to hypertension and diabetes risk. A relationship between magnesium deficiency and hypertension, diabetes, and metabolic syndrome has been suggested through epidemiologic studies. A recent cross-sectional study found that dietary calcium, magnesium, and phosphorous intakes are inversely correlated with blood pressure.57 Young adults who have higher magnesium intakes have lower risk for metabolic syndrome,58 and diets higher in magnesium-rich foods are associated with epidemiologically lower rates of type II diabetes mellitus in black women in the United States.59 An inverse relationship has been observed between high calcium intakes and obesity (body weight and fatness),60 but results from other studies suggest this link is weak and inconclusive, and to jump to a link between calcium supplementation and reduction in type II diabetes and CVD risk seems premature at this point. The SU.VI.MAX. study revealed that among other micronutrients, the effects of zinc and selenium supplementation were not beneficial in reducing CVD in subjects, even in subjects deficient at baseline.61 More research on supplementation is needed. The recommended daily allowances were formulated based on preventing mineral deficiency, not maximizing wellness or preventing chronic disease. Today, as we begin to place more emphasis on wellness and disease prevention, these recommendations may need to be adjusted to account for this new focus. STRESS
The finding that individuals who have type A personality have doubled risk for CVD62 lead to the investigation of the role of stress in CVD. Stress leads to increases in heart rate and it is well established that increased heart rate is associated with progression of atherosclerosis and mortality from CVD independent of other risk factors.24,63 The coining of the term ‘‘Takatsubo Effect,’’ or stress-related cardiomyopathy, indicates that stress contributes significantly to heart disease. High levels of catecholamines released during periods of intense emotional or physical stress seem to stun the myocardium and cause acute left ventricular dysfunction, resembling acute anterior wall myocardial infarction on EKG.64 Anger, an emotion associated with stress, correlated positively with platelet aggregation, a risk factor for CVD.65 In evaluating patients for risk for CVD, it may be useful to evaluate their emotional state and advocate for healthy methods of stress reduction. Data on meditation techniques are promising and suggest a link between meditation and decreased CVD risk.66–68 Additionally, preliminary data suggest that yoga may reduce stress and that Qi Gong and Zen Buddhist meditation significantly reduced blood pressure
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in hypertensive adults,69 but more randomized controlled trials are needed to further investigate the efficacy of various methods of stress reduction in decreasing CVD risk. ALCOHOL
In the United States, a drink of an alcoholic beverage is defined as 0.5 fl oz alcohol, 12 g alcohol, 12 oz of beer, 5 oz of wine, or 1.5 oz of liquor.70 The US Department of Health defines moderate drinking as no more than one drink per day for women and no more than two drinks per day for men. Anything less than that is defined as low drinking; and anything more than that is defined as heavy drinking.71 Studies have shown a J-shaped relationship between mortality and alcohol consumption. Di Castelnuovo and colleagues72 performed a meta-analysis of prospective studies on alcohol dosing and total mortality. They searched 34 studies published before December 2005 involving men and women (total of 1,015,835 subjects). A J-shaped relationship between alcohol consumption and mortality was found. Consumption up to four drinks per day in men and two drinks per day in women was inversely correlated with total mortality. The maximum reduction was 16% to 19% with the lowest mortality observed at 6 g of alcohol per day (0.5 drinks per day) with relative risk (RR) of 0.81 (95% CI, 0.80–0.83).72 The difference between men and women was attributed to an increased risk for cancer in women, a higher blood level of alcohol compared with equal amount of consumption, and that the benefits of alcohol may be blunted by premenopausal women having a low incidence of CAD mortality.70 As for cardiovascular mortality, Gaziano and colleagues73 and Gronbaek and colleagues74 found that the relationship between cardiovascular mortality and alcohol intake was L-shaped. The decreased risk started at one drink per day to one drink per week. This beneficial effect of alcohol is believed to occur through alcohol’s antithrombotic properties and its ability to increase high-density lipoprotein levels.75 Wine consumption has been offered as an explanation for the French paradox (high saturated fat diet and low cardiovascular disease). Red wine contains phenolic acid, flavonoid, and reseveratrol. All these may have beneficial effects as antithrombotics and antioxidants.75 Prospective studies on type of alcoholic beverage have conflicting results. One meta-analysis of observational studies showed that the associated lower CHD was secondary to the alcohol itself rather than to the other components, such as reseveratrol.76 Another meta-analysis of observational studies showed that wine has an additive beneficial effect on mortality. In this review, light to moderate drinking (8–21 drinks per week) of wine was more effective in reducing all-cause and cardiovascular mortality than beer or spirits.77 Moderate alcohol decreases the risk for CAD and MI. Observational studies have found that alcohol intake had an inverse linear relationship with risk for nonfatal MI and angina pectoris. The lowest risk was found in men who took two drinks per day with an RR for angina pectoris of 0.69 (95% CI, 0.59–0.81) and RR for MI of 0.65 (95% CI, 0.52–0.81).78–80 The beneficial effects were similar whether people had diabetes or not.81 Men at low risk on the basis of body mass index, physical activity, smoking, and diet also benefited from alcohol consumption. The RR for MI was 0.38 (95% CI, 0.16–0.89) with moderate consumption of alcohol.82 Alcoholic cardiomyopathy has been described in chronic heavy drinkers. One third of heavy drinkers (243 g of alcohol daily for 16 years) had ejection fraction less than 55%, and one fourth of patients who had idiopathic dilated cardiomyopathy were alcoholics.83,84 In asymptomatic chronic alcoholics, there was impaired LV relaxation and LV dilatation. The progression of these changes was associated with duration
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of alcohol intake.85 Moderate alcohol intake was associated with decreased risk for congestive heart failure.86,87 The US Department of Health recommends that those who choose to drink alcoholic beverages should do so sensibly and in moderation up to one drink per day for women and up to two drinks per day for men.71 ANTIOXIDANTS
Fatty streaks in the subendothelial layer are the marker of early atherosclerosis. These streaks consist of foam cells, which are cholesterol-laden macrophages or smooth muscle cells. Because macrophages lack LDL receptors, foam cells cannot be formed unless LDL is first modified by oxidation by free radicals before being absorbed and retained by macrophages. Antioxidants have been found to decrease LDL oxidation in vitro. Susceptibility to oxidation depends on the LDL particle itself and the amount of antioxidants in the environment. The Agency for Healthcare Research and Quality (AHRQ) concluded in 2003 that there is little evidence that supplementation with antioxidant vitamins, such as vitamin C, vitamin E, or coenzyme Q10, has any benefit on cardiovascular disease prevention or treatment. VITAMIN E
Observational studies have found an association between vitamin E consumption and decreased risk for CHD.88–90 Randomized controlled trials have shown that vitamin E has no beneficial effect in primary prevention of CHD, however. Virtamo and colleagues,91 conducted a randomized, double-blind, placebo-controlled trial on 27,271 Finnish male smokers aged 50 to 69 years who had no history of myocardial infarction. Vitamin E (50 mg/d) supplementation or beta carotene (20 mg/d) had no significant effect on the incidence of MI and cardiac death. De Gaetano and colleagues92 found that vitamin E supplementation does not decrease cardiovascular disease in high-risk patients. They conducted a randomized, controlled, open 2 2 factorial trial on 4495 people who had one or more of the following: hypertension, hypercholesterolemia, diabetes, obesity, family history of premature MI, or individuals who were elderly. The study group was given vitamin E 300 mg/d. Vitamin E supplementation had no effect on CHD or CVD death. It lowered the incidence of peripheral arterial disease (PAD) with a relative risk ratio of 46% (P 5 0.043). The Women’s Health Study found that supplementation of healthy women 45 years of age or older who have vitamin E (600 mg every other day) did not decrease cardiovascular events. The Women’s Health Study was a randomized, double-blind, placebo-controlled, 2 2 factorial trial involving 39,876 healthy women for 10.1 years.93 Vitamin E supplementation was not effective in secondary prevention of coronary heart disease either. Rapola and colleagues94 found in a randomized, double-blind, placebo-controlled study, that vitamin E supplementation (50 mg/d) to men who had a previous history of MI did not decrease the incidence of major coronary events. Yusuf and colleagues95 found in a randomized, double-blind, placebo-controlled trial, that vitamin E supplementation (400 IU/d) to 9541 patients who had previous vascular disease or were at high risk did not decrease the risk for cardiovascular death, MI, or stroke. The Heart Protection Study Collaborative Group found in a randomized, double-blind, placebo-controlled trial, that vitamin E (600 mg/d), vitamin C (250 mg/d), and b-carotene (20 mg/d) did not decrease cardiovascular mortality or MIs.96 Waters and colleagues97 found also that vitamin E (400 mg twice daily) and vitamin C (500 mg twice daily) supplementation to 423 postmenopausal women who had at least 15% to 75% stenosis of one coronary artery had no effect on progression of the disease.
Preventing Heart Disease
More women in the vitamin group died compared with placebo but that did not reach significance. The only benefit of vitamin E in secondary prevention was documented in the SPACE Study. SPACE was a double-blind, placebo-controlled, randomized trial involving 196 people 40 to 75 years of age followed for 519 days. In that study, Boaz and colleagues found that vitamin E (800 mg/d) supplementation to patients who had pre-existing cardiovascular disease and on hemodialysis reduced cardiovascular events with a RR 0.46 (95% CI, 0.27–0.78) and MI with a RR of 0.3 (95% CI, 0.11– 0.78).98 VITAMIN C
The effects of vitamin C alone were studied in observational studies with conflicting results. Two studies showed that vitamin C intake (R50 mg/d) was associated with lower standardized mortality and lower risk for coronary heart disease.99 Other observational studies found supplementation of vitamin C alone or with vitamin E was not associated with decreased risk for coronary heart disease.90,100 The AHRQ in 2003 reported that there is good evidence that supplementation with vitamin E or vitamin C has no benefit in all-cause mortality, cardiovascular mortality, myocardial infarction, or blood lipids.101 b-CAROTENE
b-Carotene has not been found to be helpful in reducing the risk for coronary heart disease. Hennekens and colleagues102 conducted a randomized, double-blind, placebocontrolled trial involving 2201 men. They found that b-carotene (50 mg on alternate days) supplementation did not decrease the incidence of cardiovascular disease.102 Omenn and colleagues,103 in The Beta Carotene and Retinol Efficacy Trial, found that b-carotene (30 mg/d) and retinol (vitamin A, 25,000 IU) supplementation did not decrease cardiovascular mortality. There was an increase in all-cause mortality, however. The Beta Carotene and Retinol Efficacy Trial was a randomized, double-blind, placebo-controlled primary prevention trial involving 18,314 smokers, former smokers, and workers exposed to asbestos. The Finnish Alpha Tocopherol Beta Carotene Cancer Prevention Study found that b-carotene had no significant effect on the incidence of MI and cardiac death.91 COENZYME Q10
Coenzyme Q10 (2,3 dimethoxy-5 methyl-6-decaprenyl benzoquinone) is a fat-soluble, vitamin-like quinone (the young synthesize Q10 but this ability is believed to diminish with age) commonly known as ubiquinone, CoQ, and vitamin Q10. Coenzyme Q10 (CoQ10) is produced by the human body and is necessary for the basic functioning of cells. CoQ10 levels are reported to decrease with age and to be low in patients who have some chronic diseases, such as heart conditions, muscular dystrophies, Parkinson disease, cancer, diabetes, and HIV/AIDS. Some prescription drugs may also lower CoQ10 levels. There are many conflicting reports about the effect of coenzyme Q10 on congestive heart failure. Khatta and colleagues104 found in a small (n 5 55), double-blind, randomized, placebo-controlled trial that coenzyme Q10 (200 mg/d) supplementation to men who had congestive heart failure had no effect on ejection fraction, peak oxygen consumption, or exercise duration.104 Watson and colleagues105 conducted a doubleblind and crossover trial on 30 patients who had LV dysfunction. They found no effect
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of CoQ10 supplementation on ejection fraction or quality of life. Jeejeebhoy and colleagues106 conducted a double-blind, randomized, and placebo-controlled trial on 41 subjects who had LV dysfunction (ejection fraction<40%). They found that the supplementation with coenzyme Q10, taurine, and carnitine decreases left ventricular (LV) end-diastolic volume. In 2003, the AHRQ examined cardiovascular trials with more than 60 participants followed for at least 6 months and concluded that the role of coenzyme Q10 role is still an open question.101 Sanders and colleagues107 performed a meta-analysis of randomized controlled trials about the effect of CoQ10 on heart failure. They found that supplementation of 60 to 200 mg/d of CoQ10 improved ejection fraction by 3.7% (95% CI, 1.59–5.77). CoQ10 is beneficial in lowering blood pressure in patients who have hypertension. In a meta-analysis of eight published trials of CoQ10 in hypertension, the mean decrease in systolic blood pressure was 16 mm Hg and in diastolic blood pressure, 10 mm Hg. The authors recommended CoQ10 may have a role as an adjunct or alternative to conventional agents in the treatment of hypertension.108
EXERCISE
The American College of Sports medicine and the AHA recently issued new guidelines for exercise. They recommended that all healthy adults aged 18 to 65 years need moderate-intensity aerobic physical activity (such as a brisk walk that noticeably accelerates the heart rate) for a minimum of 30 minutes on 5 days each week or vigorous-intensity aerobic physical activity, such as jogging, that causes rapid breathing and a substantial increase in heart rate for a minimum of 20 minutes on 3 days each week. In addition, every adult should perform activities that maintain or increase muscular strength and endurance a minimum of 2 days each week. Short bouts of physical activity lasting 10 minutes can accumulate toward the 30-minute goal.109 Many observational studies have proved the benefit of exercise. The distance walked per day was found to be inversely associated with mortality in elderly. The Honolulu Heart Program was a cohort prospective trial of 707 elderly (61–81 years of age) men. It found that the mortality rate among men who walked less than 1 mile per day was 1.8 times that among those who walked more than 2 miles per day (40.5% versus 23.8%, P < .001).110 The perceived level of exertion was inversely associated with the risk for CHD. Lee and colleagues111 found this association in a cohort of 66-year-old men. Cardiorespiratory fitness was found to be inversely associated with cardiovascular and all-cause mortality.112 Brisk walking was found to have the same beneficial effect on coronary events as vigorous exercise. Brisk walking for 3 or more hours a week was associated with lower coronary events.113 In a cohort study of 39,372 women aged 45 years or older, Lee and colleagues114 found that walking for at least an hour per week was associated with lower risk for CHD. The INTERHEART study is a case-control trial in 52 countries involving 15,152 cases and 14,820 controls. It showed that regular moderate exercise for 4 or more hours per week reduces risk for MI by 12.2% (odds ratio [OR] 0.86; P < .0001).13 Older adults (50–65 years of age) benefit from moderate-intensity exercise in improved fitness levels and small improvements in HDL cholesterol levels. The frequency of exercise is important for the benefit. The lower-intensity home-based exercise (three sessions per week; 4 to 4.5 Mets) had the most benefit on participation rate (average three times per week) and HDL levels after 2 years.115
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Observational studies have proved the beneficial effects of exercise in subjects who have preexisting CAD. Light to moderate activity was associated with reduced allcause and cardiovascular mortality. Wannamaethee and colleagues116 found in a cohort study of 772 men who had documented coronary heart disease that recreational activity for more than 4 hours per week, regular walking more than 40 minutes per day, or moderate to heavy gardening was associated with decreased mortality. A combined program of exercise rehabilitation and risk factor program has been found to reduce all-cause mortality and myocardial infarction. Exercise rehabilitation alone reduced mortality and myocardial infarction.117 FIBER
Dietary fiber consists of edible parts of plants or analogous carbohydrates that are resistant to digestion and absorption in the human small intestine. Fiber can be classified as a dietary source (eg, cereal, fruit, vegetable, or legume) or as a supplement. Fiber can also be divided into water-soluble (eg, b-glucans, pectin, and guar) and insoluble (eg, cellulose and lignin) forms.118 Both soluble and insoluble fibers are undigested and are not absorbed. Soluble fiber forms a gel when mixed with liquid, whereas insoluble fiber does not. Common sources of insoluble fiber are vegetables, such as green beans and dark green leafy vegetables, fruit skins and root vegetable skins, whole wheat products, wheat, oats, seeds, and nuts. Common sources of soluble fiber are oat/ oat bran, dried beans and peas, nuts, fruits, vegetables, and psyllium husk. Both insoluble and soluble fiber bind to bile acids, inhibiting the absorption of cholesterol, and improve insulin sensitivity by affecting the rate of carbohydrate absorption.119 Intake of fruits and vegetables protect against the risk for stroke. In an observational study of 832 men (The Framingham Study), Gillman and colleagues120 found that the addition of three servings of fruits and vegetables per day reduces the risk for stroke and transient ischemic attack by 22% (RR 5 0.78; 95% CI, 0.62–0.98). There is a reverse association between fiber intake and incidence of MI. Rimm and colleagues121 conducted a prospective cohort study of 43,757 men aged 40 to 75 years. They found that a high fiber intake (28.9 g/d from fruits, vegetables, and cereals) decreased the risk for MI by 41% (95% CI, 0.46–0.76) compared with low fiber intake (12.4 g/d). Pietinen and colleagues122 found that fiber intake was associated inversely with nonfatal MI, CHD, and mortality from CVD. They followed a cohort of 21,930 men who were involved in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. In this study, all fiber fractions were beneficial, but especially soluble and cereal fiber. The inverse association was also found in a cohort study of 68,782 women. The association was mainly with fiber from cereal sources. Higher intake of cereal fibers was associated with a 34% lower risk for total CHD.123 Overall, insoluble fibers, primarily contributed by cereal products, have been the most consistently associated with lower incidence rates of CVD118 but soluble fiber also decreases serum total and LDL cholesterol concentrations and improves insulin resistance.118 The US Department of Health recommends the intake of 14 g of fiber per 1000 calories consumed.71 HOMOCYSTEINE-LOWERING VITAMINS
Children who have homocystinuria have been found to have premature atherothrombotic disease. Elevated homocysteine levels are associated with CHD and stroke. A meta-analysis of prospective and population-based case-control studies showed that elevations in homocysteine were an independent graded risk factor for arteriosclerotic vascular diseases. For each increment of 5 mmol/L of homocysteine, the OR for CAD in men was 1.6 (95%CI, 1.4–1.7); the OR for CAD in women was
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1.8 (95% CI, 1.3–1.9); and the OR for cerebrovascular disease was 1.5 (95% CI, 1.3– 1.9).124 A 25% lower homocysteine level was associated with an 11% lower ischemic heart disease risk and 19% lower stroke risk in a meta-analysis of prospective studies.125 Supplementation with vitamin B6, vitamin B12, and folate has been found to be beneficial in observational studies as a means of lowering homocysteine levels. In a cohort prospective study of 40,803 people aged 40 to 59, Ishihara and colleagues found that supplementation with vitamin B6, vitamin B12, and folate has an inverse association with coronary heart disease and MI.126 In randomized controlled trials, the benefits have not been proved. A meta-analysis of randomized controlled trials showed no protective effect of vitamin B supplements on the progression of atherosclerosis.127 Supplementation of folic acid and vitamins B6 and B12 did not reduce the risk for major cardiovascular events in patients who have vascular disease. HOPE 2 investigators conducted a randomized, double-blind, placebo-controlled trial on 5522 patients 55 years of age or older who had vascular disease or diabetes. The active treatment was the combination of 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12 for an average of 5 years.128 Toole and colleagues129 conducted a double-blind randomized controlled trial involving 3680 adults who had nondisabling cerebral infarction. They found that moderate reduction of total homocysteine with folic acid and B vitamin supplements (25 mg of vitamin B6, 0.4 mg of vitamin B12, and 2.5 mg of folic acid) for 2 years had no effect on vascular outcomes. Albert and colleagues130 conducted a randomized, double-blind, placebo-controlled trial on 5442 women who were United States health professionals aged 42 years or older, with either a history of CVD or three or more coronary risk factors. They found that supplementation with folic acid and B vitamins (folic acid 2.5 mg/d, vitamin B6 50 mg/d, and vitamin B12 1 mg/d) did not reduce a combined endpoint of total cardiovascular events, despite significant reduction in homocysteine levels. The ongoing SEARCH study should eventually provide reliable evidence about the efficacy and safety of prolonged use of homocysteine-lowering therapy (folate 2 mg/d and vitamin B12 1 mg/d) in 12064 myocardial infarction survivors.131 The Canadian Task Force on Preventive Health Care searched the MEDLINE for relevant English-language articles investigating homocysteine published from January 1966 to June 1999. Their conclusion was that there was insufficient evidence to recommend the screening or management of hyperhomocysteinemia at present (grade C recommendation). They recommended adherence to recommended daily allowance of dietary sources of folate and vitamins B12 and B6. They also recommended ruling out vitamin deficiency if elevated homocysteine levels are discovered. Despite this recommendation, however, some experts may be treating high-risk people (a personal or family history of premature atherosclerosis) for elevated homocysteine levels.132 REFERENCES
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Preventing Ca ncer Ehab A. Molokhia, MDa,b,*, Allen Perkins, MD, MPHa,c KEYWORDS Cancer Prevention Diet Supplements Fitness Vaccine
Cancer is the number one cause of death in the United States, accounting for more than 500,000 deaths in 2007 alone, globally accounting for more than seven million deaths annually. It is estimated that one in every four deaths in the United States is attributable to cancer. Survival rates are improving through early detection and advancements in therapy; it is estimated that more than one third of cancer deaths are preventable.1 In the United States, tobacco use, obesity, diet, and lack of exercise account for approximately two thirds of the cancer deaths.2 The top three cancers in males are prostate cancer, lung cancer, and colorectal cancer (CRC). In females, they are breast, lung, and CRC. These are also the leading causes of cancer deaths in males and females respectively and are cancers that are preventable to a great extent through screening programs and lifestyle modifications. Abstinence from tobacco alone would reduce United States cancer deaths by 168,000 annually. The presence of a suitable extracellular microenvironment is vital to preventing cancer.3 Nutrients also play both a role in decreasing the incidence of cancer and contributing to its development. DIETS AND CANCER PREVENTION Obesity and Cancer
Several case studies have looked into the relationship between obesity (measured by an elevated body mass index [BMI]) and several cancers afflicting the human body. A large prospective study revealed an increase in all cancer deaths by 52% percent and 62% in the heaviest men and women, respectively (BMIs of at least 40).4 It has been estimated that cancer deaths caused by overweight and obesity in men and women over 50 years of age are 14% percent and 20%, respectively. There is consistent evidence drawing a link between an increased BMI and cancers of the esophagus, pancreas, colorectum, endometrium, kidneys, gallbladder, and on breast cancer in both pre- and postmenopausal women.3 The evidence also indicates a
a
Department of Family Medicine, University of South Alabama, 1504 Springhill Avenue, Suite 3414, Mobile, AL 36604, USA b USA Family Physician’s Clinic, Mobile, AL 36604, USA c USA Family Medicine Residency Program, Mobile, AL 36604, USA * Corresponding author. Department of Family Medicine, University of South Alabama, 1504 Springhill Avenue, Suite 3414, Mobile, AL 36604. E-mail address:
[email protected] (E.A. Molokhia). Prim Care Clin Office Pract 35 (2008) 609–623 doi:10.1016/j.pop.2008.07.009 primarycare.theclinics.com 0095-4543/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.
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dose–response relationship, with increasing risk of cancers with higher BMIs.3 Additionally, there is a possible association between obesity and liver cancer. The relationship between BMI and lung cancer has remained unclear, possibly because of the direct relationship of smoking cessation and weight gain. Diet and Cancer
Beliefs regarding diet and cancer based on epidemiologic data recently have been subjected to more rigorous inquiry. Observation of different cancer rates between countries with clearly dissimilar diets has fielded speculation regarding the link between specific diets and cancer incidence. Mediterranean diets, known for their high consumption of breads and cereal foods usually made from wheat, vegetables, fruits, fish, olive oil, and tree nuts, have been found to be associated with a 16% reduction in the risk of cancer mortality in women aged 40 to 49, but not in younger women, and a reduced risk of recurrence of colorectal adenomas (a precursor of colon cancer) in women but not men.5,6 Western dietary patterns composed of energy-dense, processed foods with a high content of meat, and milk, as well as fatty and sugary foods have long been suspected of an association with cancer, and there are population-based epidemiologic data supporting this. A positive relationship of Western style diet with colon cancer has been demonstrated in a prospective cohort study with a relative risk of 2.21 in women when compared with to those who consumed a healthy diet.7 The Cancer Prevention Study II showed a 30% to 40% increase of colon cancer among the highest consumers of red meat (high intake being defined as 3 oz of beef, lamb, or pork for men and 2 oz for women daily) and a 50% increase in colon cancer incidence among the highest consumers of processed meat (defined as 1 oz eaten five or six times a week for men, and two or three times a week for women).8 Dietary Fat
Diets high in total fat were long presumed to play a role in higher incidence of illness, but this is not proven to be the case for cancer.9,10 Results from cohort studies have been inconclusive and have revealed mixed results in drawing a link between dietary fat intake and lung cancer, breast cancer, prostate cancer, and CRC. The results of the Polyp Prevention Trial–Continued Follow-up Study (PPT-CFS) did not identify a relationship between a low-fat diet and the recurrence rates of adenomas, a precursor of CRC, after 8 years.11 Fruits and Vegetables
Evidence of a possible protective effect from fruits and vegetables against cancer surfaced in the 1990s, out of which a general recommendation of consuming five portions was founded. Consequently further studies were undertaken to link specific vegetables and fruits to a decrease in cancer incidence. Studies on diets high in nonstarchy vegetables revealed consistently a protective effect against cancers of the mouth, pharynx, and larynx, with a dose–response relationship.12 Other studies showed a small protective effect against esophageal cancer, stomach cancer, lung cancer, ovarian cancer, endometrial cancer, and CRC.3,13–15 A prospective study looking at the consumption of fruits and vegetables and risk of lung cancer showed a 21% reduction in the highest compared with the lowest quintile of total fruit and vegetable consumption in women and a trend toward a decrease in the incidence of lung cancer in never smokers in both men and women, although not statistically significant.16 Studies on diets high in fruits demonstrate consistently a protective effect against cancers of the mouth, pharynx, larynx, esophagus, stomach, and lungs with
Preventing Cancer
a dose–response relationship but not against breast cancer.17 Diets high in tomatobased products and specifically lycopene, a carotenoid found in tomatoes, have been linked consistently in many studies to a decreased incidence of cancers of the stomach, lung, and prostate. Some evidence also suggests a protective effect against oral cancer, cervical cancer, breast cancer, pancreatic cancer, esophageal cancer, and CRC.18 Fiber
Studies recently done on high-fiber diets and their relationship to cancers of the gastrointestinal (GI) tract revealed a trend toward decreasing incidence of CRC, although not all were statistically significant, in a dose–response fashion. Studies regarding the relationship of fiber intake with esophageal cancer were inconsistent, with limited evidence of a protective effect. Meat and Fish
Meat and fish have been studied extensively in regards to their relationship to cancer incidence. Numerous case–control and cohort studies done on meat indicate an increased risk of CRC in individuals who have the highest consumption. A prospective European study following 500,000 people revealed a 25% reduction in cancer for the lowest consumers of red meat compared with the highest.19 The same study revealed a protective effect associated with the consumption of fish, with a 30% reduction in cancer in the highest consumers compared with the lowest. The association of both was stronger for tumors of the rectum and left side of the colon. There was also an association with the consumption of processed red meat (by smoking, curing, salting, or adding preservatives) when compared with unprocessed red meat. This risk associated with the consumption of red meat is believed to be secondary to the cytotoxic effect of dietary heme, which is suggested to have damaging effects on the colonic mucosa.8 A small number of studies suggest that red meat and processed meat play a role in increasing the risk of cancers of the esophagus, lung, pancreas, and endometrium.3 Cantonese-style salted fish, characterized with the use of less salt and a high degree of fermentation, is a traditional part of the diet in southern China, Taiwan, Malaysia, and Singapore. It consistently has been linked to a higher incidence of nasopharyngeal cancer based on several case-control studies. A dose–response relationship also has been demonstrated.3 Dairy Products
There is fairly consistent evidence from cohort studies indicating that milk protects from CRC. A few studies have not demonstrated a statistically significant protective effect. In contrast, consumption of increased amounts of dairy products has been linked consistently to an increase in prostate cancer. This is consistent with the data from calcium supplementation. DIETARY SUPPLEMENTS Vitamin D and Calcium
The relationship between high calcium intake and a lower incidence of colon cancer long has been suspected. Calcium supplementation and colon cancer prevention were investigated in numerous case–control and cohort studies, with consistent evidence of a small but statistically significant protective effect. Those who take calcium supplements have a relative risk of 0.74. This is based on a comparison of those who have a total calcium intake of 1300 mg/d or more (one cup of milk contains
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approximately 300 mg of calcium) compared with those with an intake of less than 500 mg/d. This protection was found only for cancers of the distal colon and rectum, and it is highest in those who have the highest vitamin D intake.20 This protection did not hold true for prostate cancer; in fact, the opposite was true with a greater incidence of prostate cancer seen with increased calcium intake.21 A relative risk of 1.2 was demonstrated in males who had an intake of greater than 2000 mg/d of dietary calcium compared with those who had less than 700 mg/d. The relative risk rose to 2.1 if the participant had not had prostate-specific antigen (PSA) screening before enrollment in the study and consumed more than 2000 mg/d of dietary calcium. The data regarding the relationship between vitamin D, independent of calcium intake, and colon cancer has been inconsistent, with foods containing vitamin D or better vitamin D plasma levels having a protective effect against colon cancer. Achieving that protection, however, may be harmful in other ways.3 In the Health Professionals Follow-Up Study,22 a plasma 25(OH) vitamin D level of 25 nmol/L was associated with a significant reduction in total cancer incidence and mortality and an almost 50% reduction in incidence and mortality of digestive system cancer. Reaching a 25(OH) vitamin D level of 25 nmol/L, however, requires vitamin D supplementation of at least 1500 IU/d, generally regarded as safe but not encouraged. These levels also can be attained fairly easily with some skin exposure to the sun, but at an increased risk of acquiring skin cancer. Antioxidants
Antioxidants are substances that have been the center of investigations and attention and are thought to prevent cancer by neutralizing free radicals that can lead to cell DNA damage. This damage over time is believed to help initiate the development of cancer. Antioxidants are found in large quantities in fruit and vegetables, and other foods like nuts and grains. Some commonly known antioxidants include carotenoids, selenium, and vitamins A, B, C, and E. Vitamins E and C
The evidence available on vitamin E and C is spotty. Meta-analyses of data from international studies with attention to diets high in vitamin E demonstrate a small amount of protection against certain upper GI cancers23,24 and no protection against prostate cancer.25 Studies of supplemental vitamin E intake have not demonstrated such protection.26 Similarly, with Vitamin C, a meta-analysis looking at the effects of antioxidants on adenocarcinoma of the esophagus showed a 50% lower risk among those with the highest consumption of dietary vitamin C, but supplemental vitamin C has not been shown to be effective in a prospective fashion.24 Selenium and Other Trace Minerals
The Nutritional Prevention of Cancer (NPC) trial, a double-blinded, randomized, placebo-controlled study, demonstrated reduced risks of total cancer incidence (relative risk [RR] of 0.63), incidents of carcinoma of the prostate (RR of 0.51), and CRC (RR of 0.46). The trial was ended prematurely because of the reduction in cancer related mortality in the treatment group. This occurred in 1996, and only recently have there been prospective trials begun to confirm this finding. The treatment dose in the NPC trial was 200 mg/d of l-selenomethionine.27 Folic Acid
Foods containing folic acid include citrus fruits, leafy vegetables, and liver. Breakfast cereals and other foods, however, are being fortified with folic acid. A meta-analysis of
Preventing Cancer
existing case–control and cohort studies indicated a 40% to 50% reduction in the risk of esophageal squamous cell carcinoma, esophageal adenocarcinoma, and pancreatic cancer among individuals who had the highest dietary folate intake compared with the lowest.28 There is also good evidence from case–control and cohort studies suggesting a role of folate supplementation in reduction of colon cancer rates; however, the data may be affected by increased dietary fiber intake associated with diets high in folic acid.3,29 Omega-3 Fatty Acids
Despite optimism related to animal evidence regarding the effects of omega-3 fatty acids on prevention of cancers of the lung, prostate, colorectum, and skin, a 2006 Journal of the American Medical Association review of numerous prospective cohort studies from seven different countries clarified that there is no evidence of reduction of any single type of cancer.30 OTHER SUPPLEMENTS
Beta-carotenes have been studied extensively but have not been shown to reduce incidence of skin, prostate, or lung cancer in good-quality trials, with evidence of an interaction between tobacco use, beta-carotenes, and genetics resulting in an increase in the incidence of lung cancer. Other carotenoids include previously mentioned lycopene.3,31 Vitamin B6 (Pyridoxine)
Vitamin B6 is found readily as a dietary component, and exists in numerous dosage forms as supplements. Studies indicate a possible protective effect against esophageal and breast cancers. The protective effect against breast cancer is higher in postmenopausal women.32 Vitamin B12 (Cyanocobalamin)
Few studies have examined the effects of vitamin 12 on cancer. The Nurses’ Health Study involving 32,826 women found an association between high plasma levels of vitamin B12 and a reduced risk of breast cancer in premenopausal women.32 Vitamin B12 is found in eggs, meat, poultry, shellfish, milk, and as part of vitamin B complex supplementation. There are not yet prospective data for this. PERICONCEPTION VITAMIN SUPPLEMENTATION
Folic acid supplementation during pregnancy decreases the incidence of neural tubal defects.33 Vitamin supplementation typically consists of more than that. A few studies34 have demonstrated a protective effect against childhood cancers like acute lymphoblastic leukemia (ALL), neuroblastoma, and brain tumors. Children with Down syndrome (DS) have an existing 20-fold higher risk of developing leukemia than children without the genetic disorder. When vitamin supplementation was examined in the mothers of these children, the investigators demonstrated decreased incidence in ALL in DS children whose mothers reported taking multivitamins in the periconception period. Unexpectedly, the same study showed an increased risk of ALL if the vitamins were started after the pregnancy diagnosis was made. The optimal combination for prenatal vitamin supplementation has yet to be determined.34
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Aspirin
A recent randomized, double-blinded study examined the effect of aspirin intake on the recurrence of colorectal adenomas and revealed a reduction in recurrence rates of adenomas of any size, and of advanced adenomas.35 In the Aspirin/Folate Polyp Prevention Study (AFPPS), a small reduction was demonstrated in individuals randomized to low-dose aspirin (81 mg) intake, but not to those randomized to receive 325 mg/d.36 The US Preventive Service Task Force (USPSTF) recommends against the use of aspirin to prevent CRC in individuals at average risk based on the risk– benefit analysis.
ALCOHOL CONSUMPTION
Alcohol intake has been studied extensively in relation to effects on human health. One of these aspects is its effect on cancer incidence. Numerous studies37 have revealed strong evidence that is consistent that alcohol is a cause of cancers of the mouth, pharynx, and larynx. A dose–response relationship has been identified also, with death rates highest among those who drink four drinks a day or more (Box 1).38 Tobacco consumption along with alcohol intake also has been found to increase this effect on these cancers. A meta-analysis of existing cohort studies revealed convincing evidence of a moderate increase in incidence of esophageal cancer and CRC with a dose–response relationship. Evidence, based on a meta-analysis of existing cohort studies and epidemiologic studies,37 of an association with pre- and postmenopausal breast cancer is consistent, with death rates increasing 7.1% for every 10 g of alcohol consumed per day (one drink in the United States is equivalent to approximately 15 g). High levels of alcohol consumption are a cause of liver cirrhosis also, a disease process that predisposes certain individuals to liver cancer.
OTHER FOODS AND DRINKS Carbohydrate Intake
Glycemic load and carbohydrate intake have been studied to evaluate for a possible link to cancer incidence. Several ongoing population-based studies (Health Professionals Follow-up Study and the Nurses’ Health Study) revealed a 27% to 37% increase in the risk of CRC with increasing intake of carbohydrate, glycemic load, sucrose, or fructose in men. This is a consistent finding. A relationship exists between increasing incidence of pancreatic cancer with high glycemic loads in women enhanced in people with BMI greater than 25 kg/m2.39 A relationship between glycemic load and breast cancer in individuals 45 years of age and older has not been demonstrated.40 Based on these findings, avoiding dietary patterns rich in fructose and sucrose while maintaining a healthy weight will render cancer-preventive benefits.
Box 1 Death rates by daily alcohol consumption (cancer death rates per 100,000 population) No alcohol consumption—13.0 plus or minus 1.6 Less than one drink per day—18.3 plus or minus 1.8 One drink per day—18.6 plus or minus 2.4 Two to three drinks per day—19.7plus or minus 2.0 More than three drinks per day—37.0 plus or minus 3.2
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Phytoestrogens
Phytoestrogens are found in plant food and have estrogen-like activities. The most important dietary sources include isoflavones (eg, soy products) and lignans (eg, flaxseed, grains, nuts, vegetables, and fruits). There is epidemiologic evidence indicating that these exert a protective effect against hormone-dependant cancers like breast and prostate. One case–control study revealed that dietary lignan was associated with a significant decrease in CRC.41 No prospective evidence exists regarding the role of phytoestrogens in cancer prevention. BEHAVIORAL MODIFICATIONS Physical Activity
Physical activity has been shown to offer protective effects against several cancers, with fitness exerting a protective effect against colon cancer. This effect is substantial, with a 40% to 50% reduction in incidence among those who are most active. The mechanism of protection is thought to be multifactorial. Reasons include a reduction in insulin resistance, effects on body fat, effects on endogenous steroid hormone metabolism, and a reduction in gut transit time.3,42 There is strong evidence that fitness leads to a reduction of breast cancer rates in pre- and postmenopausal women of up to 40%. Investigators with the Women’s Health Initiative found that among postmenopausal women, walking 30 min/d was associated with a 20% reduction in breast cancer risk. Women who are physically active also have a 30% to 40% reduction in the risk of endometrial cancer. The results of studies done to demonstrate a protective effect against lung cancer have been weak and inconsistent. Physical activity also is linked to a reduction in the rate of prostate cancer, with evidence suggesting as much as 10% to 30% reduction in incidence, but studies are still ongoing.43,44 Sun Avoidance
Skin cancer is the most common form of cancer in the United States. The most common forms are basal cell carcinoma and squamous cell carcinoma, which are highly treatable. The third most common type of skin cancer, and much deadlier, is melanoma. Most skin cancers are attributable to sun exposure. Their prevention can be accomplished by avoidance of sun exposure through proper clothing, staying in shaded areas, or the use of sunscreen products. The Centers for Disease Control and Prevention recommends the use of Sun Protective Factor (SPF) 15 or higher with protection against both UVA and UVB rays.45 The use of such sunscreen products has been shown to decrease the incidence of squamous cell carcinoma and solar keratosis, a precursor of squamous cell carcinoma. Avoidance probably is more beneficial than exposure with protection, as some studies indicate an increase in the incidence of melanoma among those who use sunscreen products, thought to be a result of an increase in the time exposed to ultraviolet rays. The USPSTF recommends avoidance of midday exposure to the sun rays between 10 a.m. and 4 p.m. Tanning beds and sunlamps have been studied, revealing evidence of increased risk of skin cancer similar to that of exposure to sun rays, and they should be avoided.46 Breastfeeding
Clear evidence confirms that breastfeeding of infants reduces maternal breast cancer risk. The evidence is convincing and exists in pre- and postmenopausal women. The mechanism of this protection is thought to be a result of the associated period of
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amenorrhea, thus decreasing the lifetime exposure to menstrual cycles and altered hormone levels.3,47 In addition to the effects on breast cancer, the effect of breastfeeding on the ovaries has been studied in a limited number of studies. Two prospective cohort studies revealed a statistically significant decrease in incidence of ovarian cancer in women who breastfed for 18 months or more.3,48 Smoking
The number of people who smoke is believed to be in excess of one billion worldwide, and while the number of smokers in the developed world has declined, it remains high in developing countries. The effect of smoking has been studied carefully in the past few decades, and smoking has been identified as a cause of numerous cancers in people. RR for different cancers ranged from 3 (for pancreatic cancer) to 20 (for lung cancer). Lung cancer is the world’s most common cause of cancer death, claiming the lives of more than 1.2 million people annually. Cigarette smoking is believed to be the major cause of lung cancer, accounting for as much as 90% of cases. It has been found to increase the risk of developing lung cancer of all histologic types. The duration of smoking is the strongest determinant of lung cancer. This risk ceases to increase any further following smoking cessation. A causal relationship with smoking has been identified with other cancers, including those of the bladder, ureter, and renal pelvis.49 Cancers of the oral cavity increase in men and women, as well as cancers of the nasal cavity, paranasal sinuses, nasopharynx, oropharynx, hypopharynx, and larynx. The incidence of pancreatic cancer and esophageal cancers (squamous cell carcinoma and adenocarcinoma) is increased by smoking. An increased risk of developing stomach cancer has been identified even after adjusting for Helicobacter pylori infections and dietary factors. A dose– response relationship was demonstrated for the cancers mentioned, and a reduction in the risk was demonstrated after quitting. A moderate increase in the risk of developing liver cancer has been identified in recent cohort and case–control studies even after adjusting for alcohol intake. An increase in the incidence of cervical cancer has been identified also, but only for squamous cell carcinomas. Studies looking at the relationship between smoking and CRC and breast, endometrial, and prostate cancers failed to show a causal relationship.49 EFFECTIVENESS OF CERVICAL, BREAST, PROSTATE, LUNG, AND GASTROINTESTINAL CANCER SCREENING
Prostate cancer is the second leading cause of cancer deaths in men in the United States, accounting for more than 27,000 deaths in 2007. It is estimated that prostate cancer accounts for 29% of all male cancers and 9% of male cancer-related deaths. Despite the magnitude of the disease, there remains significant controversy and lack of consensus on screening recommendation. In part, this is because of the lack of a screening test with optimal sensitivity and specificity, and the unpredictable nature of the disease process, both of which render screening problematic. PSA screening and digital rectal examinations (DRE) are the preferred methods for screening. Although PSA testing is more sensitive than DRE, it has the potential of missing 10% to 20% of prostate cancers if a 4.0 ng/mL cut-off is used. Although using a lower threshold may detect more cancers, this will be at the cost of more false-positives resulting in unnecessary invasive procedures. DRE can detect only 60% of prostate
Preventing Cancer
cancers and is limited by the fact that only the lateral and posterior aspects of the gland can be detected. Combining DRE with PSA will yield higher detection rates (26% more than PSA alone), but once again at the expense of increasing false-positive results. Additionally, the treatment of prostate cancer carries significant adverse effects, which make early detection objectionable to some. There are trials underway to determine the impact of prostate cancer screening on mortality. Until the results of these trials are determined, primary care doctors should inform patients of the accuracy of screening modalities, and the consequences of a screening verses noscreening strategy. Patients should be engaged in shared decision making.50 Cervical cancer is estimated to have claimed more than 3600 lives in the United States in 2007. Rates of invasive cervical cancer and mortality rates from cervical cancer dropped by an estimated 70% between 1950 and 1970, and an additional 40% percent between 1970 and 1999. These rate drops are thought to be a direct effect of cervical cancer screening using the traditional Papanicolaou’s (PAP) test. The slow transformation of carcinoma in situ into invasive disease allows for an effective screening process with sufficient time for detection and treatment in most patients. In Iceland, the mortality rate dropped by 80% over 20 years when screening was initiated, and in Finland and Sweden by 50% and 34%, respectively. Case–control studies indicate a 3 to 10 times greater risk of developing invasive cervical cancer in women who have not been screened. The optimal interval has yet to be determined, as screening every 2 to 3 years rather than annually did not show any significant increased risk of detecting invasive disease.51 The USPSTF guidelines currently recommend screening at least every 3 years for low-risk patients. Lung cancer, the leading cause of cancer deaths in the United States, is estimated to have claimed the lives of more than 70,000 women and 89,000 men in 2007 alone. The most important risk factor is tobacco use. Other risk factors are related primarily to occupational exposures to agents such as asbestos, arsenic, and radon. Different screening modalities exist for lung cancer. The most common is chest radiograph and sputum cytology. Many studies evaluated these modalities for screening purposes but failed to report any significant benefits. Low-dose helical CT (LDCT) is more sensitive than chest radiographs and in one study was found to detect six times as many stage 1 lung cancers. The sensitivity and specificity of this modality are unclear. It is associated with an increase in diagnostic procedures with potential harms like percutaneous needle biopsy and thoracotomy for benign disease. Additionally, one sixth of all lung cancers found at autopsy were not clinically diagnosed before death. The National Cancer Institute (NCI) is conducting a randomized–control study to measure the possible impact on mortality rates.52 Until this study concludes, universal screening for lung cancer by means of CT cannot be endorsed. CRC, the third most common malignancy and the second leading cause of cancer deaths in the United States, caused more than 52,000 deaths in 2007. Acceptable screening modalities include testing for fecal occult blood, direct visualization of the sigmoid colon using a flexible sigmoidoscope, and direct visualization of the entire colon using a colonoscope. In one review, fecal occult blood testing (FOBT) was found to be associated with a 16% reduction in CRC mortality; however, it was found to have a high false-positive rate of about 80%. Flexible sigmoidoscopy has the potential to reach 65% of polyps. Two case–control studies reported a decreased risk of fatal cancer of the distal colon and rectum of 70% to 90% when evaluating the use of rigid or flexible sigmoidoscopy when compared with an unscreened population. Combining FOBT with sigmoidoscopy was found to detect 75.8% of advanced neoplasms, provided a positive finding was followed with a complete colonoscopy.53 Barium enemas and colonoscopy are other alternatives for screening. Colonoscopy is the preferred
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method for screening in the United States because of its low incidence of missed polyps (approximately 20%), the small size of those missed compared with bariumenemas, and the low risk of those missed for transformation to cancer quickly.54 The national Polyp Study in 1993 showed a 76% to 90% decrease in incidence of CRC if one or more adenomas were removed, and a 69% decrease in CRC mortality.55 Virtual colonoscopy also has been used as a screening modality but depends heavily on the size of the target lesion. A study56 published in 2007 comparing virtual colonoscopy and optical colonoscopy revealed similar detection rates for advanced neoplasia. The optical colonoscopy was found to be associated with higher incidence of complications, namely colonic perforations. DREs have not been associated with any significant reduction in distal rectal cancer.53 In the United States, breast cancer is estimated to have caused more than 40,000 deaths in 2007. Mammography is the currently acceptable screening modality. Following the widespread use of mammography in the mid-1980s, the incidence of breast cancer, as happens often with new screening programs, predictably increased. The anticipated decline in incidence, which follows implementation of a screening program, failed to materialize, however, raising worries of overdiagnosis and undue attention to clinically insignificant cancers (overdiagnosis bias). Mammography decreases breast cancer-related deaths in women ages 40 to 74. A recent Cochrane review57 concluded that the absolute reduction in breast cancer mortality was 0.1%, and for every 2000 invited to participate in screening for 10 years, one life would be extended. This benefit corresponded to a 2-day life extension, on average, per woman per 10 years of screening. No evidence was found that clinical breast examination or breast self-examination reduces breast cancer mortality.58 The risk of developing and dying from breast cancer increases with age, and the greatest increase in relative risk per year occurs before menopause. Some studies indicate that starting a screening program in women 40 years of age and above will incur tangible benefits in terms of early diagnoses and decreased mortality as opposed to limiting the screening to women 50 years and above.
ROLE OF IMMUNIZATION IN CANCER PREVENTION
Currently human papilloma virus (HPV) and hepatitis B virus (HBV) are viruses for which vaccination is indicated for cancer prevention. These viruses are causative agents for cervical and hepatic cancers, respectively. Although there are other infections that have been linked to cancer, like Epstein Barr virus as a cause of Burkitt’s lymphoma and gastroadenocarcinoma and Helicobacter pylori as a causative agent in development of stomach cancer, there has yet to be approved vaccines for these agents.
Human Papilloma Virus
HPV is the most common sexually transmitted disease in the United States. Globally, it is estimated to cause more than 500, 000 cases of cancer annually (over 90% of cervical cancers). It is contracted commonly soon after becoming sexually active and may induce cellular changes in the cervix that may progress in to cancer. A quadrivalent human papilloma vaccine against the high-risk subtypes responsible for 70% of cervical cancers recently was approved for women aged 9 to 26.59,60 The vaccine still faces numerous obstacles, including cost, cultural, and religious beliefs of the at-risk population.61
Preventing Cancer
Hepatitis B
Chronic HBV infection is believed to cause approximately 1 million deaths globally, one third of them due to hepatocellular carcinoma (HCC). The prevalence of chronic infection rises if acquired in early childhood. HBV vaccine has demonstrated a seroconversion rate greater than 95%. Preliminary reports indicate a small decrease in the incidence of HCC; however, because the peak age for HCC is 40 to 60 years of age, theoretically a larger drop would be expected 30 to 40 years after the implementation of universal vaccination against hepatitis B, which began in the late 1990’s.61 BEHAVIORAL CHANGE
Reports show that more than 70% of patients do not follow recommended lifestyle changes, and when these changes involve ending addictive behaviors such as smoking, the noncompliance rate increases to greater than 90%. Knowledge of the transtheoretical model of change62 can position the provider to better understand the patient’s stage in the change process. These stages are: (1) precontemplation stage,
Fig.1. Summary of cancer prevention through dietary and lifestyle modifications. (Data from World Cancer Research Fund/American Institute for Cancer Research. Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective. Washington DC, 2007.)
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(2) contemplation stage, (3) preparation/determination stage, (4) action stage, (5) maintenance stage, and (6) relapse stage. Patients in the precontemplation stage tend to minimize their problem and to some degree deny it. In the contemplation stage, they begin to think about their problem and possible solutions. The preparation stage is marked with increasing energy and commitment toward the solution. Once patients initiate a plan to solve their problem, they are regarded to have entered the action stage. Once success has been achieved, patients enter into the maintenance stage and should begin to prepare to encounter expected and unexpected obstacles. Relapse may occur after the maintenance stage, and often several attempts may be needed to achieve long-term success. The astute clinician should be able to identify the patient in the contemplative stage and assist him or her to move to the action phase. Familiarization with programs based on the transtheoretical model such as the US Surgeon General’s ‘‘Tobacco Cessation, you can quit smoking now’’63 are important tools in facilitating behavior change. SUMMARY
Advancements in the management protocols and chemotherapeutics have improved outcomes for patients diagnosed with cancer. Cancer, however, continues to claim many lives annually in the United States and around the world. There is a large body of evidence that is strong and consistent that through modification of diet and lifestyle habits, cancer can be a preventable disease (Fig. 1). Although some dietary components are supported by limited evidence of a protective effect, other interventions like weight reduction and smoking cessation come with stronger evidence and considerable benefits in terms of cancer prevention. REFERENCES
1. American Cancer Society. Cancer facts & figures 2007. Atlanta (GA): American Cancer Society; 2007. 2. Colditz GA, DeJong D, Hunter DJ, et al. Harvard Report on cancer prevention volume 1: causes of human cancer. Cancer causes and control. Boston: Harvard Center for Cancer Prevention; 1996. 3. World Cancer Research Fund/American Institute for Cancer Research. Food, nutrition, physical activity, and the prevention of cancer: a global perspective. Washington, DC: American Institute for Cancer Research; 2007. 4. Danaei G, Vander Hoorn S, Lopez AD, et al. Causes of cancer in the world: comparative risk assessment of nine behavioural and environmental risk factors. Lancet 2005;366(9499):1784–93. 5. Lagiou P, Trichopoulos D, Sandin S, et al. Mediterranean dietary pattern and mortality among young women: a cohort study in Sweden. Br J Nutr 2006; 96(2):384–92. 6. Cottet V, Bonithon-Kopp C, Kronborg O, et al. Dietary patterns and the risk of colorectal adenoma recurrence in a European intervention trial. Eur J Cancer Prev 2005 Feb;14(1):21–9. 7. Kim MK, Sasaki S, Otani T, et al. Dietary patterns and subsequent colorectal cancer risk by subsite: a prospective cohort study. Int J Cancer 2005;115(5): 790–8. 8. Chao Ann, Thun MJ, Connell CJ, et al. Meat consumption and risk of colorectal cancer. JAMA 2005;293:172–82. 9. Wallstro¨m P, Bjartell A, Gullberg B, et al. A prospective study on dietary fat and incidence of prostate cancer. Cancer Causes Control 2007;18(10):1107–21.
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10. Pierce JP, Natarajan Loki, Caan BJ, et al. Influence of a diet very high in vegetables, fruit, and fiber and low in fat on prognosis following treatment for breast cancer: the Women’s Healthy Eating and Living (whel) randomized trial. JAMA. 2007;298:289–98. 11. Lanza Elaine, Yu Binbing, Murphy Gwen, et al. The polyp prevention trial— continued follow-up study: no effect of a low-fat, high-fiber, high-fruit, and vegetable diet on adenoma recurrence eight years after randomization. Cancer Epidemiol Biomarkers Prev 2007;16:1745–52. 12. Boeing H, Dietrich T, Hoffmann K. Intake of fruits and vegetables and risk of cancer of the upper aero–digestive tract: the prospective EPIC study. Cancer Causes Control. 2006;17(7):957–69. 13. Vainio H, Weiderpass E. Fruit and vegetables in cancer prevention. Nutr Cancer. 2006;54(1):111–42. 14. Block G, Patterson B, Subar A. Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence. Nutr Cancer. 1992;18(1):1–29. 15. Steinmetz KA, Potter JD. Vegetables, fruit, and cancer prevention: a review. J Am Diet Assoc. 1996;96(10):1027–39. 16. Feskanich Diane, Ziegler RG, Michaud DS, et al. Prospective study of fruit and vegetable consumption and risk of lung cancer among men and women. J Natl Cancer Inst 2000;92(22):1812–23. 17. Smith-Warner SA, Spiegelman D, Yaun S-S, et al. Intake of fruit and vegetables and risk of breast cancer. JAMA 2001;285(6):769–76. 18. Giovannucci E. Tomatoes, tomato-based products, lycopene, and cancer: review of the epidemiologic literature. J Natl Cancer Inst 1999;91(4):317–31. 19. Norat T, Bingham S, Ferrari P, et al. Meat, fish, and colorectal cancer risk: the European prospective investigation into cancer and nutrition. J Natl Cancer Inst 2005;97(12):906–16. 20. Cho E, Smith-Warner SA, Spiegelman D, et al. Dairy foods, calcium, and colorectal cancer: a pooled analysis of 10 cohort studies. J Natl Cancer Inst 2004;96(13): 1015–22. 21. Rodriguez C, McCullough ML, Mondul AM, et al. Calcium, dairy products, and risk of prostate cancer in the prospective cohort of United States men. Cancer Epidemiol Biomarkers Prev 2003;12(7):597–603. 22. Giovannucci E, Liu Y, Rimm EB, et al. Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. J Natl Cancer Inst 2006;98(7):451–9. 23. Mayne ST, Risch HA, Dubrow R, et al. Nutrient intake and risk of subtypes of esophageal and gastric cancer. Cancer Epidemiol Biomarkers Prev 2001; 10(10):1055–62. 24. Kubo AI, Corley DA. Meta-analysis of antioxidant intake and the risk of esophageal and gastric cardia adenocarcinoma. Am J Gastroenterol. 2007;102(10): 2323–30. 25. Wright ME, Weinstein SJ, Lawson KA, et al. Supplemental and dietary vitamin E intakes and risk of prostate cancer in a large prospective study. Cancer Epidemiol Biomarkers Prev. 2007;16(6):1128–35. 26. Coulter ID, Hardy ML, Morton SC, et al. Antioxidants vitamin C and vitamin E for the prevention and treatment of cancer. J Gen Intern Med. 2006;21(7):735–44. 27. Combs GF Jr. Current evidence and research need to support a health claim for selenium and cancer prevention. J Nutr 2005;135:343–7. 28. Larsson SC, Giovannucci E, Wolk A. Folate intake, mthfr polymorphisms, and risk of esophageal, gastric, and pancreatic cancer: a meta-analysis. Gastroenterology 2006;131(4):1271–83.
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29. Bailey LB, Rampersaud GC, Kauwell GPA. Folic acid supplements and fortification affect the risk for neural tube defects, vascular disease, and cancer: evolving science. J Nutr 2003;133:1961S–8S. 30. MacLean CH, Newberry SJ, Mojica WA, et al. Effects of omega-3 fatty acids on cancer risk. JAMA 2006;295:403–15. 31. Bardia A, Tleyjeh IM, Cerhan JR, et al. Efficacy of antioxidant supplementation in reducing primary cancer incidence and mortality: systematic review and metaanalysis. Mayo Clin Proc 2008;83(1):23–34. 32. Zhang SM, Willett WC, Selhub J, et al. Plasma folate, vitamin b6, vitamin b12, homocysteine, and risk of breast cancer. J Natl Cancer Inst 2003;95(5):373–80. 33. Stevenson RE, Allen WP, Pai GS, et al. Decline in prevalence of neural tube defects in a high-risk region of the United States. s.I. Pediatrics 2000;106(4): 677–83. 34. Ross JA, Blair CK, Olshan AF, et al. Periconceptional vitamin use and leukemia risk in children with Down syndrome: a Children’s Oncology Group study. Cancer. 2005;104(2):405–10. 35. Logan RF, Grainge MJ, Shephard VC, et al. Aspirin and folic acid for the prevention of recurrent colorectal adenomas. Nottingham. Gastroenterology 2008;134(1):29–38. 36. Baron JA, Cole BF, Sandler RS, et al. A randomized trial of aspirin to prevent colorectal adenomas. N Engl J Med 2003;348(10):883–90. 37. Boffetta P, Hashibe M. Alcohol and cancer. Lancet Oncol 2006;7(2):149–56. 38. Thun MJ, Peto R, Lopez AD, et al. Alcohol consumption and mortality among middle-aged and elderly US adults. N Engl J Med 1997;337(24):1705–14. 39. Michaud DS, Fuchs CS, Liu S, et al. Dietary glycemic load, carbohydrate, sugar, and colorectal cancer risk in men and women. Cancer Epidemiol Biomarkers Prev 2005;14(1):138–47. 40. Higginbotham S, Khang ZF, Lee IM, et al. Dietary glycemic load and breast cancer risk in the Women’s Health Study. Cancer Epidemiol Biomarkers Prev 2004;13(1):65–70. 41. Cotterchio M, Boucher BA, Manno M, et al. Dietary phytoestrogen intake is associated with reduced colorectal cancer risk. J Nutr 2006;136(12):3046–53. 42. Friedenreich C, Norat T, Steindorf K, et al. Physical activity and risk of colon and rectal cancers: the European prospective investigation into cancer and nutrition. Cancer Epidemiol Biomarkers Prev 2006;15(12):2398–407. 43. Maruti SS, Willett WC, Feskanich D, et al. A prospective study of age-specific physical activity and premenopausal breast cancer. J Natl Cancer Inst. 2008; 100:728–37. 44. National Cancer Institute. Physical activity and cancer: fact sheet. Available at: http://www.cancer.gov/cancertopics/factsheet/physical-activity-qa. Accessed September 11, 2008. 45. Centers for Disease Control and Prevention. Skin cancer prevention and education initiative. Available at: http://www.cdc.gov/cancer/skin/pdf/0607_skin_fs.pdf. Accessed September 11, 2008. 46. Buckel TBH, Goldstein AM, Fraser MC, et al. Recent tanning bed use: a risk factor for melanoma. Arch Dermatol 2006;142:485–8. 47. Furberg H, Newman B, Moorman P. Lactation and breast cancer risk. Int J Epidemiol 1999;28(3):396–402. 48. Danforth KN, Tworoger SS, Hecht JL, et al. Breastfeeding and risk of ovarian cancer in two prospective cohorts. Cancer Causes & Control 2007;18(5):517–23.
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49. World Health Organization /International Agency for Research on Cancer. Tobacco smoke and involuntary smoking. Available at: http://monographs.iarc.fr/ENG/ Monographs/vol83/volume83.pdf. Accessed September 11, 2008. 50. National Cancer Institute. Prostate cancer screening. Available at: http://www. cancer.gov/cancertopics/pdq/screening/prostate/HealthProfessional/page1. Accessed September 11, 2008. 51. National Cancer Institute. Cervical cancer screening. Available at: http://www. cancer.gov/cancertopics/pdq/screening/cervical/healthprofessional. Accessed September 11, 2008. 52. National Cancer Institute. Lung cancer screening. Available at: http://www. cancer.gov/cancertopics/pdq/screening/lung/healthprofessional. Accessed September 11, 2008. 53. National Cancer Institute. Colorectal cancer screening. Available at: http://www. cancer.gov/cancertopics/pdq/screening/colorectal/healthprofessional. Accessed September 11, 2008. 54. Winawer SJ, Stewart ET, Zauber AG, et al. A comparison of colonoscopy and double-contrast barium enema for surveillance after polypectomy. N Engl J Med 2000;342(24):1766–72. 55. Winawer SJ, Zauber AG, Ho MN, et al. Prevention of colorectal cancer by colonoscopic polypectomy. N Engl J Med 1993;329:1977–81. 56. Kim DH, Pickhardt PJ, Taylor AJ, et al. CT colonography versus colonoscopy for the detection of advanced neoplasia. NEJM 2007; 357(14):1403–12. 57. Gøtzsche PC, Nielsen M. Screening for breast cancer with mammography. Cochrane Database Syst Rev. 2006;(4):CD001877. 58. US Preventive Service Task Force. Screening for breast cancer. AHRQ. Available at: http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid5hstat3.chapter.27509. 59. American Academy of Pediatrics. Prevention of human papillomavirus infection: provisional recommendations for immunization of girls and women with quadrivalent human papillomavirus vaccine. Pediatrics 2007;120(3):666–8. 60. The Future II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007;356(19):1915–27. 61. Frazer IH, Lowy DR, Schiller JT. Prevention of cancer through immunization: prospects and challenges for the 21st century. Eur J Immunol 2007;37(Suppl 1): S148–55. 62. Derbin K, Perkins A. Noncooperation. In: deGrey FV III, Dickinson WP, Staton EW, editors. 20 common problems in behavioral health. New York: McGraw-Hill; 2001. p. 287–308. n CR, Baker TB. Treating tobacco use and dependence: 2008 63. Fiore MC, Jae update. US Department of Health and Human Services; 2008.
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Preventing Ob esit y in the Primar y C are Set ting Samuel N. Grief, MD, FCFPa,b,*, Kathleen S.Talamayan, MD, MPHc KEYWORDS Prevention Obesity Primary care
Obesity brings to mind a combination of many objective facts and subjective feelings: epidemic, comorbidities, treatment-resistant, drug safety, frustration, disappointment, embarrassment, desperation, and resignation. This negative stigma that stubbornly clings to obesity is the main reason why so many afflicted people have been unable candidly to discuss their problem with friends, family, and medical professionals. Obesity is a chronic disease. A chronic disease is defined by the US National Center for Health Statistics as one lasting 3 months or more. Chronic diseases generally cannot be prevented by vaccines or cured by medication. These types of diseases do not just disappear. Common chronic diseases in the Western world include arthritis; cardiovascular diseases, such as heart attack and stroke; cancers, such as breast and colon cancer; diabetes; epilepsy; seizures; and obesity. It is with this background of obesity, as a negatively perceived chronic disease, that this article addresses the concept of prevention of obesity. Prevention in itself is a form of treatment. By preventing a disease or condition, one is actually making a commitment to act or carry out specific activities in a certain way, often with well-defined parameters, such as frequency, timing, and duration. Prevention entails effort and work. The cost of health care is becoming an increasing burden on United States taxpayers. In 2007, health care spending in the United States reached $2.3 trillion, and was projected to reach $3 trillion in 2011. Health care spending is projected to reach $4.2 trillion by 2016.1 Treating chronic disease costs Americans billions of dollars annually. This cannot go on indefinitely. Additionally, the excellent quality of life that is enjoyed by many Americans is at peril because of the inexorable encroachment of chronic disease on personal and professional lives. a
Department of Family Medicine, University of Illinois at Chicago, 1919 West Taylor Street, Room 159, Chicago, IL 60612, USA b Campus Care, Clinical Sciences North, University of Illinois at Chicago, 820 South Wood Street, Suite W320, Chicago, IL 60612, USA c Department of Family Medicine, University of Illinois at Chicago, 1919 West Taylor Street, Room 145, Chicago, IL 60612, USA * Corresponding author. Department of Family Medicine, University of Illinois at Chicago, 1919 West Taylor Street, Room 159, Chicago, IL 60612. E-mail address:
[email protected] (S.N. Grief). Prim Care Clin Office Pract 35 (2008) 625–643 doi:10.1016/j.pop.2008.07.002 primarycare.theclinics.com 0095-4543/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.
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Intuitively, prevention is based on doing one or more actions to lessen or eliminate the risk of a particular outcome. For example, if one knows that doing 30 minutes of aerobic activity 5 days per week staves off most chronic disease, the seemingly logical action to take is to perform 30 minutes of physical activity 5 days per week. It is simple to implement in theory, but complex and difficult in practice for many Americans to perform. Many Americans are trying to lose weight, more often with short-term success followed by long-term relapse. This article outlines steps on how to move the treatment of obesity to a new paradigm of prevention in the primary care setting. Almost all Americans visit their primary care physician or health care provider for routine health maintenance or some unexpected illness or sickness at one point or another. Primary care offices are the most likely entry point to the health care system for most of the population and should be the preferred venue to address chronic disease prevention. Prevention in the primary care setting is the short- and long-term solution to obesity. BACKGROUND: OBESITY IN THE UNITED STATES
Obesity has now become one of the leading health problems in the United States. Obesity is defined as body mass index (BMI) of more than 30 kg/m2, whereas overweight is having a BMI of 25 to 29.9 kg/m2 (Table 1).2 An estimated 97 million adults in the United States are obese or overweight.3 The magnitude of obesity all over the United States has continued to increase dramatically in recent years.4–6 Approximately two thirds of the United States adult population is overweight or obese based on a recent survey in 2003 to 2004 compared with only one half in 1988 to 1994.4,5 This increasing trend has been illustrated among states participating in the Behavioral Risk Factor Surveillance System. Based on this study in 1990, the prevalence of obesity was less than or equal to 15% for all participating states. By 1998, there were seven states with a prevalence of obesity between 20% and 24%. In 2006, there were 22 states, which had a prevalence of obesity equal to or greater than 25%.5 Obesity is not only a problem among the adult population. Obesity is now the most common chronic illness in childhood.7 One third of all children in the United States aged 2 to 19 years old are overweight (obese) or at risk for overweight.5 Among children aged 2 to 19 years old, the prevalence of at-risk for overweight, defined as BMI of 85th to less than the 95th percentile, was 19.5% (Table 2).5,7,8 The prevalence of overweight or obese, defined as BMI equal to or greater than the 95th percentile, was 17.1 based on the 2003 to 2004 NHANES study.5,7,8 In June 2007, an Expert Committee, comprised of representatives from 15 professional organizations, was convened by the American Medical Association and cofunded in collaboration with the Department of Health and Human Services’ Health Resources and Services Administration and the Centers for Disease Control and Prevention. The Expert Committee recommended
Table 1 The international classification of adult underweight, overweight, and obesity Classification
Body Mass Index (kg/m2)
Underweight
<18.50
Normal
18.50–24.99
Overweight
R25
Obese
R30
Data from World Health Organization, 1995, 2000, and 2004.
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Table 2 Body mass index for age among children Classification
Percentile Range
Underweight
<5th percentile
Normal
5th percentile to <85th percentile
At risk of overweight
85th to <95th percentile
Overweight
R95th percentile
that for children and adolescents 2 to 18 years of age, new definitions for overweight and obesity be enacted as follows: individuals with a BMI greater than or equal to 95th percentile for age and gender should be considered obese; individuals with BMI greater than or equal to 85th percentile, but less than 95th percentile for age and gender, should be considered overweight, and this term replaces ‘‘at risk of overweight’’ (Figs. 1 and 2). Unfortunately, pediatric overweight and obesity are increasing. The prevalence of overweight among children aged 6 to 11 more than doubled in the past 20 years, going from 7% in 1980 to 18.8% in 2004.4,5 The rate among adolescents aged 12 to 19 more than tripled, increasing from 5% to 17.1%.4,5 Obesity is associated with multiple medical morbidities, psychologic stress, and social stigmatization in adults and children.3,9,10 Overall morbidity and mortality escalates with increase in BMI. In adults, disease and death risk are greater among individuals with BMI greater than 25 kg/m2.3,10,11 Also, waist circumference measurement greater than 40 inches (102 cm) in men or 35 inches (89 cm) in women is associated with a higher risk of obesity-related comorbidities, such as cardiovascular diseases.3,11 Medical comorbidities include hypertension, dyslipidemia, diabetes mellitus type II, coronary artery disease, stroke, gallbladder disease, certain types of cancer, reduced fertility, osteoarthritis, orthopedic complications, sleep apnea, and asthma.3,10–14 The risk for diabetes mellitus type II with a BMI above 35 kg/m2 increases by 93-fold in women and by 42-fold in men.12 The risk for coronary artery disease is increased 86% by a 20% rise in weight in men, whereas in women there is a 3.6-fold increase in risk with BMI above 29 kg/m2.12 Gallbladder disease is increased 2.7-fold.12 The medical health problems associated with obesity in adults can also be seen in children.9,15 In addition to the medical problems, pediatric obesity greatly influences the psychologic and social aspects of childhood. The psychologic stress may be a result of altered social interactions with peer group, poor self-concept, and depression.9 Obesity during childhood is a risk factor itself for much of adult morbidity and mortality. The probability of childhood obesity persisting into adulthood is estimated to increase from 20% at 4 years of age to 80% by adolescence.9 Not surprisingly, obesity has been shown to significantly increase health care cost compared with normal-weight individuals.10–13,15–20 Obesity is associated with greater cost before the age of 56 than other at-risk populations, such as smokers.17 Estimates have shown obesity to be associated with cost increase between 21% and 57% among individuals with a BMI between 30 and 40. Individuals with a BMI greater than 40 have been shown to experience health care cost increases of up to 111% compared with normal-weight counterparts.18 In light of the effort to reduce national health care expenditures, the cost of obesity has played a large role in shaping policy surrounding intervention and treatment.17 The long-term cost-effectiveness of many treatment regimes, however, has yet to be
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CDC Growth Charts: United States BMI
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realized. A large portion of the higher health care use and charges can be seen across primary care, specialty care, emergency room visits, hospitalization, and ancillary services.19,20 This accounts for the treatment of the common obesity comorbidities mentioned previously. In addition, it has been suggested that secondary diagnosis of obesity extends the length of hospital charges for individuals being treated for traditionally unassociated conditions, such as asthma and affective disorders.19 Increasingly used treatments, such as bariatric surgery and long-term pharmacotherapy, come with a large price tag, and may not be covered by health insurance plans.18 There are also costs that are not as transparent. Workplace absenteeism is higher among obese individuals. Between 2.7 and 5.1 more days off work per year are
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CDC Growth Charts:United States BMI
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reported by obese individuals.18 Time off of work equates to reduced economic productivity when multiplied across the entire working age obese population. CAUSES AND CONTRIBUTING FACTORS ASSOCIATED WITH OBESITY
Multiple factors come into play influencing the rise of obesity in the United States. Among these factors, diet and reduced physical activity are the most commonly cited. Such issues as policy governing the United States food industry, primary education meal programs, and urban planning also play a role in the epidemic. Many of these factors do not discriminate in their impact on adults and children. Understanding
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the prevalence of obesity requires an understanding of the interactions between these factors. Obesity can be attributed to the imbalance between energy intake and energy expenditure.11 Intake of calories greater than the daily recommended level for the average American results in weight gain. Individuals eating a diet replete with high-calorie, energy-dense, processed foods and a diet depleted of fiber, micronutrients, and antioxidants are predisposed to comorbidities associated with obesity. The popularity of fast-food restaurants has only worsened the problem.21 Fast food consumption has been associated with excess total energy intake and increased bodyweight in adolescents and adults.21–24 Aside from the increase in popularity of fast food, there has been a 300% increase in the consumption of soft drinks over the past 20 years.25 The additional 120 calories of one serving of sugar-sweetened soft drink per day produces a 50 kg increase in body mass over 10 years.21 Sugar-sweetened beverage consumption has been associated with obesity among adolescents.25 Sugar-sweetened beverages have a high glycemic index, which increases the postprandial blood glucose and decreases insulin sensitivity.25 Also, a compounding effect has been shown wherein consumption of foods high in sugar results in a decreased satiety level, increasing the likelihood of greater food intake.21 An additional 835 calories are taken in by children who drink at least 8 oz of sweetened beverage per day compared with those who do not. Furthermore those who drink regular soft drinks eat more food than those who do not.26 Loose regulations on the United States food industry have influenced unhealthy food choices by inattention to highly saturated fatty foods and sugar content available in the market. Given recent media attention on the prevalence of obesity in the United States, however, lawmakers are now pressured into paying closer attention to the issue.27 Adolescents and children are not excluded when it comes to dietary behaviors. Studies suggest that both obese adolescents and their normal-weight counterparts practice dieting.28 In 2003, 73% of Americans said that they were trying to lose weight. This number decreased to 59% in 2007. Almost three quarters of the American population agree it is important to have a support network when trying to lose weight, yet it seems those support networks do not exist.29 Despite efforts to lose weight by dieting, obesity is still pervasive. Despite the flood of diets currently on the market and increased public health initiatives to target unhealthy eating behaviors, the prevalence of obesity continues to increase. This can be largely attributed to the predominantly sedentary lifestyle that Americans are living.11 Lack of physical activity and sedentary behavior has contributed to the increase in prevalence of obesity. Recent surveys on the American public’s level of physical activity continue to show a low level of participation in physical fitness activities.30 Based on a Centers for Disease Control and Prevention study, more than 50% of adults do not meet recommended levels of physical activity and 24% do not engage in physical activity at all during their leisure time.31,32 Physical inactivity is not only seen in adults, but also in the young population. Among adolescents and children between grades 9 and 12, two thirds are not participating in physical activity at the recommended level.31 Urban sprawl is a recent addition to the list of potential contributing factors to the increase of obesity. Urban sprawl can be defined as the increase in population of new low-density residential areas surrounding metropolitan areas.33 Studies suggest that there is a clear correlation between the increase of urban sprawl and obesity. The factors that link urban sprawl to obesity vary; increased use of automotive transportation, difficulty or inconvenience in walking between destinations, limited access to
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parks and recreational facilities, higher number of fast food establishments, and collective neighborhood perceptions among others have been cited.33–35 Although there is a clear correlation, it is unclear in which direction the causality flows. Some postulate that the rise of urban sprawl did not cause the rise of obesity, but rather individuals who are obese or at risk for becoming obese are more likely to settle in low residential areas. Ergo, an individual who does not enjoy physical activity may not consider proximity to parks and recreational areas when choosing where to settle.33,34 PREVENTION OF OBESITY: A NEW PARADIGM FOR PRIMARY CARE
This section sets out a preventive care approach to addressing obesity, with the goal of helping all medical providers learn a new way to promote prevention in their practice. Treatment of obesity as a chronic disease requires support, dedication, commitment, sustained effort, ongoing counseling, and vigilance. Not surprisingly, these same attributes are also required to follow a program designed to prevent obesity. It is with this in mind that the following new preventive paradigm is introduced. Any new paradigm shift brings resistance. It can be unnerving and uneasy for many, but immediate change is the only answer to this epidemic. The new paradigm can be summarized as follows: Proactive reprioritization of addressing weight issues in the office setting Medical office reminders (ie, posters, wall charts, and so forth) Patient-friendly educational material Inclusion of nutrition history in all patients as a new benchmark Exercise prescriptions Integrating treatment strategies to prevent progression of obesity Diet, physical activity, effective counseling Pharmacotherapy for weight loss and weight maintenance PROACTIVE REPRIORITIZATION OF ADDRESSING WEIGHT ISSUES IN THE OFFICE SETTING
The office setting is the most common venue for health care education between physician or health care provider and patient. Education is a key component of every patient visit, from such simple topics as the common cold to more complex topics, such as depression and diabetes. To enhance the educational experience of each patient at every visit, consider using educational materials that stimulate a person’s multiple senses. Some people prefer visual learning; others do better with listening to the information or hands-on learning.36–38 Medical Office Reminders
As a patient enters the office, they will likely wait a minute or two before checking in, allowing some time to browse health-related materials. Having materials for patients to peruse is relatively standard among medical offices. The quality and suitability of these written educational materials is not necessarily guaranteed.39 Having them prepared by health professionals in accordance with guidebooks and taking the target group into account can eliminate the inadequacy of these materials.39 Do not hesitate to display office educational pamphlets, booklets, posters, and so forth in the check-in area. Office educational materials can also be placed in highly visible areas in the patient waiting area, and in the laboratory. Examination rooms are even more likely to grab a patient’s attention, given the increased patient awareness when waiting in these rooms. It has been shown that health educational pamphlets, designed and distributed for patients, can standardize patients’ knowledge about a procedure.40
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A booklet with a focus on plain language usage and simple illustrations seems to be an advantageous educational tool even in culturally diverse populations.40 BMI wall charts and flyers pertaining to the group weight loss program have been successfully used in the authors’ family practice for years and generate many questions and concerns about weight that perhaps might never have surfaced (Fig. 3). Office-based screening for obesity is now commonplace. The American College of Cardiology and the American Heart Association have put forth their recommendations for obesity screening:41 BMI or waist circumference should be assessed on each visit BMI should be 18.5–24.9 kg/m2 and waist circumference should be <40 in for men and <35 in for women
Fig. 3. Patient-centered hand-out.
Preventing Obesity in the Primary Care Setting
Encourage weight maintenance and reduction at each visit through physical activity, caloric intake, and behavioral programs to achieve BMI and waist circumference within the previously mentioned ranges Initial goal of weight loss therapy should be to reduce body weight by approximately 10% from baseline The American Academy of Family Physicians, American Academy of Pediatrics, and American Medical Association recommend measuring height and weight as part of periodic health examination for children and adolescents.42 Knowledge of this important parameter fosters discussion between physician and patient, parent, and guardian and leads to greater communication in regards to obesity.
Patient-Friendly Educational Material and Media
Developing or using an existing patient-friendly pamphlet regarding overweight and obesity requires some sensitivity. Sharing facts for all to read and see, however, is always a good idea. A good resource is the American Academy of Family Physicians Web site at http://familydoctor.org/nutrition.43 Several educational handouts are easily downloaded, printable, and of value in discussion and counseling with at-risk patients for obesity. Taking a positive approach and highlighting the aspects of obesity that can be controlled by patients fosters more interest and enthusiasm on their part. Fig. 3 is an example of one such patient-centered handout, developed for a group weight loss program created and implemented by one of the authors.
Inclusion of Nutrition History in All Patients as a New Benchmark
The ever-shrinking office visit between patient and physician has many competing interests. Nutrition history often gets pushed aside because of time constraints or a lack of prioritization by the patient, physician, or both. Given the worsening obesity epidemic among adults and children, the time is suitable for changing how physicians and providers gather nutrition information. Traditional methods of taking a nutrition history have been tried and tested, as previously outlined in the medical literature, but difficult for mainstream physicians to implement.44 Nutrition habits are likely strong contributory factors to a patient’s obesity. It is still of paramount importance to address nutrition with the patient, albeit briefly. Newer, more concise ways of approaching nutrition data gathering are more in line with the faster-paced medical encounters in the twentieth century and may be more beneficial to both physician and patient.45 The acronym WAVE, which stands for Weight, Activity, Variety, and Excess, has been promoted in nutrition professional circles to help succinctly identify and address glaring nutritional issues.46 Open-ended questions, such as ‘‘Are you happy with your current weight?,’’ along with a general openness toward a patient’s specific nutrition concerns, and more targeted questions, such as ‘‘Do you eat breakfast’’ or ‘‘What are your favorite foods?,’’ is the best overall approach efficiently and empathically to guide a patient to newer, more healthier ways of eating. The new goal for all physicians and providers is to inquire about nutrition, in brief or in detail, and to document the discussion. Succinct, recurrent reminders about the importance of nutrition foster a more open and forthright account of the patient’s nutrition habits. These brief discussions allow for an exchange of ideas that will likely lead to change. Although there are no data regarding the efficacy of WAVE, many physicians and ancillary health care professionals are incorporating this useful and practical nutrition history tool into their daily practice.
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Exercise Prescriptions
The office encounter between patient and physician typically ends with a written prescription being given to the patient. This prescription ‘‘seals the deal,’’ akin to a formal handshake between business associates. Providing an exercise prescription is a logical extension of the therapeutic lifestyle discussion that has just occurred. Exercise prescriptions should also include a formal fitness assessment and can be simple or more detailed. Ultimately, exercise prescriptions are exercise guidelines for patients, taking into account frequency, type, duration, and intensity of the particular exercise or physical activity. Box 1 is an example of various plans that can be encouraged in an exercise prescription.47 People naive to exercise training, those who are extremely deconditioned (out of shape), and older people are, in general, better candidates for low-intensity exercise. Low-intensity exercise may result in an improvement in health status with little or no change in physical fitness. Light or moderate activity is associated with a reduced risk of death from any cause among men with established coronary artery disease. Furthermore, regular walking or moderate to heavy gardening has been shown to be sufficient in achieving these health benefits.48 Maintaining an active lifestyle or taking up light or moderate physical activity significantly reduces the risk of cardiovascular disease and death from any cause among older men (with or without established cardiovascular disease).49 This is important information given the preferred leisure activities of adults, such as walking, gardening, and homebased exercise.50 Exercise prescription for health does not need to be complicated. It can revolve around many activities of daily living. People should choose exercises and activities that they prefer and should try to do them on most days of the week for about 20 to 60 minutes. Modest and achievable levels of physical activity (30 minutes per day on most days) can decrease the risk of chronic disease including breast cancer, and coupled with appropriate dietary restraint can help overweight women lose weight.51 Structured physical training is not required for health benefits to occur, and physical activity can be accumulated throughout the day, even through short (10 minute) bouts of exercise.47
Integrating Treatment Strategies to Prevent Progression of Obesity
Chart audits are a time-tested strategy used to improve preventive care in solo or singlespecialty group family practices.52 In the case of preventing obesity, there are several opportunities that can be undertaken to identify where best to focus the group’s attention. Does the group mandate that height and weight be checked at each visit? Calculating the BMI requires both a height and weight. Rechecking the weight at every visit gives an appropriate message to all patients that these anthropometric data are important. Training medical staff in measuring and documenting BMI during clinic visits prompts primary care physicians to discuss obesity with the patient.53 Do the physicians and providers diagnose obesity? It is disappointing but true that many physicians and providers underdiagnose obesity.54,55 Documenting obesity (ICD-9: 278.00) or morbid obesity (ICD-9: 278.01) is the strongest predictor of formulating an obesity management plan.56 Historically, billing for obesity to third-party payers was an exercise in futility. Fortunately, many insurance entities now properly reimburse for caring for obesity.
Preventing Obesity in the Primary Care Setting
Box 1 Recommended levels of exercise required to improve physical activity and fitness levels for health benefits Low-intensity (light effort) aerobic exercise 20%–39% of heart rate reserve, or about 2–4 METs About 60 minutes per day Most (preferably all) days of the week Examples: light gardening, light walking Moderate-intensity aerobic exercise 40%–59% of heart rate reserve, or about 4–6 METs 20–60 minutes per day 3–5 days per week Examples: brisk walking (15–20 minutes per mile), dancing High-intensity aerobic exercise 60%–84% of heart rate reserve, or about 6–8 METs 20–60 minutes per day 3–5 days per week Examples: jogging, swimming Resistance and flexibility exercise One to two sets (each set 8–12 repetitions) of 8–10 different resistance exercises of moderate intensity that engage the large muscle groups, 2–4 days per week People over 60 years and frail people may need to engage in more repetitions (10–15) to compensate for a lower resistance requirement Gentle reaching, bending, and stretching exercises of the major muscle groups to improve flexibility (hold each stretch for 10–30 seconds) for a minimum of 2–3 days per week (preferably 4–7) Aerobic exercise can be accumulated in short (10 minute) sessions of activity throughout the day. The approximate MET values provided are estimates for middle-aged adults (40–64 years). The required METs are lower for elderly and very elderly people, and higher for younger adults.79 In general, the higher the intensity of activity, the less time required for health benefits. Each aerobic exercise session should begin with a warm-up (exercise designed to raise heart rate and body temperature) and end with a cool-down (mild exercise designed to slowly decrease heart rate and body temperature). Abbreviation: MET, metabolic equivalents.
Diet, Physical Activity, Effective Counseling
Do physicians and providers counsel their patients on obesity management, good nutrition habits, and regular physical activity? The United States Preventive Services Task Force recommends that screening for obesity and counseling to promote regular physical activity is a routine part of health visits. Tailored counseling that incorporates shared decision-making, a written prescription, printed materials, and follow-up has been shown to increase the likelihood of success.57 In one study, the number of patients who improved their physical activity level increased by 50% after receiving physician advice.58 Nutritional counseling can be delegated to ancillary health care
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providers if time constraints exist. The following are recommendations from the United States Preventive Services Task Force documents:59 Counseling to promote regular physical activity is recommended for all children and adults. This recommendation is based on the proven efficacy of regular physical activity in reducing the risk for coronary heart disease, hypertension, obesity, and diabetes (‘‘A’’ recommendation), although there is currently insufficient evidence that counseling asymptomatic primary care patients to incorporate physical activity into their daily routines will have a positive effect on their behavior (‘‘C’’ recommendation). Clinicians should determine each patient’s activity level, ascertain barriers specific to that individual, and provide information on the role of physical activity in disease prevention. The clinician may then assist the patient in selecting appropriate types of physical activity. Factors that should be considered include medical limitations and activity characteristics that both improve health (e.g., increased caloric expenditure, enhanced cardiovascular fitness, low potential adverse effects) and enhance compliance (e.g., low perceived exertion, minimal cost, and convenience). There is insufficient evidence that nutritional counseling by physicians, opposed to counseling by dietitians or community interventions, is effective in changing the dietary habits of patients (‘‘C’’ recommendation) Physical activity and good nutrition are considered essential elements to prevent chronic diseases and obesity, as outlined in the Centers for Disease Control and Prevention 2007 guide to promoting physical activity and good nutrition.60 Unfortunately, most Americans do not participate in regular physical activity or apply healthy dietary habits to everyday meals. Despite the proved benefits of physical activity, more than 50% of United States adults do not get enough physical activity to provide health benefits; 24% are not active at all in their leisure time.61 Insufficient physical activity is not limited to adults. About two thirds of young people in grades 9 to 12 are not engaged in recommended levels of physical activity.62 Based on the National Heart, Lung, and Blood Institute guidelines, physical activity is a vital component of weight loss initially. Thirty to 45 minutes of moderate physical activity on 3 to 5 days per week initially is encouraged (Evidence category A). An accumulated 30 minutes or more of moderate physical activity on most days of the week should be set as a long-term goal among adults (Evidence category B).3 On the nutrition front, educating the public on the health benefits of healthy eating patterns and helping people implement these habits is an important undertaking. A large gap remains between healthy dietary patterns and what Americans actually eat. In 2005, only one fourth of United States adults ate five or more servings of fruits and vegetables each day.63 To help people improve their eating habits, the US Department of Health and Human Services and the US Department of Agriculture publish Dietary Guidelines for Americans (available at: http://www.healthierus.gov/dietaryguidelines).64 Some proposed calorie-lowering strategies from the Dietary Guidelines for Americans include eating foods that are low in calories (eg, many kinds of vegetables and fruits and some soups). The healthiest way to reduce calorie intake is to reduce one’s intake of added sugars, fats, and alcohol, which all provide calories but few or no essential nutrients. Special attention should be given to portion sizes, which have increased significantly over the past two decades. The Dietary Guidelines for Americans’ key recommendations regarding weight are to maintain body weight in a healthy range, to balance calories from foods and beverages with calories expended, to prevent gradual weight gain over time, to make small decreases in food and beverage calories, and to increase physical activity.
Preventing Obesity in the Primary Care Setting
To more assertively promote physical activity and good nutrition, the primary care provider should establish collaborative partnerships with nutrition specialists and physical education trainers. Results of these collaborations have been highly successful in promoting widespread behavior changes and achieving weight loss in different populations.65 The use of a coordinated multidisciplinary team effort is critical to the success of medically supervised weight loss.66 Physicians often have a referral network of nutrition specialists with which they collaborate. If no such network is available, the American Dietetic Association offers a tool for locating a nutrition specialist in the area at http://www.eatright.org/cps/rde/xchg/ada/hs.xsl/home_4874_ENU_HTML. htm.67 Most medical centers have specific departments dedicated to nutrition and physical education and therapy. A growing number of medical centers have an affiliation with nutrition and wellness centers, so-called for their emphasis on nutrition, weight management, diabetes education, physical activity education, psychologic services, and in some cases bariatric surgical care. Because many third-party insurers have recognized the value of these nutrition and wellness center services, many patients can benefit from the expert counseling provided at a modest cost. Studies are conflicting regarding overall success in achieving long-term weight loss through supervised weight loss programs. Research to date supports the conclusion that scientifically supported diet regimens can produce weight loss of 9% to 13% of total body weight at 52 to 72 weeks, and that programs aided by pharmacotherapy can result at most in a 10% to 15% weight loss, even over the long-term.68 Evaluating weight loss centers is the first step toward determining whether patients will benefit from their services. There are a lot of questions patients should ask before entrusting their health to a weight loss center. How long has the program been in the area? What is its client retention? What are the success statistics of that particular center? What is its weight management philosophy and why is it better than everyone else’s approach? Are there physicians on-site? Are they available for on-call services? Are they trained and experienced in the metabolism of weight loss? How will they monitor patients’ health? How experienced is the staff? How long have they worked in that particular program? How are they trained? Traditional, supervised weight loss center–sponsored dietary approaches to weight loss can work, but attrition rates over time are high.69 Commercial weight loss diet plans, such as the Atkins diet, South Beach diet, and Zone diet, are well known for their short-term success in achieving modest weight loss of between 5% and 15% within the first 6 to 12 months.70,71 Long-term success beyond 1 year in maintaining weight loss has been rarely reviewed; results for each diet plan are almost equivalent.72 Individuals who attempt weight loss have identified specific components of a weight loss program that contribute to success and that make success difficult.72 Long-term support, having an exercise program or personal trainer, accountability and self-monitoring, and flexibility are key components to weight loss success. Difficulty making and maintaining lifestyle change, no time, lack of support, ready availability of food, and feelings of deprivation are common obstacles to success.72 Pharmacotherapy for Weight Loss and Weight Maintenance
In the area of medication therapy for obesity treatment and weight maintenance, there are fewer options than for other chronic disease states or conditions. This relative paucity of obesity-specific medications has hampered efforts to tame the rising obesity epidemic. Medications approved by the Food and Drug Administration for weight loss are included in Table 3.73
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Table 3 Medications approved by the Food and Drug Administration for weight loss Drug
Mechanism of Action
Side Effects
Sibutramine
Appetite suppressants: combined in norepinephrine and serotonin reuptake inhibitor
Modest increases heart rate and blood pressure, nervousness, insomnia
Phentermine
Appetite suppressant: sympathomimetic amine
Cardiovascular, gastrointestinal
Diethylpropion
Appetite suppressant: sympathomimetic amine
Palpitations, tachycardia, insomnia, gastrointestinal
Orlistat
Lipase inhibitor: decreased absorption of fat
Diarrhea, flatulence, bloating abdominal pain, dyspepsia
For the most part, these medications work by suppressing appetite. Orlistat, now available over the counter under the name of ‘‘Alli,’’ works differently by decreasing the absorption of fat in the small intestines. A more complete description of these medications is available elsewhere for further review.74,75 It is important to recognize that obesity-specific medications can be used not only for initial weight loss but also for short- and long-term maintenance of weight loss or secondary prevention of weight regain. Although it is hardly surprising that these medications are largely used to induce rather than sustain weight loss, the facts are that short-term use of pharmacotherapy to facilitate weight loss is by no means a cureall. Unfortunately, implementation of lifestyle changes to maintain a healthy body weight during and after obesity-specific medication therapy rarely works. Despite a proliferation of commercial weight-loss programs, diet books, and personal trainers, the documented long-term results of weight-loss attempts are modest at best.76 Evidence from randomized controlled trials showing that lifestyle changes alone can maintain substantial weight loss in the long-term still remains sparse; however, there is now abundant evidence from pharmacologic trials that such drugs as orlistat, sibutramine, and rimonabant (a newer compound, not yet approved by the Food and Drug Administration but used widely throughout Europe), when added to lifestyle interventions, can help patients maintain clinically meaningful weight loss for more than 2 years. Refusing to consider long-term antiobesity medication as an integral part of obesity treatment is, more often than not, setting the patient up for failure.77 Ideally, weight management will enter a new age where patients at-risk for overweight and obesity are managed with prevention in mind. Prevention entails wellestablished norms, including counseling on how to implement therapeutic lifestyle changes. Precedent for preventive pharmacotherapy has already been well-established for specific health conditions, including metabolic syndrome and prehypertension, and such therapy for patients at-risk for overweight and obesity is not only prevention-oriented but also may soon be considered the medical standard of care.78 Fear on the part of any health care provider of inducing adverse medication effects can be overcome by closer monitoring of all obese and at-risk patients. As in any chronic disease, a supervised medical regimen, which includes prescription pharmacotherapy, is the key to a successful outcome. Greater comfort with prescribing such medications is a positive by-product for any physician, and greater awareness of medication pitfalls.
Preventing Obesity in the Primary Care Setting
SUMMARY
From a physician’s perspective, there is no greater thrill or joy than seeing a patient become well and learn the skills to maintain this wellness. In regards to chronic disease, maintenance of patient well-being and wellness are highly desirable. Obesity is a true chronic disease with an all-too-common relapsing and remitting course. Physicians have traditionally been less than successful in their approach to motivate lifestyle change among their patients. A new paradigm is needed that involves a proactive, preventive style of engaging patients both in the office setting and beyond. This new paradigm has several benefits, the most obvious being health promotion and the resulting change in behavior among all involved. Physicians advocating for change in nutrition and physical fitness policies will also greatly impact the obesity epidemic, helping curtail the current crisis in health care.
REFERENCES
1. Poisal JA, et al. Health spending projections through 2016: modest changes obscure part D’s impact. Health Aff 2007;26(2):W242–53. 2. WHO. BMI classification. Available at: http://www.who.int/bmi/index.jsp?introPage5 intro_3.html. Accessed January 16, 2008. 3. NHLBI. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults: the evidence report 1998. Available at: http://www. nhlbi.nih.gov/guidelines/obesity/ob_gdlns.pdf. Accessed January 2008. 4. Flegal KM, Carroll MD, Ogden CL, et al. Prevalence and trends in obesity among US adults, 1999–2000. JAMA 2002;288(14):1723–7. 5. Ogden C, et al. Prevalence of overweight and obesity in the United States, 1999– 2004. JAMA 2006;295(13):1549–55. 6. Centers for Disease Control. U.S. obesity trends 1985–2006. Available at: http:// www.cdc.gov/nccdphp/dnpa/obesity/trend/maps/index.htm. Accessed January 2008. 7. O’Brien SH, Holubkov R, Reis EC. Identification, evaluation, and management of obesity in an academic primary care center. Pediatrics 2004;114(2):e154–9. 8. Centers for Disease Control. AAP classification of BMI among children. Available at: www.cdc.gov/growthcharts. Accessed January 2008. 9. Committee on Nutrition. Prevention of pediatric overweight and obesity. Pediatrics 2003;112(2):424–30. 10. Campbell I. The obesity epidemic: can we turn the tide? Heart 2003;89(Suppl II): ii22–4. 11. Mcinnis K, et al. Counselling for physical activity in overweight and obese patients. Am Fam Physician 2003;67(6):1249–56. 12. Jung R. Obesity as a disease. Br Med Bull 1997;53(2):307–21. 13. Randall OS, et al. Effect of diet and exercise on pulse pressure and cardiac function in morbid obesity: analysis of 24-hr ambulatory blood pressure. J clin Hypertens 2005;7(8):455–63. 14. Stein CJ, Colditz GA. The epidemic of obesity. J Clin Endocrinol Metab 2004; 89(25):22–5. 15. Nichols M, Schumann L, Livingston D. Preventing pediatric obesity: assessment and management in the primary care setting. J Am Acad Nurse Pract 2002;14(2): 55–62. 16. McPherson K. Does preventing obesity lead to reduced health-care cost? PLoS Med 2008;5(2):e37.
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17. van Baal PHM, Polder JJ, de Wit GA, et al. Lifetime medical costs of obesity: prevention no cure for increasing health expenditure. PLoS Med 2008;5(2):e29. 10.1371/journal.pmed.0050029. 18. Bachman KH. Obesity, weight management, and health care costs: a primer. Dis Manag 2007;10:129–37. 19. Woolford SJ, et al. Incremental hospital charges associated with obesity as a secondary diagnosis in children. Obesity (Silver Spring) 2007;15(7):1895–901. 20. Bertakis K, Azari R. Obesity and the use of health care services. Obes Res 2005; 13(2):372–9. 21. Ebbeling C, Pawlak D, Ludwig D. Childhood obesity: public-health crisis, common sense cure. Lancet 2002;360:473–82. 22. Ludwig DS, Peterson KE, Gortmaker SL. Relationship between consumption of sugar-sweetened drinks and childhood obesity: a prospective observational analysis. Lancet 2001;357(9255):505–8. 23. French SA, Story M, Neumark-Sztainer D, et al. Fast food restaurant use among adolescents: associations with nutrient intake, food choices and behavioral and psychosocial variables. International Journal of Obesity 2001;25:1823–33. 24. French SA, Harnack L, Jeffrey RW. Fast food restaurant use among women in the pound of Prevention study: dietary, behavioral and demographic correlates. Int J Obes Relat Metab Disord 2000;24:1353–9. 25. Binkley JK, Eales J, Jekanowski M. The relation between dietary change and rising US obesity. International Journal of Obesity 2000;24:1032–9. 26. Harrington S. The role of sugar-sweetened beverage consumption in adolescent obesity: a review of the literature. J Sch Nurs 2008;24(1):3–12. 27. Nestle M, Jacobson M. Halting the obesity epidemic: a public health policy approach. Obesity: a research journal 2000;115:12–24. 28. Talamayan K, et al. Prevalence of overweight misperception and weight control behaviors among normal weight adolescents in the United States. Scientific World Journal 2006;6:365–73. 29. Associated Content. Percentage of Americans actively trying to lose weight is down, Americans finding less weight loss support from social circles, 2008. Americans finding less weight loss support from social circles. Available at: http://www.associatedcontent.com/article/379294/percentage_of_americans_ actively_trying.html?page52. Accessed March 2008. 30. CDC. Adult participation in recommended levels of physical activity—United States, 2001 and 2003. MMWR Morb Mortal Wkly Rep 2005;54(47):1208–12. Available at: http://www.cdc.gov/mmwR/preview/mmwrhtml/mm5447a3.htm Accessed May 2008. 31. CDC. Physical activity and good nutrition essential elements to prevent chronic diseases and obesity 2007. Available at: http://www.cdc.gov/nccdphp/publications/ aag/dnpa.htm. Accessed March 2008. 32. Powell M, et al. Availability of physical activity-related facilities and neighborhood demographic and socioeconomic characteristics: a national study. Research and Practice 2006;96(9):1676–80. 33. Lopez R. Urban sprawl and risk for being overweight or obese. Research and Practice 2004;94(9):1574–9. 34. Ewing R, et al. Relationship between urban sprawl and weight of United States youth. Am J Prev Med 2006;31(6):464–74. 35. Cervero R, Duncan M. Walking, bicycling, and urban landscapes: evidence from the San Francisco bay area. American Journal of Public Health 2003;93(9):1478–83.
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36. Dinakar C, et al. Learning preferences of caregivers of asthmatic children. J Asthma 2005;42(8):683–7. 37. Murphy RJ, et al. Student learning preferences and teaching implications. J Dent Educ 2004;68(8):859–66. 38. Slater JA, et al. Does gender influence learning style preferences of first-year medical students? Adv Physiol Educ 2007;31(4):336–42. 39. Demir F, Ozsaker E, Ilce AO, et al. The quality and suitability of written educational materials for patients. J Clin Nurs 2008;17(2):259–65. 40. Cheung A, et al. A patient information booklet about anesthesiology improves preoperative patient education. Can J Anaesth 2007;54(5):355–60. 41. Anderson JL, Adams CD, Antman EM, et al. American College of Cardiology/ American Heart Association 2007 guidelines for the angina management of patients with unstable angina/non-ST-elevation myocardial infarction. J Am Coll Cardiol 2007;50(70):e95–6. 42. Evidence statement: obesity (screening and counseling). Available at: http:// www.businessgrouphealth.org/benefitstopics/topics/purchasers/condition_ specific/evidencestatements/obesity_es.pdf. Accessed May 2008. 43. American Academy of Family Physicians. Food and nutrition. Available at: http:// familydoctor.org/online/famdocen/home/healthy/food.html. Accessed March 2008. 44. Hark L, Deen D. Taking a nutrition history: a practical approach for family physicians. Am Fam Physician 1999;59(6):1521–8. 45. Grief SN. Try diet counseling the easier way. Med Econ 2008;36(3):45–6. 46. Gans KM, et al. REAP and WAVE: new tools to rapidly assess/discuss nutrition with patients. J Nutr 2003;133:556S–62S. 47. Warburton D, et al. Prescribing exercise as preventive therapy. Can Med Assoc J 2006;174(7):961–74. 48. Wannamethee SG, Shaper AG, Walker M. Physical activity and mortality in older men with diagnosed coronary heart disease. Circulation 2000;102: 1358–63. 49. Wannamethee SG, Shaper AG, Walker M. Changes in physical activity, mortality, and incidence of coronary heart disease in older men. Lancet 1998;351: 1603–8. 50. Devereaux MD, Ross N, Siroonian J, et al. National population health survey. 1998/99. Ottawa (Canada): Statistics Canada; 2001. 51. Jakicic JM, et al. Effect of exercise duration and intensity on weight loss in overweight, sedentary women: a randomized trial. JAMA 2003;290:1323–30, 1377–79. 52. Baskerville NB, et al. Process evaluation of a tailored multifaceted approach to changing family physician practice patterns and improving preventive care. J Fam Pract 2001;50(3):w242–9. 53. Broadley D, et al. Obesity evaluation and intervention during family medicine wellness visits. J Am Board Fam Med 2007;20(3):252–7. 54. Lemay CA, et al. Underdiagnosis of obesity at a community health center. J Am Board Fam Pract 2003;16:14–21. 55. Plourde G. Preventing and managing pediatric obesity: recommendations for family physicians. Can Fam Physician. 2006;52:322–8. 56. Bardia A, et al. Diagnosis of obesity by primary care physicians and impact on obesity management. Mayo Clin Proc 2007;82(8):927–32. 57. Merriwether RA, et al. Physical activity counseling. Am Fam Physician 2008; 77(8):1129–36, 1138.
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58. Kreuter MW, Chheda SG, Bull FC. How does physician advice influence patient behavior? Evidence for a priming effect. Arch Fam Med 2000;9(5):426–33. 59. Office of Disease Prevention and Health Promotion. Counselling to promote physical activity. Available at: http://odphp.osophs.dhhs.gov/pubs/guidecps/text/ CH55.txt. Accessed March 2008. 60. Centers for Disease Control and Prevention. Physical activity and good nutrition: essential elements to prevent chronic diseases and obesity. U.S. Department of health and human services (USDHHS) revised April 2007. 61. Centers for Disease Control and Prevention. Prevalence of no-leisure-time physical activity—35 States and the District of Columbia, 1998–2002. MMWR Morb Mortal Wkly Rep 2004;53(4):82–6. 62. Nutrition, health & physical activity during childhood and early adolescence. 2006. Available at: http://ific.org/nutrition/kids/index.cfm. Accessed March 2008. 63. Nebeling LC, et al. Still not enough: can we achieve our goals for Americans to eat more fruits and vegetables in the future? Am J Prev Med 2007;32(4): 354–5. 64. US Department of Health and Human Services. Dietary guidelines for Americans. Available at: http://www.health.gov/dietaryguidelines/dga2005/document/pdf/ DGA2005.pdf. Accessed February 2008. 65. Litchfield RE, et al. Lighten up Iowa: an interdisciplinary, collaborative health promotion campaign. Journal of Extension 2005;43(2). 66. Position of the American Dietetic Association: medical nutrition therapy and pharmacotherapy. J Am Diet Assoc 1999;99:227–30. 67. American Dietetic Association. Find a nutrition professional: registered dietitians and dietetic technicians, registered. Available at: http://www.eatright.org/cps/rde/ xchg/ada/hs.xsl/home_4874_ENU_HTML.htm. Accessed March 2008. 68. Commercial weight loss products and programs: what consumers stand to gain and lose. A Public Conference on the Information Consumers Need to Evaluate Weight Loss Products and Programs, October 16–17, 1997 Federal Trade Commission Building Sixth Street & Pennsylvania Ave., N.W. Washington, DC. 69. Bacon L, et al. Evaluating a non-diet wellness intervention for improvement of metabolic fitness, psychological well-being and eating and activity behaviors. Int J Obes 2002;26:854–65. 70. Dansinger ML, Gleason JA, Griffith JL, et al. Comparison of the Atkins, Ornish, Weight Watchers and Zone diets for weight loss and heard disease risk reduction. JAMA 2005;293:43–53. 71. Gardner CD, et al. Comparison of the atkins, zone, ornish, and learn diets for change in weight and related risk factors among overweight premenopausal women—the a to z weight loss study: a randomized trial. JAMA 2007;297(9): 969–77. 72. Burke LE, et al. A descriptive study of past experiences with weight-loss treatment. J Am Diet Assoc 2008;108(4):640–7. 73. Snow V, et al. Pharmcologic and surgical management of obesity in primary care: a clinical practice guideline from the American College of Physicians. Ann Intern Med 2005;142:625–31. 74. Waitman JA, Aronne LJ. Obesity management. Pharmacotherapy of Obesity 2005;1(1):15–9. 75. Yanovski SZ, Yanovski JA. Obesity. N Engl J Med 2002;346:591–602. 76. Tsai AG, Wadden TA. Systematic review: an evaluation of major commercial weight loss programs in the United States. Ann Intern Med 2005;142(1):56–66.
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77. Sharma AM. A weighty issue: medication as a cornerstone of medical obesity management. Can Fam Physician 2008;54:498–9. 78. Freemark M. Pharmacotherapy of childhood obesity: an evidence-based, conceptual approach. Diabetes Care 2007;30:395–402. 79. American College of Sports Medicine Position Stand: the recommended quantity and quality of exercise for developing and maintaining cardio-respiratory and muscular fitness and flexibility in healthy adults. Med Sci Sports Exerc 1998;30: 975–91.
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Preventing Typ e 2 Diab etes Jeff Unger, MDa,*, Cynthia Moriarty, MDb KEYWORDS Prediabetes Lifestyle intervention Postprandial hyperglycemia Insulin resistance Lipogenic transcription factor
Mrs. Smith comes in for her annual physical examination announcing proudly to the staff that she ‘‘has never felt better!’’ The real reason that she sees her primary care physician each year, however, is to get her pap smear and mammogram completed. After all, her mother died of unilateral ductal carcinoma of the breast at age 78 and had complications of type 2 diabetes. Mrs. Smith, however, age 48 and African American, seems to have overlooked the fact that her mother actually did have a disease that affects more than 21 million Americans,1 80% of whom die of cardiovascular complications.2 If Mrs. Smith develops diabetes, she is more than likely to experience one of the many long-term complications associated with chronic hyperglycemia exposure listed in Table 1. A prudent clinician might choose to investigate whether Mrs. Smith’s claims of being in ‘‘perfect health’’ is really valid. Is this patient at risk for developing type 2 diabetes? Does she already have prediabetes? If so, is it likely that her pancreatic b-cell mass is rapidly diminishing and she may have already lost up to 80% of her b-cell function.3,4 Mrs. Smith brings in the results of laboratory studies performed during a life insurance examination 2 weeks before this visit. The results of these studies and her pertinent physical findings are shown in Table 2. BURDEN OF DISEASE
Type 2 diabetes affects over 7% of the United States population, amounting to 20.8 million adults and youth.1 Approximately 14.6 million are diagnosed cases, leaving nearly one third of these diabetics unaware of their illness. This disease is estimated to be the sixth leading cause of death in the United States. In addition, 54 million individuals in the United States have prediabetes, the prevalence of which has tripled in recent decades.5 Minority populations are disproportionately affected by diabetes including African Americans, Hispanics, Asian Americans, Native Americans, and a
Catalina Research Institute, 12598 Central Avenue, Chino, CA 91710, USA Preventive Medicine, 1005 Dr. D.B. Todd Boulevard, 2nd Floor, Old Hospital, Nashville, TN 37208, USA * Corresponding author. E-mail address:
[email protected] (J. Unger). b
Prim Care Clin Office Pract 35 (2008) 645–662 doi:10.1016/j.pop.2008.07.004 primarycare.theclinics.com 0095-4543/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.
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Table 1 Facts related to long-term microvascular and macrovascular complications experienced by patients exposed to chronic hyperglycemia Retinopathy Diabetes is the leading cause of blindness in the United States. 12,000 to 24,000 new cases of blindness each year are caused by diabetes in adults ages 20 to 74. Hispanics are at particularly high risk for vision loss. Nephropathy Diabetes accounts for 44% of new cases of ESRD in the United States. In 2002, 44,000 patients with diabetes began dialysis or sought kidney transplantation as a result of ESRD. In 2002, 154,000 patients with diabetes were being dialyzed. Dialysis costs exceed $57,200 per patient per year. High-risk patients for ESRD include African Americans (0.5 times the risk for whites), Native Americans (0.6 times), and Hispanic Americans (0.4 times). Complications of pregnancy Poorly controlled diabetes before conception and during the first trimester results in birth defects (macrosomia, cardiac anomalies) in 5%–10% of fetuses and is responsible for spontaneous abortions in 20% of pregnancies. Patients with gestational diabetes are at higher risk of developing type 2 diabetes in the future. Babies born to mothers with gestational diabetes weighing 2.5 kg or 0.4 kg are at higher risk of developing type 2 diabetes as adolescents. Patients with pre-existing retinopathy or neuropathy may experience a significant deterioration from baseline with their pregnancy. Periodontal disease Twice as likely to occur in adults with diabetes. May be severe in diabetes, resulting in loss of the attachment of teeth to the gums. Cardiovascular disease Prevalence of fatal and nonfatal coronary heart disease events are 2–20 times higher than for nondiabetics of equal age. In-hospital and 6-mo mortality rates are twice as high for patients with diabetes compared with individuals who are normoglycemic. Patients with diabetes are more prone to irreversible, rather than reversible, ischemic brain damage and small lacunar infarcts. Abbreviation: ESRD, End-stage renal disease. From Unger J. Primary care management in diabetes: screening, diagnosis and management of diabetes-related complications. Philadelphia: Lippincott; 2006. Table 11–31. p. 604–5; with permission.
Pacific Islanders.6–8 The incidence of diabetes is also increasing in children, most likely associated with the rising rates of obesity. With people developing this disease at a younger age, and the greater risk of diabetes in offspring born to those with type 2 diabetes,6 the rate of diabetes could continue to exponentially increase. Worldwide, the number of people affected by diabetes is increasing dramatically in both developed and developing countries. It is estimated the number with the disease will double from 171 million in 2000 to approximately 366 million in 2030, creating a growing public health problem.9 It is imperative that greater understanding of the prevention and treatment strategies for this pandemic be developed. PATHOGENESIS OF TYPE 2 DIABETES
A novel treatment paradigm for preventing or delaying the onset of type 2 diabetes in high-risk patients requires a thorough understanding of the disease pathogenesis.
Preventing Type 2 Diabetes
Table 2 Patient physical findings and laboratory studies Parameter
Normal Range and Comment
Physical examination Body mass index 5 32 kg/m2
<25 kg/m2a
Blood pressure 5 146/90 mm Hg
<130/85 mm Hg
Waist circumference 5 38 in
<35 in
Loss of vibration sense in bilateral halluxes
Suggestive of peripheral neuropathy
Mild acanthosis nigricans in axilla with skin tags on neck
Suggestive of insulin resistance
Laboratory studies Fasting plasma glucose 125 mg/dL
<100 mg/dL (according to ADA criteria, patient has impaired fasting glucose, which is a prediabetic state)28
2-h postprandial blood glucose done at time of office visit is 188 mg/dL
<140 mg/dL (according to ADA criteria, patient also has impaired glucose tolerance, another form of prediabetes; however, this category of glucose intolerance increases risk of developing a cardiovascular event by two to four times when compared with euglycemic individuals28
Point of service A1C 6.2%
<6.1%
Thyroid studies and CBC: normal Serum creatinine: 1.2 mg/dL
1 mg/dL
Liver panel: slight increase in ALT and AST
Suggestive of fatty liver infiltration
Spot urine for microalbumin Spot urine albumin:creatinine ratio 5 42mg/mg creatinine
Patient has microalbuminuria, which increases risk of developing microvascular and macrovascular complications related to diabetes57
Total cholesterol 5 200 mg/dL HDL cholesterol: 32 mg/dL LDL-C 5 110 mg/dL TG 5 275 mg/dL Apolipoprotein B 5 110 mg/dL (80–90 mg/dL)
TG:HDL >3.5 suggests insulin resistance Apolipoprotein >90 mg/dL increases one’s risk of developing cardiovascular disease41
Abbreviations: ADA, American Diabetes Association; ALT, Alanine transaminase; AST, Aspartate transaminase; CBC, Complete blood count; HDL, High-density lipoprotein; TG, Triglyceride. a <23 kg/m2 if Asian American.
Type 2 diabetes is characterized by hyperglycemia, insulin resistance, and relative impairment of insulin secretion. The clinical features associated with of type 2 diabetes depend on genetic and environmental factors. Whether an individual remains euglycemic or develops hyperglycemia is determined by the ability of one’s pancreatic b cells to produce and secrete enough insulin to maintain normoglycemia. The hallmark of the metabolic dysfunction associated with type 2 diabetes includes a reduction in insulin secretion and altered insulin action, resulting in hyperglycemia. Unlike type 1 diabetes, the progression to type 2 diabetes occurs over a period of 7 to 10 years. In the prediabetes state of impaired fasting glucose and impaired glucose tolerance (IGT), pancreatic b cells excrete increasing amounts of insulin to maintain normal glycemia. The higher insulin output is accompanied by reduced insulin activity in the liver, adipose tissue, and skeletal muscles, resulting in diminished intracellular
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glucose disposal. A further decline in b-cell insulin secretion and an increase in hepatic glucose production lead to overt diabetes with fasting and postprandial hyperglycemia. Patients progress through a spectrum of abnormal glucose states, including impaired fasting glucose and IGT, until ultimately overt diabetes develops. Recent studies have demonstrated how rapidly b-cell decline occurs in patients who are genetically prone to progress from normal glucose tolerance to IGT and finally to clinically apparent type 2 diabetes. Examinations performed on cadaver pancreases demonstrated a 40% decline in pancreatic b-cell mass in obese patients with IGT when compared with obese individuals who have normal glucose tolerance.4 Hyperglucogonemia is another primary feature of both prediabetes and diabetes. Glucagon is a counterregulatory hormone secreted by the pancreatic a cells found on the periphery of the islet. Under normal conditions, a postprandial increase in glucose concentration is associated with a corresponding reduction in glucagon. As circulating glucose levels decrease, glucagon levels increase, resulting in a 60% increase in hepatic glucose production and output through gluconeogenesis.10 Glucagon secretion is regulated, in part, by endogenous insulin secretion. Insulin action results in the storage of glycogen within hepatocytes. Insulin resistance, insulinopenia, or an increase in glucagon output signal the liver to depolymerize glycogen, resulting in a rise in ambient glucose levels. Glucagon secretion is substantially elevated in the fasting state and is not suppressed during the postabsorptive phase in patients with both prediabetes and clinically apparent diabetes.11 This results in a continuous state of hyperglycemia and insulin resistance. During the past 50 years, Americans have been exposed to two historically unprecedented changes in their caloric environment resulting in deterioration of pancreatic function and unhealthy body habitus. First, meal preparation has been increasingly outsourced from family kitchens to commercial restaurants. Americans have now increased their caloric intake on average of 335 kcal/d since the days of ‘‘Ozzie and Harriet.’’12 During the same time, the level of physical activity has declined, in part because of the introduction of technology into society.13 Whereas in the past families came home to ‘‘work in the fields,’’ today adolescents return from school to work their computers. Not surprisingly, two thirds of Americans are considered overweight.14 In 1960, Yalow and Berson developed a radioimmunoassay for insulin for which they eventually won the Nobel Prize. This new technology led to the discovery that overweight individuals with normal glucose levels have higher insulin levels than lean subjects. The coexistence of hyperinsulinemia and normoglycemia implied resistance to the action of insulin. Prediabetes and overt type 2 diabetes developed in genetically prone individuals exposed to the cellular and metabolic effects of insulin resistance, although the precise mechanisms remain open to considerable debate.15 Fatty acids are now known to play a major role in the advancement of insulin resistance. Free fatty acids inhibit insulin-mediated glucose uptake by interfering with the translocation of the glucose transport protein, GLUT-4, to the plasma membrane, effectively blocking glucose uptake by muscle cells and increasing peripheral insulin resistance. In hepatocytes, free fatty acids inhibit insulin-mediated suppression of glycogenolysis and gluconeogenesis resulting in an increase in hepatic glucose production.15 Pancreatic b-cell death (apoptosis) is accelerated by the accumulation of free fatty acids within the islets.16 Elevations in free fatty acids accelerate insulin resistance and impair insulin secretion by affecting the skeletal muscle’s ability to uptake glucose, the hepatocytes ability to suppress the production of glucose, and the pancreatic b cells ability to secrete enough insulin to minimize the resulting hyperglycemia.
Preventing Type 2 Diabetes
How does insulin resistance lead to the overproduction of free fatty acids? Hyperinsulinemia downregulates insulin receptor substrate 2, while stimulating the production of sterol response element binding protein 1c (SREBP-1c), a transcription factor that stimulates lipogenesis.17 The unfortunate metabolic result leads to increased levels of free fatty acids with impaired insulin-mediated suppression of hepatic glucose production. Fig. 1 summarizes the pathogenesis of type 2 diabetes. Once these pathways are understood and placed in their proper perspective treatment plans can be initiated for preventing the progression toward hyperglycemia. MANAGING PREDIABETES USING LIFESTYLE INTERVENTIONS Lifestyle Modification Studies
Randomized controlled studies show that lifestyle interventions can be effective in preventing or delaying the onset of type 2 diabetes in high-risk individuals with impaired glycemic control. Three major studies examining the effect of diet and exercise interventions in recent years are summarized next.18–20 The Diabetes Prevention Program is a multicentered clinical trial conducted at 27 United States clinical sites (1996–2001) to evaluate the safety and efficacy of intensive lifestyle interventions in participants with IGT. A pharmacologic intervention arm of the study is further discussed later. The Diabetes Prevention Program enrolled 3234 participants who were randomized to one of three treatment groups: (1) placebo (usual care); (2) intensive lifestyle; or (3) metformin. The lifestyle intervention participant goals included achieving and maintaining a modest weight reduction of 7% of initial body weight, eating a healthy low-fat diet, and engaging in moderate-intensity physical activity for at least 150 minutes per week. A 16-lesson curriculum covering diet, exercise, and behavior change was provided to individuals on a one-on-one basis during the
Diabetes Insulin Resistance • Beta cell apoptosis • Increased hepatocyte glucose production • Decreased myocyte glucose
Increased Lipogenesis (Increased Production of Free Fatty Acids) Increased Expression Of The Lipogenic Transcription Factor SREBP-1c
Hyperinsulinemia
• Caloric Excess and Obesity • Reduced physical activity
Fig.1. Pathogenesis of type 2 diabetes. SREBP-1c, sterol response element binding protein 1c.
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first 6 months following enrollment in the study. This curriculum is available online at www.bsc.gwu.edu/dpp/lifestyle/dpp_acor.html. Follow-up with master’s level trained case managers in group or individual format was then provided regularly for behavioral modification reinforcement. Participants were followed for a period of 2 to 5 years. The resulting profile of the study group revealed the average age of the participants to be 50.6 years; the average body mass index to be 34; and the composition of the study group to be 55% white, 20% African American, 16% Hispanic, 5% Native American, and 4 % Asian American. The program was discontinued 1 year earlier than anticipated because of the observed significant benefit to the intervention groups. The study found that the lifestyle intervention reduced the risk of developing type 2 diabetes by 58%, across both genders and all ethnic groups, compared with the usual care group. Approximately 5% of the participants in the lifestyle group developed diabetes per year of the study, compared with 11% per year in the comparison group. The results support that healthy diet, modest weight loss, and regular moderate exercise can prevent or delay diabetes.18,21 The Finnish Diabetes Prevention Study also assessed the effect of diet modification and exercise on the risk of diabetes in individuals with IGT. This study, conducted from 1993 to 2000, randomized 522 enrollees to intervention or standard care groups. Participants were slightly older (average age 55) and weighed less (average body mass index 31) than those of the Diabetes Prevention Program. All participants in this study were white. The lifestyle intervention included an intensive diet-exercise counseling regimen of seven individualized counseling sessions with the study nutritionist in the first year. This was followed with sessions every 3 months (median number of sessions was 20). Personal training sessions for physical activity were also offered. Clinical examinations and interviews were completed yearly with the enrollees. Primary goals of this intervention were weight reduction of 5% or more; maintenance of a low-fat (<30% of daily caloric intake) and high-fiber intake of least 15 g/1000 kcal diet; and moderately intense physical activity of 30 minutes per day. Intervention time ranged from 1 to 6 years, with a median time of 4 years. Results of this study were markedly similar to the Diabetes Prevention Program with the diabetes risk reduction at 58% over the 6 years. A postintervention follow-up for those participants who were diabetes-free was completed to ascertain whether there was sustained lifestyle change and reduction in the incidence of diabetes. During this follow-up (median follow-up time 3 years, median total follow-up time 7 years) a 43% reduction in relative risk of diabetes development was observed.19,22,23 In the Da-Qing IGT and Diabetes Study conducted from 1986 to 1992, 577 Chinese participants were assigned to four study arms: (1) diet alone, (2) diet and exercise, (3) exercise only, and (4) control. Participants in this study were less likely to be obese; had an average body mass index of 25.8; and were significantly younger (average age 45) than the Diabetes Prevention Program or Diabetes Prevention Study. Enrollees were followed a mean of 6 years. The recommended diet for the intervention groups dictated a 55% to 60% carbohydrate and 10% to 15% protein diet. Physical activity was defined in study-specific units and participants were recommended to increase their leisure physical activity by specified units per day. The diet and exercise intervention demonstrated a 42% decrease in the risk of developing diabetes. The exerciseonly group was comparable at 46% reduction, whereas the diet-alone group reduced their diabetes risk by 31%.20 Each of these studies looked at combined effects of diet modification and exercise to achieve a reduction in the diabetes risk. The Da-Qing trial was able to show that exercise alone is able to produce a sustainable reduction in the risk of diabetes, and improvement in the risk of other components of metabolic syndrome.20 Suggested
Preventing Type 2 Diabetes
protective mechanisms include effects on body weight; insulin (decreased insulin resistance and enhanced sensitivity); glycemic control; hypertension; dyslipidemia; and inflammation. Systematic reviews of the literature reveal that regular physical activity renders a greater protective benefit in diabetes risk reduction in higher-risk participants than in their lower risk counterparts.24 A summary relative risk for 10 prospective cohort studies, including over 300,000 participants, investigating physical activity of moderate intensity and diabetes risk was found to be 0.69 (95% confidence interval, 0.58–0.83) compared with inactivity, a significant protective effect.24 Additional study is needed to determine the optimal and minimal quantity and level of exercise needed to achieve benefit. The role of dietary intake, specifically carbohydrates, in development of diabetes is less clear than that of physical activity. A number of studies have investigated the relationship of glycemic index or glycemic load and the risk of type 2 diabetes with very inconsistent results. Maintaining a low glycemic index diet has been proposed as a means of reducing risk by affecting the rate of digestion and carbohydrate absorption, and ultimately lowering the insulin demand. Positive relationships have been found with a few epidemiologic studies, whereas others show no association.25–27 The American Diabetes Association does not endorse use of glycemic index because of insufficient evidence at this time.28 There exists a predominance of evidence in support of the association between excessive weight and type 2 diabetes observed now even in developing countries.29 A common precipitating factor for this is an unhealthy diet. Epidemiologic evidence is accumulating in support of consuming a Mediterranean diet as a protective factor in the development of diabetes.30–32 This diet refers to an eating pattern including high intake of fresh fruits and vegetables and unsaturated fats as the source of dietary fat. It has demonstrated favorable effects on lipid levels, insulin resistance, metabolic syndrome, and cardiovascular mortality. Further investigation is needed to determine specific reduction in diabetes risk. Dietary Counseling Strategies
Lifestyle changes must be discussed before any pharmacologic treatment for prediabetes. Unfortunately, discussion of nutritional therapy, weight reduction, exercise prescription, smoking cessation, home blood glucose monitoring, and alcohol reduction are not second nature. Besides time restraints, lack of appropriate referral sources, and minimal reimbursement for diabetes-related education, patients usually prefer to take a pill rather than initiate a comprehensive lifestyle modification program. Physicians may choose to spend 3 to 5 minutes per visit discussing important lifestyle changes that could have a profound motivational effect on their patient’s lives. For example, a patient who has never been successful in losing weight might be asked what techniques have been used in the past and which may have been the most successful. This provides a springboard for action to encourage the patient to begin looking at other options that might allow them to achieve success once again. Exercise should be discussed briefly at each visit. Smokers should always be asked about their progress toward quitting. Patients need to feel that their physicians are concerned about every aspect of their care, both behavioral and pharmacologic. Finally, providers should find at least one point of praise that they could deliver for each patient at the time of their visit. Diabetes is a complicated disease even for physicians who live with the disorder. Patients can only do their best given the resources and educational tools with which they are provided. Praise them for trying their best during some of the most trying times of their lives: ‘‘Mrs. Smith, great job. You’ve only gained 1 lb over the past 4 months. That’s much better than the 7 lb you gained
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during the same period last year. Good work. I knew you could do it! Now let’s work together to see if we can crank up that exercise intensity a bit.’’ The most important educational aspect for patients when diagnosed with prediabetes or when at risk for developing diabetes involves dietary interventional strategies. These high-risk patients may decrease their risk or slow their disease progression by increasing their physical activity, losing weight, or at least preventing weight gain. Long-term weight loss is difficult to accomplish because energy intake and energy expenditure are controlled and regulated, in part by the central nervous system. Although understanding of the central nervous system and appetite is incomplete, the hypothalamus is thought to be the center of attention.33 Neuropeptide Y, leptin, insulin, and a variety of other neural endocrine and gastrointestinal signals also seem to be involved in satiety. Individual characteristics of central nervous system control of energy balance may be genetically determined. Furthermore, environmental factors often make losing weight difficult for those genetically predisposed to obesity. The National Weight Control Registry, the largest prospective investigation of prolonged weight reduction, has enrolled more than 3000 subjects successful at longterm maintenance of weight loss.34 A group of approximately 800 people who lost an average of 30 kg and maintained a minimum weight loss of 13.6 kg (30 lb) for 5 years were identified from the registry. Slightly more than half lost weight through formal programs, and the remainder lost weight with a program of their own. Average energy consumption was approximately 1400 kcal per day, with 24% of energy derived from fat. Average energy expenditure through added physical activity was 2800 kcal per week. Importantly, nearly 77% of this sample who were successful in achieving and maintaining weight loss reported a triggering event that preceded the weight loss. The most common triggering events were acute medical conditions and emotional problems. A new diagnosis of type 2 diabetes could trigger lifestyle changes that result in reduced fat and energy intake and increased physical activity and associated weight loss. Working diligently with Mrs. Smith might increase her likelihood of successful weight reduction. The dietary modifications recommended to manage patients with metabolic syndrome (Table 3) include the following:35,36 reduce saturated fat to less than 7% of total caloric intake, reduce dietary cholesterol to less than 200 mg/day, and achieve a weight loss of 10 lb from baseline. To assist patients with weight loss efforts, assessment of current dietary habits is useful. By obtaining a nutritional history or a food log, one can estimate the excess calories a patient consumes on a daily basis, identify problem areas, and help the patient determine where change can occur. Fig. 2 provides a nutritional history form that can be completed by patients within 3 minutes. In addition, a sample completed dietary log is presented in Fig. 3. The following are examples of common dietary pitfalls: 1. If the patient is eating only once or twice daily, there is a strong likelihood that snacks are being used to reduce hunger. Snacks can be high in calories and low in nutritional value. Patients should be advised to eat three healthy balanced meals daily or four to five small healthy meals. Snacking is reduced if hunger is better controlled. Skipping meals does not result in weight reduction. 2. Eating meals outside the home can result in excessive caloric intake, especially when patients frequent fast food restaurants. 3. Watch out for food consumption that may add unnecessary calories to the daily diet. For example, coffee houses can serve up more calories than caffeine. 4. Common food myths: one needs to eat until full, the biggest meal should be in the evening, and meat should be eaten at every meal.
Preventing Type 2 Diabetes
Table 3 Diagnostic criteria for metabolic syndrome Risk Factor
ATP-III Cutpoint forAbnormalitya
AACE Cutpointb
Abdominal obesity
Men waist circumference R40 inches Women waist circumference R35 inches
BMI 25 kg/m2
Elevated triglycerides (mg/dL)
R150
R150
Low HDL-C (mg/dL)
Men <40 Women <50
Men <40 Women <50
Elevated blood pressure (mm Hg)
Systolic R130 Diastolic >85
R130/85
Glucose intolerance
Elevated fasting glucose R110 mg/dL
Fasting plasma glucose 110–126 mg/dL 2-h post-75 g glucose challenge 140–199 mg/dL
Other risk factors
Family history of hypertension, type 2 diabetes, or cardiovascular disease Polycystic ovary syndrome Advancing age Sedentary lifestyle High-risk ethnic groups (Hispanic Americans, Asian Americans, African Americans, Pacific Islanders, Native Americans)
Abbreviations: BMI, body mass index; HDL, high-density lipoprotein. a ATP III (National Cholesterol Education Program–Adult Treatment Panel III) guidelines for metabolic syndrome diagnosis require that three of the five signs listed in the table are present. b AACE (American Association of Clinical Endocrinologists) guidelines do not specify the number of risk factors needed to meet the definition of metabolic syndrome, relegating this matter to the judgment of the individual clinician. Data from Unger J. Diagnosing and managing the metabolic syndrome in adults, children and adolescents. In: Unger J. Diabetes management in primary care. Philadelphia: Lippincott, Williams and Wilkins; 2007. p. 43–87.
5. Inactive individuals who view more than 15 hours of television per week have a three times higher risk of diabetes.37 Patients who snack while watching television result in situational food consumption and excessive daily caloric intake. 6. Find dessert alternatives. A cup of ice cream plus a slice of chocolate cake provide about 800 calories, almost one third of the daily caloric requirement of a 70-kg man. Patients should consider eating fruit or nonfat yogurt as an alternative. 7. Simple changes in food and drink choices can significantly reduce the daily caloric intake. Skimmed milk has approximately 50% less calories than whole milk (150 cal per cup). Switching from regular to diet colas eliminates 175 cal per 12 oz consumed. Light beer has 100 cal per 12-oz serving, whereas regular beer on average has 150 cal. Exercise Counseling Strategies
Providers should do their best to change a patient’s perception of exercise. To achieve this, four principles should be considered. (1) Exercise is more likely to be attempted
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Name___________________ 1. 2. 3. 4. 5. 6. 7.
8. 9. 10. 11.
12. 13.
Date______________________
How many meals do you eat each day?________ Do you eat breakfast (Y/N), lunch (Y/N) and dinner (Y/N) each day? How many snacks a day do you eat?______________ What type of snacks to you typically eat?_____________________________________________________ How many times each week do you eat the following meals AWAY from home? Breakfast_________Lunch__________Dinner How many times a week do you visit the following eating places? Fast food restaurants_____Donut shops_______ Starbucks_________Diner/Cafeteria____________________Resturant_________ Convenience store for a quick snack_______________ On average, how many 8 oz glasses of juice do you drink daily?_____________ How many hours of TV do you watch each day________________ Do you snack while watching TV? Yes______No____________ How many times a week do you do any continuous exercise for at least 30-45 minutes exercise (in a gym, riding a bike, doing aerobics, practicing martial arts or kick boxing, walking around a track, running, swimming, with a personal trainer, or resistance training) ________ How many times each week will you eat at least 1 dessert?_____________ How many servings of the following do you consume DAILY?
8 OZ juice________ Whole milk_______ Sports drinks______ Wine_________ Hard liquor________
Glasses of water________ 2 milk_________ Diet soda__________ Sweetened Tea______ Fruit smoothies_______
Lite Beer___________ Skim milk__________ Regular soda__________ Regular coffee__________
Fig. 2. Nutritional assessment form.
when the patient perceives the individual benefits of increasing activity on his or her own diabetes control. The type of exercise needs to be chosen by the patient rather than the physician and viewed by the patient as being valuable and reinforcing. (2) Exercise is likely to be sustained if the specific activity chosen has few barriers to implementation. Exercise must integrate easily within the patient’s lifestyle, beliefs, and attitudes. Physicians can help patients make their choice. (3) The physician should not use exercise as a punishment. The rationale for exercise is promoted as a means of avoiding complications (ie, punishment). This rationale is a negative reinforcement Date ______________________
Day _______________________ Food (type and amount)
Drinks
Breakfast
Skipped Breakfast [1]
Coffee
Mid Morning Snack
Corn Chips from vending machine [1]
12 oz. can of coke [7]
Lunch
Quarter Pound Burger, Large French Fries [2]
16 oz. coke
Afternoon Snack
Dinner
Starbucks Caramel Frappucino [3] Sliced Roast Beef, Mashed Potatoes, Corn, Side Salad, Garlic Toast [4] 1 cup Chocolate Ice Cream (6]
Evening Snack
Fig. 3. Daily food log.
3 cups buttered popcorn [5]
8 oz. Fruit Punch
Preventing Type 2 Diabetes
paradigm in which patients are asked to do something to prevent a negative consequence. The motivating power is diminished and positive effects often do not occur for several years. (4) Exercise is more likely to be sustained if consistently reinforced by the health care management team and staff. When initiating a discussion about exercise, the health care provider should emphasize (1) the health benefits, such as improvements in glucose regulation, weight control, lipid profiles, hypertension, and increased work capacity; (2) the social benefits, such as increased interaction with family members, ‘‘social others’’ (ie, training partners), and participation in organized, community-based activities; and (3) the psychologic benefits, most notably reduced anxiety and depression, stress reduction, and enhanced feelings of well-being. After beginning an exercise program, helping patients stay motivated to continue their physical activity is critical to successful diabetes lifestyle management. Clinicians should always remember that despite their best efforts, not all patients have interest to become more active. Directing one’s personal frustration toward these patients is counterproductive. Those patients who do increase their activity level undoubtedly appreciate the time and effort put forth by their primary care doctor. Physicians who can successfully motivate patients into becoming more active enjoy coaching them toward having a better mind and body. MANAGING PREDIABETES USING PHARMACOLOGIC INTERVENTION
Pharmacologic intervention for patients who have impaired fasting glucose or IGT is debated. Safe medications should be considered, however, if they can improve insulin sensitivity and pancreatic b-cell function, reduce cardiovascular inflammation, and minimize insulin resistance while limiting weight gain. The American Diabetes Association has not endorsed or published any recommendations for the use of medications for patients with prediabetes. The American Diabetes Association published guidelines suggest that metformin and lifestyle intervention be initiated once the patient’s A1C is greater than or equal to 7%. Unfortunately, this ‘‘benchmark’’ to initiate drug therapy is unrealistic if one hopes to preserve, restore, and prolong any remaining pancreatic b-cell function. Mrs. Smith’s 2-hour postprandial glucose level is 188 mg/dL, suggesting that she has already lost at least 80% of her b-cell function. She has a normal A1C. If her physician waits until her A1C reaches 7% there is a high likelihood that Mrs. Smith will have lost nearly all of her b-cell function and developed additional microvascular and macrovascular diabetes-related complications. Preservation of b-cell function requires an aggressive, proactive, and physiologic approach at the appropriate time. The use of the insulin sensitizers metformin and the thiazolidinediones has been shown to be beneficial in delaying the progression from prediabetes to diabetes.18,38 In the Diabetes Prevention Program,18 metformin, 850 mg twice daily, reduced the relative risk of progression to type 2 diabetes by 31%. Metformin may additionally improve outcomes by inducing weight loss. Metformin was found to be most effective in reducing progression toward diabetes in subjects younger than 45 years and in individuals with a body mass index greater than 35 kg/m2.18 The diagnosis of the primary outcome, diabetes, was based either on a 75-g oral glucose tolerance test with fasting plasma glucose (FPG) or 2-hour glucose exceeding 125 or 199 mg/dL, respectively. Metformin was particularly effective in decreasing diabetes among individuals with FPG exceeding 110 mg/dL, whereas the lifestyle intervention was similarly effective in persons above and below this level. Half of those treated with metformin experienced gastrointestinal side effects, and some reduced the dose to 850 mg
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once daily. No evidence indicates whether combined lifestyle-metformin treatment has an additive benefit. Patients with prediabetes who are unable or unwilling to participate in lifestyle-intervention programs might benefit from pharmacologic therapy using metformin. Metformin has been shown to improve inflammatory markers linked to cardiovascular risk. The drug reduces triglyceride levels by 10% to 30%39 and low-density lipoprotein cholesterol and total cholesterol by 5% to 10%,40 while having no significant influence on high-density lipoprotein cholesterol levels.41 Metformin has no effect on blood pressure.39 Levels of fibrinogen42 and C-reactive protein43 are also lower in metformin-treated patients. The UKPDS showed that obese patients on metformin as monotherapy had a lower risk of myocardial infarction and stroke when compared with subjects taking metformin with a sulfonylurea.44 Although conducted in women who had a history of gestational diabetes, the Troglitazone in the Prevention of Diabetes study38 demonstrated a 56% reduction in relative risk in progression of prediabetes to diabetes. Treatment was terminated prematurely because of the withdrawal of troglitazone from the United States market, yet persistent protective effects were observed more than 8 months after the drug was discontinued. Long-term clinical trial data are not yet available for the newer thiazolidinediones, but there is a reasonable expectation that the currently available medications in this drug class may provide similar benefits. The Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) study45 followed 5269 subjects who had impaired fasting glucose or IGT (prediabetes) for 3 years. It evaluated the development of diabetes, death, and regression to normoglycemia. Participants were randomized to receive placebo or ramipril, 15 mg/ day, or to receive placebo or rosiglitazone, 8 mg/day. The rosiglitazone cohort demonstrated a 60% reduction in the primary outcome of progression to diabetes or death compared with those given placebo, and a 62% reduction in the rate of diabetes development alone. The DREAM trial investigators suggested that for every 1000 people treated with rosiglitazone for about 3 years, 144 cases of diabetes will be prevented and 200 people who have prediabetes will progress to normoglycemia. Although rosiglitazone may be associated with a slight increase in the risk of heart failure, especially in individuals who have diastolic dysfunction, this study did suggest that patients who have either impaired fasting glucose or IGT can benefit from chemoprevention. Besides improving insulin resistance, thiazolidinediones have a positive effect on other metabolic parameters in patients with type 2 diabetes. For example, pioglitazone has been shown to ameliorate all components of the insulin resistance syndrome while improving insulin sensitivity. In the PROACTIVE study (a study of 5238 type 2 diabetes high-risk patients who had a previous macrovascular event),46 pioglitazone decreased the risk of myocardial infarction, stroke, all-cause mortality, acute coronary syndrome, coronary artery revascularization, and leg amputation by 10% to 16%. These results are in contrast to rosiglitazone, which may increase the hazard ratio for cardiovascular events.47 The A Diabetes Outcome Progression Trial evaluated the efficacy of a thiazolidinedione (rosiglitazone), metformin, and glyburide as initial treatments for patients newly diagnosed with type 2 diabetes.48 The 4360 patients treated in this randomized placebo-controlled trial were treated for a median period of 4 years. The primary outcome was the time to monotherapy failure (defined as a confirmed FPG >180 mg/dL). Secondary outcomes included levels of FPG and A1C, insulin sensitivity, and b-cell function. Patients randomized to the rosiglitazone arm demonstrated a 32% risk of treatment failure compared with metformin and a 63% reduction in risk of failure compared with glyburide over 4 years. Rosiglitazone was associated with weight gain.
Preventing Type 2 Diabetes
On average, patients gained 6.9 kg compared with metformin and 2.5 kg compared with glyburide. Cardiovascular events were similar in the rosiglitazone and metformin arms but lower in the glyburide arm. Rosiglitazone was most effective, probably because of its effects on insulin sensitivity and b-cell function. Despite the positive effects of rosiglitazone on modest improvements in progression from prediabetes to clinical diabetes, one must also consider the drug’s long-term adverse effects, such as weight gain, fluid retention, cardiovascular risk, and a higher incidence of long-bone fractures before initiating therapy.49 ACT NOW was a recently completed randomized, placebo-controlled trial in which 602 subjects with IGT received either pioglitazone, 45 mg/day, or placebo.50 Patients were observed for an average of 3.75 years to determine if they progressed from IGT to clinical diabetes. Patients randomized to the pioglitazone treatment showed an 82% reduction in progression versus those treated with placebo. This study clearly suggests that patients with prediabetes who are aggressively managed with pioglitazone can improve their insulin sensitivity and restore their pancreatic b-cell function. Although incretin hormones have been shown to preserve b-cell function in animal models, their role in human b-cell preservation remains to be established. Incretins play an important role in lowering postprandial secretion of glucagon, thereby lowering postabsorbtive glucose levels, reducing oxidative stress, and preventing weight gain.11 Glucagon-like peptide-1 (GLP-1) is an incretin hormone rapidly released by the L cells of the distal ileum and colon as food is being ingested by neurohormonal mechanisms. This hormone works by glucose-dependent action. As long as glucose levels remain elevated, GLP-1 suppresses glucagon secretion from the pancreatic a cells while enhancing the secretion of insulin from pancreatic b cells. As glucose levels normalize, glucagon and endogenous insulin levels normalize so that the patient does not experience hypoglycemia. Enzymatic inactivation by dipeptidyl peptidase IV (DPP-IV) shortens the biologic activity of GLP-1 to less than 2 minutes,11 making certain that the effects of this hormone are not prolonged and induce hypoglycemia. GLP-1 controls both fasting and postprandial blood glucose concentrations by multiple actions, primarily by stimulating insulin secretion from pancreatic b cells while inhibiting glucagon secretion. GLP-1 also slows gastric emptying and enhances satiety, thereby reducing food intake. Whereas short-term administration of a GLP-1 agonist limits food intake, long-term subcutaneous infusion of GLP-1 results in weight loss.51 In animal models, GLP-1 promotes expansion of b-cell mass while inhibiting b-cell death (apoptosis).52 These b-cell protective actions have also been observed in human islets cultured in vitro.53 GLP-1 receptors also are present in heart myocytes. Interestingly, shortterm administration of GLP-1 improves myocardial contractility in patients after a myocardial infarction or revascularization procedure.54 Exenatide (Byetta) is a novel GLP-1 incretin mimetic hormone that has been approved for use in poorly controlled type 2 diabetes patients taking metformin, a sulfonylurea, a thiazolidinedione, a combination of metformin plus sulfonylurea, or a combination of metformin and a thiazolidinedione. Gila monsters, which are native to the Sonora Desert, harbor a naturally occurring GLP-1 agonist called ‘‘exendin-4’’ in their salivary glands. Although the Gila monster’s exendin-4 is only 53% homologous with human GLP-1, the analogue is not rapidly degraded by DPP-IV and has equal affinity to GLP-1 receptor sites. Exenatide is a synthetic form of exendin-4. Because exenatide is not rapidly degraded by DPP-IV, the drug has a half-life of 2.4 hours and is present in the plasma for up to 10 hours, allowing twice-daily administration. On average, weight loss in an open-label extension trial of 393 patients using exenatide, 10 mg twice daily for 82 weeks, lost on average 8 to 10 lb.54 Weight loss was steady and continuous as long as the patients remained on the drug.
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Exenatide reduces the secretion of glucagon by pancreatic a cells thereby minimizing postabsortive hyperglycemia and oxidative stress. Intracellular oxidative stress occurs when the production of reactive oxygen species (which are by-products of normal metabolism) exceeds the capacity of the cell’s antioxidants to neutralize them.55 Endothelial cells chronically exposed to oxidative stress favor the induction of specific long-term complication pathways. High postprandial glucose excursions also result in programmed death of the pancreatic b cells and heightened peripheral insulin resistance.56 DPP-IV inhibitors may lower A1C by 0.8 %. Patients with prediabetes, however, should direct their efforts more toward weight reduction, b-cell preservation, and
Table 4 Recommendations for managing patients with prediabetesa Interventional Strategy
Comment
Lifestyle interventions Weight reduction
5%–10 % of initial body weight Initial goal may be 10 lb from baseline
Increase physical activity
150 minutes of moderate activity, such as walking, each week At least 30 minutes 5 days each week with no more than 24 hours in between days of inactivity Aerobic physical activity should be performed at 50%–70% of one’s maximum predicted heart rate
Medical nutritional therapy
Reduce carbohydrate intake Promote fiber and whole grain intake Limit saturated fat intake to <7% of total daily calories Minimize transfat intake Reduce dietary cholesterol to <200 mg/day
Monitor blood glucose levels
Fasting and 2-hour postprandial first 7 days of each month
Diabetes education
Begin diabetes education with the goal of changing self-management behavior Address psychosocial issues Address nutritional issues Address physical activity
Pharmacotherapy
a
Metformin
Reduces cardiovascular risk Insulin sensitizer
Pioglitazone
Insulin sensitizer Preserves pancreatic b-cell function Reduces risk of myocardial infarction, stroke, all-cause mortality, acute coronary syndrome Prevents progression of impaired fasting glucose and impaired glucose tolerance to clinical diabetes
Exenatide
Reduces hyperglucogonemia Enhances satiety Promotes weight loss Reduces oxidative stress Reduces postprandial hyperglycemia Promotes expansion of pancreatic b-cell mass Improves first-phase insulin response
Prediabetes is defined as follows: fasting glucose levels: 100–125 mg/dL 5 impaired fasting glucose; 2-hour postprandial glucose levels: 140–199 mg/dL 5 impaired glucose tolerance.
Preventing Type 2 Diabetes
Table 5 Annual costs associated with long-term diabetes-related complications Complication
Total Cost for 1 Year After Onset of Acute Eventa
Stroke
$26,000
Acute myocardial infarction
$24,500
Amputation
$37,600
End-stage renal failure requiring dialysis
$57,200
a
For subjects who survived first year after onset of the event. Data from Brandle M, Zhou H, Smith BRK, et al. The direct medical cost of type 2 diabetes. Diabetes Care 2003;26:2300–4.
reduction in cardiovascular risk. The reason that DPP-IV inhibitors do not result in weight reduction is that at their prescribed doses, these drugs are unable to affect an increase in circulating GLP-1 levels. DPP-IV drugs simply prevent the degradation of GLP-1; they do not raise the GLP-1 plasma concentration. In contrast, exogenous GLP-1 therapy (exenatide) achieves supraphysiologic levels of GLP-1 to DPP-IV inhibitors, potentially improving the therapeutic potential for weight loss and glucose reduction. A CALL FOR ACTION
The rapid and often relentless progression of type 2 diabetes suggests that high-risk patients should be provided with an equally aggressive strategy to protect their remaining b-cell function and endogenous insulin secretion. Management of patients with prediabetes should incorporate both lifestyle and pharmacologic intervention. Table 4 lists suggested lifestyle and pharmacologic interventions that should be introduced when the diagnosis of prediabetes is made. As such, Mrs. Smith, should be encouraged to begin an exercise program and reduce her caloric intake. She will be started on metformin, 500 mg twice daily; pioglitazone, 15 mg daily; and exenatide, 5 mg before breakfast and dinner. Her blood glucose levels will be monitored before breakfast and at bedtime for the first 7 days of each month. The goal is to maintain her A1C levels less than 6%, increasing the dose of her medications as the A1C rises. Although no specific recommendations are published for the management of prediabetes, one can assume that preservation of pancreatic b-cell function, improvement in peripheral insulin resistance and pancreatic insulin secretion, reducing pancreatic a-cell secretion of glucagon, preventing long- and short-term diabetes-related complications, and assisting patients to lose weight is beneficial. Although triple-drug therapy in prediabetes is expensive, one should consider the cost society spends on microvascular and macrovascular complications (Table 5). Aggressive, timely, and physiologic management of prediabetes should be advocated. REFERENCES
1. CDC national diabetes fact sheet United States 2005. Available at: http://www. cdc.gov/nccdphp/publications/aag/pdf/aag_ddt2005.pdf. Accessed March 25, 2008. 2. Haffner SM, Lehto S, Ronemaa T, et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:229–34.
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3. Gastaldelli A, Ferrannini E, Miyazaki Y, et al. Beta-cell dysfunction and glucose intolerance: results from the San Antonio Metabolism (SAM) study. Diabetologia 2004;47:160–7. 4. Butler AE, Janson J, Bonner-Weir S, et al. ß-Cell deficit and increased ß-cell apoptosis in humans with type 2 diabetes. Diabetes 2003;52:102–10. 5. Pre-diabetes: American Diabetes Association. Available at: http://www.diabetes. org/diabetes-prevention/pre-diabetes.jsp. Accessed May 14, 2008. 6. Type 2 diabetes. National Institutes of Health fact sheet. Available at: http://www.nih. gov/about/researchresultsforthepublic/Type2Diabetes.pdf. Accessed May 12, 2008. 7. Reaven GM. Banting Lecture 1988. Role of insulin resistance in human disease. Diabetes 1988;37:1595–607. 8. Packard CJ, Ford I, Robertson M, et al. Plasma lipoproteins and apolipoproteins as predictors of cardiovascular risk and treatment benefit in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Circulation 2005;112:3058–65. 9. Hu G, Lakka TA, Kilpela¨inen TO, et al. Epidemiological studies of exercise in diabetes prevention. Appl Physiol Nutr Metab 2007;32:583–95. 10. Unger RH. Glucagon physiology and pathophysiology in the light of new advances. Diabetologia 1985;28:574–8. 11. Unger J. Amylin, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase IV (DPP-IV) inhibitors as novel treatments for diabetes. In: Unger J, editor. Diabetes management in primary care. Philadelphia: Lippincott, Williams and Wilkins; 2007. p. 618–46. 12. Trends in intake of energy and macronutrients—United States. 1971–2000. MMWR Morb Mortal Wkly Rep 2004;53(4):80–2. 13. Eaton DK, Kann L, Kinchen S, et al. Youth risk behavior surveillance—United States. 2005. MMWR. Surveill Summ 2006;55(5):1–108. 14. Ogden CL, Carroll MD, Curtin LR, et al. Prevalence of overweight and obesity in the United States, 1999–2004. JAMA 2006;295(13):1549–55. 15. Unger RH. Reinventing type 2 diabetes: pathogenesis, treatment and prevention. JAMA 2008;299(10):1185–7. 16. Lee Y, Hirose H, Ohneda M, et al. Beta-cell lipotoxicity in the pathogenesis of noninsulin dependent diabetes mellitus of obese rats: impairment in adipocyte-betacell relationships. Proc Natl Acad Sci U S A 1994;91(23):10878–82. 17. Shimomura I, Matsuda M, Hammer RE, et al. Decreased IRS-2 and increased SREBP-Ic lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice. Mol Cell 2000;6(1):77–86. 18. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346: 393–403. 19. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001;344:1343–50. 20. Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes study. Diabetes Care 1997;20:537–44. 21. Ratner RE. An update on the diabetes prevention program. Endocr Pract 2006; 12:20–4. 22. Laaksonen DE, Lindstrom J, Lakka TA, et al. Physical activity in the prevention of type 2 diabetes: the Finnish Diabetes Prevention Study. Diabetes 2005;54:158–65.
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23. Lindstro¨m J, Llanne-Parikka P, Peltonen M, et al. Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: follow-up of the Finnish Diabetes Prevention Study. Lancet 2006;368:1673–9. 24. Jeon CY, Lokken RP, Hu FB, et al. Physical activity of moderate intensity and risk of type 2 diabetes: a systematic review. Diabetes Care 2007;30:744–52. 25. Livesey G, Taylor R, Hulshof T, et al. Glycemic response and health: a systematic review and meta-analysis: relations between dietary glycemic properties and health outcomes. Am J Clin Nutr 2008;87:258S–68S. 26. Riccardi G, Rivellese AA, Giacco R. Role of glycemic index and glycemic load in the healthy state, in pre-diabetes, and in diabetes. Am J Clin Nutr 2008;87: 269S–74S. 27. Sahyoun NR, Anderson AL, Tylavsky FA, et al. Dietary glycemic index and glycemic load and the risk of type 2 diabetes in older adults. Am J Clin Nutr 2008;87: 126–31. 28. American Diabetes Association. Clinical practice recommendations 2005. Diabetes Care 2005;28(Suppl 1):S5–7. 29. Hossain P, Kawar B, El Nahas M. Obesity and diabetes in the developing worlda growing challenge. N Engl J Med 2007;356:213–5. 30. Giugliano D, Esposito K. Mediterranean diet and metabolic diseases. Curr Opin Lipidol 2008;19:63–8. 31. Schro¨der H. Protective mechanisms of the Mediterranean diet in obesity and type 2 diabetes. J Nutr Biochem 2007;18:149–60. 32. Knoops K, de Groot L, Kromhout D, et al. Mediterranean diet, lifestyle factors, and 10-year mortality in elderly European men and women. The HALE Project. JAMA 2004;292:1433–9. 33. Unger J. Lifestyle interventions for patients with diabetes. In: Unger J, editor. Diabetes management in primary care. Philadelphia: Lippincott, Williams and Wilkins; 2007. p. 405–64. 34. Wing RR, Hill JO. Successful weight loss maintenance. Annu Rev Nutr 2001;21: 323–41. 35. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation and treatment of high blood cholesterol in adults (adult treatment panel III). Baltimore (MD): US Department of Health and Human Services. National Institutes of Health. National Heart, Lung and Blood Institute; September 2002. (NIH publication 02–5215). 36. Unger J. Diagnosing and managing the metabolic syndrome in adults, children and adolescents. In: Unger J, editor. Diabetes management in primary care. Philadelphia: Lippincott, Williams and Wilkins; 2007. p. 43–87. 37. Hu FB, Leitzmann MF, Stampfer MJ, et al. Physical activity and television watching in relation to risk for type 2 diabetes mellitus in men. Arch Intern Med 2001; 161:1542–8. 38. Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic (beta)-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes 2002;51:2796–803. 39. Nagi D, Yudkin J. Effects of metformin on insulin resistance, risk factors for cardiovascular disease, and plasminogen activator inhibitor in NIDDM subjects. Diabetes Care 1993;16:621–9. 40. DeFronzo R, Goodman A. The multicenter study group: efficacy of metformin in patients with non-insulin dependent diabetes mellitus. N Engl J Med 1995;333: 541–9.
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41. Grant P. The effects of high- and medium-dose metformin therapy on cardiovascular risk factors in patients with type II diabetes. Diabetes Care 1996;19:64–6. 42. Grant PJ. The effects of metformin on the fibrinolytic system in diabetic and nondiabetic subjects. Diabete Metab 1991;17:168–73. 43. Chu NV, Kong APS, Kim DD, et al. Differential effects of metformin and troglitazone on cardiovascular risk factors in patients with type 2 diabetes. Diabetes Care 2002;25:542–9. 44. Johnson JA, Majumdar SR, Simpson SH, et al. Decreased mortality associated with the use of metformin compared with sulfonylurea monotherapy in type 2 diabetes. Diabetes Care 2002;25:2244–8. 45. Gerstein HC, Yusuf S, Bosch J, et al. DREAM (Diabetes Reduction Assessment with ramipril and rosiglitazone Medication). Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 2006;368:1096–105. 46. Dormandy JA, Charbonnel B, Eckland DJA, et al. On behalf of the PROactive investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005;366(9493): 1279–89. 47. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:2457–71. 48. Kahn SE, Haffner SM, Heise MA, et al. For the ADOPT Study Group. Glycemic durability of rosiglitazone, metformin or glyburide monotherapy. N Engl J Med 2006;355:2427–43. 49. Unger J. Managing type 2 diabetes in adults. In: Unger J, editor. Diabetes management in primary care. Philadelphia: Lippincott, Williams and Wilkins; 2007. p. 118–91. 50. DeFronzo R. Presented at the 55th Annual Advance Postgraduate Course. San Francisco (CA): American Diabetes Association; February 1, 2008. 51. Baggio LL, Huang Q, Brown TJ, et al. A recombinant human glucagon-like peptide(GLP)-1 albumin protein (albugon) mimics peptidergic activation of GLP-1 receptor–dependent pathways coupled with satiety, gastrointestinal motility, and glucose homeostasis. Diabetes 2004;53:2492–500. 52. Li Y, Hansotia T, Yusta B, et al. Glucagon-like peptide-1 receptor signaling modulates beta cell apoptosis. J Biol Chem 2003;278:471–8. 53. Buteau J, El-Assaad W, Rhodes CJ, et al. Glucagon-like peptide-1 prevents beta cell glucolipotoxicity. Diabetologia 2004;47:806–15. 54. Blonde L, Klein EJ, Han J, et al. Interim analysis of the effects of exenatide treatment on A1C, weight and cardiovascular risk factors over 82 weeks in 314 overweight patients with type 2 diabetes. Diabetes Obes Metab 2006;8:436–47. 55. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001;414(6865):813–20. 56. Mooradian AD, Thurman JE. Drug therapy of postprandial hyperglycaemia. Drugs 1999;57(1):19–29. 57. Unger J. Screening, diagnosis, and management of diabetes-related complications. In: Unger J, editor. Diabetes management in primary care. Philadelphia: Lippincott, Williams and Wilkins; 2007. p. 504–617.
Dis eas e Prevention a nd Wellness in the Twent y - fir st Centur y Roger Zoorob, MD, MPH*,Vincent Morelli, MD KEYWORDS Wellness Prevention
The United States spends more per capita on health care than any other country in the world: more than $6000 dollars per person last year, a full 16% of the Gross Domestic Product. This amount is more than twice that spent by most other developed nations,1 and yet the United States continues to rank unexpectedly low in several health care indices. One recent study2 ranked the United States last among developed nations in preventing avoidable deaths. PREVENTION
Although there are many reasons for such low rankings (eg, high numbers of uninsured, poverty rates, selection criteria), one commonly held idea is that the United States focuses too much on disease treatment and too little on disease prevention. Indeed, in the United States only 3% to 4% of the $2.1 trillion annual health care budget is spent on prevention.3,4 The need for emphasis on prevention is highlighted by two recent articles5,6 published in the New England Journal of Medicine and the Journal of the American Medical Association. The authors estimate that modifiable/preventable behaviors such as smoking, poor diet, inactivity, and alcohol consumption account for nearly 900,000 premature deaths each year, an astounding 40% of the total yearly mortality. They show that although health outcomes generally are influenced by factors in five domains (genetics, social circumstances, environmental exposures, behavioral patterns, and health care),6 the ‘‘greatest means for impacting health and reducing premature deaths lies in altering personal behavior.’’6 Clearly, it is important that these modifiable behaviors be targeted by primary care physicians,7 because such emphasis costs relatively little and has the potential for great impact. One notable example of effectively influencing modifiable behavior was noted in a recent article in Health Services Research.8 The authors surveyed
Family and Community Medicine, Meharry Medical College, 1005 Dr. DB Todd Boulevard, Nashville, TN 37208, USA * Corresponding author. E-mail address:
[email protected] (R. Zoorob). Prim Care Clin Office Pract 35 (2008) 663–667 doi:10.1016/j.pop.2008.07.005 primarycare.theclinics.com 0095-4543/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.
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data from the 2001 National Health Survey and concluded that the chances of success in smoking cessation programs doubled (from 7% to 14%) with counseling input from health care providers. Although focus on modifiable behavior is essential, other prevention efforts such as immunizations and cancer screening remain important and should continue to be part of proper medical care. Such prevention efforts should be prioritized in a cost-effective manner, because allocating resources otherwise would result in a greater number of preventable deaths, and society would be forced to pay the higher costs of disease treatment rather than the often lower costs of prevention.7 Researchers point out that although some prevention strategies are actually cost saving (ie, the cost of implementing prevention is less than the cost of treating disease cases that would arise without such prevention efforts) others, although not cost saving, are still deemed cost effective by society. An example of a cost-saving strategy is water fluoridation: for every $1 spent on water fluoridation, $38 is saved in dental restorative treatment.9 Other examples of cost-saving interventions would be hepatitis B vaccination of infants and a one-time colonoscopy for men over age 60 years in the United States.10 Examples of cost-effective prevention vary, depending on society’s moral compass and ability to pay. For example, in the United States, screening the entire female population for ovarian cancer by ultrasound is considered prohibitively expensive (not cost effective), whereas universal screening for cervical cancer, although not cost saving, can be done at a cost that is acceptable to society; therefore screening for cervical cancer is considered cost effective. (It would be cheaper if we did not screen and instead just treated disease cases.)11 In addition to these cost/policy concerns, it must be remembered that the broad topic of disease prevention may be viewed from several different vantage points. For example, from an international perspective, prevention usually connotes efforts to reduce infectious disease, especially malaria, tuberculosis, and HIV. Although it is true that these maladies accounted for 5.1 million deaths worldwide in 2005,12 such statistics should not overshadow the fact that in the same low- and middle-income countries, 26.5 million deaths are caused each year by chronic diseases, such as cardiovascular disease, diabetes, and cancer. A recent series of articles in Lancet13–17 concluded that that tobacco control, salt restriction, and multidrug regimens for the prevention of heart disease are important and cost-effective weapons in any country’s health promotion efforts. Discussions of prevention on the national level generally focus on preventing chronic diseases, such as cardiovascular disease, diabetes, smoking-induced lung disease, and cancer, because these diseases are the principal preventable causes of premature mortality and morbidity in the United States. Indeed, 7 of 10 Americans who die each year die of chronic disease.18 Despite the need to focus efforts in this area, it also is important to combat the full scope of preventable disease, continuing efforts against infectious agents such as polio, whooping cough, hepatitis, tetanus, and measles. Extraordinary advances have been made in these realms, and primary care physicians must be vigilant to hold the ground gained. Although the news media highlight international and national prevention strategies by groups such as the World Health Organization, the Gates Foundation, and the United States Preventive Services Task Force (USPSTF), there also is a need for locally focused prevention. For example, a physician practicing in an economically depressed rural or inner city area may have to spend more time combating violence, depression, and alcohol abuse than a counterpart operating in a thriving urban or suburban environment where stress and cardiovascular disease may predominate.
Disease Prevention and Wellness
In addition to these international, national, and local perspectives, primary care physicians also must keep in mind that ethnic and cultural variations are important. Disease prevalence, the level of trust in Western medicine, and the approach to wellness may vary considerably among different cultures and must be taken into account. For example hepatitis, tuberculosis, and stomach cancer should be screened for more assiduously in Asian immigrant populations, whereas diabetes, hypertension, and prostate cancer may be more prevalent in Latinos and African Americans.19–21 Clearly, the task of disease prevention is not a ‘‘one size fits all’’ proposition, and efforts should be tailored to address the needs of unique individuals living in distinct communities. Making this task even more difficult, the USPSTF (http://www.ahrq. gov/clinic/USpstfix.htm) and the National Guideline Clearing House (http://www. guideline.gov/) publish more than 1100 different prevention and wellness guidelines and recommendations, covering topics from immunization and cancer screening to fall prevention and suicide awareness. This wealth of age-specific, evidence-based recommendations from governmental agencies, professional societies, and public and private organizations makes the primary care physician’s job of discernment and prevention implementation daunting, to say the least. WELLNESS
Although the physician’s traditional role in disease prevention and disease treatment will remain, the world today is changing. More than 62% of Americans consider themselves to be in excellent or very good health,22 and because this demographic represents a majority of the population, physicians must expand their purview to encompass the needs of these ‘‘healthy people’’ as well. Such patients usually are more interested in health enhancement than in disease prevention, often taking the latter for granted. The fact that such a large cohort exists is evidenced clearly by the large market for ‘‘self health’’ books, and the high use of complementary and alternative medicine. Indeed almost 40% of adults in the United States reported using complementary and alternative medicine in 200223 (most commonly herbs, massage, chiropractics, diet, megavitamin therapy, yoga, breathing, and guided imagery) and spent an estimated $27 billion on such therapies, an amount comparable to the amount spent on all physician services combined that year.24 Such data demonstrate that there is indeed a large group clearly interested and invested in health enhancement who are taking it upon themselves to ‘‘self maximalize.’’ This trend fits nicely with the primary goals of the ‘‘Healthy People 2010 Initiative’’ put out by US Office of Disease Prevention and Health Promotion (http://www. healthypeople.gov). The initiative states, ‘‘The first goal of Healthy People 2010 is to help individuals of all ages increase life expectancy and improve their quality of life.’’ Primary care physicians should support this trend. In addition to continuing to focus on prevention in an international, national, local, and cultural fashion, there is a growing need to focus also on wellness. The Healthy People 2010 Initiative and most patients seem to demand this focus. Primary care physicians are uniquely positioned to help such patients navigate today’s sea of health and wellness information, through the flood of confounding and conflicting information and misinformation that is promulgated on television, the Internet, and in the lay press. This issue of Primary Care Clinics in Office Practice proposes that primary care physicians not only should continue their progress in disease prevention but also should expand their scope of service to support national goals and their patients’ interests in wellness and health optimization.
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The articles that follow focus on two areas. First they review the latest evidence in prevention as it concerns the most pressing national health issues: heart disease, diabetes, smoking, obesity, and exercise. Part two reviews selected ‘‘wellness topics’’ (antioxidants, vitamins, foods and farming methods, toxins, water) to provide reliable information to patients and ultimately to enhance their health. It proposes a new focus for primary care physicians, namely acting as informed ‘‘wellness’’ educators. The authors believe that this wellness education should be provided in a dedicated annual wellness and prevention counseling session (ICD9–V65.4 Other counseling, not elsewhere classified—Health: advice, education, instruction) in which adequate time can be allocated for discussion and questions. Taking on this role will require additional time and continuing education, but by knowledgeably helping patients to maximize their health, physicians will provide a needed service, contribute to the health of their patients and reap the rewards of a stronger doctor–patient bond.
REFERENCES
1. OECD health data 2006. Available at: www.oecd.org/health/healthdata. Accessed May 11, 2008. 2. Nolte E, McKee CM. Measuring the health of nations: updating an earlier analysis. Health Aff (Millwood). 2008;27(1):58–71. 3. HHS.gov. Office of the Actuary. Available at: http://www.cms.hhs.gov/cmsleadership/ 09_office_oact.asp. Accessed May 2, 2008. 4. Economist.com. Public Health Programmes. Available at: http://www.economist. com/markets/indicators/displaystory.cfm?story_id5E1_VTSGTSD. The Economist. Nov 17, 2005. Accessed April 5, 08. 5. Mokdad AH, Marks JS, Stroup DF, et al. Actual causes of death in the United States, 2000. JAMA 2004;291(10):1238–45. 6. Schroeder SA. We can do better—improving the health of the American people. N Engl J Med 2007;357(12):1221–8. 7. Woolf SH. Potential health and economic consequences of misplaced priorities. JAMA 2007;297(5):523–6. 8. Bao Y, Duan N, Fox SA. Is some provider advice on smoking cessation better than no advice? An instrumental variable analysis of the 2001 National Health Interview Survey. Health Serv Res 2006;41(6):2114–35. 9. Schieber SJ. From baby boom to elder boom: providing health care for an aging population. Washington, DC: Watson Wyatt; 1996. 10. Cohen JT, Neumann PJ, Weinstein MC. Does preventive care save money? Health economics and the presidential candidates. N Engl J Med 2008;358(7): 661–3. 11. Cohen L, Fishman DA. Ultrasound and ovarian cancer. Cancer Treat Res 2002; 107:119–32. 12. At a glance: causes of death. The Economist, August 13, 2007. Available at: http://www.economist.com/displaystory.cfm?story_id59640634. Accessed April 13, 2008. 13. Abegunde DO, Mathers CD, Adam T, et al. The burden and costs of chronic diseases in low-income and middle-income countries. Lancet 2007;370(9603): 1929–38. 14. Gaziano TA, Galea G, Reddy KS. Scaling up interventions for chronic disease prevention: the evidence. Lancet 2007;370(9603):1939–46.
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15. Asaria P, Chisholm D, Mathers C, et al. Chronic disease prevention: health effects and financial costs of strategies to reduce salt intake and control tobacco use. Lancet 2007;370(9604):2044–53. 16. Beaglehole R, Ebrahim S, Reddy S, et al. Prevention of chronic diseases: a call to action. Lancet 2007;370(9605):2152–7. 17. Lim SS, Gaziano TA, Gakidou E, et al. Prevention of cardiovascular disease in high-risk individuals in low-income and middle-income countries: health effects and costs. Lancet 2007;370(9604):2054–62. 18. Centers for Disease Control and Prevention. Chronic disease overview. Available at: http://www.cdc.gov/nccdphp/overview.htm. Accessed May 5, 2008. 19. Witt D, Brawer R, Plumb J. Cultural factors in preventive care: African-Americans. Prim Care 2002;29(3):487–93. 20. Au C. Cultural factors in preventive care: Asian-Americans. Prim Care 2002;29(3): 495–502, viii. 21. Diaz VA Jr. Cultural factors in preventive care: Latinos. Prim Care 2002;29(3): 503–17, viii. 22. Adams PF, Dey AN, Vickerie JL. Summary health statistics for the U.S. population: National Health Interview Survey, 2005. Vital Health Stat 10 2007;233:1–104. 23. Stokley S, Cullen KA, Kennedy A, et al. Adult vaccination coverage levels among users of complementary/alternative medicine—results from the 2002 National Health Interview Survey (NHIS). BMC Complement Altern Med. 2008;8:6. 24. Gaylord SA, Mann JD. Rationales for CAM education in health professions training programs. CAM education. Acad Med. 82(10):927–33.
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Hormones in Wellness and Diseas e Prevention : Common Prac tices, Current St ate of the Evidence, a nd Questions for the Future Erika T. Schwartz, MDa,*, Kent Holtorf, MDb KEYWORDS Hormones Estrogen Progesterone Testosterone Thyroid Growth hormone Wellness Prevention
The study and use of hormones have long been the domains of endocrinology, which is primarily focused on the pathologic phenomena encountered in the human body as they relate to hormones. No specific field in medicine has been designated to study and analyze the effects of hormones on wellness and disease prevention. As the field of wellness and disease prevention expands rapidly, it behooves the primary care practitioner, the first physician contact between the patient and the health care system, to become conversant and comfortable with hormone treatments as they relate to wellness and disease prevention. Extensive scientific literature addresses the crucial role hormones play in the physiologic processes that maintain homeostasis. Much controversy surrounds the clinical use of various hormone therapies to support and maintain these processes in the aging patient. This article attempts to clarify some of the confusion and controversy surrounding estrogen, progesterone, testosterone, growth hormone, and thyroid hormones and discuss their roles as supported by the present state of evidence in disease prevention and aging as they apply to the primary care practice. Hormones represent specific proteins produced by the human endocrine organs: pituitary, adrenals, thyroid, testes, and ovaries. Our focus is limited to estrogen, progesterone, testosterone, growth hormone, and thyroid. In health, all hormones are individually and wholly integral participants to the maintenance of cellular function
a
10 West 74 Street, Suite 1A, New York, NY 10023, USA 23456 Hawthorne Boulevard, Suite 160, Torrance, CA 90505, USA * Corresponding author. E-mail address:
[email protected] (E. Schwartz). b
Prim Care Clin Office Pract 35 (2008) 669–705 doi:10.1016/j.pop.2008.07.015 primarycare.theclinics.com 0095-4543/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.
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and homeostasis. Hormone levels undergo diurnal variation and levels change in response to our environment, thought processes, stress levels, and food intake. Environmental toxins, medications, and pollutants also significantly affect hormone balance. With the aging process, hormone levels decrease naturally. As these levels decline, problems with health maintenance arise. The diminution in hormone levels that occurs as a result of aging may or may not be compounded by concomitant disease states and environmental factors. In this article, we discuss age-related hormone loss and supplementation therapies for age-related hormonal deficiencies as possible firstline therapeutic modalities to be considered in our search to improve quality of life, prevent chronic illnesses, and maintain wellness.
ESTROGEN, PROGESTERONE,TESTOSTERONE
Scientists have determined the existence of three true end-organ sex hormones: estrogen, progesterone, and testosterone. Both men and women have all three hormones, although levels and ratios of these hormones vary according to gender. Estrogen and progesterone are the dominant hormones in women. We are often faced with the misconception that estrogen, progesterone, and testosterone act independently of one another. Without fully understanding the inseparable nature of the interaction between all sex hormones, we cannot solve the problems caused by imbalances in their individual levels and the symptoms these imbalances cause. Estrogen is made in the ovaries, the corpus luteum, adrenal glands, and fat cells. Estrogen is not one big molecule; rather, it is a group of molecules. In humans, the three main identified estrogen molecules are estriol, estradiol, and estrone. Estradiol is the most active form of estrogen made by the ovaries, adrenals, and fat cells postmenopause. Estradiol directly affects a wide range of cellular functions, as estrogen receptors are ubiquitous. Estriol is the weakest of estrogens. Estriol is primarily manufactured during pregnancy by the placenta. It attaches to cell receptors affecting hair, nails, and skin. Recorded data on estriol’s function demonstrate that estriol’s effects are limited mainly to the vaginal walls with a little effect on the heart and bones in nonpregnant women. In the nonpregnant, young, and premenopausal woman, estriol is made in the liver in small doses. Studies on the use of estriol in menopausal women and women with multiple sclerosis have demonstrated promising results.1 Estrone is manufactured in fat cells after menopause primarily from testosterone derivatives (androstenedione). Estrone levels tend to rise after menopause and the increase in estrone has been implicated in an increased incidence of breast tumors but most data have been obtained from animal studies. Overweight older women have high circulating levels of estrone. When the scientific and lay communities refer to estrogen, they typically refer to its three components as one. At times, this oversimplification leads to errors in separating the individual function of the estrogens, particularly when discussing the differences between estrogen preparations used as hormone-replacement therapy available on the market. Although their actions are perceived and often recorded as one, the component molecules of estrogen have different potencies and effects.2–6 During the aging process, the ovaries stop producing estrogen on a regular basis. Thereafter the main source of estrogen is from the adrenal glands, primarily in the form of estrone. The body transforms unused testosterone into estrogen (primarily estrone) and releases estrogen stored in fat cells.
Hormones in Wellness and Disease Prevention
Estrogen and progesterone are antagonists. Their actions are designed to balance each other and keep each other in check.7 We cannot live in a healthy state without hormonal balance. At no time do hormones act independently under normal circumstances in healthy bodies.7 For example, estrogen increases cell proliferation in the endometrium, while progesterone inhibits cell proliferation. Without progesterone, endometrial hyperplasia occurs in the uterus.6–8 Progesterone is manufactured primarily by the corpus luteum (the follicle transformed after ovulation) and also to a small degree by the adrenals. In the ovary, progesterone production is activated at ovulation (15 days before the next menstruation),7 stimulated by the release of luteinizing hormone from the pituitary gland and is crucial to the survival of the ovum once fertilized. When pregnancy occurs, progesterone production increases rapidly and its manufacture is taken over by the placenta. If a woman does not get pregnant, the corpus luteum involutes and progesterone production diminishes and eventually disappears in parallel with estrogen production, heralding menstruation. Progesterone is a precursor to most sex hormones, including estrogen in the ovaries, testosterone, all androgens, and other adrenal hormones, making it an extremely important hormone for reasons far beyond its role as a sex hormone. Progesterone in the breast and uterus counteracts the stimulation of cell growth, which is a direct action of estrogen. It accomplishes this action by activating the progesterone receptor, which in turn, down-regulates the estrogen receptor. Because progesterone suppresses estrogen-driven cell proliferation, progesterone in the natural state helps keep breast cell growth in healthy balance.9 ESTROGEN AND PROGESTERONE: NOMENCLATURE, COMMERCIAL AVAILABILITY
Among the medications approved by the Food and Drug Administration (FDA) for hormone therapy are two classes of sex steroid hormones: estrogens and progestogens (which broadly include progesterone and progestogens or progestagens, also referred to as ‘‘progestins’’ or ‘‘progestational agents’’). For better clarification, these medications must further be divided into two groups: (1) bioidentical hormones with molecular structure identical to that of the human hormones and (2) preparations with molecular structures different from that of human hormones (nonidentical). The molecular difference between these two types of hormone formulations affect their actions in the human body.2,4,7,10 In 2001, a literature review by Stanczyk5 scrutinized the various estrogen preparations available on the market. The investigator noted that the scarcity of comparative pharmacokinetic information between various formulas of estrogens created a void in our knowledge of their differential effects and thus hindered our ability to serve the patient. He encouraged comparative studies to help determine the best type of estrogen to be used as therapeutic options to enable individualized treatments and approaches that would fit each woman’s risk profile and personal preference. Hormone Preparations with Molecular Formulas Unlike Those of Human Hormones
Hormone preparations that are molecularly different from human hormones are the most commonly used and marketed hormone-replacement therapy in the United States. They are commonly referred to in the popular literature as synthetic estrogens or pregnant horse urine estrogens. The most popular estrogenic preparations in this category include such oral estrogens as conjugated equine estrogen (Premarin), esterified estrogen (Estaratab, Menest, Cenestin), estrone sulfate (Ogen), and ethinyl
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estradiol (Estinyl); and such vaginal creams as estropipate (Ogen) and dienestrol (Ortho-dienestrol). Progestins
Progestins, which include drug formulations that are also molecularly different from those for human progesterone, were developed to balance the endometrial hypertrophy associated with the use of unopposed conjugated estrogens on the uterus.7–9,11,12 Progestins are chemical compounds manufactured with two types of primary characteristics: androgenic and nonandrogenic properties. Progestins are manufactured in the laboratory and are not extracted from any known animal sources. They include medroxyprogesterone (Provera, Amen, Cycrin), norethindrone (Micronor, Norlutin), and norethindrone acetate (Norlutate). Combination Products
Combination products contain combinations of both estrogenic and progestogenic compounds. Some include one hormone that is molecularly identical to human hormones and one that is not, while some contain both the estrogen and the progestogens that are molecularly different from human estrogen and progesterone. They include conjugated estrogen (nonidentical) and synthetic progestin (nonidentical) (Prempro, Premphase);17-beta-estradiol (bioidentical) and norgestimate (nonidentical) (Orthopresfest); ethinyl stradiol (nonidentical) and norethindrone acetate (nonidentical) (FemHRT); and esterified estrogens (nonidentical) and methyltestosterone (nonidentical) (Estratest). Bioidentical Hormone Preparations
Bioidentical hormones are manufactured to be molecularly identical to hormones found in the human body. Bioidentical preparations include estradiol, estriol, progesterone, and testosterone. Bioidentical hormones are available both in commercial and compounded forms. Bioidentical hormones are not a marketing term. The term has been used for more than a decade in the inserts to all FDA-approved commercial hormone preparations that contain hormones molecularly identical to human hormones. Commercially and compounded available bioidentical hormone preparations include: 17-Beta estradiol (Alora, Climara, Esclim, Estrace) 17-Beta estradiol patches (FemPatch, Vivelle-Dot, Vivelle, Estraderm) Estradiol transdermal spray (Evamist) Progesterone in peanut oil capsule (Prometrium) Progesterone vaginal gel (Crinone) Micronized progesterone in various compounded forms (capsules, troches, transdermal creams, vaginal suppositories) Combinations of estradiol and progesterone in compounded formulations as above Combinations of estradiol, estriol, and progesterone in compounded formulations as above Beyond the commercial bioidentical hormone formulations, individually compounded preparations of bioidentical hormones are prepared in compounding pharmacies or laboratories (some are FDA approved; all are regulated by the state they operate in) on an individualized basis as prescribed by a physician. These products contain the same active estrogens, progesterone, and testosterone as those found in the commercial preparations listed above. The difference is that they are
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individually mixed in tablet, capsule, troches, gels, or creams to the specifications of the prescribing physician for the individual patient. Unlike the commercial preparations, compounded hormone preparations are not manufactured on a large scale and can only be produced for individual patients as prescribed by a physician or other licensed practitioner, depending on the particular state rules. In a recent review of bioidentical hormones in menopause, Boothby and colleagues13 reviewed only the compounded formulations of bioidentical. The investigators made no mention of the commercially available bioidentical hormones. This omission inadvertently perpetuated the confusion, credibility, and even existence of bioidentical hormones in FDA-approved commercially available preparations. Much of the confusion surrounding estrogen and progesterone formulations comes from the lack of clear distinction between their molecular formulas, the lack of focus on their different effects in the human body, and the use of nonspecific nomenclature when referring to estrogen and progesterone regardless of formulaic or activity differences. The molecular differences between bioidentical and nonhuman identical hormone preparations are illustrated in (Fig. 1). Controversy
The differences in behavior of various hormone formulations in vivo and vitro are directly connected to the differences in molecular structure as described in the scientific literature.10,14–16 As early as 1976, scientific data demonstrating the safety of bioidentical hormones appeared in the conventional medical literature.17 Reports of increased risk of endometrial and breast carcinoma among users of synthetic conjugated estrogens also appeared in the scientific literature.3,8,9,11 By January 1978, the Journal of the American Geriatrics Society addressed the growing concern that treatment with exogenous estrogen alone causes cancer and reported on progestogen as the solution. Adding small doses of a progestogen to either estradiol or conjugated estrogen in a cycled manner was determined to be a safe solution to the concern of increased carcinogenicity found with the use of unopposed estrogen.18 It is noteworthy that, in 1983, the options for treatment studied included bioidentical estradiol and conjugated estrogens with medroxyprogesterone. The stated goal of the treatment was to help women feel better as they aged and ‘‘not to harm’’ them in the process.19 As early as 1980 and continuing into the recent literature, untoward side effects of synthetic progestins, such as thrombotic phenomena; breast tissue cell hyperplastic changes; and cardiovascular, cholesterol, carbohydrate, and lipid metabolism changes,7,10,14 prompted more research into bioidentical (micronized) progesterone as a safer option. An article in the British Medical Journal in March 1980 noted: ‘‘Clinically, oral bioidentical progesterone may be of value when synthetic progestogens have caused adverse symptoms that necessitate stopping treatment.’’20 Recommendations for the use of bioidentical progesterone as a safer alternative were found in the medical literature from Europe as well as the United States throughout the early 1980s.21–23 In the 1980s and early 1990s, research scientists expressed concern that the synthetic progestins in hormone therapy could increase the risk of breast cancer.24,25 About this same time, the scientific literature was replete with studies of safer alternatives in the form of bioidentical estradiol and progesterone, as well as studies comparing bioidenticals to the synthetic hormones and comparing various methods of administration with transdermal method of administration demonstrating the most promise in the area of safety and efficacy. Examples of such scientific literature
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PROGESTERONE
CH3 CH3
CH3
OCOCH
H H
CH3
CO
H CH3
O
C O
CH3
H
C O
Provera(MPA)
HO
HO
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Human Progesterone
ESTROGEN Premarin is composed of numerous molecules of pregnant mare’s urine estrogen metabolites. Formula unavailable
Premarin OH
HO
Bioidentical Estradiol
OH
HO
Human Estradiol
Fig. 1. The molecular formulas of various types of progestagens and estrogens. (Adapted from United States Pharmacopeia; and United States National Formulary.)
included an article by Foidart and colleagues,12 who demonstrated that estradiol and progesterone had less proliferative effects on breast tissue cancer cell lines than did progestins and conjugated estrogens. Franke and Vermes14 showed that progesterone-induced apoptosis in breast cancer cell lines that were conversely stimulated by synthetic progestins and other androgenic progestins. Place and colleagues26 conducted a double-blind comparison of estradiol in transdermal form and Premarin that demonstrated improved relief of postmenopausal symptoms in the patient group on estradiol with no side effects. Riis and colleagues,27 in a double-blind clinical controlled study, demonstrated that bioidentical estradiol and micronized progesterone helped improve bone density in postmenopausal women. Moorjani and colleagues31 reported on the improved lipoprotein profile in patients receiving oral bioidentical estrogen with progesterone over those on progestins with androgenic action.9–17,26–33 Notably, the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, a longterm randomized trial of hormone-replacement therapy, compared multiple effects,
Hormones in Wellness and Disease Prevention
including cardiovascular effects, of both synthetic progestins and micronized progesterone in combination with conjugated equine estrogen. The PEPI trial confirmed that over the course of 3 years, oral conjugated estrogen taken alone or with synthetic progestins or micronized progesterone was associated with clinically significant improvement in lipoprotein profile and lowered fibrinogen levels. PEPI also demonstrated significant losses in high-density lipoprotein cholesterol when synthetic progestin was added (significantly reducing the beneficial effects of estrogen). However, when bioidentical progesterone was added, there appeared to be statistically significant endometrial sparing and the bulk of estrogen’s favorable effects on risk factors, including high-density lipoprotein cholesterol, were also preserved.34 In 1994, the National Institutes of Health began the Women’s Health Initiative (WHI), a large-scale prospective double-blind placebo-controlled study. The goal of the study was to evaluate the long-term effect of hormone-replacement therapy versus placebo in the prevention of heart disease, osteoporosis, cancer, and strokes in postmenopausal women. The only form of hormone-replacement therapy used in the study was conjugated equine estrogens (conjugated estrogen [Premarin]) and medroxyprogesterone (synthetic progestins [Provera]). Unfortunately, the WHI did not include a bioidentical arm even though bioidentical hormone usage and statistically significant studies consistently demonstrated positive results and sustainable safety and efficacy records for this therapeutic modality.10,35–42 Studies comparing the effectiveness and safety of different methods of administration (oral versus transdermal or vaginal),26,27,29–33 the use of synthetic versus bioidentical replacement,26,34,38,40 and the use of estrogen only versus combined estrogen and progesterone10,34,37,40–42 have raised more questions about the logic and safety of using conjugated estrogen and synthetic progestins in our patients. Large-scale studies have been conducted in Europe where bioidentical hormone replacement therapy is the main type of hormone supplementation in menopausal women. These studies repeatedly demonstrated effective elimination of menopausal symptoms and a lack of long-term negative side effects with the use of bioidentical preparations. Foidart and colleagues12 showed in a small study that, within 14 days, exposure to progesterone reduced the estradiol-induced proliferation of the breast epithelial cells in vivo in 40 postmenopausal women. E3N is a large prospective French cohort study that investigated breast cancer risk factors in 98,997 women born between 1925 and 1950. The data were analyzed every 2 years and the conclusion emerged that micronized progesterone regimens, compared to synthetic progestin regimens, were associated with significantly lower breast cancer risks. Additionally, women who took the hormone-replacement therapy consistently were at lower risk than women who took the hormones occasionally.43 De Lignie`res and colleagues44 reported the results of an 8.9-year study of a cohort of 3175 postmenopausal women using mainly transdermal estradiol and progesterone. No increased risk of breast cancer was found (risk ratio [RR] of breast cancer per year of use was 1.005). Stahlberg and colleagues40 reported on the Danish Nurse Cohort Study commenced in 1993, which followed 19,898 women aged 45 and above. The highest risk of cancer was found in the women who used continuous combined estrogen with synthetic progestin. Nelson41 reviewed the studies that evaluated the short-term effectiveness of conjugated estrogen and estradiol as treatments for relief of hot flashes. The conclusion was that they both have comparable short-term effects. The overarching problem with conjugated estrogen is the long-term increased risk of breast cancer, stroke, and myocardial infarction, which was proven by the WHI initiative. This situation leaves us with the very important knowledge that hormonereplacement therapy is an important tool in wellness and prevention. The type of
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hormone therapies we choose for our patients is what makes the difference and must be carefully considered.10,12,21,22,25,40–44 Risks/Benefits
Scientific reviews of the pharmacology and action of progestins demonstrate that all progestins and progestogens are not created equal, and their action varies significantly according to their molecular structure. In the studies reviewed, bioidentical progesterone proved to be safer and more effective in all trials that involved its usage10,43,44 and numerous studies have shown that any estrogen (conjugated estrogen or bioidentical estradiol) combined with synthetic progestin doubles the risk of breast cancer.28,45–49 Unlike synthetic progestins, bioidentical progesterone has been shown to have a consistently beneficial effect on breast cell proliferation.50 The E3N and Danish Nurses studies, which address large populations taking various types of hormone-replacement therapy for more than 5 years, did not find progesterone to be an increased risk factor for breast cancer while progestin was. When estradiol was used in studies that evaluated its effectiveness in relieving menopausal symptoms, including hot flashes, night sweats, insomnia, and mood swings,51,52 and in improving sleep patterns53,54 and lipid profiles,55 the results were consistently positive. The WHI study came to an abrupt halt in July 2002 primarily because the interim data demonstrated increased risk of myocardial infarction, stroke, and breast cancer in the conjugated estrogen and synthetic progestin arm of the study.56–59 Since that time, the suggestions to use hormone-replacement therapy in menopausal women has raised fears, doubts, and confusion. Millions of women, exposed to the media frenzy caused by the WHI’s unsettling results, abruptly stopped taking their hormone therapies at the advice of their physician and on their own. This situation required physicians to rethink hormone-replacement therapy and to look at other options for relief. Much time and effort has been spent on reevaluating the results of the WHI. This reexamination has brought to light many questions about the validity of the findings and soundness of the study.60–66 Despite questions raised about the validity of the WHI study, the study itself still provides grounds for caution. The use of synthetic estrogen and progestin replacement remains questionable at best. Even though the only long-term study on hormone-replacement therapy in the United States was conducted on synthetic hormones and the data clearly established increased risk of cancers and strokes with the use of conjugated estrogen and progestins, hormone therapies are still the most effective therapeutic modalities for the elimination of symptoms of menopause and should be considered an integral part of the overall well-being of the aging woman. While in the short term, the type of hormones used may or may not be as significant as in the long run, the question is: What are the best options for the short and long terms for the women we treat? An epidemiologic review of the rise in incidence in breast cancer in 1990 looked at the receptor status and the relationship to stage. Of interest is the fact that the investigator found that the incidence in older women increased and the cancers were more likely to be estrogen receptor positive. These cancers carry better prognosis because they tend to grow more slowly and are sensitive to hormonal manipulation.25 This information is useful for the primary care physician when deciding therapeutic course of action over the long term. Subsequent to the discontinuation of the WHI study, hormones that are synthetic and molecularly dissimilar to human hormones can no longer be prescribed without hesitation. A growing number of physicians involved in prevention and wellness, in response to concerns raised by the WHI and to requests and demands from patients,
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have created study groups and forums within alternative and integrative medical organizations, have written books, and are conducting seminars sharing their clinical experience and research data on the use of bioidentical formulations of estrogen and progesterone. Risks associated with the use of conjugated estrogen and progestins, including the increased risks of breast cancer and cardiovascular events,10,40,43–46, 56–59 have not been reported with the use of bioidentical hormones.50–55 Based on the extensive scientific data we have reviewed for this article, it is unclear whether any absolute circumstance calls for synthetic versions of hormonereplacement therapy and such use appears unwise. Given the easy commercial availability of bioidentical formulations and the lack of negative data on these hormones, primary care physicians can easily access them for their patients. When faced with the need to treat a woman with hot flashes, night sweats, insomnia, mood changes, loss of libido, and other symptoms of menopause, the primary care physician must choose wisely the safest and most effective way of improving the quality of life for the patient. While further long-term randomized trials would be helpful to quantify the difference in RRs between synthetic and bioidentical hormone replacement over the long term, the current state of evidence demonstrates bioidentical hormones as a safe and effective option to be considered separate and distinct from its synthetic counterparts. TESTOSTERONE Female
Although estrogen remains the central female hormone most frequently used in both wellness and disease prevention, much less controversy surrounds the use of testosterone in women, though the evidence either supporting or discouraging its use is scarce. Nicknamed ‘‘the hormone of desire’’ and promoted in the popular media as the rescuer from the plight of decreasing libido in aging women, testosterone has gained rapid acceptance in the prevention and wellness arenas at a time when controversy and confusion surround estrogen and progesterone therapies. Testosterone is produced by the ovaries and adrenals in young women in low doses (free testosterone levels range between 2–8 pg/mL). The bulk of the present research on the use of testosterone has been conducted on women with surgical menopause, hypopituitarianism, anorexia nervosa, and primary adrenal insufficiency; patients with HIV and low body weight;67 and patients with glucocorticoid- and oral contraceptive– induced suppression of endogenous androgens. There has been little if any formal study on testosterone use in normal aging in women. Benefits Muscle mass The addition of testosterone to conjugated estrogen results in an increase
in fat-free body mass and mitigates central fat deposition associated with estrogen use.68,69 In a double-blind placebo-controlled small study of androgen-deficient women, testosterone replacement demonstrably increased thigh muscle mass as measured by CT scanning.70 The data is very limited and its value and usefulness on large populations unknown. Further evaluation and research must be conducted as we address the possibility of usage of testosterone in the aging female to help improve muscle mass and decrease central adiposity. Libido Loss of libido in the aging female is the most common complaint that leads phy-
sicians to consider testosterone deficiency as a possible cause and the main consideration for treatment with testosterone. Multiple factors directly affect sexual inclination. Poor relationship status, self-image issues, multiple medications and their
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side effects, other stress factors, aging, and concurrent chronic or acute illnesses are some of the most frequently encountered deterrents of sex drive. Many of these factors cannot be altered, and all factors should be taken into account. Even so, testosterone appears to be effective in offsetting some of the effects from these factors, leading primary care physicians involved in integrative and wellness practices to make testosterone supplementation more popular. Lack of training in the area of loss of libido and lack of concrete diagnostic criteria have created difficulties for the primary practitioner when attempting to address this problem. While circulating testosterone levels are not very helpful in diagnosing low testosterone as the cause for loss of libido, it may be helpful to keep in mind that premenopausal women have a range of 20 to 75 ng/dL total testosterone while postmenopausal women can present with values as low as 5 to 10 ng/dL. Because we rarely have comparative levels of testosterone on a patient before they come in with the complaint, it is almost impossible to determine whether the testosterone levels correlate in any way with the appearance of symptoms.71 The seminal study on impaired sexual function improvement with supplemental testosterone comes from oophorectomized women. Seventy-five women 31 to 56 years old postoophorectomy and -hysterectomy were randomly assigned to receive conjugated estrogen and various doses of transdermal testosterone. The women who received the higher dose of testosterone reported a two- to threefold increase in sexual desire, masturbation, sexual intercourse, and sense of positive well-being as compared with placebo or conjugated estrogen alone.72 Breast cancer Acting through androgen receptors, testosterone opposes estradiol-
induced proliferation of human breast cell lines.73 Cases where endogenous testosterone levels are elevated, such as with polycystic ovary syndrome, are associated with breast tissue atrophy and a decreased risk of breast cancer.74 There are, however, conflicting data on the potential role of supplemental testosterone in the development of breast cancer and under no circumstances should testosterone be given without regular follow-ups. Testosterone replacement considerations
Variation in dosing, method of administration, and duration of treatment are important determinants of safety and efficacy. To date, the medical literature contains little data on this topic. One is left with a smattering of information to help the patient rely on hopeful but dubious information obtained on the Internet and from popular literature. Under these circumstances, a growing number of physicians involved with menopausal women’s wellness are using testosterone supplementation to provide improvement in libido and mood simply based on clinical findings and blood levels. A popular literature book The Hormone Of Desire by Susan Rako, MD, published in 1999, was followed by hundreds of articles in popular science that led to the rise of testosterone supplementation as a potentially helpful resource in the plight of aging women. Formulations
Testosterone formulations include testosterone gel (Androgel), which is not FDAapproved for women, and various compounded formulations of testosterone in cream, subcutaneous pellets, oral, and sublingual forms. In summary, though treatment with testosterone in the aging woman is gaining popularity, there is a definitive need for studies specific to this population to evaluate the safety and efficacy of testosterone as a therapeutic modality for postmenopausal women, as well as for younger women with loss of libido, to define its best use in prevention and wellness. Studies are
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needed to help determine the safest and most efficacious methods for aging females to use testosterone. Male
Testosterone is the primary androgen produced by the testes and it plays an essential role in the health of the male. Beyond determining the male sex characteristics, testosterone is a determinant of muscle strength, bone mass, libido, potency, and spermatogenesis. Androgen deficiency
Androgen deficiency includes but is not limited to symptoms of decreased body hair, reduction in muscle mass and strength, increase in fat mass, decreased hematocrit, decreased libido, erectile dysfunction, infertility, osteoporosis, depression, and mood changes. Androgen deficiency may occur secondary to testicular or pelvic trauma or surgical removal, hypogonatropic hypogonadism, or with normal aging.75 The normal aging process leads to adult hypogonadism with a decrease in levels of testosterone with age and the development of some or all of the symptoms enumerated above. The condition of androgen deficiency in aging is also known as andropause. Androgen deficiency or hypogonadism is the result of subnormal production of testosterone by the testes. Its prevalence in healthy males over the age of 40 is demonstrated in observational studies, but there is no agreed upon blood level that defines deficiency. Common causes of hypogonadism include but are not limited to: Primary testicular failure Klinefelter syndrome Cryptorchidism Orchitis Trauma HIV/AIDS Myotonic muscular deficiency Retroperitoneal fibrosis Aging Hypogonadotropic hypogonadism Kallman syndrome Prader-Willi syndrome Idiopathic hypopituitarism Pituitary tumors Suprasellar tumors Hemochromatosis Inflammatory, traumatic, vascular lesions of pituitary and hypothalamus Obesity Severe chronic illnesses Medication Andropause The risk of having low testosterone levels is significantly higher in men with hypertension (RR 1.84), hyperlipidemia (RR 1.47), diabetes (RR 2.09), obesity (RR 2.38) and asthma or chronic obstructive pulmonary disease (RR 1.40) than in men without these conditions. The prevalence of hypogonadism (defined as a total testosterone level below 300ng/dL) in 2162 men aged 45 years or older presenting to primary care offices was 38.7% in a study by Mulligan and colleagues.76
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Controversy
Perhaps the most significant controversy related to testosterone is the debate over its role in prostate health. For more than 60 years, traditional medical wisdom regarded testosterone as a significant risk factor for prostate hypertrophy and assumed that high testosterone levels served as fuel for prostate cancer. Hormone blockade and or estrogen therapy are still standard of care for prostate cancer therapy even today. Clinicians have hesitated to treat aging males with testosterone because of the belief that high levels of testosterone cause prostate cancer or speed up its growth. More than a decade ago, Shippen, Fryer, and Wright took the view that testosterone is actually protective and should be used.77 A ground-breaking study released in November 2007 provided a whole new set of data and a new perspective on testosterone.78 The results of this large-scale prospective study revealed that high endogenous levels of testosterone are associated with low mortality from all causes. The study suggests that low testosterone may be a predictive marker for those at high risk of cardiovascular disease. Shores and colleagues79 investigated the correlation between testosterone levels (defined as total testosterone <250 ng/dL or free testosterone <0.75 ng/dL) and mortality in 858 males followed for up to 8 years. The results demonstrated that men with low circulating levels of testosterone had an 88% increased risk of mortality. Benefits Cardiovascular Experimental studies suggest that androgens induce coronary vasodi-
latation. A placebo-controlled double-blind (PCDB) study performed in the United Kingdom followed 46 men with stable angina randomized to receive either a 5-mg testosterone patch or placebo in addition to their current medicines for 12 weeks. Both groups were then monitored for changes in treadmill exercise time before the onset of myocardial ischemia. The results of the treatment group compared with the placebo group were statistically significant (22% improvement in exercise time before onset of ST depression) without effect on prostate-specific antigen (PSA), hemoglobin, lipids, or coagulation profile during the duration of the study. Low-dose supplemental testosterone treatment in men with chronic stable angina increased exercise time preceding induced myocardial ischemia as defined by ST depression on EKG.80 Testosterone replacement therapy has also been proven to reduce insulin resistance, visceral adiposity, and cardiovascular risk.81–83 Additionally, a relatively low testosterone, independent of adiposity, is a risk factor for insulin resistance and type II diabetes and vice versa (insulin resistance and diabetes mellitus II are risk factors for low testosterone).84–86 Anemia Anemia is a frequent feature of male hypogonadism and antiandrogenic
therapies. In a study that evaluated hemoglobin levels in 905 persons 65 years or older, of which 31 men and 57 women had anemia, hemoglobin levels were evaluated after 3 years. The participants were patients without cancer, renal insufficiency, or antiandrogenic treatments. Statistical evaluation of the results showed that older men and women with low testosterone levels had a higher risk of anemia.87 Mood and quality of life There is a compelling need for therapies that prevent Alzheimer’s disease, defer its onset, slow its progression, and alleviate its symptoms. In a study that evaluated the effects of testosterone therapy on cognition, neuropsychiatric symptoms, and quality of life in male patients with Alzheimer’s disease and healthy elderly men, 16 male patients with Alzheimer’s disease and 22 healthy male controls were treated with testosterone and a placebo gel daily. Patients receiving testosterone had significant improvement in quality-of-life scores and the treatment was well
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tolerated. Testosterone had minimal effects on cognition and the treated group showed more numerical improvement and less decline in visuospatial functions.88 Osteoporosis and musculoskeletal Untreated hypogonadism is a prominent cause of
osteoporosis in men89 and bone mineral density significantly increases with testosterone treatment.90 Older men are as responsive to the anabolic effects of testosterone as young men. Testosterone induces skeletal muscle hypertrophy that leads to improved muscle strength in the leg as demonstrated in this study. A reciprocal change in lean and fat mass is observed but further studies are needed to determine the exact mechanism of change and the therapeutic doses needed for older men to obtain optimal results with minimum side effects.91 Libido and sexual function Treatment with testosterone improved sexual function in hypogonadal males in this very small study as measured by frequency and duration of erection and frequency of ejaculation.92–95 More studies in this important area must be undertaken to provide much-needed information. Perceived risks associated with testosterone treatments and its abuse in the areas of athletic enhancement have caused much confusion without scientific basis. Risks Prostate cancer The connection between higher testosterone levels and growth of
prostate cancer originated in 1941 with the publication of two papers by Huggins and colleagues.96,97 The data reported were based on one patient and, despite 67 years of subsequent studies that failed to establish scientific support for this theory, we are still faced with reluctance to treat men with testosterone supplementation for fear of giving them prostate cancer or fueling prostate cancer already present at a subclinical or microscopic level. More than 430,000 men were part of longitudinal studies over the course of the past 67 years, and no well-designed study has ever shown a direct correlation between total testosterone levels and prostate cancer. A 2007 review out of Harvard concluded that: Although there is yet to be a large, long term, controlled study on the effect of TRT [testosterone replacement therapy] on PCa [prostate cancer] risk, it should be abundantly clear that raising T [testosterone] in hypogonadal men has little, if any, impact on PCa risk or growth in the short to medium term. The withholding of TRT in men because of fear of PCa risk or progression is no longer tenable in an age of evidence-based medicine, because neither evidence nor theory supports this position. This article reviewed the state of the evidence and, based on the prospective longitudinal studies, concluded that ‘‘men who develop prostate cancer do not have higher baseline testosterone levels and men with higher testosterone levels are at no greater risk for developing prostate cancer than men with lower testosterone levels.’’98 The primary care physician needs to address each patient individually and decide on the use of testosterone based on more than just testosterone levels or fear of prostate cancer. Follow-up with serial blood tests and PSAs is still an important part of the clinical follow-up and should be used for the protection of the patient. Aromatase One of the most important factors affecting testosterone levels in aging men is the enzyme aromatase, which is found in fat tissue. Aromatase converts testosterone into estrogen, thus changing the ratio of estrogen to testosterone.99,100 Men who have excessive body and abdominal fat are likely to have increased estrogen
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levels caused by aromatase activity. This condition has been linked to decreased insulin sensitivity and metabolic syndrome.100 Diagnosis
When a history and symptoms of hypogonadism are clear, the diagnosis is relatively easy. However, often the patient presents with nonspecific history and symptoms and an unremarkable clinical history, making the diagnosis more difficult. Clinically, the typical adult hypogonadism patient is above 50, fatigued, has difficulty building muscle in spite of consistent workout regimen, complains of unexplained weight gain, may be mildly depressed, and may experience erectile dysfunction and loss of libido. In this clinical setting without diagnosable disease, the diagnosis of a relative age-related adult-onset hypogonadism is gaining popularity and treatment with testosterone is becoming more common in the integrative medicine and urology fields. Thus, it becomes important for the primary care physician, who is the first line of diagnosis and treatment, to feel comfortable with the use of testosterone as a viable and safe short- and medium-term option in the therapeutic armamentarium of healthy aging and wellness preservation. Understanding and considering hypogonadism in every adult aging male is an integral part of prevention and wellness. Primary testicular failure is associated with elevated follicle-stimulating hormone and luteinizing hormone levels. A baseline PSA and a complete blood cell count should be obtained before starting testosterone supplementation. Estrogen, progesterone, and dihydrotestosterone levels may also be of value. There is no agreed total or free testosterone cut-off level to define testosterone deficiency.101 Total testosterone is the most common measure of androgen activity, but is a poor indicator of tissue activity, demonstrating little correlation with clinical status, and is an unreliable indicator of response to therapy. Free testosterone is a more accurate indicator of hypogonadism,102 but normal ranges for total and free testosterone vary widely among laboratories, even among those using the same assay, and the reference ranges show little or no correlation to clinical findings.103 When testing the testosterone levels of a patient who is considering testosterone supplementation to maintain and improve wellness, it is unusual to have available prior testosterone levels when that patient was younger, healthier, and symptom free. Thus, a result that appears to be within normal range may not necessarily reflect what is normal for that particular patient. This situation must be taken into account since it emphasizes the importance of clinical assessment and patient involvement in the decision to treat. The use of population-based statistically determined normal testing ranges is also limited by the fact that the average testosterone level in men today is less than the average level in men of the same age 15 years ago. This concerning fact is possibly due to environmental suppression of the hypothalamic-pituitary-testicular axis104 and may also be a contributing factor to diminished sperm counts and increased incidence of infertility.105 Testosterone levels decrease with age and illness. Typically, men with hypogonadotropic hypogonadism have low plasma testosterone and luteinizing hormone levels. Prolactin levels should be checked if the total testosterone level is below 250 ng/dL to rule-out a pituitary tumor. Fifty percent of circulating testosterone is bound to sex hormone–binding globulin, which directly affects free testosterone levels. Free testosterone levels can be obtained to clarify testosterone status. However, variations are greater among free testosterone assays than among total testosterone assays. Also, reference ranges are not as standardized for free testosterone assays as they are for total testosterone
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assays. When borderline levels of testosterone are found, or the clinical picture and the blood tests disagree, a low or low-normal free or total testosterone level may be used to support a clinical diagnosis of androgen deficiency, but should not be used to exclude it.101 Treatment
Testosterone supplementation has gained popularity over the past 20 years. The benefits of testosterone supplementation include improved energy, greater muscle mass, increased stamina, greater strength, increased confidence, greater motivation, and enhanced libido.102–106 Present formulations of testosterone include the following: Testosterone gel (Androgel) Testosterone patches (Androderm) Compounded testosterone creams or gels Injectable testosterone Subcutaneous testosterone implants Monitoring
While it is useful to follow PSA levels during the course of testosterone replacement and supplementation, it is more important to track the velocity PSA increase. There is often a slight bump, a rise above 4.0 ng/mL, or a sudden increase in PSA with the initiation of testosterone therapy, followed by a stable constant level. An increase in PSA more than 0.35 ng/mL per year warrants further evaluation and a referral to the urologist.107 While using testosterone in disease prevention and wellness is relatively new to the primary care field, it holds much promise and meets with much support and enthusiasm from patients. The data we reviewed and our clinical experience support the use of testosterone as a first-line hormone supplementation in the aging male. More research is needed to substantiate and define the parameters necessary for its long-term use. For now, as the esteemed Dr. Morgantaler said: . the diagnosis of androgen deficiency requires only an ear attuned to the characteristic symptoms and blood test providing evidence of reduced levels of total or free testosterone. Treatment provides an opportunity for gratifying results, for patients and clinicians alike.108
GROWTH HORMONE
As the proportion of aging people continues to rapidly rise, reducing the burden of age-related diseases becomes increasingly important in primary care. A controversial hormone that is center stage in the debate over the use of hormone therapies in prevention and wellness is growth hormone. Growth hormone, a single-chain polypeptide produced in the pituitary gland, has a wide range of metabolic and cellular effects. Growth hormone plays an important role in the regulation of body composition, lipid profiles, tissue repair, cardiac and neuronal functioning, and maintenance of bone mineral density. Growth hormone is secreted in pulsatile fashion, especially during stage III and IV deep sleep. It acts on liver and other tissues to stimulate the production of insulinlike growth factors (IGFs), including IGF-1, which is also known as somatomedin C, and the production of IGF-binding proteins (IGFBPs), which also have direct cellular actions. The most abundant IGFBP is IGFBP-3.
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A large percentage of growth hormone effects are mediated through IGF-1. Because of the pulsatile nature of growth hormone production and short half-life (20–50 minutes), routine serum growth hormone levels cannot be used to determine overall production. While there are many influences on the production of IGF-1, levels correlate with overall growth hormone production, are relatively stable in the serum, and are currently the best estimate of growth hormone production and effect. While a low IGF-1 is a strong indicator of abnormally low growth-hormone production, an IGF-1 level in the normal reference range does not rule out deficiency.109 While there is considerable variation in growth hormone production among individuals of the same age, there is a progressive decline in average growth-hormone production and IFG-1 levels after age 20, with average levels declining by 30% to 60% by age 40 to 60, and by 50% to 80% after age 60.110–114 Low growth-hormone levels and production are associated with low quality of life as measured by numerous criteria, including the Nottingham Health Profile and the Psychologic General Well-Being Index.113,115–118 Gibney and colleagues119 reviewed 10 years of use of growth hormone in adult growth-hormone deficient patients and found it to be of significant benefit. A large number of peer-reviewed research, including long-term randomized controlled trial data, has demonstrated that growth hormone replacement improves energy,119,120 strength,119 cardiac function,121–123 blood pressure,124 cholesterol levels,124–126 insulin sensitivity124,127 cognitive function,128,129 immunity,130,131 and psychologic well-being;113,116,118,126 decreases body fat;121,124,125,127–133 increases lean muscle;121,124,132 prevents and reverses heart disease;121,134,135 prevents and improves osteoporosis;121,125,136 and improves quality of life.116,118,119,126 Controversy
Controversial issues regarding growth hormone supplementation include the use of growth hormone as a therapeutic modality for age-related deficiency; the accuracy and necessity of commonly used stimulation testing when considering growth hormone usage in well patients; the need for guidelines for safe and effective treatment; and potential side effects of treatment. Diagnostic Testing
The diagnosis of growth hormone deficiency is difficult for a number of reasons. As discussed, random serum growth-hormone levels are not indicative of the overall growth hormone production and, while IGF-1 levels do correlate with overall growth hormone production, IGF-1 levels lack sensitivity to detect significant deficiency (IGF-1 levels are often in the normal range even if a significant deficiency exists). With growth hormone stimulation testing, serum growth-hormone levels are measured after a variety of agents and protocols are used to stimulate the release of growth hormone from the pituitary. Such tests are often promoted as the means of differentiating growth hormone deficiency from normal state. Many endocrinologists believe the diagnosis of adult growth-hormone deficiency can only be made with the use of growth hormone stimulation testing. Such testing has proven to be inaccurate, highly variable, nonphysiologic, and lacking adequate sensitivity to detect relative growth-hormone deficiencies. The use of arbitrary cutoffs to define abnormality does not correlate with response to therapy.137–145 Studies demonstrate that using the same agent to perform stimulation tests multiple times on one patient do not consistently produce congruous results, thus bringing the usefulness of the test into question.138,139 Side effects of stimulation testing include significant hypotension, venous thrombosis, nausea, and vomiting.129 Deaths and neurologic damage have also been reported.134
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Because stimulation tests are clinically and physiologically unreliable, they are also unreliable for determining growth hormone deficiency. Currently the most appropriate means of diagnosing age-related growth-hormone deficiency is clinical recognition and a low-normal (below the mean) IGF-1 level. Clinical Diagnosis
The adult age-related clinical syndrome of growth hormone deficiency includes increased fat mass, decreased muscle mass and strength, decreased bone density, elevated lipids, insulin resistance, decreased psychosocial well-being and depression, fatigue, increased social isolation, inability to handle stress, cardiovascular disease, memory decline, overall deterioration in quality of life, frailty, thin dry skin, increased wrinkles, and diminished exercise tolerance. Clinicians commonly encounter these clinical symptoms in the aging patient. If considered appropriate by physician and patient, a 6-month therapeutic trial with growth hormone could be considered, dosed to keep IGF-1 levels in the upper quartile. Patients should be evaluated for symptomatic and metabolic improvements at a minimum at 3 and 6 months to decide if treatment should be continued. Treatment
The treatment of age-related adult growth-hormone deficiency remains controversial even though the literature reports significant benefits from growth hormone supplementation. The main sources of concern associated with growth hormone replacement in somatopause include, in no particular order, significant cost of therapy from $250 to $1500 per month (depending on dose and manufacturer), side effects of water retention resulting in joint pain and carpal tunnel syndrome, temporary reduction in insulin sensitivity, and theoretic risk of cancer. Most short-term side effects are diminished with reduction in dose.146–148 While there is a long-held theoretic belief of an increased risk of cancer, based on the growth hormone’s antiapoptotic and mitogenic effects, neither long-term nor short-term data support this theory. Conflicting data on the relationship between IGF-1 levels and the risk of cancer abound. Some frequently cited epidemiologic studies have found an increased correlation between elevated IGF-1 and breast,149 prostate,150 and colorectal cancers,151 while the majority of studies failed to document increased risk of cancer (or have shown a decreased risk) with increasing IGF-1 levels.152–165 In addition, one frequently cited study that did connect increased IGF-1 levels and cancer, by Chan and colleagues,150 is very controversial because the blood was stored for 5 to 15 years before it was tested. Also, IGF-1 levels in the highest quartile group were over three times the upper limit of normal for this age group, suggesting that IGF-1 in the patients studied may not have been measured accurately. Hankinson and colleagues149 found a trend for decreased risk of breast cancer in postmenopausal women with increased IGF-1 levels but an increased risk in premenopausal women. Palmqvist and colleagues151 reported increased association between IGF-1 and colon cancer, but a decreased risk of rectal cancer. The secretion and regulation of IGF-1 is extremely complex and their reported association with cancer must also take into consideration numerous other potential confounding etiologic factors, whether environmental, nutritional, or other yet unidentified. Growth hormone stimulates the production of IGFBP-3, which has cancerprotective characteristics and may counteract increased risk of cancer associated with an increase in IGF-1, if present. There is evidence that tumors secrete IGF-1, which makes it a potential marker for cancer in some individuals and not necessarily a cause. Typical growth hormone supplementation for an age-related deficiency
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results in small increases in IGF-1 that remain in the normal age-matched references range, so risk would not be expected to be different than that for controls. None of the long- and short-term studies have shown an increased risk of cancer, recurrent or de novo, with the use of growth hormone,166–177 and some of the studies have shown a decreased risk. Among these studies are studies on more than 19,000 children representing of 47,000 patient years of growth hormone treatment;176 a prospective study of 100 adult growth hormone–deficient patients followed for 1 to 4 years,177 a study of 910 children treated with growth hormone for 11 years,175 a study of 32 adults and children followed for up to 40 years treated with growth hormone (average 10.8 years);166 a study of 180 growth hormone–treated children followed for over 6 years with reduced cancer recurrence risk (RR 0.6);169 a prospective analysis of 289 growth hormone–deficient adults who, after 5 years of growth hormone therapy, showed lower risk of malignancy (RR 0.25) and decreased risk of myocardial infarction (RR 0.19) and early mortality (RR 0.22) compared with the untreated group.172 In 2001, the consensus statement by the Growth Hormone Research Society noted that the data demonstrate that the concern for increasing the risk of cancer with the use of growth hormone is unfounded: The current labeling for GH [growth hormone] states that active malignancy is a contraindication of GH treatment. There are, however, no data to support this labeling. Current knowledge does not warrant additional warning about cancer risk on the product label. Supraphysiologic doses of growth hormone are shown to antagonize the effects of insulin. While short-term studies using large doses of growth hormone may potentially worsen insulin resistance,178 low physiologic doses of growth hormone have demonstrated improvement in insulin resistance and decreased risk of diabetes.179–182 If treatment is contemplated, low physiologic doses should be used to keep IGF-1 in the upper limit of normal. In conclusion, aging adults have a relative deficiency of growth hormone and supplementation with growth hormone may be of significant benefit. A clinical diagnosis of growth hormone deficiency can be made with support of low-normal IGF-1 levels alone. Although no long-term studies have assessed side effects with low physiologic doses of growth hormone supplementation in somatopause, the studies we reviewed above have confirmed that low doses, titrated to keep IGF-1 levels in the upper limit of normal, are safe, well tolerated, and associated with a plethora of clinical benefits. Treatment with growth hormone is presently limited to an affluent and highly motivated population. Cost and risk/benefit ratio over time must be taken into consideration. As our patients age, the challenge of maintaining quality of life for them becomes more difficult and must be considered in the design of future studies. For supplementation with growth hormone to become a first-line therapeutic option in the aging population, additional and more extensive randomized trials that evaluate results of growth hormone treatment in age-related deficiency must be undertaken, and cost factors must be addressed. THYROID
Hypothyroidism is a common disorder with inadequate amounts of thyroid hormone present at the cellular level. Typical symptoms include fatigue, weakness, weight gain, cold intolerance, muscle aches, headaches, decreased libido, depression, hair
Hormones in Wellness and Disease Prevention
loss, and dry skin. Signs include edema, dry skin, pallor, hair loss, loss of temporal eyebrow hair, and cold extremities. Conditions associated with hypothyroidism include hypertension, atherosclerosis, hypercholesterolemia, hyperhomocysteinemia, menstrual irregularities, infertility, premenstrual syndrome, chronic fatigue syndrome, fibromyalgia, fibrocystic breasts, polycystic ovary syndrome, depression, diabetes, and insulin resistance. There is a two- to threefold increase in the incidence of thyroid dysfunction with age, including overt and subclinical hypothyroidism (elevated thyrotropin with normal thyroxine and triiodothyronine levels).183 There is also an age-related decrease in thyroid function that results in diminished tissue thyroid levels and may result in clinically symptomatic hypothyroidism that is not detected with the standard use of thyrotropin, thyroxine, or triiodothyronine levels. Historically, an elevated thyrotropin with normal thyroxine and triiodothyronine levels has been considered compensated or subclinical hypothyroidism and diagnosed as euthyroid with no requirement for treatment. A plethora of studies have, however, demonstrated that, in spite of the normal triiodothyronine and thyroxine values, subclinical and nondiagnosed hypothyroidism is often associated with significant symptoms and an increased risk of morbidity and mortality.184–211 In light of this, it has been proposed that the term subclinical hypothyroidism be replaced by the term mild thyroid failure (MTF).184 The diagnosis of MTF is particularly important in the aging population in the areas of prevention and wellness. MTF is a treatable condition associated with increased cardiovascular risk and numerous signs and symptoms that might otherwise be attributed to ‘‘usual’’ signs and symptoms of aging, including fatigue, depression, memory loss, cognitive dysfunction, dry skin, constipation, leg cramps, cold intolerance, weakness, water retention, diminished sweating, weight gain, and diminished exercise tolerance.184–211 Significant improvements may occur with treatment.185,190,192,193,196,198,202 Numerous studies have demonstrated increased cholesterol levels in patients with MTF.184,202,206,207,211 Thyroid replacement results in a significant reduction in the cholesterol levels.205–207 In addition to the increase in total and low-density cholesterol seen with MTF, endothelial dysfunction with impaired vasodilatation have also been demonstrated, further increasing the risk of cardiovascular events.210 The Rotterdam study investigated the association between MTF and aortic atherosclerosis and myocardial infarction in 1149 menopausal women. After adjustment for multiple known coronary artery disease risk factors, the investigators found that MTF significantly increased the risk for arthrosclerosis (odds ratio 1.9) and myocardial infarction (odds ratio 3.1).204 This important study found that subclinical hypothyroidism was a greater risk for myocardial infarction than hypercholesterolemia, hypertension, smoking, or even diabetes, and that MTF was a contributing factor in 60% of the myocardial infarctions in the patients studied. In a 20-year longitudinal study, Walsh and colleagues211 also examined the association between MTF, cardiovascular disease, and mortality in over 2000 individuals (approximately half men and half women) with a mean age of 50 years (age range 17–89). In this study, MTF was associated with a 2.2-fold increased risk of coronary artery disease and 1.5-fold increased risk of cardiovascular mortality after adjustment for multiple known cardiovascular risk factors. Diagnostic Testing
Thyrotropin is considered the most sensitive marker of peripheral tissue levels of thyroid hormone, and it is widely assumed that thyrotropin levels within the normal
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range indicate the person is euthyroid. With significant physiologic stress, illness, inflammation and aging, however, there is demonstrable suppression of thyrotropin, making the thyrotropin test unreliable.212–231 With significant physiologic stress, illness, inflammation, and aging, tissue-specific alterations also reduce tissue triiodothyronine levels by reducing uptake of thyroxine into tissues and decreasing thyroxine-to-triiodothyronine conversion.217–228 The decreased serum thyroxine levels caused by the suppressed thyrotropin production is offset to varying degrees by the diminished uptake of thyroxine into the cell and the decreased thyroxine-to-triiodothyronine conversion. This situation tends to be misread as an indication of adequate tissue thyroid levels and makes thyroxine levels of little use, except in extreme cases.223–225 With physiologic stress, inflammation, illness, and aging, the correlation between serum thyrotropin and thyroxine levels and peripheral thyroid activity no longer follows.212–231 Thyrotropin and thyroxine levels cannot be relied upon to detect diminished cellular triiodothyronine levels for aging patients and patients under stress. Instead of thyroxine normally converting intracellular to the active triiodothyronine in peripheral tissue, thyroxine is preferentially converted to reverse triiodothyronine. Serum reverse triiodothyronine levels may be useful because diminished cellular uptake of thyroxine, diminished thyroxine-to-triiodothyronine conversion, and diminished cellular triiodothyronine levels inversely correlate with serum reverse triiodothyronine levels.212,222,223,225,229,230 When the physiologic stress or illness is acute and severe, the significantly diminished thyroid levels in the peripheral tissues no longer correlate with thyrotropin levels. This is termed nonthyroidal illness or euthyroid sick syndrome. In these cases, the thyrotropin level cannot be relied upon as an accurate measure of tissue thyroid effect.212,213,226 The same physiologic changes also occur with chronic physiologic stress, chronic illness, inflammation, calorie reduction, and aging.216–245 Changes can be metabolically significant and can cause serious symptoms. Treatment may be warranted despite normal thyrotropin and thyroxine levels.224,235,246,247 The use of thyroxine preparations in the treatment of nonthyroidal illness found in acute conditions, such as trauma, surgery, and sepsis, has shown little benefit. The ineffectiveness of thyroxine preparations in these cases is most likely due to the diminished use and uptake of thyroxine in these conditions. In contrast, treatment with triiodothyronine has proven quite beneficial in studies of severely ill patients,247–252 as well as in chronic conditions,246,253–255 which correlate well to the aging patient. Similar to significant physiologic stress and illness, aging is associated with significant alterations in the hypothalamic-pituitary-thyroid axis that result in a reduction of thyrotropin levels244,250 (in contrast to MTF’s increase in thyrotropin) while tissue-specific alterations reduce the supply of triiodothyronine (via reduced thyroxine-to-triiodothyronine conversion and reduced uptake of thyroxine) to the body tissues.244,256–262 With aging, as with nonthyroidal illness, thyrotropin and thyroxine are not indicative of tissue levels of triiodothyronine, making the interpretation of thyroid function tests increasingly complicated and difficult. Aging may be considered a chronic nonthyroidal illness leading to decrease in basal metabolic rate259,263,264 and reduction in thyrotropin and triiodothyronine levels without a significant decrease in thyroxine and free thyroxine244,256–258,261,262 (Fig. 2). Elevation in reverse triiodothyronine level is also seen240,244,265,266 as a consequence of diminished use of thyroxine, diminished thyroxine-to-triiodothyronine conversion, and diminished tissue levels of triiodothyronine.212,222,223,225,232 Another finding in the aging patient is the significantly reduced thyrotropin response to thyrotropin-releasing hormone
Hormones in Wellness and Disease Prevention
Fig. 2. Age-dependent variations in (A) free thyroxine (FT4), (B) free triiodothyronine (FT3), and (C) thyrotropin (TSH). All healthy subjects in the study (groups A–C) were pooled for this analysis. (From Mariotti S, Barbesino G, Caturegli P, et al. Complex alteration of thyroid function in healthy centenarians. J Clin Endocrinol Met 1993;77(5):1132; with permission. Copyright ª 1993, The Endocrine Society.)
that is similar to that found in severely ill patients with documented nonthyroidal illness.260,262,267 Further contributing to potential inaccuracies of standard thyroid testing in this population is the increasing incidence of systemic illness and the increased use of medications that directly affect thyroid function. In aging patients who present with
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symptoms consistent with hypothyroidism but have a normal thyrotropin and thyroxine level, obtaining free triiodothyronine, reverse triiodothyronine, and triiodothyronine/reverse-triiodothyronine ratios may help obtain a more accurate evaluation of tissue thyroid status and may be useful to predict those who may respond favorably to triiodothyronine supplementation.212,222,223,225,232 The inaccuracy of thyrotropin and thyroxine levels in this potentially large group of individuals, including those with chronic physiologic stress, illness, and advancing age, has potentially profound implications. Studies that do not address the complex interactions of the aging thyroid and illness and use thyrotropin and thyroxine levels alone to determine thyroid status may be significantly flawed. With increasing knowledge of the complexities of thyroid function at the cellular level, it is becoming increasingly clear that the thyrotropin may not be as reliable a marker of tissue thyroid levels as once thought, especially with chronic physiologic stress, illness, inflammation, and aging. It is possible that many symptomatic patients with low tissue levels of active thyroid but normal thyrotropin and thyroxine levels would benefit from thyroid replacement both short and long term. Increasing evidence shows that thyroxine is not an optimal treatment for conditions associated with diminished use of thyroxine. Conversion of thyroxine to triiodothyronine (increased formation of reverse triiodothyronine) should lead the clinician to consider treatment with triiodothyronine. Thyroid Preparations
Thyroid preparations include triiodothyronine (Cytomel); thyroxine (Synthroid, Levothyroxine); combinations of triiodothyronine, thyroxine; and compounded thyroid formulations (including thyroxine/triiodothyronine and timed-released triiodothyronine preparations). Further studies are needed regarding the use of triiodothyronine preparations in the aging population and long-term outcomes based on treatment strategies that use improved methods for determining tissue thyroid levels instead of sole reliance on thyrotropin testing. With so much potential for inaccuracy in our present standard thyroid testing, the importance of additional or alternative methods for clinical assessment cannot be overemphasized. New methods of determining tissue levels of thyroid in the aging patient must be developed and used to better assess both short-term and long-term treatment effects and to help the primary practitioner assess tissue thyroid activity in the aging patient with symptoms and normal thyrotropin, thyroxine, and triiodothyronine levels.
SUMMARY
In summary, we believe the well-informed use of hormones in wellness and disease prevention will result in symptomatic improvement and should be considered an integral part in the armamentarium of options we offer our patients. Definitions and testing of hormone deficiency that apply to illnesses do not apply to wellness and prevention and need to be reevaluated while we develop new treatment paradigms to best care for our patients. With the limited amount of research focused primarily on the areas of wellness and prevention, we must acknowledge the infinite number of variables that confound the results of every study. Ultimately we must focus on the individual patient and his or her need and that is the area where the doctor–patient relationship is of utmost importance and is the key to true prevention and wellness.
Hormones in Wellness and Disease Prevention
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n T, et al. Malignant disease and cardiovascu172. Svensson J, Bengtsson BA˚, Rose lar morbidity in hypopituitary adults with or without hormone replacement therapy. J Clin Endocrinol Metab 2004;89(7):3306–12. 173. Shalet SM, Brennan BM, Reddingius RE. Growth hormone therapy and malignancy. Horm Res 1997;48(Suppl 4):29–32. 174. Pollak M. Insulin-like growth factors and prostate cancer. Epidemiol Rev 2001; 23(1):59–66. 175. Leung W, Zhou Y, Hancock ML, et al. Outcomes of growth hormone replacement therapy in survivors of childhood acute lymphoblastic leukemia. J Clin Oncol 2002;20(13):2959–64. 176. Blethen SL, Allen DB, Graves D, et al. Safety of recombinant deoxyribonucleic acid–derived growth hormone: the national cooperative growth study experience. J Clin Endocrinol Metab 1996;81:1704–10. 177. Frajese G, Drake WM, Loureiro RA, et al. Hypothalamopituitary surveillance imaging in hypopituitary patients receiving long-term GH replacement therapy. J Clin Endocrinol Metab 2001;86(11):5572–5. 178. Blackman M, Sorkin DJ, Munzer T, et al. Growth hormone and sex steroid administration in healthy aged women and men: a randomized controlled trial. JAMA 2002;288(18):2282–92. 179. Yuen KC, Frystyk J, White DK, et al. Improvement in insulin sensitivity without concomitant changes in body composition and cardiovascular risk markers following fixed administration of a very low growth hormone (GH) dose in adults with severe GH deficiency. Clin Endocrinol (Oxf) 2005;63(4):428–36. 180. Yuen KC, Dunger DB. Impact of treatment with recombinant human GH and IGF-1 on visceral adipose tissue and glucose homeostasis in adults. Growth Horm IGF Res 2006;16:S55–61. 181. Svensson J, Fowelin J, Landin K, et al. Effects of seven years of GHreplacement therapy on insulin sensitivity in GH-deficient adults. J Clin Endocrinol Metab 2002;87:2121–7. 182. Ahn C, Kim C, Nam J, et al. Effects of growth hormone on insulin resistance and atherosclerotic risk factors in obese type 2 diabetic patients with poor glycaemic control. Clin Endocrinol 2006;64:444–9. 183. Canaris GJ, Manowitz NR, Mayor G, et al. The Colorado thyroid disease prevalence study. Arch Intern Med 2000;160:526–34. 184. Mcdermott MT, Ridgway C. Subclinical hypothyroidism is mild thyroid failure and should be treated. J Clin Endocrinol Met 2001;86(10):4585–90. 185. Monzani F, Del Guerra P, Caraccio N, et al. Subclinical hypothyroidism: neurobehavioral features and beneficial effect of l-thyroxine treatment. Clin Invest 1993;71:367–71. 186. Tappy L, Randin JP, Schwed P, et al. Prevalence of thyroid disorders in psychogeriatric inpatients. A possible relationship of hypothyroidism with neurotic depression but not dementia. J Am Geriatr Soc 1987;35:526–31. 187. Joffe RT, Levitt AJ. Major depression and subclinical (grade 2) hypothyroidism. Psychoneuroendocrinology 1992;17:215–21. 188. Haggerty JJ Jr, Stern RA, Mason GA, et al. Subclinical hypothyroidism: a modifiable risk factor for depression? Am J Psychiatry 1993;150(3):508–10. 189. Manciet G, Dartigues JF, Decamps A, et al. The PAQUID survey and correlates of subclinical hypothyroidism in elderly community residents in the southwest of France. Age Ageing 1995;24:235–41. 190. Baldini IM, Vita A, Maura MC, et al. 1997 Psychological and cognitive features in subclinical hypothyroidism. Prog Neurophychopharmacol Biol Psychiatry 1997; 21:925–35.
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191. Ganguli M, Burmeister LA, Seaberg EC, et al. Association between dementia and elevated TSH: a community-based study. Biol Psychiatry 1996;40:714–25. 192. Monzani F, Caraccio N, Siciliano G, et al. Clinical and biochemical features of muscle dysfunction in subclinical hypothyroidism. J Clin Endocrinol Metab 1997;82:3315–8. 193. Monzani F, Caraccio N, Del Guerra P, et al. Neuromuscular symptoms and dysfunction in subclinical hypothyroid patients: beneficial effect of L-T4 replacement therapy. Clin Endocrinol 1999;51:237–42. 194. Misiunas A, Ravera HN, Faraj G, et al. Peripheral neuropathy in subclinical hypothyroidism. Thyroid 1995;5:283–6. 195. Goulis DG, Tsimpiris N, Delaroudis S, et al. Stapedial reflex: a biological index found to be abnormal in clinical and subclinical hypothyroidism. Thyroid 1998; 8:583–7. 196. Ridgway EC, Cooper DS, Walker H, et al. Peripheral responses to thyroid hormone before and after L-thyroxine therapy in patients with subclinical hypothyroidism. J Clin Endocrinol Metab 1981;53:1238–42. 197. Cooper DS, Halpern R, Wood LC, et al. l-thyroxine therapy in subclinical hypothyroidism. Ann Intern Med 1984;101:18–24. 198. Nystrom E, Caidahl K, Fager G, et al. A double-blind cross-over 12-month study of L-thyroxine treatment of women with ‘subclinical’ hypothyroidism. Clin Endocrinol 1988;29:63–76. 199. Bell GM, Todd WT, Forfar JC, et al. End-organ responses to thyroxine therapy in subclinical hypothyroidism. Clin Endocrinol (Oxf) 1995;22:83–9. 200. Forfar JC, Wathen CG, Todd WT, et al. Left ventricular performance in subclinical hypothyroidism. QJM 1985;57:857–65. 201. Foldes J, Istvanfy M, Halmagyi M, et al. Hypothyroidism and the heart. Examination of left ventricular function in subclinical hypothyroidism. Acta Med Hung 1987;44:337–47. 202. Kahaly GJ. Cardiovascular and atherogenic aspects of subclinical hypothyroidism. Thyroid 2000;10:665–79. 203. Monzani F, Di Bello V, Caraccio N, et al. Effect of levothyroxine on cardiac function and structure in subclinical hypothyroidism: a double blind, placebocontrolled study. J Clin Endocrinol Metab 2001;86:1110–5. 204. Hak EA, Pols HA, Visser TJ, et al. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam study. Ann Intern Med 2000;4:270–8. 205. Tanis BC, Westendorp RGJ, Smelt AHM. Effect of thyroid substitution on hypercholesterolaemia in patients with subclinical hypothyroidism: a re-analysis of intervention studies. Clin Endocrinol 1996;44:643–9. 206. Danese MD, Ladenson PW, Meinert CL, et al. Effect of thyroxine therapy on serum lipoproteins in patients with mild thyroid failure: a quantitative review of the literature. J Clin Endocrinol Metab 2000;85:2993–3001. 207. Michalopoulou G, Alevizaki M, Piperingos G, et al. High serum cholesterol levels in persons with ‘high normal’ TSH levels: Should one extend the definition of subclinical hypothyroidism. Eur J Endocrinol 1998;138:141–5. 208. Bindels AJ, Westendorp RG, Frolich M, et al. The prevalence of subclinical hypothyroidism at different total plasma cholesterol levels in middle aged men and women: a need for case-finding? Clin Endocrinol 1999;50:217–20. 209. Bakker SJL, Ter Matten JC, Popp-Snijders C, et al. The relationship between thyrotropin and low density lipoprotein cholesterol is modified by insulin sensitivity in healthy euthyroid subjects. J Clin Endocrinol Metab 2001;86:1206–11.
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210. Lekakis J, Papamichael C, Alevizaki M, et al. Flow-mediated, endotheliumdependent vasodilatation is impaired in subjects with hypothyroidism, borderline hypothyroidism, and high-normal serum thyrotropin (TSH) values. Thyroid 1997;7:411–4. 211. Walsh JP, Bremner AP, Bulsara MK, et al. Subclinical thyroid dysfunction as a risk factor for cardiovascular disease. Arch Intern Med 2005;165(21):2467–72. 212. Peeters RP, Geyten SV, Wouters PJ, et al. Tissue thyroid hormone levels in critical illness. J Clin Endocrinol Metab 2005;12:6498–507. 213. Docter R, Krenning EP, de Jong M, et al. The sick euthyroid syndrome: changes in thyroid hormone serum parameters and hormone metabolism. Clin Endocrinol (Oxf) 1993;39:499–518. 214. Fliers E, Alkemade A, Wiersinga WM. The hypothalamic-pituitary-thyroid axis in critical illness. Best Practice & Research Clinical Endocrinology & Metabolism 2001;15(4):453–64. 215. Chopra IJ. Euthyroid sick syndrome: Is it a misnomer? J Clin Endocrinol Metab 1997;82(2):329–34. 216. van der Poll T, Romijn JA, Wiersinga WM, et al. Tumor necrosis factor: a putative mediator of the sick euthyroid syndrome in man. J Clin Endocrinol Metab 1990; 71(6):1567–72. 217. Stouthard JM, van der Poll T, Endert E, et al. Effects of acute and chronic interleukin-6 administration on thyroid hormone metabolism in humans. J Clin Endocrinol Metab 1994;79(5):1342–6. 218. Corssmit EP, Heyligenberg R, Endert E, et al. Acute effects of interferon-alpha administration on thyroid hormone metabolism in healthy men. Clin Endocrinol Metab 1995;80(11):3140–4. 219. Nagaya T, Fujieda M, Otsuka G, et al. A potential role of activated NF-Kappa B in the pathogenesis of euthyroid sick syndrome. J Clin Invest 2000;106(3): 393–402. 220. Bianco AC, Salvatore D, Gereben B, et al. Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodieidinases. Endocr Rev 2002;23:38–89. 221. Chopra IJ, Huang TS, Beredo A, et al. Evidence for an inhibitor of extrathyroidal conversion of thyroxine to 3,5,3’-triiodothyronine in sera of patients with nonthyroidal illnesses. J Clin Endocrinol Metab 1985;60:666–72. 222. Peeters RP, Wouters PJ, Kaptein E, et al. Reduced activation and increased inactivation of thyroid hormone in tissues of critically ill patients. J Clin Endocrinol Metab 2003;88:3202–11. 223. Chopra IJ, Chopra U, Smith SR, et al. Reciprocal changes in serum concentrations of 3,3’,5-triiodothyronine (T3) in systemic illnesses. J Clin Endocrinol Metab 1975;41:1043–9. 224. Iervasi G, Pinitore A, Landi P, et al. Low-T3 syndrome a strong prognostic predictor of death in patients with heart disease. Circulation 2003;107(5): 708–13. 225. Peeters RP, Wouters PJ, van Toor H, et al. Serum 3,3’,5’-triiodothyronine (rT3) and 3,5,3’-triiodothyronine/rT3 are prognostic markers in critically ill patients and are associated with postmortem tissue deiodinase activities. J Clin Endocrinol Metab 2005;90(8):4559–65. 226. Wartofsky L, Burman K. Alterations in thyroid function in patients with systemic illness; the ‘‘euthyroid sick syndrome’’. Endocr Rev 1982;3(2):164–217. 227. Hennemann G, Everts ME, de Jong, et al. The significance of plasma membrane transport in the bioavailability of thyroid hormone. Clin Endocrinol 1998;48:1–8.
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228. Vos RA, de Jong M, Bernard HF, et al. Impaired thyroxine and 3,5,3’-triodothyronine handling by rat hepatocytes in the presence of serum of patients with nonthryoidal illness. J Clin Endocrinology met 1995;80:2364–70. 229. Chopra IJ, Solomon DH, Hepner GW, et al. Misleadingly low free thyroxine index and usefulness of reverse triiodothyronine measurement in nonthyroidal illnesses. Ann Intern Med 1979;90(6):905–12. 230. De Jong M, Docter R, Van Der Hoek HJ, et al. Transport of 3,5,3’-triiodothyronine into the perfused rat liver and subsequent metabolism are inhibited by fasting. Endocrinology 1992;131:463–70. 231. Mooradian AD, Reed RL, Osterweil D, et al. Decreased serum triiodothyronine is associated with increased concentrations of tumor necrosis factor. J Clin Endocrinol Metab 1990;71(5):1239–42. 232. de Jong F, den Heijer T, Visser TJ, et al. Thyroid hormones, dementia, and atrophy of the medical temporal lobe. J Clin Endocrinol Met 2006;91(7): 2569–73. 233. Carrero JJ, Qureshi AR, Axelsson J, et al. Clinical and biochemical implications of low thyroid hormone levels (total and free forms) in euthyroid patients with chronic kidney disease. J Intern Med 2007;262:690–701. 234. Zoccali C, Tripepi G, Cutrupi S, et al. Low triiodothyronine: a new facet of inflammation in end-stage renal disease. J Am Soc Nephrol 2005;16:2789–95. 235. Zoccali C, Mallamaci F, Tripepi G, et al. Low triiodothyronine and survival in endstage renal disease. Kidney Int 2006;70:523–8. 236. Naslund E, Andersson I, Degerblad M, et al. Associations of leptin, insulin resistance and thyroid function with long-term weight loss in dieting obese men. J Int Med 2000;248:299–308. 237. Pingitore A, Landi P, Taddei MC, et al. Triiodothyronine levels for risk stratification of patients with chronic heart failure. Am J Med 2005;118(2):132–6. 238. Kozdag G, Ural D, Vural A, et al. Relation between free triiodothyronine/free thyroxine ratio, echocardiographic parameters and mortality in dilated cardiomyopathy. Eur J Heart Fail 2005;7(1):113–8. 239. Karadag F, Ozcan H, Karul AB, et al. Correlates of non-thyroidal illness syndrome in chronic obstructive pulmonary disease. Respir Med 2007;101: 1439–46. 240. Kok P, Roelfsema F, Langendonk JG, et al. High circulating thyrotropin levels in obese women are reduced after body weight loss induced by caloric restriction. J Clin Endocrinol Metab 2005;90:4659–63. 241. Ohyama T, Aono T, Nakai A, et al. Circulation free T3 in pregnancy, liver disease, diabetes mellitus and thyroid disease. Nippon Naibunpi Gakkai Zasshi 1984;60: 1227–34. 242. Parr JH. The effect of long-term metabolic control on free thyroid hormone levels in diabetics during insulin treatment. Ann Clin Biochem 1987;24(5):466–9. 243. Dimopoulou I, Ilias I, Mastorakos G, et al. Effects of severity of chronic obstructive pulmonary disease on thyroid function. Metabolism 2001;50(12):1397–401. 244. Mariotti S, Barbesino G, Caturegli P, et al. Complex alterations of thyroid function in healthy centenarians. J Clin Endocrinol Met 1993;77(5):1130–4. 245. Nomura S, Pittman CS, Chambers JB, et al. Reduced peripheral conversion of thyroxine to triiodothyronine in patients with hepatic cirrhosis. J Clin Invest 1975; 56:643–8. 246. Pingitore A, Galli E, Barison A, et al. Acute effects of triiodothyronine replacement therapy in patients with chronic heart failure and low T3 syndrome: a randomized placebo-controlled study. J Clin Endocrinol Met 2008;93:1351–8.
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247. Dulchavsky SA, Kennedy PR, Geller ER, et al. T3 preserves respiratory function in sepsis. J Trauma 1991;31:753–9. 248. Hesch RD, Husch M, Kodding R, et al. Treatment of dopamine-dependent shock with triiodothyronine. Endocr Res Commun 1981;8:299–301. 249. Dulchavsky SA, Hendrick SR, Dutta S. Pulmonary biophysical effects of triidothyronine (T3) augmentation during sepsis-induced hypothyroidism. J Trauma 1993;35:104–9. 250. Meyer T, Husch M, van den Berg E, et al. Treatment of dopamine-dependent shock with triiodothyronine: preliminary results. Dtsch Med Wochenschr 1979; 104:1711–4. 251. Novitzky D, Cooper DK, Reichart B. Hemodynamic and metabolic responses to hormonal therapy in brain-dead potential organ donors. Transplantation 1987; 43:852–5. 252. Dulchavsky SA, Maitra SR, Maurer J, et al. Beneficial effects of thyroid hormone administration on metabolic and hemodynamic function in hemorrhagic shock. FASEB J 1990;4:A952. 253. Hamilton MA, Stevenson LW, Fonarow GC, et al. Safety and hemodynamic effects of intravenous triiodothyronine in advanced congestive heart failure. Am J Cardiol 1998;81:443–7. 254. Klemperer JD, Klein IL, Ojamaa K, et al. Triidothyronine therapy lowers the incidence of atrial fibrillation after cardiac operations. Ann Thorac Surg 1996;61: 1323–9. 255. Smidt-Ott UM, Ascheim DD. Thyroid hormone and heart failure. Curr Heart Fail Rep 2006;3:114–9. 256. Carle A, Laurberg P, Pedersen IB, et al. Thyrotropin secretion decreases with age in patients with hypothyroidism. Clinical Thyroidology 2007;17:139–44. 257. van den Beld AW, Visser TJ, Feelders RA, et al. Thyroid hormone concentrations, disease, physical function and mortality in elderly men. J Clin Endocrinol Metab 2005;90(12):6403–9. 258. Hermann J, Heinen E, Kroll HJ, et al. Thyroid function and thyroid hormone metabolism in elderly people low T3–syndrome in old age. Klin Wochenschr 1981; 59:315–23. 259. Fukagawa NK, Bandini LG, Young JB. Effect of age on body composition and resting metabolic rate. Am J Physiol Endocrinol Metab 1990;259:E233–8. 260. van Coevorden A, Laurent E, Decoster C, et al. Decreased basal and stimulated thyrotropin secretion in healthy elderly men. J Clin Endocrinol Metab 1989;69: 177–85. 261. Rubenstein HA, Butler VPJ, Werner SC. Progressive decrease in serum triiodothyronine concentrations with human aging: radioimmunoassay following extraction of serum. J Clin Endocrinol Metab 1973;37:247–53. 262. Chakraborti S, Chakraborti T, Mandal M, et al. Hypothalamic–pituitary–thyroid axis status of humans during development of ageing process. Clin Chim Acta 1999;288(1-2):137–45. 263. Piers LS, Soars MJ, McCormack LM, et al. Is there evidence for an age-related reduction in metabolic rate? J Appl Phys 1998;85:2196–204. 264. Poehlman ET, Berke EM, Joseph JR, et al. Influence of aerobic capacity, body composition, and thyroid hormones on the age-related decline in resting metabolic rate. Metabolism 1992;41:915–21. 265. Magri F, Fioravanti CM, vignati G, et al. Thyroid function in old and very old healthy subjects. J Endocrinol Invest 2002;25(10):60–3.
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266. Goichot B, Schlienger JL, Grunenberger F, et al. Thyroid hormone status and nutrient intake in the free-living elderly. Interest of reverse triiodothyronine assessment. Eur J Endocrinol 1994;130:244–52. 267. Cizza G, Brady LS, Calogero AE, et al. Central hypothyroidism is associated with advanced age in male Fischer 344/n rats: in vivo and in vitro studies. Endocrinology 1992;131:2672–80.
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Toxins in Ever yday Life Howard Chey, MD, MPH, Susan Buchanan, MD, MPH* KEYWORDS Environmental health Environmental history Toxicants
Starting with the Industrial Revolution in the ninetheenth century, the production of synthetic chemicals has mushroomed. Approximately 6.5 billion pounds of chemicals are released into the air in the United States each year.1 With the establishment of the United States Environmental Protection Agency (EPA) in 1970, the general public came to expect protection from exposure to substances that could cause acute or long-term health effects. In 1976, the passage of the Toxics Substances Control Act required chemical manufacturers to submit health and safety information on new chemicals.2 Thousands of chemicals in current use, however, were grandfathered in. Therefore, everyday activities, such as eating, drinking, commuting, working, and relaxing at home, can result in exposures that can lead to adverse health outcomes.3 It has been estimated that 740 cancers per million people are caused by air pollutants1 and that many chronic diseases, such as diabetes, cardiovascular disease, and obesity, may have etiologies in environmental toxicant ingestion or inhalation or dermal absorption. Peripheral neuropathy, developmental delay, some birth defects, and infertility are examples of medical conditions that may have a basis in toxicant exposure. Primary care physicians are in the unique position to educate, screen, and intervene with their patients to prevent harmful effects of exposures to environmental toxicants in their homes, workplaces, and communities. Unfortunately, training in environmental medicine is sorely lacking. Despite a 1988 recommendation by the Institute of Medicine for basic competency in environmental medicine, almost a quarter of all United States medical schools do not provide any curriculum content in environmental health.4 Currently, only 68% of family medicine residencies offer training in occupational and environmental medicine.5 This article reviews the role primary care physicians can play in the prevention of environmental disease. The most common everyday toxin exposures are introduced, including diagnostic and prevention tools that can be used in the outpatient setting to mitigate or reduce these exposures.
Funding support: National Institute for Occupational Safety and Health, Education and Research Center grant NIOSH #T42/CCT522954-01. Division of Environmental and Occupational Health Sciences, University of Illinois at Chicago School of Public Health, 835 South Wolcott, MC 684, Chicago, IL 60612, USA * Corresponding author. E-mail address:
[email protected] (S. Buchanan). Prim Care Clin Office Pract 35 (2008) 707–727 doi:10.1016/j.pop.2008.07.001 primarycare.theclinics.com 0095-4543/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.
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TAKING AN ENVIRONMENTAL HISTORY
Primary care physicians need to be aware of their patients’ exposures to environmental toxicants. An environmental history can be performed by office staff or patients may fill out a standardized form, which then can be reviewed quickly by busy clinicians. Several environmental history tools have been developed and are available on the Internet. Fig. 1 shows a commonly used environmental history form.6 Topics covered include hobbies (exposures to paints, thinners, strippers, glues, and lead) and recent home renovation or redecoration (exposure to formaldehydes, lead, paints, and solvents). It also is important to ascertain the age of the home (lead and poor ventilation) and type of heating (carbon monoxide [CO] and poor ventilation). Finally,
Fig. 1. Environmental history form. (Courtesy of Agency for Toxic Substances and Disease Registry, Washington, DC.)
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a section on nearby industries or sources of pollution should be included in the complete environmental history. TOXICANTS Indoor Air Pollutants
In contrast to outdoor air pollution, the quality of indoor air may affect human health more greatly because American adults spend more than 90% of their lives indoors.7,8 Ventilation in residential settings often is worse than in the workplace or in schools. Contaminants in indoor air, such as mold spores, volatile organic chemicals (VOCs), and products of combustion, can cause health effects ranging from upper respiratory irritation to cancer.8 Living or working with a smoker may result in exposure to environmental tobacco smoke (ETS). Homes built with certain construction materials or in certain geographic areas can result in the build-up of radon in basements and other confined spaces. Primary care physicians should be aware of the range of indoor air contaminants and their potential health effects. Mold
Molds are ubiquitous in the environment. With water damage caused by leaking pipes or flooding, porous materials, such as carpets, drywall, and furniture, may become inundated with mold growth. Mold spores, such as aspergillium, penicillium, and stachybotrys, can be found in indoor air samples in levels higher than outdoor levels, indicating mold overgrowth. In 1997 several cases of pulmonary hemorrhage in infants were linked to exposure to Stachybotrys chartarum.9 This led to a plethora of frightening stories in the media that generated a public fear of possible pulmonary hemorrhage or other health effects from exposure to molds in the home. In 2004, however, the Institute of Medicine published a summary report on mold in the home and work environments clarifying the health effects known to be linked to exposure.10 The report concluded that mold was linked to allergic symptoms, respiratory irritation, and asthma exacerbations but not to other health effects, such as pulmonary hemorrhage and cancer. There are no diagnostic tests for exposure to mold except for routine allergy testing for sensitivity to specific mold species. Many worried homeowners pay private contractors to test their homes for mold. Unfortunately, this often is not helpful because there is no current standard for ‘‘normal’’ mold levels, and indoor levels always should be compared with concurrent outdoor mold levels, which often are not measured. Because of individual susceptibility, levels may be high indoors and cause no health effects in some while causing dramatic allergic, irritation, or asthma symptoms in others. Visual inspection usually is sufficient to determine if mold is present. ‘‘A Brief Guide to Mold, Moisture, and Your Home,’’ available on the EPA Web site,11 offers practical advice regarding mold recognition and remediation for providers and patients. In summary, primary care providers presented with patients complaining of respiratory symptoms who have visible mold growth in the common areas of the home likely are suffering from reactions to mold overgrowth. They should be treated symptomatically and referred to the EPA guide for advice on mold clean-up. Volatile organic chemicals
VOCs are compounds of carbon and hydrogen, usually including at least one phenol ring. They are used in industry as paint stabilizers and adhesives and in some pesticides and wood preservatives. Therefore, newly painted walls and new furniture and carpeting all can release VOCs via ‘‘off-gassing’’ into the indoor air.12 The acute health effects of VOCs include respiratory and mucous membrane irritation symptoms, such
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as burning, itchy eyes, cough, and nasal congestion. Chronic effects may include cancer but definitive evidence is lacking. There are no recommended tests for exposure to VOCs. Physicians should be aware of the potential contribution of VOC exposure to patients who present with worsening allergy or asthma symptoms, or mucous membrane irritation and should inquire about recent home or workplace renovation activities. Radon
Radon gas is released during the radioactive decay of radium, a ubiquitous element in rock mined for use in home foundations and building materials. Basements constructed with radon-containing building materials or homes built on land formations containing radon may be contaminated with this radioactive substance. The inhalation of radon decay products increases the risk for lung cancer, especially in smokers, and may be the second-most common cause of lung cancer.13 There are no acute health effects of exposure to radon. Although the level of radon and the duration of radon exposure required to cause lung cancer are not known, EPA recommends remediation at home radon levels of 4 pCi/L, and in 1988, the EPA recommended that all United States homes below the third floor be tested.13 Radon detectors may be purchased from most hardware stores. Home inspectors also may be hired. If radon is found, remediation includes continuous venting of basement air to the outside. Products of combustion (carbon monoxide, nitrogen dioxide, and particulate matter)
Cooking with gas ranges, burning wood in fireplaces or wood stoves, and back draft of exhaust flues can all generate by-products, such as CO, nitrogen dioxide (NO2), and particulate matter (PM), that are irritating to the mucous membranes and can exacerbate asthma and increase susceptibility to lung infections.13 CO displaces oxygen from hemoglobin causing tissue hypoxia headache, nausea, sleepiness, and, in high doses, coma and death. ETS also is a product of combustion containing many dangerous hazardous chemicals. Smoking in the home can leave residues in the air that cause increased lower respiratory tract infections, mucous membrane irritation, and lung cancer. Summary
Physicians treating patients who have respiratory or allergic symptoms should inquire about indoor air quality, including the possibility of exposure to molds, VOCs, and products of combustion in addition to the more common allergens. Spirometry or peak flow measurements performed while at home and away, methacholine challenge testing, and allergy skin testing may be used to solidify the diagnosis. Once a possible indoor air contaminant is identified by history, an industrial hygienist may be consulted to inspect the home and determine levels of common indoor air pollutants. Finally, smokers should be urged to refrain from smoking in any indoor environments, because ETS (secondhand smoke) has been classified as a known human carcinogen and is a known cause of cardiovascular disease and death.12 Outdoor Air Pollutants
The term, air pollution, signifies a heterogeneous mixture of substances in the air that may produce harmful health effects in susceptible individuals.14 The recognition of outdoor air pollution as a public health nuisance dates back to the Roman Empire and scientific evidence linking outdoor air pollution to human health has been documented since the early twentieth century.15 Over the past decade, increased research efforts have illuminated the effects of outdoor air pollution on asthma, allergies, and cardiovascular disease.16 This section provides a brief review of important
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background information regarding the most notable outdoor air pollutants and their adverse health effects. Environmental Protection Agency criteria pollutants
National jurisdiction of air quality is governed by the EPA.17 Established by the passage of the Clean Air Act in 1970, the EPA was authorized to created exposure limits called the National Ambient Air Quality Standards. These standards set limits on a pollutant’s air concentration over a time-weighted average with considerations made for weather effects.18 There are currently six ‘‘criteria pollutants’’ regulated by such standards.15 These include PM, NO2, ground-level ozone (O3), sulfur dioxide (SO2), CO, and lead. Particulate matter PM is a term pertaining to dirt, dust, smoke, or droplets resulting
from combustion or chemical reactions that produce aerosols.18 Many studies have shown a strong association between PM in the ambient air and increases in respiratory tract symptoms and acute illness, reactive active disease exacerbations, bronchospasm events in persons who do not have reactive active disease, and mortality. The evidence to date suggests that PM induces inflammatory responses within the airways that may increase the likelihood of adverse health effects, such as reductions in forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and increased frequency of bronchodilator use in children who have severe asthma. Exposure to PM also may increase the risk for lung cancer.14 As with all criteria air pollutants, there are no home tests for PM, and it is not known with certainty what concentration results in adverse health effects. Physicians and patients should access their local Air Quality Index (AQI), discussed later, for information on the air pollution levels in their communities. Recommendations for avoidance of exposure to the criteria air pollutants are explained in the later in this section. Nitrogen dioxide NO2 is generated through fossil fuel combustion and through the ox-
idation of nitrogen oxide (NO), also produced through combustion of fossil fuels. NO2 is a known respiratory tract irritant and is associated with a variety of adverse respiratory health effects, probably via pro-inflammatory and anti-inflammatory responses. Examples of respiratory effects of exposure to NO include an increase in susceptibility to respiratory infections (especially in pediatric and elderly patient groups), worsening asthma symptoms, and severe lung injury resulting in death when exposure occurs in confined spaces without adequate ventilation. Some observational studies have suggested an association between NO2 exposure and an increased risk for hospital admissions for cardiovascular disease (cardiac failure, ischemic heart disease, and myocardial infarction).19 Physicians should be aware of their local AQI and advise patients accordingly (discussed later). Ground-level ozone Although ground-level O3 serves a vital function in the Earth’s up-
per atmosphere by blocking harmful radiation, it is linked to adverse health effects when it accumulates at ground level. O3 is a respiratory irritant created by a series of chemical reactions involving precursor agents, such as NO2 and VOCs. Generated primarily by internal combustion engines, these precursor pollutants react in the presence of light and combine to form O3 molecules. Peak O3 concentrations occur most frequently during summer months and during the midday as a result of the increased intensity of sunlight and temperature at these times.15 Exposure to O3 seems to exert an inflammatory and irritative effect on the respiratory tract, causing dyspnea, upper airway irritation, coughing, and chest tightness. In addition, exposure studies have found associations with acute decreases in FEV1 and
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FVC in healthy and asthmatic study participants and a possible increased risk for cardiopulmonary morbidity and mortality.20 No long-term effects of exposure to low-level O3 have been reported. Home test kits and tools to measure local O3 levels do not exist; the only public tool that exists is the AQI (described later). Sulfur dioxide Sulfur-containing substances, such as coal, crude oil, and metal ores, contribute to the generation of SO2 when combusted or processed.15 When susceptible individuals are exposed to SO2, they can experience acute health effects, including cough and decreased lung function, and aggravation of pre-existing cardiovascular and respiratory illnesses. As with the other criteria air pollutants, no home testing kits are routinely available. Providers should access their local AQI. The health effects of long-term, lower-dose ambient SO2 exposure are not clear at this time and require further research.19 Carbon monoxide CO is produced from incomplete combustion that occurs in automo-
bile engines, indoor stoves, heaters, and lamps that are fueled by wood, gas, or kerosene. These sources of indoor combustion can be particularly hazardous during winter months when fuel is burned in closed and poorly ventilated spaces. An important source of outdoor CO exposure is vehicle exhaust produced at busy roads or in tunnels.15 Acute or chronic exposure to CO can cause headache, nausea, vomiting, and lightheadedness. Chronic CO exposure has been associated with adverse cardiovascular events, such as angina. In terms of direct pulmonary effects, the scientific literature has not established a strong link between adverse pulmonary health outcomes and CO exposure.19 Although CO detectors are commonly used indoors to prevent CO poisoning, there is no comparable home-test tool for measuring outdoor CO levels. Lead Lead can be released into the ambient air by processes that include coal and waste burning, metal mining/smelting and other industrial processes, and volcanic emissions.16 The replacement of leaded gasoline with unleaded gasoline in the 1970s resulted in a marked decline in lead air pollution in the United States. The current concern for lead exposure is the ingestion of pulverized lead paint dust by children living in older homes and is discussed later. What the primary care practitioner can do to prevent the health effects resulting from outdoor air pollutants
The AQI is a tool used by the EPA to inform clinicians and patients about the quality of local air and is available on the EPA Web site and many local weather station Web sites. An AQI value of 100 generally corresponds to the national air quality standard for the pollutant whereas values below 100 are considered satisfactory. AQI values above 100 generally are considered unhealthy, particularly for individuals who have underlying respiratory illnesses. Patients and physicians may access their local AQI via the Web or local news and radio stations. Physicians should make recommendations regarding outdoor activities based on current pollution levels. For example, vigorous activities during times of higher air pollutant concentrations (AQI > 150) can be discouraged, and patients who have chronic respiratory illnesses can be instructed to be attuned to symptoms when outdoors. To obtain a better understanding of the AQI and the outdoor activity restrictions related to the AQI, readers are encouraged to access the AIRNow Web site.17 Heavy Metals
Although the human body is dependent on trace amounts of certain metals to function, many metals do not serve any meaningful purpose when ingested or inhaled. This
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section reviews four metals that serve no known benefit and can cause disruptive effects when absorbed. Lead
As discussed previously, a major source of lead exposure in the past was through inhalation of airborne lead particles from the combustion of leaded gasoline. Although this still is a problem in developing countries, lead toxicity through this route has not been a major source of exposure in the United States since the 1970s. The important sources of lead exposure at this time include car battery production, living in older homes containing lead paint, demolition of older homes painted with lead paint, lead paint removal activities, and, more recently, toys painted with leaded paint. Herbal remedies imported from other parts of the world, such as Ayurvedic herbal medicine products and herbal supplements from China and Vietnam, have been demonstrated to contain heavy metal toxicants, such as lead, mercury, and arsenic.21,22 Lead exposure is associated with dysfunction of the neurologic, hematologic, renal, and reproductive systems in humans. Acute lead poisoning can cause headache, irritability, abdominal pain, sleeplessness, restlessness, confusion, and, in severe cases, reduced consciousness and acute psychosis. Chronic lead exposures are associated with encephalopathy, nephropathy, hypertension, and anemia. Studies also have shown deficits in memory and learning capability among those who have elevated blood lead levels.23 Other neurologic manifestations of lead toxicity include peripheral motor neuropathy, slowing of sensory motor reaction, cognitive function disturbance, and subtle changes in neuropsychologic function (visual/motor performance, memory, attention, and verbal comprehension).24 Chronic low-level lead exposure has been associated with chronic blood pressure elevation, but the supporting data are inconsistent. High amounts of lead exposure can produce renal tubular damage and resultant saturnine gout. Existing studies inconsistently have shown a linear relation between serum creatinine levels and blood lead levels. Also, lead is well described in the literature as a disruptor of the heme synthesis pathway that results in anemia. Lead exposure also is linked with adverse reproductive health effects, such as spontaneous abortion and low birth weight. Studies of lead effect on the male reproductive system have demonstrated reduced sperm count and motility, but too few studies exist to make conclusions about its effect on reproductive capability.24 Pediatric health effects Children are at particular risk for lead exposure because of their hand-to-mouth activity, their proximity to the ground where lead dust accumulates, and their possible exposure from lead-contaminated work clothes brought home by their parents. Other potential sources of lead exposure in the home include leadcontaining jewelry and ceramics.25 Lead is potent enough to result in brain damage and cognitive deficits in children even at low exposure levels.23 Subtle neuropsychologic effects include poor behavior, decreased learning and concentration, and subtle changes in the neuropsychology profile.24,26 Screening The American Academy of Pediatrics27 recommends that physicians should screen children at risk. Lead screening should begin at 9 to 12 months of age and be considered again at about 24 months of age when blood lead levels peak. The Centers for Disease Control and Prevention (CDC) adds that children 36 to 72 months of age who have not been screened previously and who meet one of the following criteria should be screened: (1) living in community where more than 26% of the housing was built before 1950; (2) receiving public assistance for the poor, such as Medicaid
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or the Women, Infants, and Children Program; and (3) a parent/guardian answers, ‘‘yes,’’ to the following: (a) Does the child live in or regularly visit a house that was built before 1950? (b) Does the child live in or regularly visit a house built before 1978 with recent remodeling or renovations with the last 6 months? and (c) Does the child have a sibling or playmate who has or had lead poisoning?28 Mercury
Mercury exposure can arise from several different routes and settings depending on its form. Exposure can occur to its different forms (elemental, inorganic, or organic) in settings, such as mercury leaks from broken mercury thermometers, dental amalgams, and certain types of batteries. It is released during the burning of medical waste and is a component of fluorescent light bulbs and gas regulators. It is used in some ethnic religious practices.29 Inhalation of elemental mercury vapor is the primary route of human exposure, and more than 80% of the inhaled vapor is taken up by the lungs.30 Exposure to organic mercury occurs primarily through eating certain types of fish, marine mammals, and crustaceans.30 Methylmercury, one form of organic mercury, is taken up by fish as they feed in lakes, streams, or oceans contaminated by mercury from coal-fired power plant emissions or natural sources, such as from products of volcanic activity. Marine waters throughout the world are affected by mercury poisoning, as its unique characteristics allow mercury to volatilize and become transported globally.31 Larger, more predatory fish feed on large numbers of these smaller fish and accumulate methylmercury through the course of their longer life spans. Ingestion of larger, long-lived predatory fish by humans results in exposure to excessive amounts of methylmercury. The EPA has published worldwide fish advisories that can be accessed on the Web. Community-level data may be obtained from local health departments. Whales are known to accumulate higher amounts of methylmercury as are fish, including pike, walleye, bass, tuna, tilefish, swordfish, shark, and jack mackerel.29 Health effects Acute and chronic exposure to elemental mercury may induce cough,
dyspnea, fever, tremors, malaise, axonal sensorimotor polyneuropathy, gingivitis, delusions, and hallucinations. Erethism, a syndrome that consists of intention tremor, excitability, memory loss, insomnia, timidity, and delirium, is caused by chronic exposure to elemental mercury.32 The primary exposure to mercury from dental amalgam is believed to occur through the inhalation of elemental mercury that evaporates from the dental filling within the oral cavity. Despite considerable debate over this issue, there currently is no scientific evidence that supports the association between amalgam mercury exposure and adverse health effects in adults or children. Reviews of the literature performed by national and international expert organizations, such as the World Health Organization, the United States Department of Health and Human Services, the European Commission, and Health Canada, have come to similar conclusions regarding the lack of evidence supporting this association.33 Modest inorganic mercury exposures among dentists, however, have been linked to neurobehavioral changes, such as decreased motor speed, poorer visual scanning, declines in verbal and visual memory, and visuomotor coordination disturbances.32 Inhaled elemental mercury vapors absorbed during pregnancy may diffuse across the placenta and accumulate in the fetal brain, resulting in neurodevelopmental anomalies.30 Acute adult methylmercury cases, such as from occupational accidents or poisonings, can manifest as blurred vision, hearing impairment, olfactory disturbances, gustatory abnormalities, ataxic gait, clumsiness of the hands, dysarthria, and
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somatosensory and psychiatric disorders. Levels at greater than 5 mg/L urine, typically ordered in consultation with a toxicologist or an occupational/environmental medicine specialist, are associated with health effects. Chronic methylmercury poisoning results in distal extremity paresthesias that may persist even after exposure ceases. Cerebellar ataxia also may be seen but tends to improve after exposure ceases. Patients have complained of distal extremity and perioral paresthesias 30 years after their last exposure to mercury and after blood levels have returned to normal.34 The most severe effects of chronic high-dose organic mercury exposure have been observed in 1950s Japan, where local inhabitants of the Minamata Bay region consumed organic mercury-laden fish. The resultant high-dose, long-term ingestion of the contaminated fish by expectant mothers led to manifestations of neurologic toxicity seen among their children. Mothers who were asymptomatic or showed symptoms of mild toxicity gave birth to infants who eventually developed severe neurologic dysfunction. The spectrum of neurologic damage seen in Minamata disease included any of the following: mental retardation, primitive reflexes, hyperkinesis, deafness, blindness, cerebral palsy, cerebellar ataxia, seizures, strabismus, dysarthria, and limb deformities.29 Recent longitudinal epidemiologic studies have demonstrated conflicting results of chronic low-dose exposure to organic mercury.30 A more recent concern regarding organic mercury exposure in children pertains to the presence of thimerosal, which is a preservative used in routine pediatric vaccines, including diphtheria/tetanus/acellular pertussis, hepatitis B, and some Haemophilus influenzae type b vaccines.30 After injection, the thimerosal contained in these vaccines is metabolized into ethylmercury.29 During the 1990s, it was hypothesized that the apparent increase in the incidence of autism and attention-deficit/hyperactivity disorder was associated with the increased exposure to mercury through routine vaccination with thimerosal-containing products.29 To date, the majority of studies do not provide compelling epidemiologic evidence to establish an association between thimerosal-containing vaccines and autism. Moreover, the Immunization Safety Review Committee of the Institute of Medicine issued a statement in 2004 supporting no causal relationship between thimerosal-containing vaccines and autism. The World Health Organization supports the use of thimerosal-containing vaccines based on the lack of scientific evidence to recommend otherwise.29 Screening/evaluation As with any other medical evaluation, patients who have suspected mercury poisoning should have a complete history and physical examination, including a detailed environmental and parental occupational history. Confirmatory laboratory testing may involve a 24-hour urine level, whole blood or red blood cell mercury levels, hair mercury levels, and urine levels. Testing and treatment for mercury poisoning usually is conducted in consultation with a toxicologist or an occupational/environmental medicine specialist. The United States Food and Drug Administration (FDA) advises that women who plan to be pregnant, pregnant women, nursing mothers, and children avoid eating shark, swordfish, king mackerel, and tilefish. Furthermore, the FDA indicated that it is safe for these groups to eat up to 12 ounces per week of low–mercury content seafood (shrimp, canned light tuna, salmon, pollock, and catfish). In the case of albacore tuna, intake should be limited to 6 ounces per week.35,36 Arsenic
Arsenic is found throughout the environment in low concentrations, and humans, therefore, are exposed to low levels daily. Arsenic is used in the agricultural sector
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as insecticides, herbicides, fungicides, algicides, sheep dips, wood preservatives, dyestuffs, and medicines for the eradication of tapeworms in sheep and cattle. Other occupational settings that increase risk for arsenic exposure include vineyards, ceramic work, glass-making, smelting, pharmaceutical manufacturing, refining of metallic ores, pesticide manufacturing and application, wood preservation, semiconductor manufacturing, and hazardous waste site management. Exposure may occur via ingestion, inhalation, dermal contact, and, in the case of some medications, parenterally. The primary route of exposure for the general population occurs through naturally occurring levels in the water supply and from the diet.37 Approximately 90% of the arsenic that the American population ingests through their diet comes from eating various types of seafood (finfish, crustaceans, mollusks, and seaweed).38 Certain regions of the world, such as in rural areas of Argentina, Bangladesh, Chile, India, Taiwan, and Thailand, have naturally elevated levels of arsenic within the well water, which thus serve as an important source of arsenic exposure in these regions.37 The EPA has been regulating arsenic levels in drinking water since 1975, with the previous limit set at 50 parts per billion (ppb).39 This limit was revised to 10 ppb by the EPA in 2001 after a review demonstrated that such a change would result in a substantial decline in the number of bladder and lung cancer cases.40 Health effects Ingestion of large quantities of inorganic arsenic results in the development of acute toxicity symptoms involving the following systems: gastrointestinal (hemorrhagic gastroenteritis), cardiovascular (fluid loss, shock), renal (renal failure), and central nervous system (seizures).32 Survivors of acute toxic arsenic ingestion may have bone marrow depression, hemolysis, hepatomegaly, melanosis, polyneuropathy, peripheral vascular disease, and encephalopathy.26 Chronic low-level arsenic ingestion through drinking water clearly is associated with an elevated risk for mortality from lung, bladder, and kidney cancer. Reports have documented concentrations of arsenic as low as 10 mg/L in local drinking water being associated with an elevated risk for these health effects.37 Similar long-term, low-level exposures have been associated with an increased risk for skin cancer and skin lesions, such as hyperkeratotic and hyperpigmentation changes. Other health effects associated with low-dose arsenic exposure include hypertension/cardiovascular disease, diabetes, reproductive effects, cerebrovascular disease, neurologic effects, and cancer at sites other than the ones discussed previously. Of these, only cardiovascular diseases, such as hypertension, coronary heart disease, and an elevated mortality rate related to cardiovascular disease, have strong supporting evidence.26 Although health effects of arsenic intoxication have been well documented in adults, little is known about its effects in children. Some studies suggested a possible detrimental effect of arsenic exposure on the physical growth of children and poorer performance in verbal ability and long-term memory, but these studies contained some methodologic flaws (small sample size, confounding, and poor allocation of controls). A few recent reports suggested a relationship between chronic arsenic exposure and adverse reproductive outcomes. More research needs to be performed to make firmer statements about chronic arsenic poisoning in children.41 Monitoring In cases of suspected arsenic poisoning, measurements of arsenic in hair, nails, or 24-hour urinary specimens may be obtained depending on the time since last exposure. Hair and nail sampling for arsenic can be useful tools for determining past arsenic exposure as it is deposited during exposure and remains in the hair and nails until cut. Care must be taken to avoid contaminating these samples with other sources of arsenic, such as dietary intake of seafood. Currently, there is no recommendation for routine testing of patients who may have ingested arsenic-containing foods or
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water because levels usually are extremely low and not known to cause health effects at such low levels.26 Cadmium
Cadmium can be found naturally throughout the earth in the form of ore and appears in batteries, pigments, metal coatings, plastics, and as a contaminant of some commercial fertilizers. Industrial activities, such as metal production, waste incineration, battery manufacturing, and oil combustion, result in the release of cadmium into the environment. Cadmium can travel long distances through the air and water and bind strongly to soil. Plants (in particular leafy vegetables) can take up cadmium, which subsequently enters the food chain, ultimately resulting in human consumption.42 Cigarette smoking also is a major source of exposure to cadmium, and it has been demonstrated that smoking may result in significant increases in blood cadmium levels up to 4 to 5 times higher than among nonsmokers.26 Cadmium is excreted very slowly, thus accumulates within the body, primarily in the kidneys, where it may remain for decades.43 Exposure at any point in life may lead to effects many years later.42 Health effects Acute, high-level inhalational exposure to cadmium fumes or particles
may lead to life-threatening pulmonary effects and death, although this is uncommon. Low-level cadmium exposure may not present an immediate threat, but any cadmium retained in the body can pose a long-term problem if the cumulative retained dose reaches levels that produce toxic effects. Accumulation of cadmium in the kidneys causes tubular dysfunction, which results in the excretion of low molecular weight proteins, such as b2-microglobulin and b1-microglobulin, into the urine. Severe, irreversible tubular damage can lead to end-stage renal disease.43 Long-term high-level cadmium exposure disrupts the signaling pathways responsible for calcium homeostasis and may lead to osteomalacia and osteoporosis.26,42 The International Agency for Research on Cancer (IARC)44 classifies cadmium as a group I human carcinogen, indicating that high-quality scientific evidence exists regarding the association of cadmium with carcinogenicity. This classification was based on studies linking cadmium exposure with elevated risk for lung cancer. As in the case of arsenic, few studies exist regarding the health effects of cadmium exposure in children. A few investigations have found associations between cadmium exposures and birth weight, but these results have been questioned because of confounding by concurrent lead and zinc exposure. Other studies have demonstrated negative effects of cadmium on the motor abilities, perceptual abilities, and verbal IQ of children but more research studies with stronger methodology are needed to confirm these associations.42 Monitoring Cumulative cadmium exposure can be monitored over time by the measurement of blood and urine levels. Blood cadmium levels indicate the severity of more recent exposure. Urine level measurements quantify cumulative renal concentrations of cadmium, which essentially reflects the total body burden.42 Monitoring for low-level cadmium exposures, such as from secondhand smoke inhalation or ingestion of cadmium-contaminated foods, is unlikely to lead to health interventions and is not recommended. Household Pesticides
The pesticide group of toxicants, including insecticides and herbicides, is defined as ‘‘any agent used to kill or control undesired insects, weeds, rodents, fungi, bacteria, or other organisms.’’45 Given this broad definition, it is reasonable to say that many households in the United States contain pesticides and, if mishandled, humans are
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at risk for toxicity from these agents. Common household pesticide agents, including cockroach sprays and baits, indoor insect sprays and repellents, termite control products, rat poisons, flea and tick sprays/powders, and lawn/garden agents, such as weed killers, all pose a potential danger if used improperly or too frequently, especially when children are able to access them.46 The age group associated with the highest mortality rates related to injury (including accidental pesticide ingestions) within the average American household is infants less than 1 year old. Greater than 90% of injury-related deaths in this age group occur in the home.47 Primary care providers should be aware of this risk among the general patient population and be able to provide safety counseling about these agents, particularly during well-child encounters. To provide information regarding pesticides to patients and family members, care providers should have a basic understanding of potential pesticide agents that can exist in the home. The following provides a broad description of the agent groups of concern: Rodenticides
Rodenticides are used to control the presence of rodents. Rodenticide bait products include anticoagulants, nerve toxicity agents, hypercalcemics, and zinc phosphide. Children are at special risk for inadvertently ingesting these agents because of their exploratory nature and the requirement to deploy rodenticides at floor level. Evidence from 1990 through 1997 New York State Department of Health data demonstrates that African American and Latino children living below the poverty level are disproportionately exposed to rodenticides, which result in a disproportionate number of hospitalizations.48 Almost all deaths associated with this class of rodenticides were secondary to intentional suicidal ingestions of the long-acting anticoagulant agents. Acute toxicity, usually from a single, high-dose ingestion, presents as bleeding from the nose, gums, and gastrointestinal tract and easy bruising. Primary care doctors should consider rodenticide ingestion in patients presenting with these symptoms. Because few laboratories are able to measure levels of specific toxicants, an index of suspicion is the key to the determining a causal association. There is no standard laboratory test for rodenticide poisonings; if a physician suspects anticoagulant poisoning, coagulation studies should be ordered and a toxicologist or poison control center consulted. Strychnine is a nonanticoagulant rodenticide and causes the rapid onset of violent seizures. It continues to be reported to poison control centers as a source of toxicity in the United States.49 Insecticides
Insecticides are used against cockroaches and other common household nuisance insects. They often present in the form of a colorless and odorless gel bait and therefore tend to be unobtrusive and do not attract the attention of pets and children.50 Other types of insecticides include hydromethylnon, a newer pesticide available in gel bait form that is considered effective and safe. Fipronyl, sulfluramide, and abamectin also are more effective or safer than older substances, such as boric acid, organophosphates, and pyrethroids. Chlorpyrifos had its certification for indoor use removed by the EPA in 2000 over concern for neurotoxic and adverse developmental effects in humans. Pyrethrins are another older group of agents that were considered effective but are used less frequently because of unpleasant odor and concerns about chronic toxicity.50 In addition to home interiors, pesticides may be present in the home on pets as flea and tick control products that are popular and widely available in pet stores. The EPA recommends careful adherence to the directions located on the labels of these products to minimize toxicity to humans and pets.51
Toxins in Everyday Life
Use of pest strips, termite treatments, flea collars for pets, and garden treatments in the home are associated with an increased risk for pediatric cancers, in particular leukemia and brain tumors. The risk also is shown elevated for children who live with parents who experience regular occupational exposure to pesticides.49 Herbicides
Herbicides are agents used to reduce the presence of weeds and other unwanted types of vegetation. Common herbicides that are used in the domestic setting include diquat, glyphosate, and chlorophenoxy herbicides. These agents are widely used in North America, including on residential landscapes. Examples of chlorophenoxy herbicides include 2,4-dichlorophenoxyacetic acid and mecoprop.49 Diquat is severely toxic with acute exposure. Diquat toxicity presents with erosive gastroenteritis, airway injury, and renal failure and may result in severe central nervous system toxicity. The central nervous system toxicity may manifest as mental status changes, disorientation, confusion, coma, and seizures. Death may result.49 Toxicity to chlorophenoxy herbicides tends to be less severe, and severe cases are associated mainly with high-dose oral exposures. Exposure to most chlorophenoxy compounds results in irritation to the mucous membranes and skin from local action. The more severe toxic presentations of toxicity to this type of herbicide may manifest with mental status changes, vomiting, diarrhea, and headache. More severe exposures may result in systemic toxicity and present as acidosis, electrolyte imbalance, renal failure, or potential multiple organ failure in high-exposure cases.49 Glyphosate is a newer herbicide associated with some reports of acute toxicity. Toxicity to this agent presents as skin, upper respiratory tract, and eye irritation. Because glyphosate is mixed in a hydrocarbon vehicle, local hydrocarbon toxicity effects, such as chemical pneumonitis, may result.49 Pesticide residuals
In addition to rodenticides, insecticides, and herbicides, another major potential source of home pesticide exposure is pesticide residuals. Pesticide residuals are the small amount of pesticides (insecticides or herbicides) that remain on cultivated foods. The different types of pesticides used to treat crops are numerous and can be classified as organophosphates, carbamates, and pyrethroids. Research is sparse regarding the risk of ingesting pesticide residue-contaminated foods on the health of the general public. In a review of recent scientific articles regarding organically grown foods versus conventionally raised foods, investigators concluded that the current body of scientific knowledge does not support or refute claims that organic food is safer than conventional food.52 The EPA closely regulates the pesticides used in conventionally grown food. Before a pesticide may be used on crops in the United States, it must be approved for specific use by the EPA.53 In addition to approving a chemical agent’s use, the EPA has the authority to limit the amount of pesticide applied, restrict the frequency or location of application, and determine proper storage and disposal practices. The EPA also sets limits on the maximum amount of pesticide residue that can lawfully remain in or on each treated food item.54 With protections set by the EPA and the lack of strong evidence to indicate otherwise, it seems that the current foods available in markets are safe to eat. Because of the absence of high-quality studies regarding dietary pesticide exposure, however, there is no certainty about the hazards of consuming conventionally grown foods. Mitigation
Clinicians can play a vital role in minimizing the risk for pesticide-related toxicity events among their patients. One way is to become proficient in obtaining a thorough
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environmental history regarding potential sources of home pesticide exposures. A review of chemical products stored the home, such as garden, lawn, rodenticide, and insectide products, should be performed to generate awareness of potential home hazards. In addition to increasing awareness about home hazards, care providers should instruct parents about storing these substances appropriately and using cabinet locks where younger members of the household can reach them. Patients should be instructed to use home pesticide products only in the manner directed by the product label and only for their intended uses.55 To minimize exposure to pesticide residues on food, studies have demonstrated the effectiveness of simple rinsing with tap water. In one study, reductions in 9 out of 12 pesticides were recorded in produce that were rinsed with tap water for 15 to 30 seconds, without correlation to water solubility of the pesticide.56 OCCUPATIONAL EXPOSURES Obtaining an Occupational History Worker exposure history
Worker exposure history Because of the multitude of possible hazardous exposures in the workplace, primary care physicians should be proficient in obtaining an occupational history. Given the time constraints of today’s practice environment, physicians evaluating patients for suspected occupational illnesses should focus on five key questions:52 1. 2. 3. 4.
What type of work do you do? Do you think your health problems might be related to your work? Are your symptoms different at work and at home? Are you currently exposed to chemicals, dusts, metals, radiation, noise, or repetitive work? Have you been exposed to chemicals, dusts, metals, radiation, noise, or repetitive work in the past? 5. Are any of your coworkers experiencing similar symptoms? Additional information should include details about the job history, including dates of employment, job title, job duties, company name, and known major exposures for each previous job. Examples of possible hazardous exposures include metals, chemical agents, ambient dusts, noise, radiation, repetitive motion, biohazards, and stress.57 In terms of respirable hazards, such as dusts, fumes, and vapors, patients should be asked about the adequacy of ventilation at their workstations and the buildings in which they work. Workers also should be asked if they are provided adequate personal protective equipment, such as respirators, gloves, and earplugs, and, if so, whether or not they use them. Clinicians also may consider asking their patients to supply any monitoring data or Material Safety Data Sheets from the workplace.58 Assessing exposure of the worker’s family
Assessing exposure of the worker’s family take-home exposures to the family are important to consider because family members can develop ill health effects from toxicants that are brought home by a worker. In the absence of proper hygiene measures, workers may carry home hazardous substances from the workplace on their clothes, shoes, and work equipment. For example, a meta-analysis of studies on take-home lead exposure in children suggested that children living in households with leadexposed workers are at increased risk for elevated blood lead levels. The highest blood lead levels were found among children whose cohabitants work in battery production, ceramics, radiator repair, laborer jobs, construction, and firing ranges.59 These industries are known sites for lead exposure. In a study of lead-exposed construction workers who had elevated blood lead levels, workers were found to have
Toxins in Everyday Life
lead contamination on their hands, clothing, and shoes. Lead contamination also was found to be measurable in the workers’ car interiors and within their homes.60 To prevent take-home exposures, workers exposed to hazardous substances should be counseled about hygiene measures to take before leaving the workplace. Behaviors, such as changing from contaminated work clothes and showering at the worksite, are simple actions that a worker can take to prevent bringing known toxicants, such as lead, beryllium, and asbestos, home to their families.61,62 ELECTROMAGNETIC FIELDS
Although ubiquitous in everyday life, exposure to electromagnetic (EM) fields often goes undetected because of its invisible nature. This form of energy is classified into extremely low-frequency (ELF) fields and radiofrequency (RF) radiation. ELF fields are produced from devices through which electric current is run, such as electronic appliances and high-voltage power lines. RF energy is emitted by wireless devices, such as cell phones, cordless phones, cellular antennas, cellular towers, and broadcast transmission towers. Both types of fields are nonionizing; they do not have the energy to break electrons from their orbits and, therefore, do not transmit energy to the absorbing tissue.63 This discussion focuses on the common types of EM radiation that primary care providers may be asked about during clinical encounters. ELF EM fields are generated through the electric power generation process, transmission, and use. Electric and magnetic fields increase in strength with higher voltages and currents. They diminish in intensity as distance increases from the source. The electrical and magnetic field components of an ELF EM field have differing penetration characteristics in relation to the human body. The electrical field component of an ELF EM field can be absorbed by physical objects, such as buildings and tissue (skin or muscle). The magnetic field component can penetrate physical barriers and is able to penetrate deeply into the body.64 To date, the scientific literature has not supported a relationship between ELF EM fields and health effects in adults. The health outcomes assessed by a large body of research spanning more than 25 years include cancer (breast and testicular), cardiovascular disease, sleep disorders, fatigue, and Alzheimer’s disease. Examples of different settings in which ELF radiation effects were studied include radar monitor sites, arc-welding facilities, and railways. ELF EM from electric appliances is not a known threat to human health.65 The effects of ELF fields on children have been studied extensively. So far, only childhood leukemia has supporting evidence. This association was first reported in 1979 and has been followed by dozens of increasingly complex studies, many comprehensive reviews, meta-analyses, and pooled analyses.64 Data gathered from a recent study in Japan suggested an association between exposure of children to elevated levels of ELF EM (0.4 mT, within 100 m of their homes) from nearby power lines and acute lymphocytic leukemia.66 This more recent study supports earlier data that allowed an association to be established between ELF EM emitted from power lines and childhood leukemia. The IARC (part of the World Health Organization) classifies these fields as ‘‘possibly carcinogenic to humans.’’67 Regarding brain tumors, evidence has not been able to consistently support the relationship between tumors and exposure to ELF fields.64,65 The proliferation of wireless devices makes exposure to RF radiation a ubiquitous occurrence for most Americans. Cellular phones, wireless local area network devices, cordless phones and radios, television sets, and microwave ovens use technology that depends on the generation or reception of RF waves. Occupational RF exposures
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can occur in industrial processes, such as using dielectric heaters to laminate wood and seal plastics. Other fields of work that can result in increased exposures to RF include broadcasting, transport, military communications, and various medical settings, such as MRI work.68 With the widespread use of wireless devices in today’s society, it is reassuring that the evidence to date has not demonstrated an association between RF exposure and adverse health outcomes. From a theoretic standpoint, RF waves do not possess sufficient energy to break electrons away from DNA molecules and thus are unable to produce genotoxic effects. The only known physical consequence of RF exposure is the local heating effect of RF waves.68 RF waves are easily absorbed by the skin and underlying tissues that prevent RF waves from penetrating deeply into the body. Although the outer tissues that absorb the RF energy are heated, the heat is readily dissipated by local blood flow and air conduction.65 Although no existing data have demonstrated health effects (ie, brain cancer, acoustic neuroma, or leukemia) from RF exposures, the studies that have been published to date are based on conclusions that do not take into account disease processes that require long latency periods to manifest, such as malignancies. It may take several decades for RF-related exposures to manifest adverse health effects in susceptible individuals. Because handheld mobile phones have been in mainstream use only since the 1990s, diseases, such as malignancies that appear up to 30 years after exposure, might not be included in existing studies to date. The changing nature of cellular phone technology, such as the erection of new base stations, the use of different RF frequencies between different time periods and locations, and the high variation of actual RF exposure to individual members of a study population, make it difficult to draw solid conclusions regarding health effects.68 The state of research in this field is immature and further studies are required to better understand the relationship between RF exposure and health outcomes.64 Perhaps to the dismay of parents, children and teenagers are increasingly avid users of wireless technologies, such as cellular phones. Because of slight differences in their biology compared with adults, some concerns have arisen in the literature regarding pediatric exposure to RF waves. Among the theoretic concerns that possibly may make children more vulnerable to RF exposures are the higher elasticity of children’s ears leading to greater RF energy absorption and the unknown behavior of RF in a developing brain.65 With a few exceptions, population studies to date have not included children in their analyses. Thus, little is known about the potential hazards of RF exposures among the pediatric population.68 EMERGING ISSUESçENDOCRINE DISRUPTING CHEMICALS
Evidence is growing that synthetic chemicals can mimic estrogens, androgens, and thyroid hormones. These endocrine disruptors are ubiquitous in everyday life and may cause long-term effects on human health even at low doses.69 In 2005, researchers at the CDC found the endocrine disruptor, bisphenol A (BPA), a common additive to food and beverage containers, in 95% of urine samples examined.70 Moreover, another CDC study found phthalates, a common plasticizer, in virtually all of 289 urine samples of randomly selected participants tested.71 Phthalates are a family of compounds added to plastics to confer flexibility. They are found in such household items as children’s toys, food packaging, and products containing polyvinyl chloride. DHEP, one of the most commonly produced phthalates, has been shown to cause dysfunction of the testes, cancer, and reproductive effects in laboratory animals.72 BPA is used in polycarbonate plastics, such as water bottles,
Toxins in Everyday Life
baby bottles, and food containers. When these products are heated, BPA, which is estrogenic, can leach into food or liquids. An expert panel convened by the National Institutes of Health and EPA concluded that recent trends in prostate cancer, declining semen quality, and early onset of puberty in girls are related to similar adverse effects observed in experimental animals exposed to low doses of BPA.69 Currently there is no testing available for exposure to BPA or phthalates. Because they are ubiquitous in the everyday environment it can be assumed that the vast majority of the United States population has been exposed. Some states are considering legislation restricting the production and importation of products containing BPA. Those who are interested in reducing their risk for health effects from BPA ingestion are advised to use glass or #5 plastic bottles instead of #7 plastic (polycarbonate), to not use harsh detergents or put plastic bottles in the dishwasher, to avoid heating foods in #7 plastic containers, and to reduce consumption of canned food and beverages.73 Polybrominated diphenyl ethers (PBDEs) are commonly added to fabrics, foam, and upholstery as flame retardants. In 2007, a CDC study found PBDEs in almost all serum samples from 2070 subjects selected from the general population.74 Health effects in animals have focused on thyroid, liver, reproductive, and neurodevelopmental effects. Neonatal exposure to PBDEs in laboratory animals has been shown to cause hyperactivity and memory problems, impairment of sperm development, and cryptorchidism.75 Because of concern over possible health effects, penta-, octa- and decaBDEs have been phased out in the European Union, and some states in the United States have followed suit, banning several forms of PBDEs in consumer products.75 There currently are no recommendations for routine testing for PBDE exposure or for avoidance of exposure. Personal care products, such as shampoo, deodorant, and makeup, contain a multitude of chemicals, plasticizers, and fragrances, most of which have not been tested for human health effects. They are easily absorbed from the dermis and often are used daily or multiple times per day on young children and adults, leading to growing concern for reproductive and developmental effects. In one study, 57 of 72 off-the-shelf beauty products tested were found to contain phthalates.76 In another, 61% of the brand-name lipsticks tested contained lead.77 Although there are no current recommendations regarding testing for exposure to or avoidance of beauty products, it is likely that the issue of endocrine disruptors and other toxins in everyday household items will continue to garner public attention. Future research hopefully will illuminate the specific risks for human health from exposure to these ubiquitous chemicals.
SUMMARY
Primary care physicians can play an important role in the diagnosis and management of conditions associated with environmental exposures. Awareness of toxicants and their effects is essential, however, for raising the index of suspicion of home and workplace exposures. Moreover, including an environmental history in all new patient intakes will add essential information to the permanent medical record. Staying informed is much easier in the electronic age, and the following are on-line resources primary care clinicians should be aware of and access regularly: United States Environmental Protection Agency. Available at: www.epa.gov Agency for Toxic Substances and Disease Registry. Available at: www.atsdr.cdc.gov Association of Occupational and Environmental Clinics. Available at: www.aoec.org Centers for Disease Control Environmental Health. Available at: http://www.cdc. gov/Environmental/
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1. LaDou J, editor. Current occupational and environmental medicine. 3rd edition. Chicago: Lange Medical Books/McGraw-Hill; 2004. p. 667. 2. US Environmental Protection Agency. Summary of the Toxic Substances Control Act. Laws, regulations, guidances, and dockets. March 6th, 2008. Available at: http://www.epa.gov/regulations/laws/tsca.html. Accessed April 17, 2008. 3. Phillips ML. Obstructing authority: does the EPA have the power to ensure commercial chemicals are safe? Environ Health Perspect 2006;114(12): A706–9. 4. Schenk M, Popp SM, Neale AV, et al. Environmental medicine content in medical school curricula. Acad Med 1996;71(5):499–501. 5. Michas MG, Iacono CU. Overview of occupational medicine training among US family medicine residency programs. Fam Med 2008;40(2):102–6. 6. Agency for Toxic Substances and Disease Registry. Case studies in environmental medicine. Taking an exposure history. Available at: http://www.atsdr.cdc.gov/ csem/exphistory/docs/exposure_history.pdf. Accessed April 16, 2008. 7. US Environmental Protection Agency. Indoor air pollution: an introduction for health professionals. August 9th, 2007. Available at: http://www.epa.gov/iaq/ pubs/hpguide.html#Intro. Accessed March 3, 2008. 8. US Environmental Protection Agency. The inside story: a guide to indoor air quality. April 25th, 2008. Available at: http://www.epa.gov/iaq/pubs/insidest.html. Accessed March 3, 2008. 9. CDC. Update: pulmonary hemorrhage/hemosiderosis among infants—Cleveland, Ohio, 1993–1996. MMWR Morb Mortal Wkly Rep 1997;46(2):33–5. 10. Institute of Medicine (US). Indoor mold, building dampness linked to respiratory problems and require better prevention; evidence does not support links to wider array of illnesses. The National Academies News. May 25th, 2004. Available at: http://www8.nationalacademies.org/onpinews/newsitem.aspx?RecordID511011. Accessed May 20, 2008. 11. US Environmental Protection Agency. A brief guide to mold, moisture, and your home. US EPA Office of Air and Radiation, Indoor Environments Division. April 30th, 2008. Available at: http://www.epa.gov/iaq/molds/moldguide.html. Accessed May 20, 2008. 12. Samet JM, Spengler JD, Mitchell CS. Indoor air pollution in environmental and occupational medicine. In: Rom WN, editor. Environmental and occupational medicine. 3rd edition. Philadelphia: Lippincott-Raven; 1998. p. 1523–39. 13. Agency for Toxic Substances and Disease Registry. Case studies in environmental medicine. Radon toxicity. Available at: http://www.atsdr.cdc.gov/csem/radon/ index.html. Accessed March 3, 2008. 14. Chen TM, Gokhale J, Shofer S, et al. Outdoor air pollution: particulate matter health effects. Am J Med Sci 2007;333(4):235–43. 15. Chen TM, Shofer S, Gokhale J, et al. Outdoor air pollution: overview and historical perspective. Am J Med Sci 2007;333(4):230–4. 16. Curtis L, Rea W, Smith-Willis P, et al. Adverse health effects of outdoor air pollutants. Environ Int 2006;32(6):815–30. 17. US Environmental Protection Agency. Air quality index—a guide to air quality and your health. November 27th, 2007. Available at: http://www.airnow.gov/. Accessed March 24, 2008. 18. Neher JO, Koenig JQ. Health effects of outdoor air pollution. Am Fam Physician 1994;49(6):1397–404.
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19. Chen TM, Gokhale J, Shofer S, et al. Outdoor air pollution: nitrogen dioxide, sulfur dioxide, and carbon monoxide health effects. Am J Med Sci 2007;333(4):249–56. 20. Chen TM, Gokhale J, Shofer S, et al. Outdoor air pollution: ozone health effects. Am J Med Sci 2007;333(4):244–8. 21. Saper RB, Kales SN, Paquin J, et al. Ayurvedic herbal medicine products. JAMA 2004;292(23):2868–73. 22. Garvey GJ, Hahn G, Lee RV, et al. Heavy metal hazards of Asian traditional remedies. Int J Environ Health Res 2001;11(1):63–71. 23. Florea AM, Busselberg D. Occurrence, use and potential toxic effects of metals and metal compounds. Biometals 2006;19(4):419–27. 24. Gidlow DA. Lead Toxicity. Occup Med (Lond) 2004;54(2):76–81. 25. Guidotti TL, Gitterman BA. Global pediatric environmental health. Pediatr Clin North Am 2007;54(2):335–50, ix. 26. Ja¨rup L. Hazards of heavy metal contamination. Br Med Bull 2003;68:167–82. 27. American Academy of Pediatrics Committee on Environmental Health. Screening for elevated blood lead levels. Pediatrics 1998;101(6):1072–8. 28. Centers for Disease Control and Prevention. Screening young children for lead poisoning: guidance for state and local public health officials. November 3rd, 1997. Available at: http://www.cdc.gov/nceh/lead/guide/guide97.htm. Accessed May 25, 2008. 29. Clifton JC 2nd. Mercury exposure and public health. Pediatr Clin North Am 2007; 54(2):237–69, viii. 30. Counter SA, Buchanan LH. Mercury exposure in children: a review. Toxicol Appl Pharmacol 2004;198(2):209–30. 31. Hylander LD, Goodsite ME. Environmental costs of mercury pollution. Sci Total Environ 2006;368(1):352–70. 32. Hu H. Exposure to metals. Prim Care 2000;27(4):983–96. 33. Clarkson TW, Magos L. The toxicology of mercury and its chemical compounds. Crit Rev Toxicol 2006;36(8):609–62. 34. Ekino S, Susa M, Ninomiya T, et al. Minamata disease revisited: an update on the acute and chronic manifestations of methyl mercury poisoning. J Neurol Sci 2007; 262(1–2):131–44. 35. U.S. Food and Drug Administration. Chapter 10. Methylmercury. Fish and fisheries products hazards and controls guidance. June 2001. Available at: http://www. cfsan.fda.gov/~comm/haccp4j.html. Accessed March 29, 2008. 36. U.S. Department of Health and Human Services and Environmental Protection Agency. What you need to know about mercury in fish and shellfish. March 2004. Available at: http://www.cfsan.fda.gov/wdms/admehg3.html. Accessed March 29, 2008. 37. Tchouwou PB, Patlolla AK, Centeno JA. Carcinogenic and systemic health effects associated with arsenic exposure—a critical review. Toxicol Pathol 2003;31(6): 575–88. 38. Borak J, Hosgood HD. Seafood arsenic: implications for human risk assessment. Regul Toxicol Pharmacol 2007;47(2):204–12. 39. US Environmental Protection Agency. Fact sheet: drinking water standard for arsenic. Arsenic in drinking water January 2001. Available at: http://www.epa. gov/safewater/arsenic/regulations_factsheet.html. Accessed May 25, 2008. 40. US Environmental Protection Agency Office of Water. Arsenic and clarifications to compliance and new source monitoring rule: a quick reference guide. January 2001. Available at: http://www.epa.gov/safewater/arsenic/pdfs/quickguide.pdf. Accessed May 25, 2008.
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41. Watanabe C, Inaoka T, Matsui T, et al. Effects of arsenic on younger generations. J Environ Sci Health A Tox Hazard Subst Environ Eng 2003;38(1):129–39. 42. Schoeters G, Den Hond E, Zuurbier M, et al. Cadmium and children: exposure and health effects. Acta Paediatr Suppl 2006;95(453):50–4. 43. Satarug S, Moore MR. Adverse health effects of chronic exposure to low-level cadmium in foodstuffs and cigarette smoke. Environ Health Perspect 2004; 112(10):1099–103. 44. International Agency for Research on Cancer. Volume 58. Beryllium, cadmium, mercury, and exposures in the glass manufacturing industry. IARC monographs on the evaluation of carcinogenic risks to humans. August 22nd, 1997. Available at: http://monographs.iarc.fr/ENG/Monographs/vol58/volume58.pdf. Accessed May 25, 2008. 45. US Environmental Protection Agency. The EPA and food security. Pesticides: topical & chemical fact sheets. March 13th, 2008. Available at: http://www.epa. gov/pesticides/factsheets/securty.htm. Accessed April 2, 2008. 46. US Environmental Protection Agency. Citizen’s guide to pest control and pesticide safety. September 1995. Available at: http://www.epa.gov/oppfead1/ Publications/Cit_Guide/citguide.pdf. Accessed April 6, 2008. 47. Stone KE, Eastman EM, Gielen AC, et al. Home safety in inner cities: prevalence and feasibility of home safety-product use in inner-city housing. Pediatrics 2007; 120(2):e346–53. 48. Edwards D. Proposed risk mitigation for nine rodenticides. US Environmental Protection Agency, Office of Prevention, Pesticides, and Toxic Substances; January 17th, 2007. 49. Reigart JR, Roberts JR. Pesticides in children. Pediatr Clin North Am 2001;48(5): 1185–98, ix. 50. Eggleston PA. Cockroach allergen abatement: the good, the bad, and the ugly. J Allergy Clin Immunol 2003;112(2):265–7. 51. US Environmental Protection Agency. Hartz flea and tick drops for cats and kittens to be cancelled. Pesticides: topical & chemical fact sheets. July 24th, 2007. Available at: http://www.epa.gov/pesticides/factsheets/flea-tick-drops.htm. Accessed April 3, 2008. 52. Magkos F, Arvaniti F, Zampelas A. Organic food: buying more safety or just a peace of mind? A critical review of the literature. Crit Rev Food Sci Nutr 2006;46(1):23–56. 53. US Environmental Protection Agency. Setting tolerances for pesticide residues in foods. Pesticides: topical and chemical fact sheets. March 13th, 2008. Available at: http://www.epa.gov/pesticides/factsheets/stprf.htm. Accessed May 25, 2008. 54. US Environmental Protection Agency. Registering pesticides. Pesticides: regulating pesticides. May 2nd, 2008. Available at: http://www.epa.gov/pesticides/ regulating/registering/index.htm. Accessed May 25, 2008. 55. Weiss B, Amler S, Amler RW. Pesticides. Pediatrics 2004;113(4 Suppl):1030–6. 56. Krol WJ. Reduction of pesticide exposures on produce by rinsing. J Agric Food Chem 2000;48(10):4666–70. 57. Frank AL. Approach to the patient with an environmental or occupational illness. Prim Care 2000;27(4):877–94. 58. Lax MB, Manetti FA, Klein R. Recognizing occupational disease—taking an effective occupational history. Am Fam Physician 1998;58(4):935–44. 59. Roscoe RJ, Gittleman JL, Deddens JA, et al. Blood lead levels among children of lead-exposed workers: a meta-analysis. Am J Ind Med 1999;36(4):475–81.
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60. Piacitelli GM, Whelan EA, Sieber WK, et al. Elevated lead contamination in homes of construction workers. Am Ind Hyg Assoc J 1997;58(6):447–54. 61. Sanderson WT, Henneberger PK, Martyny J, et al. Beryllium contamination inside vehicles of machine shop workers. Appl Occup Environ Hyg 1999;14(4):223–30. 62. Miller A. Mesothelioma in household members of asbestos-exposed workers: 32 United States cases since 1990. Am J Ind Med 2005;47(5):458–62. 63. Hardell L, Sage C. Biological effects from electromagnetic field exposure and public exposure standards. Biomed Pharmacother 2008;62(2):104–9. 64. Feycthting M, Ahlbom A, Kheifets L. EMF and health. Annu Rev Public Health 2005;26:165–89. 65. Otto M, von Muhlendahl KE. Electromagnetic fields (EMF): do they play a role in children’s environmental health (CEH)? Int J Hyg Environ Health 2007;210(5): 635–44. 66. Kabuto M, Nitta H, Yamamoto S, et al. Childhood leukemia and magnetic fields in Japan: a case-control study of childhood leukemia and residential powerfrequency magnetic fields in Japan. Int J Cancer 2006;119(3):643–50. 67. International Agency for Research on Cancer. Volume 80. Non-ionizing radiation, part 1: static and extremely low-frequency (ELF) electric and magnetic fields. IARC monographs on the evaluation of carcinogenic risks to humans. March 7th, 2002. Available at: http://monographs.iarc.fr/ENG/Monographs/vol80/ volume80.pdf. Accessed May 25, 2008. 68. Ahlbom A, Green A, Kheifets L, et al. Epidemiology of the health effects of radiofrequency exposure. Environ Health Perspect 2004;112(17):1741–54. 69. vom Saal FS, Akingbemi BT, Belcher SM, et al. Chapel Hill bisphenol A expert panel consensus statement: integration of mechanisms, effects in animals and potential to impact human health at current levels of exposure. Reprod Toxicol 2007;24(2):131–8. 70. Calafat A, Kuklenyik Z, Reidy JA, et al. Urinary concentrations of bisphenol A and 4-nonylphenol in a human reference population. Environ Health Perspect 2005; 113(4):391–5. 71. Blount BC, Silva MJ, Caudill SP, et al. Levels of seven urinary phthalate metabolites in a human reference population. Environ Health Perspect 2000;108(10): 979–82. 72. US Environmental Protection Agency. Consumer factsheet on: di (2-ethylhexyl) phthalate. Ground water & drinking water. Available at: http://www.epa.gov/ safewater/dwh/c-soc/phthalat.html. Accessed April 16, 2008. 73. Center for Health, Environment, and Justice. What you can do—reducing your exposure to BPA. Available at: http://www.chej.org/documents/what%20parents% 20can%20do%20page%20for%20web.pdf. Accessed May 20, 2008. 74. Environmental Health CDC. Spotlight on polybrominated diphenyl ethers and polybrominated biphenyls. February 2008. Available at: http://www.cdc.gov/ exposurereport/pdf/factsheet_pbde.pdf. Accessed April 16, 2008. 75. Alaska Community Action on Toxics. PBDEs and your health. Available at: http:// www.akaction.org/. Accessed May 25, 2008. 76. Houlihan J, Brody C, Schwan B. Not too pretty, phthalates, beauty products and the FDA. Environmental Working Group. July 2002. Available at: http://www. safecosmetics.org/docUploads/NotTooPretty_r51.pdf. Accessed April 16, 2008. 77. A poison kiss: the problem of lead in lipstick. Campaign for safe cosmetics. October 2007. Available at: http://www.safecosmetics.org/docUploads/A%20 Poison%20Kiss.pdf. Accessed April 16, 2008.
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Vitamin and Mineral Supplements Irene Hamrick, MDa,*, Sandra H. Counts, PharmDb KEYWORDS Vitamins Minerals Wellness Prevention
Vitamin and mineral deficiencies have been associated with several diseases, such as scurvy and rickets. Improved nutrition in the population and fortification of the food supply have eliminated most deficiency diseases in the United States. Certain populations, however, including women of childbearing age, the elderly, and patients on certain diets or medications, still benefit from vitamin and mineral supplements (Table 1). Evidence-based information on the benefits and risks of vitamins and minerals is beginning to accumulate. Some vitamins and minerals once thought to have protective or preventive effects have actually been shown to have harmful or negligible effects. For example, there is no conclusive evidence that vitamin C prevents colds, heart disease, or cancer. Similarly, vitamin E has not proved to prevent heart disease or cancer. The supplement betacarotene has not shown to prevent cancer and actually may increase the risk of lung cancer in smokers. A recent Cochrane16 and JAMA17 review of 68 trials showed that treatment with betacarotene, vitamin A, and vitamin E may increase mortality, and effects of vitamin C and selenium need further study. This article presents the latest evidence for the appropriate use of vitamin and mineral supplements to promote wellness and prevent disease. Although a comprehensive two-part review of this topic was published in JAMA in 2002,18,19 there have been many important updates since then. Most patients do not list vitamins and minerals when giving medication histories unless so prompted. Because several vitamins and minerals can have risks and interactions, it is important to address supplement intake. The Institute of Medicine (www.iom.edu) lists dietary reference intakes, the amount needed to prevent deficiency, the optimal amount for health, the upper tolerable limits, and risks and benefits.11 It is also important to recommend that patients add certain vitamins and minerals if there is evidence that doing so benefits them. This article concentrates on the use of Dr. Hamrick’s work was supported by grant HRSA: 1 K01 HP00159-01, Geriatric Academic Career Award. a Department of Family Medicine, Division of Geriatrics, Brody School of Medicine at East Carolina University, Brody 4N-72A, 600 Moye Boulevard, Greenville, NC 27834, USA b Medical University of South Carolina, AnMed Health Family Medicine Residency Program, 2000 East Greenville Street, Suite 3600, Anderson, SC 29621, USA * Corresponding author. E-mail address:
[email protected] (I. Hamrick). Prim Care Clin Office Pract 35 (2008) 729–747 doi:10.1016/j.pop.2008.07.012 primarycare.theclinics.com 0095-4543/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.
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Group
Supplement
Action
Notes
Teens with poor eating habits
Multivitamin with minerals, calcium
Multiple, build bone
Daily multivitamin Elemental calcium, 1300 mg daily
Women of childbearing age
Maternal multivitamin with folate, calcium, vitamin D
Prevent NTDs
To prevent NTDs >400 mg folate daily Women with a previous NTD pregnancy take 4 mg/daily beginning 1 month before and continuing for 3 months after conception1 Not enough evidence to evaluate the use of vitamin D in pregnancy2
Pregnancy, lactation
Folic acid, calcium
Pregnancy: 0.6 mg folic acid daily Breastfeeding: 0.5 mg folic acid daily Increases fetal bone density
Prenatal vitamins usually contain 0.8–1 mg folic acid and 200–300 mg calcium per tablet Less than 19 years, 1300 mg calcium daily; >19–50 years, 1000 mg calcium daily
Perimenopause and menopause
Calcium, vitamin D
Maintains bone
Rapid bone loss in menopausal years
Adults with low caloric intake
Multivitamin
Various
The elderly consume on average 1200 calories a day, versus the 2000 calories daily needed to meet the RDA daily for vitamins and minerals
Elderly
Calcium multivitamin vitamin D3 vitamin B124 selenium for men
Bone loss Falls Muscle weakness Anemia Neurologic problems Prostate cancer
Calcium, 1200–1500 mg in divided doses Vitamin D, 800–1000 IU Vitamin B12, 1000 mg Selenium, 200 mg
Gastric bypass,malabsorption syndrome
Risk of several vitamin deficiencies: B12,5–7 iron6,7
B12 deficiency increases each postoperative year, and can be seen in up to 70% of patients Oral multivitamins do not provide sufficient amount; need sublingual or IM B12 Commonly seen in menstruating women It may be difficult for patients to absorb oral iron, so may need IV or IM
Be alert for deficiencies Check vitamin levels in patients at risk because about 10% of patients need IM dosing Monitor ferritin or iron levels even months or years after surgery because iron stores continuously decline for up to 7 years
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Table 1 Special populations and vitamin and mineral needs
Vitamin C
In postmenopausal women with diabetes, vitamin C in doses >300 mg daily increases risk of cardiovascular mortality8
Avoid high-dose vitamin C
ESRD, hemodialysis
Extra folic acid (0.8–1 mg) and B6 (10 mg or more) are needed daily; vitamin D must be given as calcitriol9
ESRD patients should not take regular multivitamins but rather special renal formula multivitamins, usually prescribed by the nephrologist Do not give extra vitamin A, C, or betacarotene because they may accumulate
Overview of vitamin supplementation in ESRD can be found at: http://links.nephron.com/ nephsites/adp/vits.htm
Chronic use of alcohol10
B vitamins, vitamin K
Patients have very poor nutrition, often getting over half their calories from alcohol Malabsorption is also a problem
These patients should take a daily multivitamin Additional B vitamins may also need to be prescribed for those with low levels and additional vitamin K for those with extensive liver disease
Smokers
Vitamin C
Smokers need 35 mg more than the RDA for vitamin C in nonsmokers11
RDA male smokers: 125 mg RDA female smokers: 110 mg
Vegetarians or vegans
B12 calcium
Anemia, neuropathy Patients who eat eggs or dairy products likely get enough B12; pure vegans, however, may have a deficiency of vitamins B2, B12,12 and D, calcium, iron, and zinc13
B12 is found almost exclusively in animal products, so vegans need to consume fortified foods or take a B12 supplement of 10 mg daily.14 Most multivitamins contain 6 mg (100% of the RDA)
Prostate cancer
Selenium zinc
Reduces prostate cancer High-dose or long-term zinc use increases risk of fatal or advanced prostate cancer
Selenium, 200 mg daily Avoid supplemental zinc
Wrist fractures in the elderly
Vitamin C
Reduced the risk of reflex sympathetic dystrophy (complex regional pain syndrome) by 83% in a randomized trial15
500 mg daily for 50 days post wrist fracture
Abbreviations: ESRD, end-stage renal disease; IM, intramuscularly; IV, intravenously; NTDs, neural tube defects; RDA, recommended daily allowance.
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Diabetes
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vitamin and mineral supplements for preventing illness or promoting wellness in adults. It does not include the use of vitamins and minerals to treat existing diseases or the benefits of boosting vitamin and mineral intake through dietary means.
THE BENEFITS OF SUPPLEMENTATION WITH VITAMINS AND MINERALS Cardiovascular Disease
For a long time, it was thought that vitamin E was protective of cardiovascular disease, and this was supported by the Nurses’ Health Study in women20 and a large study in men.21 One study in dialysis patients showed decreased cardiovascular deaths.22 Newer trials, however, including the Heart Outcomes Prevention Evaluation Study, revealed that about 9000 men and women at high risk for heart disease who took 400 IU of vitamin E for 4 to 5 years experienced no cardiovascular benefit.23 The recent Women’s Antioxidant and Folic Acid Cardiovascular study,24 with 5442 high-risk women, did not show any reduction in cardiovascular events, taking a combination folic acid, B6, and B12 supplement over 7 years. The American Heart Association does not recommend supplementing with antioxidants including C, E, and betacarotene for the general public or for those with heart disease. They do, however, recommend diets rich in fruits, vegetables, and whole grains.25 A higher quintile of vitamin C supplement intake in diabetic women was directly related to increased cardiovascular mortality.8 The Women’s Health Study showed that 600 IU vitamin E every other day showed a nonsignificant trend to reduce the risk of venous thromboembolism.26 Randomized controlled trials are needed to support both findings. Vitamin D at 800 IU daily decreased blood pressure by 9.3% in vitamin D–deficient women over 70 years old.27 For magnesium, a Cochrane review of studies did not find evidence that supplementation reduces high blood pressure in adults.28 Cancer
Diets high in antioxidants are shown to reduce the risk of cancer,29 but antioxidant vitamins and minerals as supplements have not shown a protective effect. In 2003 the United States Preventive Services Task Force30 and Cochrane database of systematic reviews31 found insufficient evidence for the prevention of cancer with antioxidants, vitamins A, C, or E; folic acid; or multivitamins. Furthermore, studies found an increased risk of lung cancer with betacarotene in smokers.32–34 Likewise, zinc supplementation may double the risk of developing prostate cancer if taken in doses greater than 100 mg daily or for 10 or more years.35 The 5-year National Institutes of Health–American Association of Retired Persons Diet and Health Study revealed that regular multivitamin use is not associated with the risk of early or localized prostate cancer and a meta-analysis of cohort studies has shown a decrease of the risk of prostate cancer with selenium intake.36 Men taking high levels of multivitamins (more than seven times a week), particularly those taking additional selenium, betacarotene, or zinc, and those with a family history, however, have increased risk of advanced and fatal prostate cancers.37 Large randomized controlled trials are needed to confirm this effect and are under way.38 A recent double-blind placebo-controlled trial has shown that 1100 IU of vitamin D plus 1400 mg of calcium per day decreased cancer incidence by 40% in 1179 women in Nebraska over age 55.39 The calcium-only arm of the 4-year study did not show an effect. The apoptotic effect of vitamin D is postulated to be the cause.
Vitamin and Mineral Supplements
An intriguing study suggests that women who take prenatal multivitamins with folic acid before and during pregnancy may protect against certain childhood cancers in their babies. The systematic review and meta-analysis of seven United States studies showed a 39% lower risk of leukemia, a 47% lower risk of neuroblastoma, and a 27% lower risk of brain tumors. Further study is needed to determine which components of the multivitamin led to the benefit.40 Respiratory Disease
In populations with a high likelihood of vitamin C deficiency, or low plasma vitamin C levels, supplementation has preventive and therapeutic effects on reducing the incidence and duration of pneumonia. Current evidence, however, is too weak to advocate widespread prophylactic use of vitamin C to prevent pneumonia in the general population.41 Counter to popular belief, vitamin C supplementation does not reduce the incidence of colds in the normal population. Studies in people exposed to brief periods of severe physical exercise or cold environments, however, have shown a significant preventive effect of vitamin C on the incidence of colds.42 Zinc lozenges given once daily for prophylaxis have reduced the incidence of colds in 178 school children from 1.7 to 1.28 per season. Given four times daily, therapeutically, it reduced the duration of cold symptoms from 9 to 6.9 days.43 In 100 adults, zinc lozenges started within 48 hours of symptom onset decrease the duration of the common cold from 7.6 to 4.4 days. The lozenges (either zinc gluconate or acetate) contain 9 to 24 mg elemental zinc per dose and are taken every 2 hours while awake.44 Other clinical trials with zinc supplements have not shown a benefit.45,46 Some negative results may have been caused by the flavoring agents chelating the zinc and preventing it from working. Review studies of 847 and 14 clinical trials48 did not show a benefit of zinc lozenges on prevention or duration of colds. Although mostly considered safe,49 zinc lozenges have an unpleasant metallic taste and may cause nausea. Zinc nasal sprays may lead to permanent anosmia.50,51 Zinc is safe in amounts that do not exceed 40 mg orally a day.11 Doses greater than 100 mg daily, however, may reduce copper absorption and could lead to deficiency and sideroblastic anemia.52 The doses used short term for shortening colds should not pose this risk. Patients need to be informed of the risks and benefits for this over-the-counter mineral. Musculoskeletal Problem
Vitamin D has been shown to reduce falls by 19% to 72%53–57 depending on the population studied, through improved muscle strength.55 Vitamin D, 700 to 800 IU daily, reduces hip (26%) and nonvertebral fractures (23%) in patients over age 60 (number needed to treat 5 45).54 No fracture reduction was seen in the group taking a lower dose of vitamin E (400 IU).58 In the very old, average age 83, even greater hip fracture reduction of 43% was seen.59 Calcium alone60 and in combination with vitamin D has been shown to reduce fractures in the elderly58,59,61 and in patients at high risk, such as those with kidney disease, or those on corticosteroids.62,63 Adequate amounts of vitamin D and calcium are needed by all age groups to slow bone loss, and in cases of inadequate dietary intake, supplementation is a reasonable alternative. Recent reports from the Women’s Health Initiative reveal calcium and vitamin D supplements did not reduce fractures in postmenopausal women. This effect was likely caused by low compliance rates of 54%64 and 59%.65 A subanalysis of women who took 80% of calcium and vitamin D doses showed a 29% reduction in the risk of hip fractures.65
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Limiting sodium intake to less than 2 g daily decreases calcium resorption from bone.66 High sodium intake causes excessive renal calcium losses. A clinical trial of calcium and vitamin D supplementation in patients over 65 showed a 14% reduction in tooth loss over placebo.67 Vitamin K supplementation has been shown to improve bone density in an American trial and reduce the risk of fractures in Japanese trials.68 In a retrospective cohort study of atrial fibrillation patients, the blood thinner warfarin increases the risk of fracture by 25%.69 This effect was more pronounced in men, 63% but not statistically significant in women. No data on prevention of fractures with vitamin K in the American population are available. Vitamin A (retinol) intake of greater than 3000 IU has been shown to increase hip fracture risk by 48% in a prospective analysis of the Nurses’ Health Study.70,71 A nested case control study in northern Europe showed a 68% increased risk of hip fracture with every 3333 IU (1 mg) increase in dietary vitamin A.70 Randomized controlled trials need to be done in this area to define the risk of vitamin A supplementation. The Food Standards Agency recommends limiting vitamin A intake to 5000 IU (1.5 mg) daily to reduce the risk of osteoporosis.72 Vitamin C (500 mg daily for 50 days) reduced the risk of reflex sympathetic dystrophy (complex regional pain syndrome) by 83% in a randomized trial of elderly patients after a wrist fracture.15 It has been postulated that the antioxidant defense system is impaired in rheumatoid arthritis.73 Small clinical trials have shown benefit in symptom control with 1200 IU of vitamin E daily in divided doses74–76 and antioxidant combinations75 in rheumatoid arthritis. In osteoarthritis, a trial of 133 patients showed benefit in hip and knee pain with 1000 mg of calcium ascorbate.77 In a small (N 5 26) trial, hand osteoarthritis symptoms improved with 6400 mg folate and 20 mg vitamin B12.78 A double-blind, randomized controlled trial did not show any benefit in osteoarthritis, however, from a combination of selenium and vitamins A, C, and E.79 Boron has been cited to be beneficial in arthritis80,81 and a small trial of 20 arthritic patients showed that 50% of those taking 6 mg boron daily had a reduction in pain compared with 10% in the placebo group.82 In 12 patients, boron was shown to reduce urinary calcium excretion.83 Although this preliminary evidence is interesting, there has not been any further clinical research published on this use. The amount of boron in a typical diet is 1.5 to 3 mg. Boron is safe in amounts less than 20 mg orally a day, but higher doses increase estradiol-17b levels in women.83,84 Until further clinical studies are done and safety issues are defined, it is best to avoid boron supplements. Diabetes
Vitamin D has been shown to decrease the risk of diabetes in populations at high risk in a review of observational studies and small trials.85 Large randomized controlled trials are needed for confirmation. The pancreatic beta cells have vitamin D receptors and vitamin D facilitates transcription of the activation of the insulin gene and the insulin gene promoter. Insulin secretion is also a calcium-dependent process by calbindin, a cytosolic calcium-binding protein. Chromium picolinate has been found to reduce insulin resistance in one study but a systematic review and meta-analysis showed no benefit of chromium in nondiabetics and inconclusive evidence in diabetic patients.86 The Food and Drug Administration has not supported chromium supplementation based on five additional studies that have shown no effect.87
Vitamin and Mineral Supplements
Neurologic Problems
Vitamin B12 and folic acid deficiency can cause dementia and checking levels is recommended as part of a dementia work-up. Several Cochrane reviews have shown no benefit, however, from vitamins B6, B12, and E, folic acid, and selenium supplementation in preventing cognitive decline in elderly or in treatment of dementia.88–92 Vitamin E has been shown to reduce the risk of tardive dyskinesia by increasing the level of superoxide dismutase, which is thought to prevent oxidative tissue injury in patients on antipsychotics.93 Patients have to use extremely high doses of 1200 IU because only high levels can cross the blood-brain barrier. High doses of vitamin E, however, can lead to excessive bleeding and should be used with caution, particularly in patients on blood thinners or antiplatelet drugs. The hemorrhagic effects are thought to be caused by its inhibition of thrombin generation94 and platelet adhesion95 and antagonism of vitamin K.96 Multiple sclerosis has a higher incidence in latitudes with less sunshine, and a correlation with vitamin D deficiency is plausible. Data from the Nurses’ Health Study show an inverse relationship of supplemental vitamin D intake and incidence of multiple sclerosis.97 Despite these observational findings, no randomized controlled trial examining preventive supplementation exists. Eye Disease
Although some observational studies have suggest that people who eat a diet rich in antioxidant vitamins (carotenoids, vitamins C and E) or minerals (selenium and zinc) may be less likely to develop age-related macular degeneration, a Cochrane review showed no benefit for preventing age-related macular degeneration in patients.98 A Cochrane review of eight trials, however, showed that supplementation with antioxidant vitamins and zinc slowed the progression of age-related macular degeneration by 32% and improved visual acuity.99 The role of lutein, a carotenoid, in the prevention of age-related macular degeneration is discussed elsewhere in this issue. In developing countries vitamin A deficiency causes blindness, but not in the United States because the American diet is replete with vitamin A. WOMEN’S HEALTH
A Cochrane review100 shows benefits from 100 mg of vitamin B1 daily in reducing pain from menstrual cramps. The same review examines three trials using varying doses of magnesium and found them beneficial but no dosage recommendation was made. Vitamin B6 has been shown to help with menstrual pain in a small trial, but the combination of vitamin B6 and magnesium did not reduce symptoms over placebo. Considering the potential toxicity with vitamin B6, caution should be used in recommending it until larger trials are done. Vitamin E added to ibuprofen showed no difference in menstrual cramps from the ibuprofen-alone control group. In doses of 1200 to 1600 mg daily, calcium helps prevent premenstrual syndrome, or late luteal dysphoric disorder.101–103 The 17 parameter symptom score was reduced by 48% in the calcium group compared with an 18% reduction in the placebo group.103 It is thought that calcium dysregulation with secondary hyperparathyroidism and vitamin D deficiency is the underlying cause.101 Birth Defects
Folic acid given to childbearing women has been shown to prevent neural tube defects.104,105 Conversely, vitamin A has been shown to cause fetal craniofacial
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malformation with supplemental doses of just 15,000 IU daily, which is only three times the United States daily recommended intake.106 PRESCRIBING PEARLS Calcium
Calcium carbonate contains twice as much elemental calcium (40%) as calcium citrate (21%), and is the preferred formulation. Most calcium citrate formulations require the intake of two pills for the 500- or 600-mg dose compared with one pill of calcium carbonate. Patients should be cautioned to read the label carefully to get adequate amounts of elemental calcium. Taking calcium with meals improves absorption by 20% to 25%.107 Although calcium citrate is better absorbed in a low acid environment and on an empty stomach, no difference in absorption is shown as long as either formulation is taken with food.108,109 Absorption of calcium decreases with increasing doses, and drops off sharply over 500 mg because the small bowel is easily saturated.110 It is recommended to separate the daily intake to three or four daily doses.109,111 Calcium is a divalent cation and competes for absorption if taken at the same time with other divalent cations (iron, zinc, magnesium). Calcium can also interfere with the absorption of some antibiotics, such as tetracyclines and fluoroquinolones,112 and with levothyroxine113 where calcium is thought to form insoluble complexes, preventing absorption. Patients should be advised to take these drugs at least 2 hours before, or 4 to 6 hours after calcium supplements. For many elderly who take a number of medications, complex dosing may be too challenging. It may be necessary to suspend the administration of calcium for the short duration of antibiotic therapy. Coadministration with thyroid medication is acceptable if therapeutic and stable thyroid-stimulating hormone levels can be reached. Some patients taking calcium supplements may raise concerns about increasing risks for kidney stones. The most common type of kidney stone is calcium oxalate. Absorption of oxalate from foods causes it to bind with serum calcium in the blood and precipitate in the kidneys as stones. Providing adequate calcium in the diet actually decreases kidney stone formation by binding oxalate in the gut and preventing its absorption. A prospective study of more than 45,000 subjects showed that kidney stone incidents were inversely related to dietary calcium.114 Calcium is absorbed with the aid of vitamin D, but ingestion does not have to occur at the same time.109 Corticosteroids inhibit vitamin D–mediated calcium absorbtion in the gut and deposition in the bone.62 Vitamin B12
Vitamin B12 was long thought to require parenteral administration. Ample evidence shows that oral administration is equally effective or superior to intramuscular injection.115 Advertisements abound for intranasal B12, but it is much more expensive and no more effective than oral B12. Various oral doses are effective depending on the cause of deficiency, but even patients with pernicious anemia can effectively be treated with oral doses of 1000 mg daily.116 High-risk patients and patients taking certain medications may need B12 supplements or close monitoring of blood levels (Table 2). A review on vitamin B12 explains the complex absorption.117 Vitamin C
The body absorbs very little vitamin C beyond 200 mg. Using larger doses adds to gastrointestinal toxic effects.132
Table 2 Patients on selected medications Vitamin Affected
Mechanism
Treatment
Anticonvulsants (phenytoin, phenobarbital, carbamazepine, and primidone)
Vitamin D
These drugs induce CYP enzyme 3A4, which increases the metabolism of vitamin D to inactive compounds, which in turn reduces calcium absorption Hypocalcemia, osteomalacia, and osteoporosis can occur with long-term use, >6 months
Vitamin D levels should be monitored in high-risk patients and supplemented as needed118
Bisphosphonates (alendronate (Fosamax), ibandronate (Boniva), risedronate (Actonel)
Calcium Vitamin D
Patients should be taking supplemental calcium and vitamin D to facilitate retention of calcium in bone
Elemental calcium, 1500 mg daily Vitamin D, 800–1000 IU daily
Colchicine
Vitamin B12
Colchicine inhibits the development of vitamin B12 receptor in the rapidly proliferating ileal mucosal cells119
Monitor B12 levels in patients on high doses (>1.9 mg) for long periods
Corticosteroids
Calcium Vitamin D Potassium
Steroids inhibit vitamin D–mediated calcium absorbtion in the gut and deposition in the bone62 Steroids cause sodium retention, resulting in potassium loss
High dose prednisone 7.5 mg per day and long-term >6 months steroids Supplement with calcium, 1500 mg daily and vitamin D, 800 IU daily Monitor potassium level and supplement as needed
DMPA depot medroxyprogesterone contraceptive (Depo Provera)
Calcium Vitamin D
Women who use DMPA for >2 years have significantly reduced bone mineral density of the lumbar spine and femoral neck
Elemental calcium, 1300 mg daily Vitamin D, 400 IU daily
Metformin (Glucophage)
Vitamin B12
Metformin competes with calcium in the calcium-dependent intrinsic factor-B12 receptor of the ileum120,121
Reduced serum levels occur in up to 30% of patients on chronic dosing122 Supplementation with 1200 mg elemental calcium daily negates this effect, allowing appropriate vitamin B12 absorption122
Vitamin and Mineral Supplements
Medication
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Vitamin B12
Cobalamine is oxidized by nitrous oxide, rendering it unusable123
Check levels before and supplement after surgery
Orlistat(Rx Xenical or OTC Alli)
Fat soluble vitamins: A, D, E, K, and betacarotene
Orlistat blocks absorption of fat and fat-soluble vitamins
Supplement with a multivitamin daily, space dose from orlistat by 2 hours before or after orlistat
Proton pump inhibitors
Calcium B12
Absorbtion of calcium carbonate is decreased by increased gastric pH Bone proton pump inhibition leads to osteoporosis124 Decreased gastric acid reduces cleavage of protein-bound dietary B12 and absorption125 but not in fortified foods or B12 supplements
Take calcium carbonate with food or use calcium citrate No deficiencies with H2 blockers4 Clinically significant B12 deficiency occurs after R4 years126 Multivitamins are often adequate to replace decreased dietary absorption
Rifampin
Vitamin D
Increases hepatic metabolism of vitamin D127,128
Monitor serum levels of calcium and vitamin D INH (isoniazid), a hepatic enzyme inhibitor, negates effect of rifampin (enzyme inducer) and vitamin D levels are not affected129,130
Sulfasalazine (Azulfidine)
Folic acid
Colon cancer risk is reduced by 62% with folate supplementation130 Sulfazalazineinduced hemolysis can also increase folate requirements for red blood cell formation Sulfasalazine inhibits folate absorption and interferes with breakdown of dietary folate to absorbable form131
Give folic acid as 1 mg daily (sole supplement) or as 0.4 mg daily in a multivitamin to ensure enough folate to prevent deficiency and to decrease risk of colorectal cancer
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Nitrous oxide anesthesia
Vitamin and Mineral Supplements
Vitamin D
The classic NHANES III study (approx 3500 women) showed 70% of patients aged 50 to 70 and greater than 90% over age 70 do not get adequate dietary vitamin D.133 Skin exposure to sunlight provides as much as 80% to 90% of the body’s vitamin D134 but recommendations for sunscreen use and indoor lifestyles decrease this proportion. Elderly and institutionalized patients require supplemental doses of vitamin D to prevent deficiency.135 Serum levels of less than 20 ng/mL of 25-OH vitamin D are a commonly accepted cutoff for vitamin D deficiency, whereas levels between 20 and 30 ng/mL are considered insufficiency. It has been shown that about 30% of people living in the northern United States are deficient. Surprisingly, a recent study of 637 adults in southern Arizona also found deficiency in 23% of whites, 38% of Hispanics, and 56% of blacks, so deficiencies are common even in sunny locales.136 The National Osteoporosis Foundation has increased its recommendations in March of 2007 to 400 to 800 IU daily for adults under 50, and to 800 to 1000 IU daily for adults 50 and over.137 Two forms of vitamin D are available: cholecalciferol, vitamin D3, is produced in the skin by sun exposure; and ergocalciferol, vitamin D2 is synthesized by yeast. Although some studies138–140 have found ergocalciferol to be only 70% as bioavailable as cholecalciferol, other studies have shown no difference.141,142 Differences in clinical outcomes between the two formulations have not been studied. Patients taking bisphosphonates for osteoporosis should be taking supplemental calcium and vitamin D to facilitate retention of calcium in bone. Depo-Provera (depot medroxyprogesterone acetate contraceptive injection) has been shown to cause bone loss.143 Women who use Depo-Provera for more than 2 years have a significantly reduced bone mineral density of the lumbar spine and femoral neck. In 2004, the Food and Drug Administration added a black box warning to the package insert describing the risk and warning that the loss is greater the longer the drug is administered and that it may not be completely reversible after the drug is discontinued.144 A detailed position paper was published in 2006 on this topic by the Society for Adolescent Medicine.145 They recommend that adolescents taking Depo-Provera receive 1300 mg of calcium carbonate plus 400 IU a day of vitamin D along with weight-bearing exercise. They also acknowledge that it has not been established whether these practices offset the bone mineral density changes or prevent future fractures. SUMMARY
It is important to be proactive in questioning patients about their vitamin and supplement use and to communicate with them about the importance of taking or avoiding certain vitamins and minerals, depending on their individual circumstances. Many patients eat inadequate diets, and the food supply is not as nutrient dense as it used to be (see the article on food and farming methods elsewhere in this issue). The elderly consume on average 1200 calories a day, compared with the 2000 calories recommended to meet the minimum daily allowances for vitamins and minerals. It is reasonable to recommend a daily multivitamin for all adults,18,146 although well done studies supporting this stance are not available. Most information on vitamins and minerals is based on observational data. Conclusive evidence in properly conducted prospective studies exists for folate in the prevention of neural tube defects, and for vitamin D supplementation in the prevention of falls and fractures. Because information is changing rapidly, it is important for the primary care physician to keep abreast of changes so that he or she may best advise patients. Numerous reports exist describing supplements that do not contain the
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labeled amount of active ingredient or contain dangerous contaminants. The following Internet resources are recommended for keeping up with this challenging and important area of patient care: Cochrane Library: www.cochrane.org Evidence-based reviews Institute of Medicine for dietary reference intakes: www.iom.edu National Institutes of Health: www.cc.nih.gov/ccc/vitamins and minerals National Institutes of Health Office of Dietary Supplements: http://ods.od.nih. gov/health_information/health_information.aspx Detailed fact sheets on over 70 vitamin, mineral, and herbal products Consumer Labs: www.consumerlab.com Identifies quality supplements through independent testing, has free newsletter Natural Medicines Comprehensive Database: www.naturaldatabase.com, $92/y Evidence-based, clinical information, and concise patient handouts on 11001 products, also provides brand ratings for over 30,000 products
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69. Gage BF, Birman-Deych E, Radford MJ, et al. Risk of osteoporotic fracture in elderly patients taking warfarin: results from the national registry of atrial fibrillation 2. Arch Intern Med 2006;166(2):241–6. 70. Melhus H, Michaelsson K, Kindmark A, et al. Excessive dietary intake of vitamin A is associated with reduced bone mineral density and increased risk for hip fracture. Ann Intern Med 1998;129(10):770–8. 71. Feskanich D, Singh V, Willett WC, et al. Vitamin A intake and hip fractures among postmenopausal women. JAMA 2002;287(1):47–54. 72. Ages and stages, older people. 2008. Available at: http://www.eatwell.gov.uk/ agesandstages/olderpeople/. Accessed May 10, 2008. 73. Jaswal S, Mehta HC, Sood AK, et al. Antioxidant status in rheumatoid arthritis and role of antioxidant therapy. Clin Chim Acta 2003;338(1–2):123–9. 74. Edmonds SE, Winyard PG, Guo R, et al. Putative analgesic activity of repeated oral doses of vitamin E in the treatment of rheumatoid arthritis: results of a prospective placebo controlled double blind trial. Ann Rheum Dis 1997;56(11): 649–55. 75. Helmy M, Shohayeb M, Helmy MH, et al. Antioxidants as adjuvant therapy in rheumatoid disease: a preliminary study. Arzneimittelforschung 2001;51(4): 293–8. 76. Wittenborg A, Petersen G, Lorkowski G, et al. Effectiveness of vitamin E in comparison with diclofenac sodium in treatment of patients with chronic polyarthritis. Z Rheumatol 1998;57(4):215–21. 77. Jensen NH. Reduced pain from osteoarthritis in hip joint or knee joint during treatment with calcium ascorbate: a randomized, placebo-controlled crossover trial in general practice. Ugeskr Laeger 2003;165(25):2563–6. 78. Flynn MA, Irvin W, Krause G. The effect of folate and cobalamin on osteoarthritic hands. J Am Coll Nutr 1994;13(4):351–6. 79. Hill J, Bird HA. Failure of selenium-ace to improve osteoarthritis. Br J Rheumatol 1990;29(3):211–3. 80. Devirian TA, Volpe SL. The physiological effects of dietary boron. Crit Rev Food Sci Nutr 2003;43(2):219–31. 81. Boron. EBSCO, 2007. Available at: http://healthlibrary.epnet.com/GetContent. aspx?token5e0498803-7f62-4563-8d47-5fe33da65dd4&chunkiid521616. Accessed June 3, 2008. 82. Newnham RE. Essentiality of boron for healthy bones and joints. Environ Health Perspect 1994;102(Suppl 7):83–5. 83. Nielsen FH, Hunt CD, Mullen LM, et al. Effect of dietary boron on mineral, estrogen, and testosterone metabolism in postmenopausal women. FASEB J 1987; 1(5):394–7. 84. Miljkovic D, Miljkovic N, McCarty MF. Up-regulatory impact of boron on vitamin D function: does it reflect inhibition of 24-hydroxylase? Med Hypotheses 2004; 63(6):1054–6. 85. Pittas AG, Lau J, Hu FB, et al. The role of vitamin D and calcium in type 2 diabetes: a systematic review and meta-analysis. J Clin Endocrinol Metab 2007; 92(6):2017–29. 86. Althuis MD, Jordan NE, Ludington EA, et al. Glucose and insulin responses to dietary chromium supplements: a meta-analysis. Am J Clin Nutr 2002;76(1): 148–55. 87. Chromium picolinate and insulin resistance. Office of nutritional products, labelin, and dietary supplements. Available at: http://www.cfsan.fda.gov/wdms/ qhccr.html. Accessed August 17, 2008.
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88. Malouf R, Grimley Evans J. The effect of vitamin B6 on cognition. Cochrane Database Syst Rev 2003;(4):CD004393. 89. Blacker D. Neither vitamin E nor donepezil delays progression from amnestic mild cognitive impairment to Alzheimer’s disease in the long term. Evid Based Ment Health 2006;9(1):20. 90. Malouf R, Areosa Sastre A. Vitamin B12 for cognition. Cochrane Database Syst Rev 2003;(3):CD004326. 91. Malouf M, Grimley EJ, Areosa SA. Folic acid with or without vitamin B12 for cognition and dementia. Cochrane Database Syst Rev 2003;(4):CD004514. 92. Eussen SJ, de Groot LC, Joosten LW, et al. Effect of oral vitamin B12 with or without folic acid on cognitive function in older people with mild vitamin B12 deficiency: a randomized, placebo-controlled trial. Am J Clin Nutr 2006;84(2):361–70. 93. Zhang XY, Zhou DF, Cao LY, et al. The effect of vitamin E treatment on tardive dyskinesia and blood superoxide dismutase: a double-blind placebo-controlled trial. J Clin Psychopharmacol 2004;24(1):83–6. 94. Rota S, McWilliam NA, Baglin TP, et al. Atherogenic lipoproteins support assembly of the prothrombinase complex and thrombin generation: modulation by oxidation and vitamin E. Blood 1998;91(2):508–15. 95. Higashi O, Kikuchi Y. Effects of vitamin E on the aggregation and the lipid peroxidation of platelets exposed to hydrogen peroxide. Tohoku J Exp Med 1974; 112(3):271–8. 96. Booth SL, Golly I, Sacheck JM, et al. Effect of vitamin E supplementation on vitamin K status in adults with normal coagulation status. Am J Clin Nutr 2004; 80(1):143–8. 97. Munger KL, Zhang SM, O’Reilly E, et al. Vitamin D intake and incidence of multiple sclerosis. Neurology 2004;62(1):60–5. 98. Evans JR, Henshaw K. Antioxidant vitamin and mineral supplementation for preventing age-related macular degeneration. Cochrane Database Syst Rev 2000;(2):CD000253. 99. Evans JR. Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration. Cochrane Database Syst Rev 2006;(2):CD000254. 100. Proctor ML, Murphy PA. Herbal and dietary therapies for primary and secondary dysmenorrhoea. Cochrane Database Syst Rev 2001;(3):CD002124. 101. Thys-Jacobs S. Micronutrients and the premenstrual syndrome: the case for calcium. J Am Coll Nutr 2000;19(2):220–7. 102. Ward MW, Holimon TD. Calcium treatment for premenstrual syndrome. Ann Pharmacother 1999;33(12):1356–8. 103. Thys-Jacobs S, Starkey P, Bernstein D, et al. Calcium carbonate and the premenstrual syndrome: effects on premenstrual and menstrual symptoms. Premenstrual Syndrome Study Group. Am J Obstet Gynecol 1998;179(2):444–52. 104. Czeizel AE, Dudas I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med 1992;327(26):1832–5. 105. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group. Lancet 1991;338(8760):131–7. 106. Rothman KJ, Moore LL, Singer MR, et al. Teratogenicity of high vitamin A intake. N Engl J Med 1995;333(21):1369–73. 107. Heaney RP, Smith KT, Recker RR, et al. Meal effects on calcium absorption. Am J Clin Nutr 1989;49(2):372–6. 108. Recker RR. Calcium absorption and achlorhydria. N Engl J Med 1985;313(2): 70–3.
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109. Heaney RP. Calcium supplements: practical considerations. Osteoporos Int 1991;1(2):65–71. 110. Heller HJ, Greer LG, Haynes SD, et al. Pharmacokinetic and pharmacodynamic comparison of two calcium supplements in postmenopausal women. J Clin Pharmacol 2000;40(11):1237–44. 111. Heaney RP, Weaver CM, Fitzsimmons ML. Influence of calcium load on absorption fraction. J Bone Miner Res 1990;5(11):1135–8. 112. Aminimanizani A, Beringer P, Jelliffe R. Comparative pharmacokinetics and pharmacodynamics of the newer fluoroquinolone antibacterials. Clin Pharm 2001;40(3):169–87. 113. Schneyer CR. Calcium carbonate and reduction of levothyroxine efficacy. JAMA 1998;279(10):750. 114. Curhan GC, Willett WC, Rimm EB, et al. A prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones. N Engl J Med 1993;328(12):833–8. 115. Kuzminski AM, Del Giacco EJ, Allen RH, et al. Effective treatment of cobalamin deficiency with oral cobalamin. Blood 1998;92(4):1191–8. 116. Berlin H, Berlin R, Brante G. Oral treatment of pernicious anemia with high doses of vitamin B12 without intrinsic factor. Acta Med Scand 1968;184(4):247–58. 117. Hamrick I. Vitamin B12 deficiency in the elderly: a new look at deficiency and treatment. Family Practice Recertification 2003;25(6):17–20. 118. Collins N, Maher J, Cole M, et al. A prospective study to evaluate the dose of vitamin D required to correct low 25-hydroxyvitamin D levels, calcium, and alkaline phosphatase in patients at risk of developing antiepileptic drug-induced osteomalacia. QJM 1991;78(286):113–22. 119. Webb DI, Chodos RB, Mahar CQ, et al. Mechanism of vitamin B12 malabsorption in patients receiving colchicine. N Engl J Med 1968;279(16):845–50. 120. Caspary WF, Zavada I, Reimold W, et al. Alteration of bile acid metabolism and vitamin-B12-absorption in diabetics on biguanides. Diabetologia 1977;13(3): 187–93. 121. Gilligan MA. Metformin and vitamin B12 deficiency. Arch Intern Med 2002; 162(4):484–5. 122. Bauman WA, Shaw S, Jayatilleke E, et al. Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. Diabetes Care 2000;23(9): 1227–31. 123. Flippo TS, Holder WD Jr. Neurologic degeneration associated with nitrous oxide anesthesia in patients with vitamin B12 deficiency. Arch Surg 1993;128(12): 1391–5. 124. Yang YX, Lewis JD, Epstein S, et al. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA 2006;296(24):2947–53. 125. Marcuard SP, Albernaz L, Khazanie PG. Omeprazole therapy causes malabsorption of cyanocobalamin (vitamin B12). Ann Intern Med 1994;120(3):211–5. 126. Ruscin JM, Page RL II, Valuck RJ. Vitamin B(12) deficiency associated with histamine(2)-receptor antagonists and a proton-pump inhibitor. Ann Pharmacother 2002;36(5):812–6. 127. Shah SC, Sharma RK, Hemangini, et al. Rifampicin induced osteomalacia. Tubercle 1981;62(3):207–9. 128. Williams SE, Wardman AG, Taylor GA, et al. Long term study of the effect of rifampicin and isoniazid on vitamin D metabolism. Tubercle 1985;66(1):49–54. 129. Brodie MJ, Boobis AR, Hillyard CJ, et al. Effect of rifampicin and isoniazid on vitamin D metabolism. Clin Pharmacol Ther 1982;32(4):525–30.
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130. Lashner BA, Heidenreich PA, Su GL, et al. Effect of folate supplementation on the incidence of dysplasia and cancer in chronic ulcerative colitis: a casecontrol study. Gastroenterology 1989;97(2):255–9. 131. Halsted CH, Gandhi G, Tamura T. Sulfasalazine inhibits the absorption of folates in ulcerative colitis. N Engl J Med 1981;305(25):1513–7. 132. Levine M, Conry-Cantilena C, Wang Y, et al. Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance. Proc Natl Acad Sci U S A 1996;93(8):3704–9. 133. Moore C, Murphy MM, Keast DR, et al. Vitamin D intake in the United States. J Am Diet Assoc 2004;104(6):980–3. 134. Shearer MJ. The roles of vitamins D and K in bone health and osteoporosis prevention. Proc Nutr Soc 1997;56(3):915–37. 135. Dawson-Hughes B, Heaney RP, Holick MF, et al. Estimates of optimal vitamin D status. Osteoporos Int 2005;16(7):713–6. 136. Jacobs ET, Alberts DS, Foote JA, et al. Vitamin D insufficiency in southern Arizona. Am J Clin Nutr 2008;87(3):608–13. 137. NOF. National Osteoporosis Foundation Recommendations for Vitamin D. Washington DC: National Osteoporosis Foundation; 2007. 138. Trang HM, Cole DE, Rubin LA, et al. Evidence that vitamin D3 increases serum 25-hydroxyvitamin D more efficiently than does vitamin D2. Am J Clin Nutr 1998; 68(4):854–8. 139. Drinka PJ, Krause PF, Nest LJ, et al. Determinants of vitamin D levels in nursing home residents. J Am Med Dir Assoc 2007;8(2):76–9. 140. Armas LA, Hollis BW, Heaney RP. Vitamin D2 is much less effective than vitamin D3 in humans. J Clin Endocrinol Metab 2004;89(11):5387–91. 141. Theiler R, Bischoff H, Tyndall A, et al. Elevated PTH levels in hypovitaminosis D are more rapidly suppressed by the administration of 1,25-dihydroxy-vitamin D3 than by vitamin D3. Int J Vitam Nutr Res 1998;68(1):36–41. 142. Holick MF, Biancuzzo RM, Chen TC, et al. Vitamin D2 is as effective as vitamin D3 in maintaining circulating concentrations of 25-hydroxyvitamin D. J Clin Endocrinol Metab 2008;93(3):677–81. 143. Scholes D, LaCroix AZ, Ichikawa LE, et al. Injectable hormone contraception and bone density: results from a prospective study. Epidemiology 2002;13(5): 581–7. 144. Black box warning added concerning long-term use of depo-provera contraceptive injection. 2004. Available at: http://www.fda.gov/bbs/topics/ANSWERS/ 2004/ANS01325.html. Accessed May 10, 2008. 145. Cromer BA, Scholes D, Berenson A, et al. Depot medroxyprogesterone acetate and bone mineral density in adolescents–the black box warning: a position paper of the society for adolescent medicine. J Adolesc Health 2006;39(2): 296–301. 146. Oakley GP Jr. Eat right and take a multivitamin. N Engl J Med 1998;338(15): 1060–1.
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Dietar y Supplements Commonly Us e d for Prevention Wadie Najm, MD, MEda,*, Desiree Lie, MD, MEdb KEYWORDS Complementary & alternative medicine Herbals Evidence Prevention Benefit Harm
Surveys in the United States and other countries show that 30% to 90% of the population are using or have used some form of complementary and alternative medicine (CAM) for managing health problems and in particular chronic medical conditions. Recent studies show that approximately 20% of people in the United States report using herbal supplements to treat a medical condition and/or for health promotion.1 In fact, herbal supplements have become so popular that it is estimated that expenditures exceeds $4.2 billion per year in the United States.2 A dietary supplement, as defined by the Dietary Supplement Health and Education Act,3 is a product taken orally and meant to supplement a diet. These dietary ingredients may include: vitamins, minerals, amino acids, herbs or other botanicals, and substances such as enzymes, organ tissues, glandulars, and metabolites. Dietary supplements may be offered as tablets, capsules, extracts, concentrates, soft gels, gelcaps, liquids, or powders. Dietary supplements do not need approval from the US Food and Drug Administration (FDA) before they are marketed, except in the case of a new dietary ingredient (not sold in the United States as a dietary supplement before October 15, 1994), where premarket review for safety data and other information is required by law. REGULATION AND USAGE IN THE UNITED STATES
Unlike medications, the manufacturer, and not the FDA, is responsible for ensuring that its dietary supplement products are safe before they are marketed. Once marketed, the FDA only can take action or remove it from the market after showing that a dietary supplement is unsafe. The popular use of herbal supplements, together
a
Predoctoral Education, Department of Family Medicine, University of California, Irvine School of Medicine, 101 The City Drive South, Building 200, Suite 512, Irvine, CA 92868, USA b Faculty Development, University of California, Irvine School of Medicine, 101 The City Drive South, Building 200, Suite 512, Irvine, CA 92868, USA * Corresponding author. E-mail address:
[email protected] (W. Najm). Prim Care Clin Office Pract 35 (2008) 749–767 doi:10.1016/j.pop.2008.07.010 primarycare.theclinics.com 0095-4543/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.
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with the limited regulation by the FDA, creates a dilemma for users and health care providers alike. In addition, people taking these products are often unaware of the safety, efficacy, and possible adverse reactions they can cause. In addition to managing chronic medical conditions, recent reports have identified disease prevention and improving general wellness as additional reasons for which people use herbal supplements.4 A useful framework for health care providers to consider when reviewing or discussing supplements or other CAM therapies with their patients was put forth by Eisenberg.5 He proposed to carefully review the safety and efficacy data for each of those herbal supplements. An herbal supplement can be recommended if evidence exists for its safety and efficacy. Herbal supplements lacking evidence of efficacy and safety or showing evidence of harm should be avoided. Clinicians, however, should be very careful and use good judgment for those supplements that fall in between ie, where there is paucity of evidence for safety, harm, or efficacy. The most used herbal supplements vary by year depending on their popularity and marketing. The top 20 commonly sold herbal supplements in 2005 included garlic, echinacea, saw palmetto, ginkgo, cranberry, soy, ginseng, black cohosh, St. John’s wort, milk thistle, green tea, evening primrose, valerian, horny goat weed, grape seed extract, bilberry, red clover, yohimbe, horse chestnut seed, and ginger.6 This article reviews some of the commonly used herbal supplements and others focusing mainly on disease prevention. A summary table of medical conditions is provided, and when possible, a summary of efficacy and safety is provided to facilitate decision making. REVIEW OF BESTSELLING SUPPLEMENTS
Dietary supplements may be indicated or used for various conditions related to wellness and prevention. The following section provides an outline of the most commonly purchased supplements in the US.7 For each supplement, a discussion of evidence to support efficacy, potential harms, and safety considerations are provided with references. Table 1 offers an outline of some available reparations and commonly used dosages and evidence for efficacy and safety allowing relative benefits and risks to be assessed for individual supplements. Black Cohosh (Cimicifuga Racemosa)
Black cohosh (Cimicifuga racemosa) is obtained from the root of the plant and should not be confused with blue cohosh (Caulophyllum thalictroides), which may cause hypertension and cardiac problems. It also is known as actaea macrotys, actaea racemosa L, amerikanisches Wanzekraut, black snakeroot, bugwort, cimifuga, rattle root, and squaw root among other names. The herb has been used in Native American cultures in traditional medicine practices, and in the United States has been used for over 100 years, mainly for gynecologic complaints.8,9 Most studies use the brand name product Remifemin, which is standardized to contain 1 mg of 27-deoxyacteine at a dose of 20 mg per tablet.10 Evidence for the efficacy of black cohosh comes from clinical trials on Remifemin11–13 compared with placebo or conjugated estrogens; an aqueous/ethanolic extract compared with placebo; and from studies comparing black cohosh alone or in combination with isoflavones, with placebo, and with conjugated estrogens.14–17 Duration of trials tends to be short, limited to 12 to 14 weeks, with follow-up of up to 1 year. Outcomes examined include measures of vasomotor symptoms, vaginal dryness, depression, quality of life, and adverse effects. Several randomized trials
Dietary Supplements Commonly Used for Prevention
suggest a benefit of black cohosh over placebo. Some, however, suggest a lack of benefit, while in others, benefit is not demonstrated clearly in comparison with conjugated estrogens. Limitations of the studies include the tendency of vasomotor symptoms to decline over time, a strong placebo effect, and uncertainty about the effect of individual components when combination herbs were studied. The most convincing evidence for efficacy in hot flashes comes from a 2005 well-designed multicenter randomized trial using Remifemin 20 mg twice daily versus placebo. Results showed Remifemin’s superiority over placebo and its equivalence to low-dose transdermal estradiol or conjugated estrogens.11 Black cohosh has been reported to be tolerated well for up to 6 months, with infrequent occurrence of adverse effects such as rash and gastrointestinal (GI) symptoms, headache, nausea, dizziness, seizures, sweating, or constipation. Hypotension has also been reported, and its safety during pregnancy and breastfeeding has not been established.10 Cranberry (Vacinicum Macrocarpon)
Cranberry is used widely to prevent urinary tract infection (UTI), with the primary mechanism of action believed to be antiadhesive properties of proanthocyanadin, preventing bacteria from adhering to uroepithelial cells.18 A recent Cochrane review affirmed its efficacy for prophylaxis of UTI.19 Most studies have focused on preventing Escherichia coli UTI in well patients20 and those with chronic illnesses21–24 with variable dosing. Although it has been used for treating UTIs,25 evidence for this indication is lacking.26 It is available in juice (pure and mixed), capsule, concentrate, and tincture forms, but optimal dosing and dosing frequency are not established. There is no evidence to support efficacy as an antifungal or antiviral agent and limited data on antioxidant properties of cranberry. Other uses, including prevention of Helicobacter pylori infection and dental plaque, are under investigation.10 There is no standardization of cranberry products. Doses of up to 300 mL/d of cranberry juice for 3 months in children and 4 L per day in adults have not been shown to be toxic.10 Adverse effects reported include oxalate urinary stones27 and theoretic potential for interaction with warfarin and proton pump inhibitors. Echinacea
Echinacea species are perennial plants originating in Eastern North America, and both the roots and herbs are used for their immune stimulant properties, for a range of infections and malignancies.10 In the United States, echinacea sales represent up to 10% of the supplement market. Echinacea extract has been standardized to 4% to 5% echinoside or cichoric acid, but the active ingredient has not been definitively identified. The quality and availability of echinacea in commercial preparations are variable.28 Echinacea preparations are available as capsules, expressed juice, tincture, tea and a semisolid reparation for oral intake and a topical preparation for external use for skin infection. The most recent studies consisting of randomized, placebocontrolled trials29–31 refute earlier reports of efficacy in reducing the duration and severity of upper respiratory infection or the common cold in adults32,33 and update conclusions from a Cochrane review.34 More studies are expected to be reported in the future to address the conflicting evidence. Efficacy for other uses including hastening recovery from skin infections and atopic dermatitis, acne, bee stings, boils, burn wounds, lower respiratory infections, and malignancies are unproven by randomized clinical trials. Safety has been established for up to 8 weeks of use, with reported allergic reactions in atopic patients a concern. In children, the risk of rash suggests that risks outweigh benefits.30 Safety during pregnancy has not been established.
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Table 1 Dietary supplements (United States) and evidence for disease prevention Level of Evidence
Conditions and Product
Products Used (Examples)
Form Used
Common Dosages (Adults)
Efficacy
Safety
Common cold
Echinacea
Capsule
500–1000 mg three times daily 5–7 days
0
1
Tincture
0.75–1.5 mL gargled and swallowed 2–5 times daily
0
1
Tea
4 g echinacea in water for 5 days
0
1
Juice
90–480 mL cocktail or 15–30 mL unsweetened 100% juice daily
1
1
Capsule
1–6 300–400 mg capsules hard gelatin extract twice daily
1
1
Concentrate
45 mL frozen concentrate twice daily
D
D
230 g/d
1
1
No established dose
0
1
0
1
Urinary tract infection prophylaxis
Cranberry
Cancer prevention – breast and prostate
Grapes
Cancer (general)
Fish oil Remifemin
20–40 mg twice daily
Tablets Menopause–wellness
Black cohosh
Rhizome
40–200 g/d
Tea
1–2 g/d
Tincture
4–6 mL/d
Flaxseed
Same dose as lipoprotein profile
0
1
Gastrointestinal–Constipation
Flaxseed
Same dose as lipoprotein profile
1
1
Inflammatory bowel disease
Fish oil
No established dose
0
1
Cardiovascular disease–general
red grape polyphenol extract
600 mg
1
1
Cardiovascular–secondary prevention
Fish oil
EPA and DHA –850 to 1800 mg/d
1
1
Liver health
Capsule
Lipoprotein profile
Grape Flaxseed
Powder
36 g
1
1
Juice
100 mL/d
1
1
Tablet
1 three times daily with water
0
1
Powder
10–60 g powder/d 0
1 1
Flaxseed oil
15 mL/d Capsule
Musculoskeletal osteoarthritis (knee) Cognitive function dementia, Alzheimer’s disease
1000 mg/d
Glucosamine
Capsule
500 mg three times daily liquid
1
Chondroitin
Capsule
400 mg three times daily liquid
1
1
No established dose
0
1
Fish oil Ginger
Tablet
1g
1
1
Gingko
Tablet
120 mg twice daily
-
Memory enhancement (mild impairment)
Gingko
Tablet
120 mg twice daily
Mountain sickness
Gingko
Tablet
80 mg three times daily
Cancer (general)
Green tea
Tea
1–10 cups/d
1
Cardiovascular disease
Green tea
Tea
1–10 cups/d
1
1
Cancer (prostate)
Lycopene
Tomato/vegetables
5 servings
1
Benign prostatic hypertrophy (BPH)
Lycopene
Tablets
15 mg/d
1
1
Age-related macular degeneration (ARMD)
Lutein
Tablets
10 mg
1
1
Cataracts
Lutein
Tablets
10 mg
1
1
Liver inflammation
Milk thistle
Tablets
200–400 mg
1
Travelers’ diarrhea
Probiotics
Tablets
10–100 billion live organismsa
1
1
Pouchitis
Probiotics
Packets/capsules (VSL#3)
3 g twice daily
1
1
Crohn’s disease
Probiotics
Tablets
10–100 billion live organisms
1
Level of evidence. Efficacy (1 good evidence for efficacy, - evidence suggests no efficacy, 0 evidence is equivocal). Safety (1 no harm, - harm, 0 insufficient information). a For preventing diarrhea in children, 5 to 10 billion live Lactobacillus GGs have been used twice daily.
Dietary Supplements Commonly Used for Prevention
Nausea/vomiting Memory enhancement (healthy adults)
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Other less-commonly reported adverse effects include transient nausea or vomiting, urticaria, and possible leucopenia and renal toxicity from case reports.10 Fish Oil
The beneficial components in fish oil and fish oil supplements are the omega-3 acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), while nuts and vegetable oils (such as canola, soybean, olive, and flaxseed) contain alpha-linoleic acid (ALA).10 There is good evidence from randomized clinical trials and prospective cohort studies to support the cardioprotective role of fish oil and fish oil supplements for secondary prevention35 by means of multiple mechanisms including an antioxidant action, lowering triglycerides, reducing risk of arrhythmias and platelet aggregation, and lowering blood pressure. The evidence for primary prevention of cardiovascular disease is more controversial,36,37 and more evidence is needed. The evidence available does not support the role of fish oils in cancer prevention,38 prevention of dementia or Alzheimer’s disease39,40 or relapse of inflammatory conditions such as inflammatory bowel disease,41,42 or improvement of intermittent claudication.43 Dosing for fish oil is based on DHA and EPA content, and 5 g of fish oil contains approximately 170 to 560 mg of EPA and 72 to 310 mg of DHA. The World Health Organization (WHO) recommends an daily intake of 300 to 500 mg of EPA and DHA, while 850 to 1800 mg of EPA and DHA are recommended for secondary cardiovascular prevention.10 Flaxseed
Flaxseed and its derivatives flaxseed and linseed oil are a rich source of ALA, a precursor of omega-3 fatty acids used for cardiovascular protection. Flaxseed is a source of fiber and a rich source of lignans, a class of phytoestrogens, and it is available as a food product in the form of flour, bruised flaxseed, and meal, ground, and whole flaxseed. Flaxseed oil, however, available as capsule or liquid, contains only the ALA and not the lignan component in flaxseed.10 Although uses of flaxseed have been cited based on some studies, for promoting wellness related to lipid control44–46 constipation,47–49 menstrual conditions such as mastalgia,50 and menopausal symptoms,51 the quality of evidence for these indications is poor. A recent review52 concluded that the quality of evidence for 13 conditions for which flaxseed has been studied was insufficient to recommend flaxseed and its derivatives for any of these indications. Flaxseed should be taken with caution in patients at risk of intestinal obstruction because of its potential to exacerbate or trigger this problem, and in men who have prostate cancer and women who have estrogen-dependent cancers because of its theoretical hormonal effects.10 Ginger (Zingiber Officinale)
Ginger is a valuable spice and condiment used in traditional medical practices for digestive problems, arthritis, and for treating and preventing nausea and vomiting. Ginger contains phenolic compounds that may enhance GI motility, bile excretion, inhibit platelet aggregation, and act as an antioxidant.53 Recent studies provide new evidence that ginger may act on serotonin receptors, primarily on 5-HT3 receptors in the ileum, which are the same receptors used by ondansetron (Zofran), a well-known antiemetic.54 A meta-analysis of five randomized trials (total of 363 patients) demonstrated that a fixed dose (at least 1 g of ginger) is more effective than placebo for preventing postoperative nausea and vomiting relative risk [RR] 0.69 (95% CI 0.54 to 0.89) and postoperative vomiting (RR 0.61 (95% CI 0.45 to 0.84)).55 Ginger, in some studies, is found
Dietary Supplements Commonly Used for Prevention
to reduce the severity of nausea and vomiting in some pregnant patients with morning sickness.56 Ginger generally is tolerated well. Common adverse effects include abdominal discomfort, heartburn, and diarrhea. A theoretic risk of bleeding exists because of the antiplatelet activity; however, increased risk of bleeding has not been demonstrated with doses up to 4 g/d.57 Glucosamine and Chondroitin
Chondroitin sulfate is manufactured from shark or bovine cartilage and is used to treat osteoarthritis (OA). It is available alone or in combination with other products such as manganese ascorbate, glucosamine sulfate, or glucosamine hydrochloride and is also available in combination with iron for treating iron deficiency anemia. Glucosamine is available as a hydrochloride and a sulfate preparation, and both have been examined in clinical trials on OA. Glucosamine is derived from marine exoskeletons or manufactured synthetically, and based on in vitro animal studies, it is theorized to act by stimulating the metabolism of chondrocytes in articular cartilage and synovial cells in synovial tissue.10 For OA, a dose of 500 mg of glucosamine hydrochloride three times daily alone or with chondroitin sulfate 400 mg three times daily has been recommended10 based on doses used in available clinical trials. A preparation containing 1500 mg/d of glucosamine hydrochloride and 1200 mg/d of chondroitin sulfate with 228 mg/d of manganese ascorbate is available. The tolerable upper limit for manganese is 11 mg/d, however, and caution is suggested when using combinations containing manganese because of the potential for central nervous system (CNS) toxicity.10,58 A meta-analysis59 examining 20 studies found superiority of a preparation of glucosamine compared with placebo for pain and function in patients who had OA, but did not commit to specific doses linked to specific beneficial outcomes. Glucosamine sulfate alone has been examined for up to 3 years,60,61 demonstrating radiologic slowing of OA progression and a 20% decrease in knee pain, respectively. In a large randomized clinical trial, when glucosamine alone, chondroitin alone, and the two combined were examined for their impact on painful knee OA in older adults62 compared with placebo or celecoxib, clinical response was slightly greater for the combination than for either agent alone compared with placebo. Only the combination, however, was significantly better than placebo, with the magnitude of response still lower than that seen with celecoxib (6.5 % points versus 10.0 % points). Overall, response was better in patients who had moderate-to-severe baseline pain than mild pain. A topical preparation containing both glucosamine and chondroitin used in the short term (8 weeks) has been found to be useful for pain control in a small pilot study of 63 patients in knee OA compared with placebo.63 Adverse effects of chondroitin are rare, and reported effects include occasional epigastric pain and nausea, eyelid edema, alopecia, and extrasystoles.10 Potential adverse effects of glucosamine, although uncommon, center around theoretic concerns about metabolic effects on glucose metabolism, although long-term studies of up to 3 years did not indicate adverse effects on HbA1c, glucose, or lipid levels.64–67 Asthma exacerbation and GI effects also have been described.10 Green Tea (Camellia Sinensis)
Green tea and black tea both come from the same plant. A main difference between them is in the preparation process. Green tea is made by lightly steaming the fresh tealeaf, whereas black tea is made by fermentation of the tea leaf. Steaming maintains the polyphenols and preserves flavanols including epigallocatechin gallate (EGCG)
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responsible for many the benefits (antioxidant and anti-inflammatory). Green tea is also a source of caffeine, a methylxanthine, known to stimulate the CNS, relax the smooth muscle, and act as a diuretic. Green tea is used commonly for managing various chronic medical conditions and disease prevention including cancer prevention. Studies demonstrate that EGCG inhibits mitogen-activated protein kinases (MAPK), growth factor-related cell signaling activator protein 1 (AP-1) and nuclear factor-B (NF-kappaB), topoisomerase 1, matrix metalloproteinases and other cancer cell targets, hence inhibiting carcinogenesis in various tissues.68,69 The clinical evidence looking at green tea for cancer prevention, however, is not strong. Studies looking at ovarian cancer are encouraging but not sufficient to draw conclusions. Studies for gastric and colorectal cancer prevention are mainly epidemiologic and remain inconclusive; however, evidence is slightly better for bladder, esophageal,70,71 and pancreatic cancer prevention.72–74 Green tea also is proposed to be helpful for preventing cardiovascular diseases in which oxidative stress and inflammation are principal causes. EGCG lowers the inflammatory reaction and reduces the lipid peroxidation and nitric oxide (NO)- generated radicals.75 Epidemiologic observations indicate that an inverse correlation exists between habitual consumption of green tea beverages and the incidence of cardiovascular events.76 Although all the evidence from research on green tea is very promising, future well-designed prospective studies are necessary to asses whether the observational data on cardiovascular benefit holds up in the clinical setting. To date, no specific dose of green tea has been identified. Doses used in the different studies vary significantly, but usually range between 1 and 10 cups daily based on common use in Asian countries. Green tea is generally safe if used in moderation. Adverse effects are mainly theoretic and based on its caffeine content. Lutein
Lutein is a carotenoid found in dark green leafy vegetables such as spinach, plus various fruits, corn, and egg yolks. Lutein and zeaxanthin are the two major carotenoid pigments found in human macula and retina.77 Lutein and zeaxanthin are antioxidants thought to filter the high-energy, blue wavelengths of light from the visible light spectrum. Epidemiologic studies repeatedly have documented that those who have high intake of vegetables and fruits have a lower risk of age-related macular degeneration (ARMD).78–80 In a 12-month randomized double-blind study of 90 subjects with ARMD receiving lutein (10 mg), lutein with antioxidants, or placebo, visual function was improved with lutein alone or lutein together with other nutrients.81 In a follow-up study, Richer and colleagues82 reported that individuals who had the lowest macular pigment optical density (MPOD) were the most likely to benefit from either the lutein (10 mg) or lutein plus antioxidant supplementation. They also noted that in those individuals who responded to supplementation, their macular pigment optical density continued to improve after 12 months of supplementation. The Physicians’ Health Study and Nurses’ Health Study both reported 20% protection against cataract in subjects who had the highest levels of serum lutein.83,84 In a 2-year prospective study, Olmedilla and colleagues85 confirmed those findings, suggesting that a higher intake of lutein, through lutein-rich fruit and vegetables or supplements, enabled patients with age-related cataracts to have a better visual function. Subjects taking a 10 mg supplement of lutein in the Lutein Antioxidant Supplementation Trail (LAST) experienced better visual function, acuity, glare sensitivity, and improved macular pigmentation. There are no known adverse effects reported. Lutein supplements of 10 mg/d have been shown to be safe after 1 year.
Dietary Supplements Commonly Used for Prevention
Lycopene
Lycopene is a red pigment, found most abundantly in tomatoes, tomato-based products, strawberries, and watermelon. Lycopene is an antioxidant in the carotenoid family.86 Interest and use of lycopene remain high for its potential protective effect against prostate and other cancers. Several case–control and large prospective studies focusing on dietary assessment show that the intake of tomatoes and tomato products may be associated with a lower risk of prostate cancer.87 Lycopene in one clinical study was found to decrease by 53% insulin-like growth factor 1 (IGF-1, a mediator of prostate cancer) at a dose of 15 mg twice daily over 3 to 4 weeks. In a clinical study, supplementation with lycopene 4 mg twice daily showed improvement in men who had high-grade prostate intraepithelial cancer.88 Evidence of the usefulness of lycopene remains controversial, with studies on both sides of the issue. This is well-illustrated in one study that does not support the hypothesis that greater consumption of lycopene/tomato products protects from prostate cancer.89 Another study following subjects for 4.2 years indicates that vegetable and fruit consumption was not related to prostate cancer risk overall. Risk of extraprostatic prostate cancer (stage 3 or 4 tumors), however, decreased with increasing vegetable intake (RR 5 0.41, 95% CI 5 0.22 to 0.74, for high versus low intake; P 5 .01).90 A recent small study explored the effect of 15 mg/d of lycopene on benign prostatic hyperplasia (BPH). After 6 months, the authors concluded that lycopene at a dose of 15 mg/d decreased prostate-specific antigen (PSA) levels in men (P < .05), whereas there was no change in the placebo group. The progression of BPH occurred in the placebo group as assessed by transrectal ultrasound (P < .05) and digital rectal examination (P < .01); however, the prostate did not enlarge in the lycopene group. Symptoms of the disease, as assessed by means of the International Prostate Symptom Score questionnaire, were improved in both groups, with a significantly greater effect in men taking lycopene supplements.91 No adverse effects have been identified . No specific amount of has been established in cancer prevention studies. Lycopene supplements of 30 mg/d have been used safely.
Milk Thistle (Silybum Marianum)
Milk thistle is part of the daisy family. The seeds contain sylmarin, a mixture of flavonolignans, of which silybinin is the most common. Milk thistle is used commonly to protect the liver from hepatotoxins or to treat liver disease. Its exact mechanism of action is not clear; however, silybinin is known to be an antioxidant, a free radical scavenger, and an inhibitor of lipid peroxidation.92,93 In vitro silybinin has shown an affinity for binding to p-glycoprotein94 and inhibits 5-lipoxygenase, hence reducing the formation of inflammatory leukotrienes.95 Silybinin also has been shown in vitro to have a regenerating effect on the livers96 by stimulating DNA polymerase, increasing the synthesis of ribosomal RNA, and stimulating liver cell regeneration.97 Most clinical trials studying milk thistle focused on treatment of established alcoholic and nonalcoholic (drug- or toxin-induced) liver disease. Existing evidence suggest benefits of milk thistle; however most effect sizes are small or not statistically significant. Systematic reviews concluded that the clinical efficacy of milk thistle for liver disease could not be established.98,99 Few studies focused on prevention: Twenty-nine subjects who had normal liver function tests were randomized to receive antituberculosis therapy alone or with milk thistle. A 28% decrease in the risk of developing liver injury was seen in the milk thistle compared with the control group.100
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Interest also exists in the use of milk thistle for cancer treatment and prevention based on animal and laboratory studies. Because of absence of human clinical trials, there is insufficient evidence to recommend milk thistle for cancer prevention. In animal studies, milk thistle was found to have a protective effect on rat cardiomyocytes exposed to doxorubicin comparable to that of dexrasoxane.101 Milk thistle usually is tolerated well, with some minor GI (nausea, vomiting, diarrhea, dyspepsia, bloating) and allergic adverse effects. Although evidence is not conclusive, caution should be used when combining milk thistle with medications metabolized through the CYP450 system.102 Probiotics
The WHO defines probiotics as ‘‘live microorganisms which, when administered in adequate amounts, confer a health benefit on the host.’’ Probiotics normally are found in the GI tract or as components of foods and beverages. They should be differentiated from prebiotics, which are complex carbohydrates that stimulate the growth or activity of beneficial bacteria already in the colon. Most probiotics are either Lactobacillus or Bifidobacterium and their different species and strains (eg, Lactobacillus acidophilus and Bifidobacterium bifidus). Other common probiotics are yeasts (eg, Saccharomyces boulardii). Probiotics are thought to reinforce the integrity of the intestinal lining as a protective barrier to prevent harmful organisms and in keeping harmful bacteria or yeast under control. Probiotics are available as tablets, powders, capsules, and in beverages such as yogurt or juice. Probiotics offer a safe and effective method to prevent traveler’s diarrhea (TD). Several probiotics (Saccharomyces boulardii and a mixture of Lactobacillus acidophilus and Bifidobacterium bifidum) show significant efficacy. A meta-analysis of current studies indicates that probiotics significantly prevent TD (RR 5 0.85, 95% CI 0.79 to 0.91, P < .001).103,104 In a meta-analysis of current studies, D’Souza and colleagues found that the odds ratio in favor of active treatment over placebo in preventing diarrhea associated with antibiotics was 0.39 (95% CI 0.25 to 0.62; P < .001) for the yeast and 0.34 (CI 0.19 to 0.61; P < .01 for lactobacilli). The combined odds ratio was 0.37 (0.26 to 0.53; P < .001) in favor of active treatment over placebo.105,106 A recent randomized study using 100 g of a drink containing Lactobacillus casei, Lactobacillus bulgaricus, and Streptococcus thermophilus taken twice daily during 1 week after a course of antibiotics reduced the incidence of antibiotic-associated diarrhea and Clostridium difficile- associated diarrhea.107 Ulcerative colitis
The best evidence for the use of probiotics in ulcerative colitis (UC) comes from the use of a combination of lactobacilli, bifidobacteria and Streptococcus thermophilus (VSL#3) taken daily in the primary. Secondary prevention of pouchitis maintains remission in 85% of patients.108,109 Other studies reported that Lactobacillus GG or bifidobacteria, alone or in combination with mesalazine, showed no difference in relapse rate at 6 (P 5 .44) and 12 months (P 5 .77) among the treatment groups. The treatment with Lactobacillus GG (18 10(9) viable bacteria/d), however, is more effective than standard treatment with mesalazine (2400 mg/d) in prolonging relapse-free time (P < .05).110 Crohn’s disease
The evidence for the use of probiotics in the maintenance of remission in Crohn’s disease is not as supportive. Although some studies did show a positive outcome,111
Dietary Supplements Commonly Used for Prevention
most of the studies were small and lacked statistical power to draw any major conclusions.112 Two Cochrane reviews looking at the prevention of allergic disease and food hypersensitivity in infants found positive evidence (studies using Lactobacillus rhamnosus) in favor of atopic dermatitis prevention.113 When the review was restricted to atopic dermatitis or to the use of prebiotics alone, however, findings were not statistically significant.114 A recent literature review looking at the use of probiotics for preventing nosocomial pneumonia in critically ill patients found insufficient evidence of efficacy because of the small study samples and poor design.115 Resveratrol
Resveratrol is a polyphenol identified in many plant species including grapes, nuts, mulberries, pine trees, and red wine. Animal and laboratory studies have identified antioxidant, anticancer, antiproliferative, and antibacterial effects. Recently, attention has been directed toward resveratrol for its chemopreventive activities against several cancers116–119 and for its potential health benefits against coronary artery disease (CAD).120–122 Cancer
laboratory studies suggest that resveratol regulates proliferation, cell cycle, apoptosis, and angiogenesis through regulation of multiple signaling pathways. Moreover, it inhibits growth of several cancer lines and potentiates the apoptotic effects of cytokines, chemotherapy, and gamma-radiation.116,123 Clinical studies to verify laboratory findings are pending. Cardiovascular
Resveratrol exerts its cardioprotective effects through inhibition of platelet aggregation both in vitro and in vivo,124,125 strongly inhibiting NO generation in macrophages while stimulating NO synthesis in endothelial cells and inhibiting cyclooxygenase2 generation116,126 and tumor necrosis factor (TNF)-a induced NF-kappa B activation and inflammatory gene expression.127,128 As a general rule, 4 oz of red wine provide approximately 320 mg of resveratrol. In most cases, when consumed in its natural sources, resveratrol has no evidence of toxicity. EVALUATING EVIDENCE FOR PATIENTS
The Natural Standard10 and Natural Medicine Comprehensive databases are comprehensive resources of use to physicians and patients to maintain updated knowledge of supplements (doses, preparations, and forms) and evidence supporting or refuting their use, and citing potential harms. There are an increasing number of systematic reviews available in the Cochrane Database of Systematic reviews and in journals that clinicians should consult before advising their patients on the latest evidence. A principle of ’’first do no harm’’ is a sound guide, and clinicians should balance this principle with evidence of benefit for wellness and health maintenance when discussing or assessing supplements. Respect for the patient’s own values and beliefs, and appreciation for limited patient resources for purchasing the supplements versus other therapies with greater evidence of efficacy are important principles to recognize and consider. By including supplements and herbals among the many forms of treatment (such as exercise, meditation, yoga, and consulting shamans) patients already use, clinicians can give sound advice and play a pivotal role in providing a holistic approach to health care that improves adherence and overall health maintenance.
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ACKNOWLEDGMENTS
The authors gratefully acknowledge the contributions of Jennifer Encinas, BA, for technical assistance and manuscript preparation. FURTHER READINGS
National Center for Complementary and Alternative Medicine (NCCAM): http://nccam. nih.gov/ NCCAM provides a great scientific review of common therapies and dietary supplements, and offers the opportunity for online training in specific areas. It also highlights excellent resources of information. Natural Medicine Comprehensive Database: http://www.naturaldatabase.com/ This is a comprehensive database that provides evidence-based, clinical information on natural products. It is designed for medical professionals and updated regularly. Product search is available by scientific name, common name, brand name or ingredient. Natural Standard: http://www.naturalstandard.com/ This database allows one to review information by product, medical condition, brand name, or modality. The information is reviewed and updated regularly. Levels of scientific evidence for each herbal supplement and condition are outlined and easy to follow. Office of Cancer Complementary and Alternative Medicine (OCCAM): http://www. cancer.gov/cam/ Established in 1998, it provides evidence-based CAM practice and the sciences that support it as well as the availability of high-quality information for the health care community, researchers, and the general public. Office of Dietary Supplements (ODS): http://ods.od.nih.gov/ The ODS provides information about the potential role of dietary supplements to improve health care, promotes scientific research, and disseminates research results. One of its services is the International Bibliographic Information on Dietary Supplements (IBIDS) database (http://ods.od.nih.gov/Health_Information/IBIDS.aspx). REFERENCES
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47. Tarpila S, Kivinen A. Ground flaxseed is an effective hypolipidemic bulk laxative. Gastroenterology 1997;112:A836. 48. Dahl WJ, Lockert EA, Cammer AL, et al. Effects of flax fiber on laxative and glycemic response in healthy volunteers. J Med Food 2005;8(4):508–11. 49. Cunnane SC, Hamadeh MJ, Liede AC, et al. Nutritional attributes of traditional flaxseed in healthy young adults. Am J Clin Nutr 1995;61(1):62–8. 50. Goss PE, Li T, Theriault M, et al. Effects of dietary flaxseed in women with cyclical mastalgia. Breast Cancer Res Treat 2000;64(1):49. 51. Lewis JE, Nickell LA, Thompson LU, et al. A randomized–controlled trial of the effect of dietary soy and flaxseed muffins on quality of life and hot flashes during menopause. Menopause 2006;13(4):631–42. 52. Basch E, Bent S, Collins J, et al. Natural Standard Resource Collaboration. Flax and flaxseed oil (linum usitatissimum): a review by the Natural Standard Research Collaboration. J Soc Integr Oncol 2007;5(3):92–105. 53. Micklefield GH, Redeker Y, Meister V, et al. Effects of ginger on gastroduodenal motility. Int J Clin Pharmacol Ther 1999;37(7):341–6. 54. Lumb AB. Mechanism of antiemetic effect of ginger. Anaesthesia 1993;48(12): 1118. 55. Chaiyakunapruk N, Kitikannakorn P, Nathisuwan S, et al. The efficacy of ginger for the prevention of postoperative nausea and vomiting: a meta-analysis. Am J Obstet Gynecol 2006;194(1):95–9. 56. Betz O, Kranke P, Geldner G, et al. Is ginger a clinically relevant antiemetic? A systematic review of randomized–controlled trials. Forsch Komplementarmed Klass Naturheilkd 2005;12(1):14–23. 57. Lumb AB. Effect of dried ginger on human platelet function. Thromb Haemost 1994;71(1):110–1. 58. Food and Nutrition Board, Institute of Medicine. Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Available at: www. nap.edu/books/0309072794/html/. Washington, DC: National Academy Press; 2002. Accessed August 30, 2007. 59. Towheed TE, Maxwell L, Anastassiades TP, et al. Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst Rev 2005;2:CD002946. 60. Pavelka K, Gatterova J, Olejarova M, et al. Glucosamine sulfate use and delay of progression of knee osteoarthritis: a 3-year, randomized, placebo-controlled, double-blind study. Arch Intern Med 2002;162:2113–23. 61. Clegg DO, Reda DJ, Harris CL, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med 2006;354:795–808. 62. Rother Matthias, Lavins JBernard, Kneer Werner, et al. Transfersome (IDEA-033) versus oral celecoxib and placebo in osteoarthritis of the knee: multicentre randomised–controlled trial and placebo in osteoarthritis of the knee. Ann Rheum Dis 2007;66:1178–83 [originally published online 15 Mar 2007]. 63. Cohen M, Wolfe R, Mai T, et al. A randomized, double-blind, placebo-controlled trial of a topical cream containing glucosamine sulfate, chondroitin sulfate, and camphor for osteoarthritis of the knee. J Rheumatol 2003;30:523–8. 64. Pham T, Cornea A, Blick KE, et al. Oral glucosamine in doses used to treat osteoarthritis worsens insulin resistance. Am J Med Sci 2007;333:333–9. 65. Scroggie DA, Albright A, Harris MD. The effect of glucosamine–chondroitin supplementation on glycosylated hemoglobin levels in patients with type 2 diabetes mellitus: a placebo-controlled, double-blinded, randomized clinical trial. Arch Intern Med 2003;163:1587–90.
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66. Muniyappa R, Karne RJ, Hall G, et al. Oral glucosamine for 6 weeks at standard doses does not cause or worsen insulin resistance or endothelial dysfunction in lean or obese subjects. Diabetes 2006;55:3142–50. 67. Tannis AJ, Barban J, Conquer JA. Effect of glucosamine supplementation on fasting and nonfasting plasma glucose and serum insulin concentrations in healthy individuals. Osteoarthritis Cartilage 2004;12:506–11. 68. Chen L, Zhang HY. Cancer preventive mechanisms of the green tea polyphenol (-)-epigallocatechin-3-gallate. Molecules 2007;12(5):946–57. 69. Syed DN, Afaq F, Kweon MH, et al. Green tea polyphenol EGCG suppresses cigarette smoke condensate-induced NF-kappaB activation in normal human bronchial epithelial cells. Oncogene 2007;26(5):673–82. 70. Wang LD, Zhou Q, Feng CW, et al. Intervention and follow-up on human esophageal precancerous lesions in Henan, northern China, a high-incidence area for esophageal cancer. Gan To Kagaku Ryoho 2002;29(Suppl 1):159–72. 71. Gao YT, McLaughlin JK, Blot WJ, et al. Reduced risk of esophageal cancer associated with green tea consumption. J Natl Cancer Inst 1994;86(11):855–8. 72. Tsubono Y, Nishino Y, Komatsu S, et al. Green tea and the risk of gastric cancer in Japan. N Engl J Med 2001;344(9):632–6. 73. Nagano J, Kono S, Preston DL, et al. A prospective study of green tea consumption and cancer incidence, Hiroshima and Nagasaki (Japan). Cancer Causes Control 2001;12(6):501–8. 74. Ji BT, Chow WH, Hsing AW, et al. Green tea consumption and the risk of pancreatic and colorectal cancers. Int J Cancer 1997;70(3):255–8. 75. Tipoe GL, Leung TM, Hung MW, et al. Green tea polyphenols as an antioxidant and anti-inflammatory agent for cardiovascular protection. Cardiovasc Hematol Disord Drug Targets 2007;7(2):135–44. 76. Basu A, Lucas EA. Mechanisms and effects of green tea on cardiovascular health. Nutr Rev 2007;65(8 Pt 1):361–75. 77. Sommerburg O, Keunen JE, Bird AC, et al. Fruits and vegetables that are sources for lutein and zeaxanthin: the macular pigment in human eyes. Br J Ophthalmol 1998;82(8):907–10. 78. Seddon JM, Ajani UA, Sperduto RD, et al. Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. Eye Disease Case– Control Study Group. JAMA 1994;272(18):1413–20 [erratum in: JAMA. 1995 Feb 22;273(8):622]. 79. Goldberg J, Flowerdew G, Smith E, et al. Factors associated with age-related macular degeneration. An analysis of data from the first National Health and Nutrition Examination Survey. Am J Epidemiol 1988;128(4):700–10. 80. Cho E, Seddon JM, Rosner B, et al. Prospective study of intake of fruits, vegetables, vitamins, and carotenoids and risk of age-related maculopathy. Arch Ophthalmol 2004;122(6):883–92. 81. Richer S, Stiles W, Statkute L, et al. Double-masked, placebo-controlled, randomized trial of lutein and antioxidant supplementation in the intervention of atrophic age-related macular degeneration: the Veterans LAST study (Lutein Antioxidant Supplementation Trial). Optometry 2004;75(4):216–30. 82. Richer S, Devenport J, Lang JC. LAST II: differential temporal responses of macular pigment optical density in patients with atrophic age-related macular degeneration to dietary supplementation with xanthophylls. Optometry 2007; 78(5):213–9.
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83. Chasan-Taber L, Willett WC, Seddon JM, et al. A prospective study of carotenoid and vitamin A intakes and risk of cataract extraction in US women. Am J Clin Nutr 1999;70(4):509–16. 84. Brown L, Rimm EB, Seddon JM, et al. A prospective study of carotenoid intake and risk of cataract extraction in US men. Am J Clin Nutr 1999;70(4):517–24. 85. Olmedilla B, Granado F, Blanco I, et al. Lutein, but not alpha-tocopherol, supplementation improves visual function in patients with age-related cataracts: a 2-y double-blind, placebo-controlled pilot study. Nutrition 2003;19(1):21–4. 86. Arab L, Steck S. Lycopene and cardiovascular disease. Am J Clin Nutr 2000; 71(Suppl 6):S1691–5. 87. Giovannucci E. A review of epidemiologic studies of tomatoes, lycopene, and prostate cancer. Exp Biol Med (Maywood) 2002;227(10):852–9. 88. Kucuk O, Sarkar FH, Djuric Z, et al. Effects of lycopene supplementation in patients with localized prostate cancer. Exp Biol Med (Maywood) 2002;227(10): 881–5. 89. Kirsh VA, Mayne ST, Peters U, Chatterjee N, et al. A prospective study of lycopene and tomato product intake and risk of prostate cancer. Cancer Epidemiol Biomarkers Prev 2006;15(1):92–8. 90. Kirsh VA, Peters U, Mayne ST, et al. Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Prospective study of fruit and vegetable intake and risk of prostate cancer. J Natl Cancer Inst 2007;99(15):1200–9. 91. Schwarz S, Obermu¨ller-Jevic UC, Hellmis E, et al. Lycopene inhibits disease progression in patients with benign prostate hyperplasia. J Nutr 2008;138(1):49–53. 92. Hikino H, Kiso Y, Wagner H, et al. Antihepatotoxic actions of flavonolignans from silybum marianum fruits. Planta Med 1984;50(3):248–50. 93. Gonzalez-Correa JA, de la Cruz JP, Gordillo J, et al. Effects of silymarin MZ-80 on hepatic oxidative stress in rats with biliary obstruction. Pharmacology 2002; 64(1):18–27. 94. Maitrejean M, Comte G, Barron D, et al. The flavanolignan silybin and its hemisynthetic derivatives, a novel series of potential modulators of P-glycoprotein. Bioorg Med Chem Lett 2000;10(2):157–60. 95. Dehmlow C, Murawski N, deGroot H. Scavenging of reactive oxygen species and inhibition of arachidonic acid metabolism by silybinin in human cells. Life Sci 1996;58:1591–600. 96. Sonnenbichler J, Goldberg M, Hane L, et al. Stimulatory effect of silibinin on the DNA synthesis in partially hepatectomized rat livers: nonresponse in hepatoma and other malign cell lines. Biochem Pharmacol 1986;35(3):538–41. 97. Sonnenbichler J, Scalera F, Sonnenbichler I, et al. Stimulatory effects of silibinin and silicristin from the milk thistle silybum marianum on kidney cells. J Pharmacol Exp Ther 1999;290(3):1375–83. 98. Jacobs BP, Dennehy C, Ramirez G, et al. Milk thistle for the treatment of liver disease: a systematic review and meta-analysis. Am J Med 2002;113(6):506–15. 99. Lawrence V, Jacobs B, Dennehy C, et al. Milk thistle: effects on liver disease and cirrhosis and clinical adverse effects. Summary. Evidence report/technology assessment: number 21. Rockville, MD: (Contract 290-97-0012 to the San Antonio Evidence-based Practice Center, based at the University of Texas Health Science Center at San Antonio, and The Veterans Evidence-based Research, Dissemination, and Implementation Center, a Veterans Affairs Services Research and Development Center of Excellence). October 2000
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100. Magula D, Galisova Z, Iliev N, et al. Effect of silymarin and fumaria alkaloids in the prophylaxis of drug-induced liver injury during antituberculotic treatment. Studia Pneumologica Phtiseologica et Cechoslov 1996;56(5):206–9. S, Psotova J, Miketova P, et al. Chemoprotective effect of plant 101. Chlopcıkova phenolics against anthracycline-induced toxicity on rat cardiomyocytes. Part I. Silymarin and its flavonolignans. Phytother Res 2004;18(2):107–10. 102. Beckmann-Knopp S, Rietbrock S, Weyhenmeyer R, et al. Inhibitory effects of silibinin on cytochrome P-450 enzymes in human liver microsomes. Pharmacol Toxicol 2000;86(6):250–6. 103. McFarland LV. Meta-analysis of probiotics for the prevention of traveler’s diarrhea. Travel Med infect Dis 2007;5:97–105. 104. Johnston BC, Supina AL, Vohra S. Probiotics for pediatric antibiotic-associated diarrhea: a meta-analysis of randomized placebo-controlled trials. Can Med Assoc J 2006;175:377–83. 105. D’Souza AL, Rajkumar C, Cooke J, et al. Probiotics in prevention of antibiotic associated diarrhoea: meta-analysis. BMJ 2002;324:1361–7. 106. McFarland L. Meta-analysis of probiotics for the prevention of antibiotic-associated diarrhea and the treatment of clostridium difficile disease. Am J Gastroenterol 2006;101(4):812–22. 107. Hickson M, D’Souza AL, Muthu N, et al. Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomized, double-blind, placebo-controlled trial. BMJ 2007;335(7610):80–5. 108. Gionchetti P, Rizzello F, Helwig U, et al. Prophylaxis of pouchitis onset with probiotic therapy: a double-blind placebo-controlled trial 3. 2003;124:1202–1209. 109. Mimura T, Rizzello F, Helwig U, et al. Once-daily high dose of probiotic therapy (VSL#3) for maintaining remission in recurrent or refractory pouchitis. GUT 2004; 53:108–14. 110. Zocco MA, dal Verme LZ, Cermonini F, et al. Efficacy of Lactobacillus GG in maintaining remission of ulcerative colitis. Aliment Pharmacol Ther 2006;23: 1567–74. 111. Guslandi M, Mezzi G, Sorghi M, et al. Saccharomyces boulardii in maintenance treatment of Crohn’s disease. Dig Dis Sci 2000;45(7):1462–4. 112. Rolfe VE, Fortun PJ, Hawkey CJ, et al. Probiotics for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev 2006;(4):CD004826. 113. Osborn DA, Sinn JK. Probiotics in infants for prevention of allergic disease and food hypersensitivity. Cochrane Database Syst Rev 2007;(4):CD006475. 114. Osborn DA, Sinn JK. Prebiotics in infants for prevention of allergic disease and food hypersensitivity. Cochrane Database Syst Rev 2007;(4):CD006474. 115. McNabb B, Isakow W. Probiotics for the prevention of nosocomial pneumonia: current evidence and opinions. Curr Opin Pulm Med 2008;14(3):168–75. 116. Shankar S, Singh G, Srivastava RK. Chemoprevention by resveratrol: molecular mechanisms and therapeutic potential. Front Biosci 2007;12:4839–54. 117. Aggarwal BB, Bhardwaj A, Aggarwal RS, et al. Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. Anticancer Res 2004; 24(5A):2783–840. 118. Lin JK, Tsai SH. Chemoprevention of cancer and cardiovascular disease by resveratrol. Proc Natl Sci Counc Repub China B 1999;23(3):99–106. 119. Delmas D, Lancon A, Colin D, et al. Resveratrol as a chemopreventive agent: a promising molecule for fighting cancer. Curr Drug Targets 2006;7(4):423–42. 120. Sato M, Ray PS, Maulik G, et al. Myocardial protection with red wine extract. J Cardiovasc Pharmacol 2000;35(2):263–8.
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121. Ray PS, Maulik G, Cordis GA, et al. The red wine antioxidant resveratrol protects isolated rat hearts from ischemia reperfusion injury. Free Radic Biol Med 1999; 27(1–2):160–9. 122. Dernek S, Ikizler M, Erkasap N, et al. Cardioprotection with resveratrol pretreatment: improved beneficial effects over standard treatment in rat hearts after global ischemia. Scand Cardiovasc J 2004;38(4):245–54. 123. Athar M, Back JH, Tang X, et al. Resveratrol: a review of preclinical studies for human cancer prevention. Toxicol Appl Pharmacol 2007;224(3):274–83. 124. Wang Z, Huang Y, Zou J, et al. Effects of red wine and wine polyphenol resveratrol on platelet aggregation in vivo and in vitro. Int J Mol Med 2002;9(1):77–9. 125. Zbikowska HM, Olas B. Antioxidants with carcinostatic activity (resveratrol, vitamin E, and selenium) in modulation of blood platelet adhesion. J Physiol Pharmacol 2000;51(3):513–20. 126. Surh YJ, Chun KS, Cha HH, et al. Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX2 and iNOS through suppression of NF-kappa B activation. Mutat Res 2001;(480–481):243–68. 127. Csiszar A, Smith K, Labinskyy N, et al. Resveratrol attenuates TNF-alpha-induced activation of coronary arterial endothelial cells: role of NF-kappaB inhibition. Am J Physiol Heart Circ Physiol 2006;1(4):H1694–9. 128. MacLean CH, Mojica WA, Newberry SJ, et al. Systematic review of the effects of n-3 fatty acids in inflammatory bowel disease. Am J Clin Nutr 2005;82(3):611–9.
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Common Foo ds a nd Farming Metho ds Thought to Promote Health : What the Data Show John Chahbazi, MDa,*, Shelly Grow, MSb KEYWORDS
Diet Healthy Foods Farming methods Longevity Vegetarian Vegan Organic Raw Blood type diet Designer diet Obesity Evidence Mediterranean Slow food
In 1996, dietary factors were associated with four of the leading causes of death (coronary heart disease, cancer, stroke, and diabetes) and the struggles with obesity and diabetes treatment give reason to believe that those associations may be even stronger today.1 After finding such associations, the next step one must take to give patients direction is to show causation. This leads to the question ‘‘What are the best dietary practices and farming methods to promote health?’’ The answer may depend on whether one looks at the health of individuals or the health of the planet (planetary health or PH). PH will equate to a healthy ecosphere fostered by dietary/farming practices that are less resource-intense, potentially decreasing starvation and carbon emissions as discussed later in the article. Best practices also may depend on whether by health one means lack of observable disease (such as obesity, nutritional deficiency, diabetes, or cancer), optimal health (also known as wellness), or longevity. This article attempts to give an overview of the evidence as regards all of these aspects and definitions of health. Much of the current literature focuses on secondary prevention of death or intermediate endpoints (eg, weight changes, myocardial infarction [MI]) by application of lifestyle modification to already diseased subjects. This can be problematic in that it may foster generalization to the nondiseased population when the lifestyle modification in question may not be of benefit or may cause excessive focus on an intermediate outcome, while a more important outcome worsens. An example of this phenomenon is the Healthy People 2010 Nutritional Intervention, where dietary intake of fruits and vegetables a
McLaren Family Medicine Residency, G-3245 Beecher Road, Flint, MI 48532, USA Association of Zoos and Aquariums, 8403 Colesville Road, Suite 710, Silver Spring, MD 20910, USA * Corresponding author. E-mail address:
[email protected] (J. Chahbazi). b
Prim Care Clin Office Pract 35 (2008) 769–788 doi:10.1016/j.pop.2008.07.013 primarycare.theclinics.com 0095-4543/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.
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was increased and total and saturated fat consumption was decreased. Attempts to decrease body weight and the morbidity and mortality associated with obesity, however, failed.2 Secondary prevention studies also may cause the medical community to overlook the effect of lifestyle interventions (or choices) on the health of large human populations or on PH, because they appear to be good science and because they are all that is available. Although such studies often are well-designed randomized, controlled trials and serve as high-level evidence for specific interventions in diseased individuals, Healthy People 2010 shows that it is more important to prevent disease than to treat existing disease if the goal is to improve health and increase longevity. Exercise has been shown to be a particularly healthful lifestyle choice and is often a confounding variable in dietary studies.3 The evidence for healthy farming is limited mostly to the effects of various methods on nutrient content in the resultant foods or effects on the soil and water, not long-term prospective studies of populations exclusively consuming foods produced using those methods and looking at outcomes like mortality. Absent high-level evidence that primary dietary intervention changes mortality, foods and farming methods that may lead to optimal health and longevity only can be inferred from cross-sectional studies of healthy elderly populations.4 Studies of productive and healthy individuals 80 years and older may be the best evidence of best practices because of the difficulties inherent in designing and performing lifestyle research. It quickly becomes clear that the current literature offers mostly diseaseoriented evidence (DOE), when what is needed are good studies revealing patientoriented evidence that matters (also known as POEMs). Even if the POEMs needed for evidence-based dietary counseling and farming practice recommendations are available, there is the difficulty of applying proven interventions to a population that has such a high rate of lifestyle-associated disease. This is a population that has continued to gain weight and become diabetic at everincreasing rates in the face of improved food label reading and dietary changes as reported in Healthy People 2010. Trying for different results while maintaining the basic elements of a lifestyle that already has caused poor health could explain why only a small portion of proven dietary interventions have been shown to improve longterm health or longevity. The popularity of fast food and dining out suggests that the future of lifestyle medicine may be in systems that provide prepared meals as a prescription. This method has been designed into several studies already, including the Dean Ornish study, which demonstrated regression of coronary artery stenosis5 and a study that compared subjects who consumed a prepared, prepackaged diet with those who consumed the same diet that was self-selected and prepared.6 Unfortunately, both of these studies looked at secondary prevention over a short term. Although there is not great evidence, reviewing some of the more common dietary choices and farming methods thought to promote good health is an important step toward more useful research. The following sections start with the most commonly practiced diets and finish with the more common farming methods. There is considerable overlap between them when considering PH (eg, the degree to which a population increases the proportion of organic produce in the diet will determine the farming/supply practices used). VEGETARIAN DIETS
Most who have made the choice to become vegetarians probably would identify with at least a part of what Joanna Macy states as the consequences of going away from an animal-based diet in the forward of Diet For A New America7: ‘‘The effects on our physical health are immediate. The incidence of cancer and heart attack, the nation’s biggest killers, drops precipitously. So do many other
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diseases now demonstrably and causally linked to consumption of animal proteins and fats, such as osteoporosis . hormonal imbalances causing miscarriages and aberrations of sexual development similarly drop away, as we cease ingesting with our meat, poultry and milk the drugs pumped into our livestock. So do the neurologic disorders and birth defects due to pesticides and other chemicals, as we begin to eat lower on the food chain where the poisons are far less concentrated . We find that the grain we previously fed to fatten livestock can now feed five times the U.S. population; so we have been able to alleviate malnutrition and hunger on a worldwide scale . We find ourselves also relieved of fear. For on a semiconscious level we knew all along that the old disparities in consumption were turning our planet into a tinder box, breeding resentments and desperations that could only eventuate in war.’’ Although some of what Macy writes is not evidence-based, it is easy to see how the redirection of resources she encourages could promote PH. There are several intermediary versions of vegetarianism including lacto- (consume milk products), ovo- (consume eggs), and vegan (consume no animal products). Many even include consumption of fish, chicken, pork and other white meats as different types of vegetarianism. This confusion is clear in cultural references such as the movie My Big Fat Greek Wedding when the bride-to-be’s aunt is getting to know her vegee ‘‘What, you don’t eat no meat? . That’s OK, I cook lamb.’’8 Although tarian fiance for some, eating anything but red meat is considered vegetarian, the Vegetarian Resource Group estimates that 0.3% to 1% of the United States population over 18 never eats meat, fish or fowl.9 The same group reports 20% to 30% are interested in vegetarian choices when looking for restaurants, implying a significant interest in vegetarianism in the general population. The combination of interest in vegetarian (not otherwise defined) choices with the low prevalence of vegetarianism fits well with the findings in some secondary prevention studies, indicating that the fewer animal products consumed, the greater the benefit to the subjects. One small (n 5 99) randomized study comparing vegan to American Diabetic Association diets showed a statistically and clinically significant decrease in Hba1c (1.23 points from 8.07 to 6.84 versus 0.38 points from 7.88 to 7.50), body weight (loss of 6.5 kg versus 3.1 kg), and medication use in the vegans over 22 weeks.10 Another small study (n 5 26) claimed decreased lipids over 6 weeks in lacto–ovo vegetarians versus lacto–ovo vegetarians consuming small amounts of lean meat, but it was difficult to interpret because of missing results.11 Decreasing consumption of animal products may prove to be a great intervention, but one must proceed with some caution given the possible association between strict vegan diets and iodine deficiency12 and concerns about vitamin B12 deficiency in several case reports,13,14 including a case of irreversible paraplegia in a strict vegan.15 These concerns are countered by a study showing that vitamin B deficiency does not occur in a well-designed vegan diet.16 As the Barnard study showed, a vegan diet may cause clinically significant weight loss. Given a large meta-analysis of long-term prospective studies linking weight gain with cancer17 and the now well-established link between obesity and diabetes, one must take the next step by showing that lifestyle change can prevent weight gain. To the degree these very limited studies’ findings translate to the general population, one should be cautiously encouraging progressive elimination of animal products while encouraging adequate micronutrient intake. The PH effects of vegetarianism could be much more important than the immediate human health effects, although people tend to not see such benefits until the destruction of the earth has caused personal pain. Until recently, the medical community seemed to insulate itself from this type of health threat with the idea that it did not
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appear to be in physicians’ purview. Should it now be on the agenda of all who potentially can create change? It has been known since the 1970s that rain forests are being lost to livestock grazing and, more recently, to soybean crops.18 It also is known that it takes 16 lbs of grain and soybeans to grow 1 lb of beef.7 Particularly telling of the benefits of decreased meat consumption is the amount of land necessary to support a traditional meat-eater (3.25 acres), a lacto–ovo vegetarian (0.5 acres), and a vegan (one sixth of an acre). Twenty vegans can be fed with the same amount of land as one meat-eater.7 MEDITERRANEAN DIET
The Mediterranean diet is part of the lifestyle of many inhabitants of Greece and southern Italy. Its relatively high fat content comes primarily from mono-unsaturated fatty acids (MUFAs) found in olive oil. It is also high in fresh, raw fruits and vegetables, and complex carbohydrates (bread and potatoes), but low in animal protein (mostly fish). Small amounts of red wine also generally are considered to be a part of the diet. It is hard to give an accurate estimate of the proportion of the United States population that follows this diet, but it has become a popular health diet in the past few years, as its long-lived adherents have been studied. These cross-sectional studies are often more like serial case reports, in that index cases of the very old living in various communities are interviewed and observed for common lifestyle features.4 Diet is only a part of these elders’ lifestyles. They also show a strong sense of purpose and tradition, drink clean/hard water, have a strong social network, focus on family, limit caloric intake, and exercise daily, usually by way of hard subsistence work. Even with all the confounders of the Mediterranean lifestyle, when the diet alone is observed in cross-sectional population studies and applied in randomized, controlled trials, it has been found to be associated with decreased cardiac risk.19–21 When applied less rigorously to a large group of breast cancer patients in randomized fashion for up to 5 years, however, no difference in recurrence rate or survival was found.22 This points out the problems associated with diet-only lifestyle interventions and will be discussed further when designer diets are explored. Insofar as the Mediterranean diet generally is associated with decreased consumption of animal products, it should show some of the PH benefits of a vegetarian diet. Unfortunately, there are some problems associated with introducing a diet from one part of the world to another. A person living in Michigan in January does not have access to locally grown fresh fruits or olive oil. These must be shipped in at a significant cost, both monetary and in carbon released to the environment. This will be dealt with more fully in the slow food section. RAW DIET
A raw diet is composed of uncooked foods with a preference for the highest quality nutrition and avoidance of animal products. Because many proteins denature at temperatures greater than 112 degrees Fahrenheit, the only way these foods are served at greater than room temperature is by heating the serving plate. Though there would seem to be some benefit to this treatment of the food, the only benefit reported to date in one cross-sectional study is weight loss to the point of being underweight and amenorrheic.23 There are also reports of dental erosions24 and very significant reductions in low-density lipids and triglycerides, but with elevated plasma homocysteine and low high-density lipids.25 There are no randomized, controlled trials looking at long-term risks or benefits. The PH benefits should be similar to a vegan diet in that no animal products are consumed.
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SLOW FOOD
This diet is actually a lifestyle movement. It was started in Bra, Italy, in 1986 and moved to the United States in 2000. The number of adherents to this lifestyle is unknown, but there are now close to 200 local chapters (convivia) that encourage slowing down to increase pleasure and quality in everyday life.26 They also encourage biodiversity by fighting mechanistic, high-volume production of meats and produce. Rather, they believe that food should be produced and eaten slowly and locally. Their form of globalization is to bring artisinal food producers together at jamborees where localized marketing and production plans are shared.27 Perhaps partly in homage to the founding city, breast-feeding has been proposed to be part of the slow food movement.28 Breast-feeding aside, there is no clear evidence for the health benefits of this movement, although proponents claim better quality and variety in their diet. There are also potential PH benefits, as will be see in the discussion of farming practices. DESIGNER DIETS
This is actually a group of diets that includes cardiovascular cures and blood-type diets. Weight loss diets, while they could be included in this category, are generally temporary in nature so would not be considered healthy lifestyle interventions. When these popular diets were compared head-to-head in a randomized prospective trial, the Atkins, Ornish, Weight-watchers (WW), and Zone diets all showed similar modest reductions in weight (2.1 to 3.3 kg) and cardiac risk factors at 1 year in those who maintained the diet, but all had a high dropout rate (roughly half on Ornish and Atkins and one third of those on WW and Zone diets).29 Cardiovascular diet research has exploded in terms of number of studies and variety of recommendations in the past 20 years. The idea of these diets is to introduce ostensibly heart-healthy nutrient(s) into a standard American diet to improve cardiovascular health and thereby decrease cardiac events and prolong life. Because of the very limited-quality evidence for this type of dietary intervention, there is concern about the potential harms (financial and health risks) caused by these functional foods.30 Most of these interventions are made on subjects who have existing heart disease or cardiac risk factors and cannot be applied to the general population. A classic example of how this works is found in the lifestyle recommendations developed to increase the presence of nitric oxide in the coronary arteries, because it was found to cause endothelial cell relaxation and thought to cause plaque regression in coronary arteries.31 There is no evidence that instituting these dietary changes prevents plaque formation, or, more importantly, prolongs or improves life in healthy subjects. Conversely, generalized increases in nonanimal dietary components have been successful in secondary prevention studies. A large and complex study of over 500 postmenopausal women showed that dietary changes and exercise could decrease cardiac risk factors.32 A 1000-subject randomized, controlled intervention found that increasing healthy foods such as fruits, vegetables, legumes, and nuts compared favorably with the current National Cholesterol Education Program Step 1 diet, decreasing sudden cardiac death and nonfatal MI.33 A favorite of many would be the dark chocolate diet. This intervention is based on the presumptive beneficial effect of chocolate with a high flavonoid content. Several very limited DOEs have shown short-term effects such as improved endothelial cell function34 and increased insulin sensitivity along with lowered blood pressure.35 Sadly, the largest (n 5 101) double-blind, placebo-controlled, fixed-dose study (sponsored by The Hershey Company, Hershey, Pennsylvania) looked for differences in multiple neuropsychological and cardiovascular health-related variables and found
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only increased pulse rates in those who had ingested dark chocolate for 3 and 6 weeks.36 None of these studies with 2- to 6-week treatment periods looked at weight gain on a dark chocolate diet. Blood-type diets claiming benefits from different dietary components based on genotypes37 are dismissed commonly as baseless theory.38 Evidence is scarce and limited to secondary prevention. The most interesting study showed that a particular blood type in diabetics predisposed to more effective low-density lipoprotein lowering in response to increased dietary fiber.39 Studies like this eventually may help limit expensive long-term treatments to select populations where they are more likely to make a difference, but use this type of intervention is a long way from clinical use, and there are no POEMs. There would be no PH benefit, because there is no systematic reduction in the consumption of animal products. Another form of designer diet is based on eating foods that decrease the environmental footprint in terms of carbon release to the atmosphere or damage to the soil. Examples of this are those who eat biodynamically farmed foods (discussed in detail in the farming methods section) or participate in carbon counting as opposed to calorie counting.40 One large grocery chain based in the United Kingdom (Tesco) has vowed to put carbon labels on each of the 70,000 products it sells and to decrease its own energy consumption by 50% by 2020.41 Eating biodynamically grown foods and carbon counting have not been shown to increase human health, but lead one to look more closely at the evidence for farming practices thought to improve health.
UNITED STATES FOOD SYSTEM AND HOW FARMING PRACTICES AFFECT HEALTH
The United States food production and distribution system is one of the safest in the world. It is overseen by over six federal agencies working together and with state and local agencies.42 A regulatory framework has been developed that defines the work of these agencies and ensures safety throughout the food system.43 United States farm policy generally promotes an industrial agricultural system boasting high production and cheap food, making the Organic Foods Production Act (OFPA) of 1990 a unique piece of legislation geared toward a relatively small niche within United States agriculture. In 2005, organic agriculture was one of the fastest growing segments of United States agriculture44 but only accounted for 0.5% of all United States cropland and 0.5% of all United States pasture.45 Consistent standards for marketing organically produced agricultural products has provided assurance to consumers and facilitated commerce. The regulations for the National Organic Program (http://www.ams.usda.gov/nop) were implemented in 2002 and address the methods, practices, and substances used in organic crop production, livestock management, wild crop harvesting, and the processing and handling of all organic agricultural products.46 The standards require that all organic agricultural products originate from farms and handlers certified by a US Department of Agriculture (USDA)-accredited state or private entity, unless the producer or handler sells less than $5000 in organic products per year. Third-party certification is one of the major differences between the USDA organic seal and other labels, such as natural, grass-fed, or hormone-free. National organic standards do not address food safety or nutrition. USDA regulations prohibit the use of genetic engineering, ionizing radiation, and sewage sludge in organic production and handling. As a general rule, all natural (nonsynthetic) substances are allowed, while all synthetic substances (ie, conventional pesticides and fertilizers) are prohibited. Animals raised on organic operations must
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be fed organic feed and given access to the outdoors; antibiotics and growth hormones are prohibited. Confinement indoors must be temporary and justified. Some research trials at land-grant universities show decreased per acre crop yields in organic systems compared with conventional systems, while others show equal productivity.47–49 Given premiums and lower input costs, organic systems also can be more profitable for producers.49 The price premium on organic foods ranges from 9% on oranges at the grocery store50 to over 250% on eggs purchased by the first receiver (the retailer, distributor, or manufacturer).51 In the United States, people tend to purchase organic foods because of (in decreasing order of importance) safety, freshness, general health benefits, nutritional value, environment, flavor, and general product.52 Nutritional Differences Between Organic and Conventional Produce
The nutritional content of both organic and conventionally grown produce reflects the variety of plant, the season, and the geographic location in which the produce is grown, and its overall freshness and postharvest handling, making health claims difficult.53,54 Organic produce tends to have higher levels of polyphenols and healthful fatty acids. These metabolites, produced by plants for defense purposes, are important for human disease prevention 55 and may be a result of organic crops responding to stresses without the help of chemical pest and disease controls,56,57 or because the simplified soils of industrial agriculture lack the ingredients needed to create them.58 Organic foods also have lower levels of pesticide residues, and the practices lead to improved soil quality.47,59,60 Comparative nutritional studies focus on basal components of nutrition and are product-specific. For example, one study compared the levels of two flavonoids in dried tomato samples collected between 1994 and 2004 from a single study plot.60 Flavonoids are secondary plant metabolites that demonstrate in vitro antioxidant activity61 and play an important role in preventing cancer and heart disease.62 The comparison showed that the organic tomatoes were 79% higher in their levels of one flavonoid (quercetin), 97% higher in their levels of a second flavonoid (kaempherol), and that the levels of the flavonoid increased over time in the organic tomatoes, while remaining constant in tomatoes grown in conventional plots.60 The variety of tomato grown, however, affects the nutritional content. Chassy54 found that the levels of the flavonoid were typically higher in Burbank tomatoes compared with Ropreco tomatoes, and that organically grown Burbank tomatoes had 17% higher levels of the percent soluble solids, 26% higher levels of ascorbic acid, and 30% and 17% higher levels of the flavonoid quercetin and kaempherol, respectively, compared with conventionally grown Burbank tomatoes. Organically grown Ropreco tomatoes only had higher levels of percent soluble solids and kaempherol (10% and 20%, respectively) compared with their conventionally grown counterparts. Equally complex nutrient- and product-specific analyses have been done looking at broccoli,63 bell peppers,54 frozen organic corn,64 Marionberries,64 peaches and pears,65 and vegetable soups.66 A few reviews have tried to glean definitive comparisons between organic and conventionally grown produce.52,67,68 Benbrook68 found that overall, organic produce had higher nutrient (antioxidant, vitamin, and mineral) levels in 62% of the studies reviewed, while conventionally grown produce had higher nutrient levels in 36%. Nitrate levels, high concentrations of which are unhealthy and are associated with lower concentrations of vitamin C in plants, were higher in conventionally produced foods in 83% of the comparisons. With regards to protein levels, conventionally grown food faired better in 85% of the comparisons.68
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Food Quality, Safety, and Taste
Organic foods meet the same quality and safety standards as conventionally produced foods,69 and a study comparing organic and conventional apple cider found no difference in the levels of Escherichia coli present.47 Mycotoxins, secondary metabolites produced by fungi that can be poisonous or trigger allergies in people, have been detected 1.5 times more frequently in conventional samples than in organic samples, however.70 Higher levels of microorganism diversity and lower concentrations of readily available nitrogen reduce the prevalence of mycotoxins in organic farming systems. Because organic foods are not treated with waxes or preservatives, they may spoil more quickly.69 Studies show no significant flavor differences between organic and conventional foods.62 Pesticides
Pesticide residues on foods produced in conventional agriculture are thought to be too small to pose a health risk.69 Pesticide residue safety levels, however, are set for individual pesticides, while produce tends to contain the residues of multiple chemicals.53 Safety levels do not address the effect of small doses consumed over many years.62 The presence of pesticides in children is widespread.71 In 2003, the Centers for Disease Control and Prevention (CDC) reported that children had about twice the amount of several organophosphate pesticides in their bodies as adults.72 Children are particularly susceptible to the effects of toxicants such as pesticides because of their higher metabolism rates, less mature immune systems, and activity and behavior patterns.73 Unfortunately, so little is known about the lifelong effects of pesticides on children’s learning and development that the National Academy of Sciences declared the lack of information to be a public health issue.74 Consumers can reduce, although not necessarily eliminate, dietary exposure to pesticides by buying organically grown foods.47,75 Urine analyses from children eating a conventional diet had six times the levels of organophosphate (OP) pesticide metabolites as those from children eating an organic diet.76 Although the parent pesticides of the OP metabolites could not be verified, the researchers attributed the metabolites to seven pesticides based on targeted use (ie, food versus cotton, livestock, or mosquito control). These pesticides vary in toxicity and Environmental Protection Agency (EPA)determined daily reference dose. Consuming organic produce and juice shifted children’s exposure levels from above to below the EPA’s recommended guidelines for some of the pesticides.76 Reference ranges for various OP metabolites across the United States population can be found in the Third National Report on Human Exposure to Environmental Chemicals.77 Organic Farming and Planetary Health
Organic farming practices appear to promote PH. The effects of the chemical inputs used in conventional agriculture have led to the eutrophication of waterways, population declines in nontarget organisms (insects, plants, or other organisms not intentionally targeted for management), and health concerns.78 In contrast, organic farming practices are developed to enhance soil and water conservation, reduce pollution, improve soil structures, and ensure the conservation of biodiversity.78 Studies have found improved soil quality47,79 and higher levels of biodiversity, ranging from bacterial and earthworm communities up through the food chain to mammals.79,80 Organic farming practices also keep petroleum-based fertilizers and pesticides off the land, potentially promoting both PH and farm worker health.58 On the negative side, the
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decentralized distribution system of organic products may incur a high environmental cost.81 Meat and Poultry
The United States is the world’s leading producer of poultry and the second largest producer of eggs.82 In 2006, United States farms produced almost 8.9 billion broilers,83 primarily in high-density housing. Most broilers are raised in houses of 20,000 birds or more, while laying hens are kept in houses of 40,000 to 100,000 birds.51 The United States is also the world’s largest producer of beef. Eighty percent to 90% of grain-fed cattle come from feedlots (high-density areas where cattle are fattened for 3 to 4 months before slaughter) with 1000 or more head of cattle, while 40% come from feedlots with 32,000 or more head of cattle.84 Concentrated waste associated with large feedlots, combined with a lack of regulation for its treatment and disposal, is certainly a PH problem.85 Waste often is disposed of by applying it to land, resulting in excessive nutrient loads that run into surface waters and stimulate bacterial and algal growth. This lowers dissolved oxygen concentrations and suffocates fish and other organisms.85 Air quality also is impacted negatively by large animal operations, as toxic gases, odorous substances, and particulates containing microorganisms and human pathogens are released from the feed, animals, and manure.85,86 Globally, livestock operations account for 18% of all anthropogenic greenhouse gas emissions, in particular methane and carbon dioxide.85
LABELS
Meat and poultry labels can help assess the health risks or benefits of this massive production.51,87 Numerous labels are used throughout the specialty meat, poultry, and egg sectors, but none are regulated as extensively as the organic label, and only the organic label requires third-party certification. Labels include: Free range/free roaming. Producers demonstrate to USDA that the poultry has been allowed an undetermined amount of access to the outside. This label is regulated for poultry but not for eggs. Grass (forage) fed. This term can be used when grass and forage were the only feed source consumed throughout the lifetime of the ruminant animal, with the exception of milk consumed before weaning. Animals must have continuous access to pasture during the growing season. With the establishment of this voluntary standard, livestock producers may request that USDA verify the grass (forage) fed claim. After verification, the meat sold from these approved programs can carry the label ‘‘verified by USDA.’’ Natural. The product cannot contain artificial ingredients or added colors and must be only minimally processed (the raw product is not fundamentally altered). The label must explain the use of the term ‘‘natural,’’ by including terms such as ‘‘no added colorings’’ or ‘‘minimally processed.’’ There are no requirements for feed, antibiotic or hormone use, or pasture. No hormones. The term ‘‘no hormones administered’’ may be approved for use on the label of beef products if the producer provides sufficient documentation to USDA to demonstrate that the animals were raised without hormones. The claim ‘‘no hormones added’’ cannot be used on hogs and poultry unless followed by the statement ‘‘Federal regulations prohibit the use of hormones.’’
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No antibiotics. The term ‘‘no antibiotics added’’ may be used on labels for meat or poultry products if the producer provides sufficient documentation to USDA demonstrating that the animals were raised without antibiotics. Cage-free. Birds raised for meat rarely are caged before transport, making this label on poultry products virtually meaningless. It has more meaning, however, when placed on egg cartons, because most conventionally raised laying hens are kept in cages. The label does not guarantee access to the outdoors and is not regulated by USDA. Pastured poultry. The term refers to poultry management where birds are raised on pasture but provided with shelters that can be moved manually or by tractor. The poultry often is moved daily, and chickens can get up to 20% of feed from pasture forage in these systems. USDA does not regulate this term.
Nutritional Differences Between Grass-Fed and Conventional Meat
A few health claims can be made regarding grass-fed cattle, based on a review of available studies and FDA requirements for making health claims.86 Because there is no minimum requirement of EPA/DHA needed to make this claim, any food with these omega-3 fatty acids can be labeled accordingly.86 These claims include: Steak and ground beef from grass-fed cattle can be labeled ‘‘lean’’ or ‘‘extra-lean,’’ depending on the total grams of fat per serving. Some steak from grass-fed cattle can be labeled ‘‘lower in total fat’’ than steak from conventionally raised cattle, as two thirds of the steak in studies reviewed met those requirements. Steak from grass-fed cattle can carry a health claim associating a diet low in fat with a reduced risk of cancer. Steak and ground beef from grass-fed cattle can carry FDA’s qualified (based on supportive but not conclusive research) health claim linking the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) with a lower risk of heart disease.86 Strong evidence links EPA and DHA to reducing the risk of heart disease, and some evidence links alpha-linolenic acid (ALA) to reduced risks of fatal heart attacks. Conjugated linoleic acid (CLA, a fatty acid) has had positive effects in animals in laboratory studies on heart disease, cancer, and the immune system, although the results have not yet been repeated in people. Meat from grass-fed cattle contains less total fat than that from conventionally raised cattle, and both meat and milk from grass-fed animals have higher levels of the fatty acids that scientists believe provide health benefits.86
Dairy
Large operations of 500 or more dairy cows now account for over 47% of the United States milk supply,88 and about 22% of cows are injected with the synthetic hormone bovine somatotropin (bST, also called bovine growth hormone or bht) to promote lactation.86 Dairy cows primarily are fed corn or other grains, and only about 25% of them have access to pasture.86 Dairy, along with fresh produce and soymilk, tends to be one of the first organic products that consumers try and now makes up an estimated 6% of retail milk sales.89
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Nutritional differences between grass-fed and conventional dairy
There is no appreciable difference in the total fat, saturated fat, or omega-6:omega-3 ratio in milk from grass-fed versus conventionally raised cows.86 A high omega6:omega-3 ratio contributes to lower bone density and is associated with increased heart disease.58,86 In seven of 12 studies, grass-fed cows had higher levels of the fatty acid ALA than conventionally raised cows, with no significant difference in the remaining studies, and in 11 of 16 studies, milk from grass-fed cows had higher levels of CLA.86 Nutritional differences between organic and conventional dairy
Large organic dairy operations use feed comprised primarily of organic grains, resulting in some of the same issues found in conventional feedlots. Nutritional studies comparing organic and conventional dairy products give mixed results, with one study showing higher levels in CLA and other fatty acids in organic dairy products90 and others finding no differences in these compounds.91–93 One study found higher protein content during the first 10 weeks in lactation in the organic herd,91 while another showed higher levels of polyunsaturated fatty acids and a lower omega-6:omega3 ratio in organic milk.93 Two studies found higher levels of vitamin E (a-tocopherol) and beta-carotene in organic dairy products.90,92 Antibiotics
Cattle in 83% of United States commercial beef and dairy feedlots routinely receive antibiotics for disease prevention and to promote growth,94 resulting in the use of over 24 million pounds of antimicrobials annually for nontherapeutic purposes95 and accounting for 27% of all annual antibiotic use.96 Many of these antimicrobials, such as tetracycline and penicillin, are important for human use.95 Drug-resistant bacteria and pathogens have emerged because of the widespread use of antibiotics in the animal reservoir97,98 and these theoretically are able to be passed to people through the consumption of meat products.99 Health implications of antimicrobial resistance are infections that otherwise would not have occurred and increased rates of treatment failures and infection severity.98 An antibiotic-resistant urinary tract infection already may have been linked to this practice.100 Consumers concerned about antibiotic resistance pay a premium for foods marketed as ‘‘raised without antibiotics,’’ but one study has suggested that the final meat product may not differ from conventional products in terms of pathogen or antibiotic resistant organisms present, perhaps because of pathogen contamination during processing.101 Drug residues, including those from antibiotics, are considered an unintentional food additive and are monitored by USDA’s Food Safety Inspection Service (FSIS). Ingestion of antibiotic residues could lead to toxicity, allergenicity, and infection by drug-resistant disease-causing microorganisms.102 In 1994, however, residuemonitoring testing found residue concentrations exceeding allowed limits in only 0.5% of cattle and 0.3% of poultry.102 FSIS’ annual National Residue Program Data – Red Book documents residue violations. Planetary Health Differences Between Conventional and Grass-Fed/Organic Dairy
Grass-fed cattle systems reduce greenhouse gas production through carbon sequestration and manure management in pastures, decreased soil erosion, and improved water quality.86 There are no long-term studies of organic dairy farming providing evidence, other than possibly some water quality improvements, of the environmental impact of these production systems, however.103
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Local Foods
Industrialized food systems have financial incentives to reduce costs and produce new, high-value products. They are not accountable for overconsumption or poor health that may be caused by their products. Some researchers believe that cheap food is related to the increasing costs of health care, and particularly to the cost of treating obesity-related diseases.55,96,104 New efforts are emerging to reconnect people to land, food, and agriculture to improve human and environmental health. The local foods movement (similar to the slow food movement discussed earlier) claims that eating locally promotes access to healthful foods and supports healthy ecosystems. Foods bought directly from producers are usually fresh, a state typically related to improved taste, while varieties bred for high yield and long travel make trade-offs with regards to nutrients and taste.96,105 Episodes of food contamination and outbreaks of food poisoning, and general concerns about food safety, have bolstered the movement further.58 E. coli and other pathogens thrive in feedlot habitats but not in smaller, decentralized farm systems.58 Industrialized foods systems are more susceptible to both accidental and deliberate contamination; four companies now slaughter 80% of America’s beef, and 75% of precut salads are processed by just two companies.58 In contrast, local foods bought at a farmers’ market likely were harvested that morning, have not spent long hours in transport, and the consumer knows exactly who is responsible if there are any problems.58 In a recent survey of 500 adults in the United States regarding perceptions of food chains,106 the authors found that 85% and 88% of respondents, respectively, perceived local and regional food systems to be somewhat safe or very safe, whereas only 12% felt that way about the global food system. Another survey corroborated those results, indicating that consumers’ preferred United States food over foreign-sourced food, and local, family-farmed products over those produced by large corporate industries.107 For respondents in the Pirog and Larson survey,106 57% of respondents either somewhat or strongly agreed that organic food was healthier than conventional, while 69% either somewhat or strongly agreed that local food is better for their personal health than food that traveled across the country. Forty percent of respondents either somewhat or strongly agreed that science had proven that local food was healthier than distant food. The authors of the survey were unaware of any peer-reviewed studies documenting health differences related to the consumption of locally grown foods versus food from conventional national and global markets. Biodynamic Agriculture
As organic agriculture grows and begins to resemble the industrial system, some people have looked for systems that embrace both the philosophy and the science of organic.58 Biodynamic agriculture may fit this niche, as it suggests a unified approach to agriculture that relates the ecology of the earth–organism to that of the entire cosmos.108 Biodynamic agriculture is considered a way of living and working with nature with a consciousness of the uniqueness of each landscape and each practitioner, and strives toward self-sufficiency and working with nature’s rhythms in terms of energy, fertilizers, plants, and animals.108 Those who participate in biodynamic agriculture strive to promote the health of the land and encourage healthful eating practices109; literature on this farming practice tends to focus on techniques and potential benefits to the land. There is no evidence for any risks or benefits—to human or PH—using these methods. Genetically Modified Foods
Consumer resistance to genetically modified (GM) foods tends to be based on philosophical and PH concerns, particularly with regards to potential gene contamination of
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wild plants.47,110 There is no indication that GM foods are harmful to human health, although very little research has been done on that topic.111,112 Generally, United States consumers have lower confidence in GM foods compared with conventional crops and would like GM labeling requirements.47 Ninety-two percent of respondents in one survey wanted labels on GM foods, but only 28% thought GM products made food unsafe.107 Few GM fruits or vegetables are available at stores, but most processed foods contain GM ingredients because of the prevalence of GM soybean and corn derivatives.113 In the United States, over 90% of the soybeans and over 50% of the corn planted in 2007 was genetically modified.114 SUMMARY
Multiple DOEs suggest that dietary and farm practices influence both human health and PH. Consumption of smaller amounts of animal products may improve human health and longevity while preserving PH. There is interest in vegetarianism, but this practice does not have the POEMs to support it as the preferred diet, having eliminated confounding lifestyle elements like exercise. When choosing meat and dairy products, beneficial health claims (lower fat contents, higher levels of some omega3 acids) can be made about grass-fed cattle, but the evidence for the benefits of organic versus conventional feeding systems is lacking. This may be due to the fact that while organic cattle must consume an organic diet, they still may be consuming grains known to cause health problems in ruminants. Most of the literature is focused on proving the health benefits of interventions like healthy diets and organic production methods, while it might be better to look at the harms of conventional (current) diets and farming methods, then apply the do no harm principle and eliminate diets and farming methods that have been shown to cause disease. Given the profit drive of the food industry, the only ones to raise this argument are likely to be a select group of health scientists and consumer protection organizations who believe there is potential harm from pesticides, hormonal additives, and GM practices. This could create change similar to that in the meat-packing industry after publication of The Jungle.115 Those concerned about ingesting pesticide residues or developing antibiotic resistance who have the means are choosing to eat organic foods now. In the process, they also may be getting higher dosages of health-promoting polyphenols and fatty acids in their produce and may be improving PH, because organic production promotes healthy soils, waterways, and biodiversity while removing petroleum-based chemical inputs. Local foods can be either organic or conventionally produced, but trust between the consumer and farmer make these foods particularly appealing, and they offer freshness plus support a larger array of heirloom and plant varieties. Prepackaged meals may be one way to assure that the best choices and only those choices are consumed and may be very beneficial for those on a limited budget or who have disease states that have been shown to be very responsive to dietary intervention. Because organic produce spoils more rapidly than conventional produce, healthy fast food might be a way to increase public consumption and decrease waste. Already, organic raw food bars are becoming quite popular. POEMs involving large, unselected, free-living populations as subjects ingesting diets low in animal product calories and with varying proportions of food produced with presumably healthy farming methods may give the evidence needed to perform more informed dietary/lifestyle counseling. For now, amelioration of unhealthy choices may be the best approach. Serial substitutions using nonanimal foods and snacks to reduce animal product consumption over time, encouragement of daily vigorous
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exercise, and increased consumption of organic and locally grown foods appear to be the best strategies toward that end. ACKNOWLEDGMENTS
The authors acknowledge Paul Lazar, MD, residency director, McLaren Family Medicine Residency, Flint, Michigan, for the time allowed and editorial assistance given for completion of this article. Additional thanks are given to LeaAnn McGaugh, manager, Medical Library, McLaren Regional Medical Center, Flint, Michigan, for the time and assistance given on review of the literature and putting together the manuscript. REFERENCES
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and conventionally managed tomatoes and bell peppers. J Agric Food Chem 2006;54(21):8244–52. Pollan M. The omnivore’s dilemma: a natural history of four meals. New York: Penguin Books; 2006. Brandt K, Molgaard JP. Organic agriculture: does it enhance or reduce the nutritional value of plant foods? J Sci Food Agric 2001;81:924–31. Carbonaro M, Mattera M, Nicoli S, et al. Modulation of antioxidant compounds in organic vs. conventional fruit (peach, Prunus persica L., and pear, Pyrus communis L. J Agric Food Chem 2002;50(19):5458–62. Pollan M. The vegetable-industrial complex. NY Times October 15, 2006. Ness C. Is organic better? It depends. Minneapolis Star and Tribune, 2008;Taste. Mitchell AE, Hong Y, Koh E, et al. Ten-year comparison of the influence of organic and conventional crop management practices on the content of flavonoids in tomatoes. J Agric Food Chem 2007;55(15):6154–9. Pietta PG. Flavonoids as antioxidants. J Nat Prod 2000;63(7):1035–42. Curtis CS, Misner S. Pesticide versus organically grown food. The University of Arizona Cooperative Extension, Department of Nutritional Sciences; 2006. Newswise. Difference between some organic, conventional produce. Newswise News Release 2004;2008(April/10). Asami DK, Hong YJ, Barrett DM, et al. Comparison of the total phenolic and ascorbic acid content of freeze-dried and air-dried marionberry, strawberry, and corn grown using conventional, organic, and sustainable agricultural practices. J Agric Food Chem 2003;51(5):1237–41. Carbonaro M, Mattera M. Polyphenoloxidase activity and polyphenol levels in organically and conventionally grown peach (Prunus persica L., cv. Regina Bianca) and pear (Pyrus communis L., cv. Williams). Food Chemistry 2001; 72(4):419–24. Baxter GJ, Graham AB, Lawrence JR, et al. Salicylic acid in soups prepared from organically and nonorganically grown vegetables. Eur J Nutr 2001;40(6): 289–92. Benbrook C. Elevating antioxidant levels in food through organic farming and food processing. The Organic Center State of the Science Review 2005:1–81. n˜ez J, et al. New evidence confirms the nutritional supeBenbrook C, Zhao X, Ya riority of plant-based organic foods. The Organic Center State of the Science Review 2008:1–53. Allison TG, Squires RW, Johnson BD, et al. Achieving national cholesterol education program goals for low-density lipoprotein cholesterol in cardiac patients: importance of diet, exercise, weight control, and drug therapy. Mayo Clin Proc 1999;74(5):466–73. Benbrook C. Breaking the mold—impacts of organic and conventional farming systems on mycotoxins in food and livestock feed. The Organic Center State of the Science Review 2005:1–63. Lu C, Knutson DE, Fisker-Andersen J, et al. Biological monitoring survey of organophosphorus pesticide exposure among preschool children in the Seattle metropolitan area. Environ Health Perspect 2001;109(3):299–303. Koenig V. The benefits of organic. Stonyfield Farm Moosletter 2008(April/4). p. 1. National Research Council. Pesticides in the diets of infants and children. Washington, DC: National Academy Press; 1993.
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74. Faustman EM, Silbernagel SM, Fenske RA, et al. Mechanisms underlying children’s susceptibility to environmental toxicants. Environ Health Perspect 2000; 108(Suppl 1):13–21. 75. Baker BP, Benbrook CM, Groth E 3rd, et al. Pesticide residues in conventional, integrated pest management (IPM)-grown and organic foods: insights from three US data sets. Food Addit Contam 2002;19(5):427–46. 76. Curl CL, Fenske RA, Elgethun K. Organophosphorus pesticide exposure of urban and suburban preschool children with organic and conventional diets. Environ Health Perspect 2002;111(3):377–82. 77. Centers for Disease Control and Prevention. Third national report on human exposure to environmental chemicals. CDC Report 2005;1–475. 78. International Federation of Organic Agriculture Movements. Environmental benefits of organic agriculture. Available at: http://www.ifoam.org/organic_facts/ benefits/index.html. Accessed September 10, 2008. 79. Siegrist S, Schaub DL, et al. Does organic agriculture reduce soil erodibility? The results of a long-term field study on loess in Switzerland. Agric Ecosyst Environ 1998;69(3):253–64. 80. Hole DG, Perkins AJ, Wilson JD, et al. Does organic farming benefit biodiversity? Biol Conserv 2005;122(1):113–30. 81. Foster C, Green K, Bleda M, et al. Environmental impacts of food production and consumption: a report to the department for environment. Food and Rural Affairs 2006;1–199. 82. US Department of Agriculture, Economic Research Service. Poultry and eggs: background. Available at: http://www.ers.usda.gov/briefing/poultry/background. htm. Accessed September 10, 2008. 83. US Department of Agriculture, National Agricultural Statistics Service. Poultry: production and value 2006 summary. Available at: http://usda.mannlib.cornell. edu/usda/current/PoulProdVa/PoulProdVa-04-27-2007.pdf. 84. US Department of Agriculture, Economic Research Service. Cattle: background. Available at: http://www.ers.usda.gov/briefing/cattle/Background.htm. Accessed September 10, 2008. 85. Pew Commission on Industrial Farm Animal Production. Putting meat on the table: industrial farm animal production in America. A project of the Pew Charitable Trusts and Johns Hopkins Bloomberg School of Public Health. 2008. 86. Clancy K. Greener pastures: how grass-fed beef and milk contribute to healthy eating. 2006:1–82. 87. US Department of Agriculture, Food Safety and Inspection Service. Meat and poultry labeling terms. Available at: http://www.fsis.usda.gov/FactSheets/ Meat_&_Poultry_Labeling_Terms/index.asp. Accessed September 10, 2008. 88. Miller JJ, Blayney DP. Dairy backgrounder. Outlook Report 2006;LDP-M-14501(April/10):1–25. 89. Dimitri C, Venezia KM. Retail and consumer aspects of the organic milk market. Outlook Report 2007;LDP-M-155-01:1–18. 90. Bergamo P, Fedele E, Luigi Iannibelli L, et al. Fat-soluble vitamin contents and fatty acid composition in organic and conventional Italian dairy products. Food Chemistry 2003;82(4):625–34. 91. Bystrom S, Jonsson S, Martinson K. Organic versus conventional dairy farming — ¨ jebyn Project. Proceedings of the COR Conference, March, studies from the O 26–28, 2002, Aberystwyth.
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92. Nielsen JH, Lund-Nielsen T, Skibsted L. Higher antioxidant content in organic milk than in conventional milk due to feeding strategy. Danish Research Centre for Organic Farming Newsletter, September 2004. 93. Ellis KA, Innocent G, Grove-White D, et al. Comparing the fatty acid composition of organic and conventional milk. J Dairy Sci 2006;89:1938–50. 94. Espinoza M. Food safety of organic, conventional beef not so different, Ohio State study finds. Ohio State University Extension 2004;2008(April/10):1. 95. Mellon M, Benbrook C, Benbrook KL. Hogging it: estimates of antimicrobial abuse in livestock. Report Published by the Union of Concerned Scientists 2001:1–109. 96. Kirschenmann F. Farming, Food and health. Gleanings 2006(Summer):1–6. 97. Tauxe RV. Emerging foodborne diseases: an evolving public health challenge. Emerg Infect Dis 1997;3(4):425–34. 98. Angulo FJ,et al. Evidence of an association between use of antimicrobial agents in food animals and antimicrobial resistance among bacteria isolated from humans and the human health consequences of such resistance. Journal of Veterinary Medicine Series B Infectious Diseases and Veterinary Public Health 2004;51:374–379. 99. Van den Bogaard AE, Stobberingh EE. Epidemiology of resistance to antibiotics: links between animals and humans. Int J Antimicrob Agents 2000;14:327–35. 100. Ramchandani M, Manges AR, DebRoy C, et al. Possible animal origin of humanassociated, multidrug-resistant, uropathogenic Escherichia coli. Clin Infect Dis 2005;40(2):251–7. 101. LeJeune JT, Christie NP. Microbiological quality of ground beef from conventionally-reared cattle and ‘‘Raised without Antibiotics’’ label claims. J Food Prot 2004;67(7):1433–7. 102. Committee on Drug Use in Food Animals, Panel on Animal Health, Food Safety, and Public Health, National Research Council. The use of drugs in food animals: benefits and risks. 1999. 103. Kelly T, Butcher N, Harrington K, et al. Organic–conventional dairy systems trial in New Zealand: four years’ results. Adelaide; 2005. p. 268–71. 104. Lang T, Rayner G, editors. Why health is the key to the future of food and farming: a report on the future of farming and food. A Joint Submission to the Policy Commission on the Future of Farming and Food. City University, London, Department of Health Management and Food Policy. 2002. 105. Davis DR. Trade-offs in agriculture and nutrition. Food Technol 2005;59(3):120. 106. Pirog R, Larson A. Consumer perceptions of the safety, health, and environmental impact of various scales and geographic origin of food supply chains. A Publication of the Leopold Center for Sustainable Agriculture, Iowa State University 2007;2008(April 17):1. 107. Wimberly RC, Vander May BJ, Wells BL, et al. The globalization of food and how Americans feel about it. North Carolina State University 2003:1–17. 108. Biodynamic Farming and Gardening Association. What is biodynamic agriculture? Available at: http://www.biodynamics.com/biodynamics.html. Accessed September 10, 2008. 109. Cook W. Food vitality – the almost neglected ingredient for health. Positive Health 2004;95:34–8. 110. Ervin DE. Towards an ecological systems approach in public research for environmental regulation of transgenic crops. Agriculture, Ecosystems and Environment 2003;99:1–14.
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111. Domingo JL. Health risks of gm foods: many opinions but few data. Science 2000;288(5472):1748–1749. 112. Pelletier D. FDA’s regulation of genetically engineered foods: scientific, legal, and political dimensions. Food Policy 2006;31:570–91. 113. Whitman DB. Genetically modified foods: harmful or helpful? Available at: http://www.csa.com/discoveryguides/gmfood/review.pdf. Accessed September 10, 2008. 114. US Department of Agriculture, Economic Research Service. Adoption of genetically engineered crops in the U.S.: extent of adoption. Available at: http://www. ers.usda.gov/Data/BiotechCrops/. Accessed September 10, 2008. 115. Sinclair U. The jungle. New York: The New American Library, Incorporated.; 1906.
Health Risk s and Benefits of Bottled Water Gena L. Napier, MD, Charles M. Kodner, MD* KEYWORDS Water Water purification
Essential to all known forms of life, water is an inevitable topic in each primary care clinic. Clinical concerns regarding safety and quality often arise for this dietary staple. The Food and Nutrition Board, a division of the Institute of Medicine, recommends that adults consume between 2.7 and 3.7 L (approximately 91 to 125 oz) of total water daily, including intake from beverages and foods.1 This recommendation is higher than the traditional eight glasses of water a day (approximately 64 ounces), but both recommendations lack scientific support.2 One and one half liters daily may be a more reasonable recommendation for the general population, with special considerations for active individuals and patients who have fluid-sensitive medical conditions.2,3 As physicians counsel patients to drink more fluids during a cold or to prevent urinary tract infections, patients may ask, ‘‘Bottled or tap?’’ Additionally, considering that total lifetime intake of water is substantial, patients may wonder, ‘‘Is it safe?’’ This article addresses common questions encountered regarding potable water, including tap and bottled. Regulatory standards, commercial availability, quality, and safety issues are explored. Scientific support and evidence-based guidelines are provided if available; however, sound clinical judgment remains the primary source of decision making because scientific trial data are often limited. TASTE ISSUES FOR BOTTLED VERSUS TAP WATER Does Bottled Water Taste Better?
Bottled water drinkers often cite taste as a motivation for their beverage choice. Most people expect their water to have little or no taste or odor. Rigorous scientific evidence supporting the superior taste of bottled water is lacking. Water-tasting competitions and lay press taste tests are abundant but produce conflicting results.4,5 Municipal water supplies differ widely geographically and seasonally making consistent headto-head comparisons difficult. Water can also collect tastes and odors as it travels
Department of Family and Geriatric Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA * Corresponding author. E-mail address:
[email protected] (C.M. Kodner). Prim Care Clin Office Pract 35 (2008) 789–802 doi:10.1016/j.pop.2008.07.008 primarycare.theclinics.com 0095-4543/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.
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from a community supply to individual residences, so aesthetic factors are variable from faucet to faucet. Poor taste is often attributed to chlorine, a safe and costeffective disinfection measure used by most tap water facilities.6 Bottled water manufacturers use more costly processes, such as ozone or ultraviolet light, thus avoiding the chlorine or ‘‘chemical’’ taste. Water connoisseurs generally agree most taste differences occur at room temperature. Because ice-cold water has less noticeable taste difference between types, water submitted for taste tests is often held at room temperature. On comparing different types of bottled waters, Consumer Reports noted ‘‘the major differences in taste were due to the type of plastic in the water’s bottle,’’ further stating that high-density polyethylene (HDPE) plastic imparted inferior taste. HDPE packaging resembles opaque milk cartons and typically dispenses multiple servings. The more common polyethylene terephthalate (PET) type, a clear plastic usually used in single-serving containers, contributed less taste to the water’s flavor.7 Does Bad Taste Equal Bad Water?
The US Environmental Protection Agency (EPA) specifically indicates that bad taste does not necessarily mean unhealthy water, and that lack of odor is not a reliable indicator of healthy water. For example, sulfur compounds can impart a distinct odor and salty taste but do not pose a health risk when within EPA standards. Conversely, contamination with potentially hazardous microorganisms, such as Cryptosporidium and Giardia lamblia, does not alter water’s flavor. Other contaminants related to odor and taste include chloride (salty), copper (metallic), foaming agents (bitter), iron (metallic), manganese (bitter), pH (bitter or soda taste), total dissolved solids (salty), and zinc (metallic).8 Tap water’s occasional cloudy appearance can often be attributed to air bubbles that naturally disappear on standing. For concern about aesthetic qualities, the EPA encourages consumers to contact their local public water system. TYPES AND VARIETIES OF PACKAGED WATER
The US Food and Drug Administration (FDA) established bottled water classifications in 1995. Carbonated water, flavored water, vitamin-enriched water, soda water, sparkling water, and tonic water are considered soft drinks and are regulated as food items by the FDA. This article only addresses bottled water as defined by the FDA. Table 1 describes various water sources and standards.9 Consumers should note that these designations do not describe the water’s geographic source. For example, any water source that flows naturally to the earth’s surface may be called spring water regardless of location. Bottled spring water and purified water are the most common types purchased for individual consumption in the United States. EPIDEMIOLOGIC AND SAFETY ISSUES Usage Statistics and Economic Impact How much water do we have and what does it cost?
According to US Geologic Survey (USGS) data, the earth holds about 1.46 billion km3 of water. Almost 97% of our total water is saline, whereas 2% is fresh water confined to glaciers and 1% resides in streams, lakes, and ground water. The United States uses approximately 148 trillion gal per year to support residential, commercial, agricultural, and manufacturing needs, which equates to roughly 500,000 gal per person. Domestic water usage (ie, bathing, drinking, lawn care, and so forth) represents 80 to 100 gal of water per person per day.10
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Table 1 Types and sources of drinkable water in the United States Artesian water
Originates from a well that taps a confined aquifer; may or may not undergo further treatment
Ground water
Originates from a subsurface saturated zone that is not under direct influence of surface water
Mineral water
Contains at least 250 ppm total dissolved solids, usually Ca11, Mg, Na1, K1, silica, and HCO3; typically spring water; originates from a geologically and physically protected underground source; no minerals may be added
Purified water
Does not have to list source on label; meets definition of ‘‘purified water’’ in the US Pharmacopeia, 1995; may be further classified based on method of purification (eg, deionized water, distilled water, or reverse osmosis water); essentially free of all chemicals, but not necessarily free of microbes
Sparkling bottled water
Naturally carbonated, originating from a spring; if the water loses carbonation in processing, CO2 can be replaced to equal the same amount as found at the source
Spring water
Derived from an underground formation from which water flows naturally to the earth’s surface
Sterile/sterilized water
Meets requirements under ‘‘sterility tests’’ in the US Pharmacopeia, 1995; free from all microbes
Well water
Originates from a hole constructed in the ground that taps the water in an aquifer
Data from Bullers A. Bottled water: better than the tap? FDA Consum 2002;36:4.
Tap water has been historically inexpensive in the United States, costing on average $0.002 per gal; however, over the past 5 years municipal water rates increased by 27% in the United States. Some European countries, such as Denmark and Germany, pay up to four times more than United States domestic rates.11 Who drinks bottled water and at what cost?
The United States market for bottled water grows by 10% per year, making it the second most popular beverage, behind soft drinks and surpassing beer. In 2005 the average American drank approximately 25 gal of bottled water, 51.5 gal of soft drinks, and 21 gal of beer.12 In the United States total per capita daily tap water ingestion averages 926 mL. Ingestion of bottled water is estimated to be 163 mL per capita per day when averaged over the entire population, both consumers and nonconsumers. Considering only bottled water consumers as a subpopulation, average ingestion is estimated at 736 mL per day.13 Consumers purchase water in various serving sizes from single 6-oz servings to 5-gal office water coolers. Prices range from $1.00 for a basic brand to more than $180 per gal for premium water. Standards for Water Production and Content Who regulates tap water, bottled water, and commercially available filters?
Although bottled water sold within state lines is regulated by individual state codes, such water sold across state lines is regulated by the FDA under their ‘‘Initial Standard of Identity and Quality’’ published in November 1995. If a bottled water exceeds FDA limits in a given category, the company must bear a statement of substandard quality on the label (eg, ‘‘contains excessive bromide’’ or ‘‘excessively radioactive’’) as
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appropriate. Additionally, individual companies can choose to conform to voluntary certifications of industry trade associations, one of which is the International Bottled Water Association (IBWA). The IBWA first published its Model Code in 1982 and released a revised edition in 2008. To maintain IBWA certification, companies must submit to annual inspections. Up to 90% of the bottled water sold in the United States is IBWA certified. The National Sanitation Foundation (NSF) also provides voluntary testing services. The EPA regulates tap water production and distribution under the Safe Drinking Water Act (SDWA), passed in 1974 and amended in 1986 and 1996. The drinking water standards include a list of legally enforceable, mandatory primary regulations regarding substances deemed potential health hazards. Beginning in 1996, all municipal water providers must produce a ‘‘right to know’’ or Consumer Confidence Report annually that lists the results of contaminant testing. In addition to mandatory water standards, the EPA has established a set of nonmandatory secondary standards that address tap water’s taste, color, and odor. Because these aesthetic factors do not influence the safety of the product, public water systems comply voluntarily to these secondary standards. The EPA also publishes a Contaminant Candidate List every 5 years to determine a need for future regulations. The 93 chemicals and 11 microbiologic contaminants on the list published in 2005 include ethylene glycol, methanol, and a list of enteric organisms. Because many individuals drink bottled or filtered water for its perceived advantage of purity, regulatory standards are often cited by bottled water advocates and dissenters. In regard to bottled water, the FDA must either adopt each EPA regulation or prove that the regulation governs a chemical or microbiologic agent unique to municipal water and not found in bottled water. Examples include infective organisms not believed to be found in bottled water sources, such as G lamblia and Legionella, and byproducts of chlorination, such as haloacetic acids (HAA5). Frequency of testing differs, with tap water generally tested more often than bottled. Only tap water testing requires certified laboratories as opposed to self-testing and self-selecting laboratories. In addition the Natural Resources Defense Council (NRDC) reports a trend toward laxity regarding all bottled water testing regulations, citing state-reported lack of funds for regulation enforcement.14 No standards currently in place for either bottled or tap water regulate or mandate testing for pharmaceuticals. In contrast to bottled and tap water, commercial domestic water filtration units are not federally regulated. Devices can be certified by three separate agencies: the NSF, International Underwriters Laboratory, and the Water Quality Association. Each agency certifies units using American National Standards Institute and NSF standards. Is chlorine a safe method of water disinfection?
Chlorination was the first method of large-scale water treatment, and routine disinfection of municipal water supplies in the United States began in 1908. As cities across the country adopted the procedure, the incidence of cholera and typhoid dropped dramatically. The Centers for Disease Control and Prevention (CDC) considers drinking water disinfection ‘‘one of the great public health achievements of the twentieth century.’’15 Since its inception, chlorination has come into question for potential health hazards. Chlorine reacts with naturally-occurring organic matter in water producing disinfection byproducts (DBP) including trihalomethanes (THM), HAA5, bromate, and chlorite. Published research documents associations between exposure to DBP and increased incidence of cancer, particularly bladder but also colon and renal carcinoma. A meta-analysis published in 1992 looking at case-control and cohort studies showed an association between chlorination byproducts and bladder and rectal
Health Risks and Benefits of Bottled Water
cancer.16 A case-control study in Spain involving 2490 individuals supported increased bladder cancer risk with long-term exposure to THM. Exposure can occur by ingestion, swimming, or bathing.17 A recent study in Taiwan showed an association between DBP and specific birth defects.18 There is conflicting research, however. A study in Spain involving 1061 individuals demonstrated an inverse association between water consumption and bladder cancer risk with no association to THM exposure.19 Additionally, exposure to DBP has been shown not to affect fetal survival.20 Researchers have difficulty controlling for confounding variables in these studies. Water consumption data are often based on individual recall, and DBP exposure is based on municipal water data. Accurate exposure quantification is therefore challenging to obtain because of recall bias and subjects moving municipalities through the study time frame. The World Health Organization (WHO) International Agency for Research on Cancer notes these methodologic limitations and states that there is ‘‘inadequate evidence for the carcinogenicity of chlorinated drinking water in humans.’’21 The EPA recognizes the potential hazards of DBP and regulates each contaminant as part of the SDWA. Whether these standards are sufficient remains debated and additional research is needed. What are alternatives to chlorination?
Chlorination remains the most widely used method of municipal water disinfection in the United States. In addition to being inexpensive, chlorine is unique in that it remains in treated water to the point of use; thus, it disinfects throughout the water system. Alternatives include ozonation, chlorine dioxide, chloramines, and UV disinfection. Each process has disadvantages that are beyond the scope of this article but can be reviewed.22,23 Some United States cities, including Milwaukee and Las Vegas, use ozonation, a more expensive process. Additional chemicals must be added after ozone treatment to prevent recontamination as water travels to the point of use. The WHO maintains that the carcinogenic risk for chlorination is extremely small in relation to the infectious risks of inadequate disinfection.24 Bottled Tap Water How much of bottled water is bottled tap water?
Under FDA regulations bottled water originating from a municipal source must state ‘‘from a community water system’’ or ‘‘from a municipal source’’ on the label unless the water undergoes further treatment. Manufacturers that process tap water with further purification steps are not required to post this label. Some leading brands, Dasani and Aquafina, fall into this category. Indeed, the NRDC reports that 25% to 30% of bottled water sold in the United States falls under the heading of ‘‘bottled tap water,’’ sometimes further treated, sometimes not.25 Additionally, labels can be misleading. Pictures of mountains and glaciers may provoke images of a particular water source, but the product behind the label originates from an urban water supply. Bottled tap water cannot be readily identified based on packaging information. Companies are required to disclose this information on request, and consumers can find contact information on individual bottles. Bottled Waste Product Statistics and Environmental Impact Where do water bottles come from and where do they go?
The most common, clear, individual-serving water bottles are composed of PET derived from crude oil. Approximately 17 million barrels of oil are used annually to meet the estimated 30 billion PET water bottles sold in the United States. About 86% of these bottles become waste,26 which may take an estimated 400 to 1000
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years to degrade. Other packaging options include HDPE (the opaque material of milk containers), polycarbonate jugs (water coolers), and glass. To combat the growing use of plastic bottles worldwide, governments have taken initiative to stop the purchase of bottled water with public funds. Governments involved include Paris, France; Liverpool, United Kingdom; New South Wales, Australia; San Francisco, California; Ann Arbor, Michigan; and the state of Illinois. UNICEF’s Tap Project, Inside the Bottle, and Think Outside the Bottle, are national campaigns against bottled water.27 The IBWA remains outspoken in defense of bottled water. Public statements note that PET accounted for less that one third of 1% of all waste produced in the United States in 2005. In addition, bottled water remains indispensable in emergency situations, such as hurricanes and earthquakes. Finally, implying that the bottled water industry is unfairly singled out, they note that ‘‘efforts to reduce, recycle, and conserve resources must focus on ALL packaging and not just bottled water.’’28 The United Nations has established a set of Millennium Development Goals to achieve by 2015. Environmental sustainability ranks among the objectives and aims to reduce the number of people lacking access to sustainable, safe drinking water by half. In light of the expense necessary to meet this goal, bottling water for standard consumption seems to be an expensive and ineffective way to address a natural resource. HEALTH RISKS AND BENEFITS
Assessment of the possible health risks and benefits from consuming bottled or filtered water as a significant portion of total water intake is complicated by several factors. Primarily, given the low general risk for health problems from using bottled water and the great variation in types, brands, and sources of consumed water, randomized trials on any significant scale are essentially impossible to perform. The evidence for health risks and benefits, therefore, depends heavily on observational studies and on comparisons of water product content to federal or other guidelines. The evidentiary chain from putative or possible health effect, to demonstrably increased risk factors in various water sources, to isolated cases of illness under specific circumstances, to a proven general health risk or benefit, is often incomplete. Inevitably, physicians who are called on to counsel patients regarding health effects of various water sources need to balance many factors, including: location-specific or patient-specific risks based on customary water source or supply; personal or patient beliefs or preferences balancing cost, convenience, and attitude toward possible risks; and available scientific and clinical data regarding actual benefits and risks. Understanding of the water sources, container types, and regulatory standards helps physicians assess these risks and benefits. The range of water sources is large, including tap water, filtered or boiled water, bottled water, well water, or others as described previously. This section addresses common questions related to possible health benefits or hazards of various water sources, focusing on the proposed health effects and the available evidence that these effects actually occur. The questions and evidence discussed focus on issues pertinent to more developed countries, including rural, urban, and suburban locales; the issues of water safety and purification for developing countries are different and outside the scope of this article. Even within the context of the United States and other developed areas, some communities have significant exposure to water contaminated by a known source, including industrial waste products, herbicides or other chemicals, natural disasters or other events, and many other contaminants. Health advice delivered by physicians in these communities must be customized to specific local issues.
Health Risks and Benefits of Bottled Water
A good general description of these issues, and means for physicians to address them, is available.29 Possible Health Benefits Does filtration or other methods to reduce microorganism levels prevent infection?
Current water treatment methods, including chlorination, for most public water supplies essentially prevents historically fatal illnesses, such as dysentery, cholera, or typhus.29 Waterborne organisms that can cause illness and might be present in drinkable water most commonly include parasites, such as Giardia or Cryptosporidium species, bacteria, such as Escherichia coli or others, and enteric viruses. One of the proposed benefits of using bottled or filtered water is to reduce or eliminate infectious organisms and prevent infection, primarily acute diarrhea, or other gastrointestinal illness. Specific issues include using bottled water to prepare infant formula, or using filtered water for individuals who have compromised immunity. In one case-control study30 of adults who had HIV, users of unboiled tap water were four times more likely to have cryptosporidiosis than were users of bottled water. A meta-analysis from Brazil found an increased endemic cryptosporidiosis among users of unboiled water, but not among all users of nonbottled water.31 In general, however, the evidence for the role of using bottled water to prevent infectious disease is limited. Most waterborne illnesses, particularly cryptosporidiosis, occur as a result of contaminated recreational water sources32 rather than drinking water sources, which may account for up to 12% of acute gastrointestinal illness.33 Additional information regarding waterborne illnesses can be found on the CDC Web site at http://www.epa.gov/nheerl/articles/2006/waterborne_disease.html. Given the wide variation in bottled water sources and standards for different products, it is difficult to establish that bottled water in general might reduce the risk for diarrheal illness. Even if water sources other than tap water do reduce exposure to infectious organisms, it is possible that exposure to low levels of these organisms is important for protective immunity, and that using highly filtered water might actually increase the risk for illness.34 Many individuals who have concerns about the safety of their home water supply also turn to water filters or other purification methods to prevent disease, primarily infectious diarrheal illness. A Cochrane review35 found that most interventions at the home level were effective at preventing diarrheal illness, though identifying a single useful outcome measure or quantifying the overall reduction in diarrheal illness was difficult because of the wide variation in study design. Methods studied included physical removal of pathogens (filtration, adsorption, or sedimentation), chemically treating water to kill or deactivate pathogens (most commonly with chlorine), disinfection by heat (boiling or pasteurization), UV radiation (using either the sun [solar disinfection] or an artificial UV lamp), or a combination of these approaches (filtration or flocculation combined with disinfection). Filters do not seem to alter the presence of most chemical contaminants, however, and other methods, such as distillation, adsorption, water softeners, UV light, or reverse osmosis, may be necessary if such contaminants, rather than infectious organisms, are the primary target for water purification.29 In light of available information, reasonable recommendations to patients who have questions might include the following: In general, there is no evidence that using bottled or filtered water reduces the risk for illness in immunocompetent people.
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Using bottled or filtered water may be prudent in areas or circumstances of known compromise to the safety of public water sources. Immunocompromised individuals may wish to use filtered water sources. If home water filters are used, these should be cleaned regularly to prevent unwanted exposure to bacteria. Using ‘‘absolute 1 mm’’ filters is necessary to protect against Cryptosporidium. Do higher mineral levels result in any meaningful health benefits?
Mineral water has long been touted to have various health benefits. Recent clinical trials using water supplemented with higher mineral levels than are typically present in United States bottled water products found possibly beneficial levels of calcium, magnesium, or silica.36–38 The purported benefits of higher levels of these elements include decreasing the risk for osteoporosis (calcium), ischemic heart disease or cardiac arrhythmias (magnesium),39 or Alzheimer disease (silica).37 Translation of these findings to the more general bottled water supply may be difficult. A study of commercially available bottled waters in the United States and Europe39 reviews the potential health benefits of water rich in calcium and magnesium, and low in sodium, but found wide variation in the levels of these minerals in various bottled water sources. A similar study (by the same authors) of bottled water mineral content compared with tap water40 likewise found wide variation in content, and noted that mineraldeficient waters, such as spring waters, may taste better to many consumers than mineral-rich waters. The conclusion of both studies is that bottled water mineral content varies widely, and that mineral-rich bottled water products may provide a clinically meaningful component of the total dietary requirement for minerals, such as calcium or magnesium, although they may also contribute to the total dietary load of sodium. Patients who have specific health concerns, such as a need for adequate calcium intake or a need to avoid sodium, should be counseled to check the product labels if they frequently use bottled water products, but more general statements about a global health benefit of mineral water cannot be definitively made. Do portable water purification systems prevent travel-related illness?
Given the logistic problems of carrying supplies of bottled water, international travelers or those traveling in wilderness areas typically rely on water purification methods rather than bottled water. Several water purification methods, including boiling, chlorine dioxide tablets, and portable filtration devices with an absolute pore size less than 1 mm, combined with other methods, seem to provide sufficient purification to prevent infectious diseases.41 Possible Health Risks Do higher mineral levels result in any meaningful health risks?
Although mineral content for some compounds has purported health benefits, there are also concerns about health risks for other minerals that may contaminate the drinkable water supply. The trace minerals of greatest concern include arsenic, lead, nitrates (such as potassium nitrate or ammonium nitrate used in fertilizers), and copper. Arsenic is commonly found in the soil and enters ground water supplies through erosion; in addition to acute toxicity and concerns about risk for bladder, kidney, skin, or lung cancer from long-term exposure,29,42 there is a possible risk for vascular or cardiovascular disease, diabetes,42 or peripheral neuropathy42 from sustained low-level arsenic exposure. Older water delivery systems may have lead-based plumbing despite more recent requirements for lower lead levels in plumbing materials, and children or others who have chronic exposure to water from these sources may be at risk for neurotoxicity or subtle cognitive changes from chronic lead
Health Risks and Benefits of Bottled Water
exposure. The Consumer Confidence Reports required from public water suppliers by the EPA are accessible at http://www.epa.gov/safewater/ccr/index.html and provide useful information on the safety and quality of local water supplies. A study of well water collected from 1992 to 1993 near a Wisconsin geologic formation42 identified widely varying levels of arsenic, with 20% of these sources greater than the new standard of 10 mg/L. Individuals using these water sources in which the level of arsenic was between 2 and 10 mg/L were more likely to self-report having depression, high blood pressure, circulatory problems, or a history of cardiac bypass surgery than those using wells with lower arsenic levels. Among drinking water samples collected as part of a case-control study of arsenic exposure and bladder cancer,43 the mean arsenic level was highest in private well water supplies and lowest in bottled water samples. The status of lead content in public water supplies, and the status of current efforts to reduce this exposure, has been reviewed.44 Although similar studies have not been done in the United States, and in general there is no clear evidence that using bottled water affects the risk for lead-related illness, a study of bottled water samples in India45 found elevated lead levels in 7 of 17 bottled water samples tested. Given the variable regulatory status and labeling variations for different bottled water products, and the prevalence of tap water marketed as bottled water, physicians counseling patients who have high lead levels or higher lead exposure risk may wish to recommend point-of-use water filters in addition to other measures, or particularly careful review of bottled water filtration or purification measures if bottled water is a significant source of consumed water. Are there any health risks from reusing bottled water containers, or from using bottled water after prolonged storage?
A great many public health information sources describe possible health risks from reusing water bottles (ie, refilling them with tap water), or from using water bottles after prolonged storage. Partial information and various recommendations regarding this issue have proliferated on the Internet,46 and health concerns regarding reused water bottles have reached the level of urban legends.47 The putative health concerns relate to chemical substances that enter the water from the plastic bottles, including polycarbonate, bisphenol A (with estrogen-like effects), vinyl chloride (a known carcinogen), diethylhexyl adipate, or others; and an increased risk for bacterial infection if water is allowed to stand in an opened, partially-used bottle for a prolonged time. The various chemical risks are often purported to worsen if bottles have prolonged exposure to heat or light. In particular, bisphenol A has been found to migrate from polycarbonate bottles at a much faster rate after exposure to boiling water than at room temperature, although there was no difference in old versus new water bottles.48 This compound has received attention because of its ubiquity in the production of food or beverage containers that use epoxy resins or polycarbonate plastics, and because of its long recognition as having possible estrogen-like effects. Animal studies have documented various endocrine effects from bisphenol A exposure, but human studies are generally lacking and at the present time the FDA does not recommend that consumers avoid using bottles containing bisphenol A, although it does indicate that concerned individuals may use alternatives to polycarbonate baby bottles.49 Exposure to bisphenol A remains well below the tolerable daily intake levels established by the European Food Safety Authority.50 Some recommendations emphasize the role of a ‘‘plastic taste’’ to the water indicating increased chemical content. Reliable data on these effects are also limited, but
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there is evidence of increased antimony levels in bottled water after storage for 6 months,51 and of increased bacterial counts after 48 hours after drinking once from bottled water.52 More recent public-oriented information sources on the Internet have begun to allay fears about chemical exposures as lacking any evidence for health risks, and the role of cleaning bottles between uses to limit infectious disease risk. Recognizing the importance of the above chemical studies and limited clinical data, there are essentially no reliable clinical data regarding the possible risks of reused water bottles, bottled water used after prolonged storage, or the infectious risks of partially consumed water bottles. The only published study relating to this effect does indicate that chemical effects can produce different odors in bottled water or soft drinks, but does not suggest any specific health effects related to this.53 Physicians who are asked to advise patients regarding these topics ultimately have to balance potential but unproved risks versus overall safety in the face of uncertain or nonexistent data, and advise their patients accordingly. Individual physicians should decide whether practices, such as avoiding or limiting water bottle reuse, cleaning bottles that have contained sports drinks or juices with higher sugar content to avoid bacterial colonization, or using safer but less convenient glass bottles, represent prudent behavior to avoid potential risks, or represent unnecessary work for patients who use bottled water and other beverages in an appropriate fashion and are unlikely to suffer adverse health consequences. Individual patients also have different beliefs about these practices, and physicians should elicit their concerns or beliefs as part of this counseling. For many patients, other health risks, such as smoking, routine safety counseling, or other issues, may outweigh any possible concerns about chemical exposures from water bottles. Does increased use of bottled water among infants or children increase the frequency of dental disease?
Bottled water has varying levels of maximally allowed fluoride content, and several studies have shown that fluoride levels in different brands of bottled water are significantly below the level that is considered protective from dental caries.54 There is evidence demonstrating dental erosion from some flavored waters, similar to that of more recognizably acidic beverages.55 One study of Latino and non-Latino children56 showed that immigrant families have high bottled or filtered water consumption levels, possibly because of concerns about water safety based on experience in their country of origin, and despite the higher costs of bottled water. This study raised concerns about dental caries in children already at risk, because of lower fluoride levels in bottled and some filtered water sources. A cohort study of children aged approximately 5 through 957 showed that although fluoride intake levels were lower in children who consumed bottled water, there was no association with increased number of dental caries. Although the greatest potential concern is a risk for dental caries because of lack of fluoride in bottled water, the opposite concern may also be an issue. A study in Brazil58 found that preparing infant formula with some brands of bottled water provided fluoride above the suggested threshold level for fluorosis. This topic represents one area in which physiologic evidence of a possible health risk does not smoothly translate into a demonstrable general clinical risk. Although patients who are at risk for dental caries on other grounds might be advised to limit bottled water use, or to use other sources of fluoride treatment, there is not sufficient evidence to overemphasize this as a risk for children in the general population.
Health Risks and Benefits of Bottled Water
Does the presence of small amounts of pharmaceutical compounds in water pose any significant health risk?
An Associated Press report released in 200859 described the presence of a large number of pharmaceutical compounds present in drinking water sources. The report highlighted that there are no consistent testing, screening, or reporting standards for assessing the levels of pharmaceuticals in drinking water, including bottled water products. This issue has been identified for several years,60 but has received increased attention as the number and usage of pharmaceuticals has increased. There remains, however, no direct evidence linking the presence of pharmaceutical compounds in drinking water to any known health effects. As the population increases and more pharmaceutical preparations are used, this must be seen as a growing potential risk for as-yet-unspecified health consequences. At the present time, however, there is no clear difference between bottled, tap, or other water sources in this respect, and physicians and the public must use their own judgment as to whether this issue affects their choices for drinking water. SUMMARY
Within the United States there is a wide variety of drinkable water sources, including tap water, well water, bottled water, and others. A complex array of federal, state, and industrial standards ensures that the water supply in general is remarkably safe given the broad spectrum of infectious and chemical contaminants that may lead to illness from chronic exposure through drinking water. Efforts continue on many fronts to tighten this net and further reduce the rate of contaminant-related illness, although local contamination, natural disasters, and other events highlight the possibility of unsafe water sources in many different settings. Many Americans turn to bottled water sources to reduce these risks, at a financial and environmental cost that is staggering. Bottled water product marketing strategies target these concerns, emphasizing either the purity of the bottled water or the presence of minerals or other compounds that will improve health. Variation in definitions and regulations makes it difficult to ascertain that contaminant levels in any specific bottled water product are sufficiently different from those in tap water to actually lead to measurable health outcome differences, except in situations in which the usual water source is known to be contaminated. If patients present with questions about the risks or benefits of bottled water, physicians should emphasize the overall safety of most drinkable water sources and should help patients to identify whether they have specific health concerns, or local water source concerns, that would justify or necessitate the additional cost of routinely using bottled water as a significant source of drinking water, and which product might be most appropriate for their needs. INFORMATIONAL RESOURCES Sources for Health Professionals
Tap into prevention: drinking water information for health care providers—a continuing education video. Available at: http://www.epa.gov/safewater/healthcare/index.html. Accessed May 6, 2008. CDC/EPA waterborne disease research summaries published. Available at: http://www. epa.gov/nheerl/articles/2006/waterborne_disease.html. Accessed May 4, 2008. Public Information Sources
Making sense of right to know reports. Available at: http://www.safe-drinking-water. org/index.html.
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Proper disposal of prescription drugs. Available at: http://www.whitehousedrugpolicy. gov/publications/pdf/prescrip_disposal.pdf. 5 EPA safe drinking water hotline 1-800-426-4791. REFERENCES
1. Panel on Dietary Reference Intakes for Electrolytes and Water, Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. ‘‘Dietary reference intakes: water, potassium, sodium, chloride, and sulfate.’’ food and nutrition board. Washington, DC: The National Academies Press; 2004. 2. Valtin H. ‘‘Drink at least eight glasses of water a day.’’ Really? Is there scientific evidence for ‘‘8 8’’? Am J Physiol Regul Integr Comp Physiol 2002;283: 993–1004. 3. Juan WY, Basiotis P. More than one in three older Americans may not drink enough water. Nutrition insights. United States Department of Agriculture 2002. Available at: http://www.cnpp.usda.gov/Publications/NutritionInsights/Insight27. pdf. Accessed May 6, 2008. 4. Celizic M. ‘‘Take a sip! America’s best tap water.’’ Today Shoe. Updated. Available at: http://today.msnbc.msn.com/id/19865855/; July 2007;. Accessed June 11, 2008. 5. Stossel J. ‘‘Is bottled water better than tap?’’ ABC News 20/20 May 2005. Available at: http://abcnews.go.com/2020/Health/Story?id5728070&. Accessed June 10, 2008. 6. Bullers AC. Bottled water: better than the tap? FDA Consum 2002;36(4):14–8. 7. It’s only water, right? Consum Rep 2000;65(8):17. 8. U.S. Environmental Protection Agency. Secondary drinking water regulations. Available at: http://www.epa.gov/safewater/consumer/2ndstandards.html. Accessed April 28, 2008. 9. Code of Federal RegulationsFood and Drug Administration Department of Health and Human Services. Title 21 CFR Ch. 1 x165.110 bottled water. Available at: http://www. access.gpo.gov/nara/cfr/waisidx_00/21cfr165_00.html; Apr 2000. Accessed May 7, 2008. 10. United States Geological Survey. Frequently asked questions. Available at: http:// ut.water.usgs.gov/faq/faq.html. Accessed April 28, 2008. 11. Clark E. Water prices rising worldwide. Earth policy institute. 2007. Available at: http://www.earth-policy.org/Updates/2007/Update64.htm. Accessed April 28, 2008. 12. United States Department of Agriculture Economic Research Service. Food availability: spreadsheets. Available at: http://www.ers.usda.gov/Data/FoodConsump tion/FoodAvailSpreadsheets.htm#beverage. Accessed April 28, 2008. 13. Estimated per capita water ingestion and body weight in the United States—an update. United States Environmental Protection Agency Office of Water Oct 2004. 14. Olson E. Bottled water: pure drink or pure hype? Natural Resources Defense Council. Available at: http://www.nrdc.org/water/drinking/nbw.asp; 1999. Accessed May 6, 2008. 15. CDC Features. National drinking water week is May 4–10. Available at: http:// www.cdc.gov/Features/DrinkingWater/. Accessed June 8, 2008. 16. Morris RD, Audet A-M, Angelillo IF, et al. Chlorination, chlorination by-products, and cancer: a meta-analysis. Am J Public Health 1992;82:955–63. 17. Villanueva CM, Cantor KP, Grimalt JO, et al. Bladder cancer and exposure to water disinfection by-products through ingestion, bathing, showering, and swimming in pools. Am J Epidemiol 2007;165:148–56.
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18. Hwang BF, Jaakkola J, Guo HR. Water disinfection by-products and the risk of specific birth defects: a population-based cross-sectional study in Taiwan. Environ Health 2008;7:23. 19. Michaud DS, Kogevinas M, Cantor KP, et al. Total fluid and water consumption and the joint effect of exposure to disinfection by-products on risk of bladder cancer. Environ Health Perspect 2007;115(11):1569–72. 20. Savitz DA, Singer PC, Herring AH, et al. Exposure to drinking water disinfection by-products and pregnancy loss. Am J Epidemiol 2006;164:1043–51. 21. Chlorinated drinking-water; chlorination by-products; some other halogenated compounds; cobalt and cobalt compounds: summary of data reported and evaluation. IARC monographs on the evaluation of carcinogenic risks to humans. Congresses 1991;52:45, last updated Nov 1997. 22. Anderson AC, Reimers RS, deKernion P. A brief review of the current status of alternatives to chlorine disinfection of water. Am J Public Health 1982;72:1290–3. 23. Fiessinger F, Richard Y, Montiel A, et al. Advantages and disadvantages of chemical oxidation and disinfection by ozone and chlorine dioxide. Sci Total Environ 1981;18:245–61. 24. New drinking water guidelines. IPCS News The Newsletter of the International Programme on Chemical Safety. 1993;4:1–8. 25. Olson E. ‘‘Bottled water: pure drink or pure hype?’’ Natural Resources Defense Council. Available at: http://www.nrdc.org/water/drinking/bw/chap2.asp; 1999. Accessed June 8, 2008. 26. Container Recycling Institute. Graphs: plastic bottle statistics 2006. Available at: http://container-recycling.org/plasrate/graphs.htm. Accessed April 28, 2008. 27. Larsen J. Bottled water boycotts: back-to-the-tap movement gains momentum. Earth policy institute 2007;. Available at: http://www.earth-policy.org/Updates/ 2007/Update68.htm. Accessed April 29, 2008. 28. Kay SR. IBWA sets to [sic] record straight with Reader’s Digest. Available at: http:// www.bottledwater.org/public/sitemap_main.htm; Jan 2008. Accessed May 6, 2008. 29. Chalupka S. Tainted water on tap. Am J Nurs 2005;105(11):40–52. 30. Goldstein ST. Cryptosporidiosis: an outbreak associated with drinking water despite state-of-the-art water treatment. Ann Intern Med 1996;124(5):459–68. 31. Gualberto FA, Heller L. Endemic Cryptosporidium infection and drinking water source: a systematic review and meta-analysis. Water Sci Technol 2006;54(3): 231–8. 32. Yoder JS. Cryptosporidiosis surveillance—United States, 2003–2005. MMWR Surveill Summ 2007;56(7):1–10. 33. Colford JM. A review of household drinking water intervention trials and an approach to the estimation of endemic waterborne gastroenteritis in the United States. J Water Health 2006;4(Suppl 2):71–88. 34. Frost FJ. How clean must our drinking water be: the importance of protective immunity. J Infect Dis 2005;191:809–14. 35. Clasen T, Roberts I, Rabie T, et al. Interventions to improve water quality for preventing diarrhoea. Cochrane Database Syst Rev 2006;3:CD004794. 36. Heaney RP. Absorbability and utility of calcium in mineral waters. Am J Clin Nutr 2006;84(2):371–4. 37. Gillette-Guyonnet S. Cognitive impairment and composition of drinking water in women: findings of the EPIDOS study. Am J Clin Nutr 2005;81(4):897–902. 38. Galan P. Contribution of mineral waters to dietary calcium and magnesium intake in a French adult population. J Am Diet Assoc 2002;102(11):1658–62.
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39. Azoulay A. Comparison of the mineral content of tap water and bottled waters. J Gen Intern Med 2001;16:168–75. 40. Garzon P. Variation in the mineral content of commercially available bottled waters: implications for health and disease. Am J Med 1998;105:125–30. 41. Oldham D. What is the best portable method of purifying water to prevent infectious disease? J Fam Pract 2008;57(1):46–8. 42. Zierold KM. Prevalence of chronic diseases in adults exposed to arsenic-contaminated drinking water. Am J Public Health 2004;94(11):1936–7. 43. Slotnick MJ. Effects of time and point-of-use devices on arsenic levels in Southeastern Michigan drinking water, USA. Sci Total Environ 2006;369(1–3):42–50. 44. Maas RP. Reducing lead exposure from drinking water: recent history and current status. Public Health Rep 2005;120(3):316–21. 45. Mahajan RK. Analysis of physical and chemical parameters of bottled drinking water. Int J Environ Health Res 2006;16(2):89–98. 46. Health Central: is it unhealthy to reuse a plastic water bottle?. Available at: http:// www.healthcentral.com/drdean/408/38672.html. Accessed May 6, 2008. 47. Anonymous. I received an e-mail warning that reusing plastic water bottles can cause cancer. Is this true? Johns Hopkins Medical Letter, Health after 50 2007; 19(8):8. 48. Le HH. Bisphenol A is released from polycarbonate drinking bottles and mimics the neurotoxic actions of estrogen in developing cerebellar neurons. Toxicol Lett 2008;176(2):149–56. 49. Bisphenol A (BPA). US Food and Drug Administration 2008. Available at: http:// www.fda.gov/oc/opacom/hottopics/bpa.html. Accessed June 6, 2008. 50. Maragou NC. Migration of bisphenol A from polycarbonate baby bottles under real use conditions. Food Addit Contam 2008;25(3):373–83. 51. Shotyk W, Krachler M. Contamination of bottled waters with antimony leaching from polyethylene terephthalate (PET) increases upon storage. Environ Sci Technol 2007;41(5):1560–3. 52. Raj SD. Bottled water: how safe is it? Water Environ Res 2005;77(7):3013–8. 53. Widen H. Identification of chemicals, possibly originating from misuse of refillable PET bottles, responsible for consumer complaints about off-odours in water and soft drinks. Food Addit Contam 2005;22(7):681–92. 54. Cochrane NJ. Flouride content of still bottled waters in Australia. Aust Dent J 2006;51(3):242–4. 55. Brown CJ. The erosive potential of flavoured sparkling water drinks. Int J Paediatr Dent 2007;17(2):86–91. 56. Hobson WL. Bottled, filtered, and tap water use in Latino and non-Latino children. Arch Pediatr Adolesc Med 2007;161:457–61. 57. Broffitt B. An investigation of bottled water use and caries in the mixed dentition. J Public Health Dent 2007;67(3):151–8. 58. Buzalaf MA. Risk of fluorosis associated with infant formulas prepared with bottled water. J Dent Child (Chic) 2004;71(2):110–3. 59. Associated Press. Prescription drugs found in drinking water across US. Available at: http://www.cnn.com/2008/HEALTH/03/10/pharma.water1.ap/index.html. Accessed May 6, 2008. 60. Reynolds KA. Water conditioning & purification magazine 2003. Available at: http://www.wcponline.com/NewsView.cfm?ID52199. Accessed May 6, 2008.
Exerc ise : the Dat a on its Role in Health, Ment al Health, Dis eas e Prevention, a nd Prod uc tivit y Jason J. Diehl, MDa,*, Haemi Choi, MDb KEYWORDS Exercise Evidence Health
The topic of exercise and its relationship to disease is critical to all aspects of the medical field. Exercise therapy is defined as prescribed movements of the body and muscle contractions.1 The National Institutes of Health defines physical activity as bodily movement produced by skeletal muscles that requires energy expenditure and produces progressive health benefits.2 Energy expenditure from physical activity includes intensity, duration, and frequency and is classically measured using the metabolic equivalent (MET).3,4 One MET is the energy consumed during a period of time while an individual is resting quietly.4,5 For the average 70-kg adult, one MET equals 5.04 kcal per minute or 3.5 mL of oxygen uptake/kg per minute. For instance, a 3-MET activity requires three times the metabolic energy expenditure of sitting quietly. Table 1 illustrates examples of different physical activities with its MET. Exercise can be categorized into two types: dynamic or static. Dynamic exercise increases strength throughout a full range of motion about a joint.3,5 Cardiorespiratory endurance is the ability to perform dynamic exercise involving large muscle groups at a moderate to high intensity for prolonged periods of time. It generally consists of repeated low-resistance movements.3 The majority of studies examine the effects of dynamic exercise training on different diseases. In contrast, static exercise entails isometric contraction of a muscle without any visible movement in the angle of the joint.3,5 Resistance in isometric exercises involves muscle contraction using the body’s own muscle, weights, or stationary items. Resistance exercise via mechanical
a
Department of Clinical Family Medicine, Division of Sports Medicine, The Ohio State University Sports Medicine Center, 2050 Kenny Road, Suite 3100, Columbus, OH 43221, USA b Department of Family Medicine, Division of Sports Medicine, Loyola University Medical Center, 2160 South First Avenue, Maywood, IL 60153, USA * Corresponding author. E-mail address:
[email protected] (J.J. Diehl). Prim Care Clin Office Pract 35 (2008) 803–816 doi:10.1016/j.pop.2008.07.014 primarycare.theclinics.com 0095-4543/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.
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Table 1 Examples of general physical activities defined by level of intensity Moderate Activity 3.0 to 6.0 MET 5 14.7 to 29.4 kJ
Vigorous Activity >6.0 MET 5 >29.4 kJ
Walking: moderate to brisk pace (3 to 4.5 mph) Walking: downstairs or down a hill Hiking Roller skating or in-line skating (leisurely pace)
Walking: >5 mph Jogging or running Walking up a hill Backpacking Rock climbing Roller skating or in-line skating (briskly)
Bicycling: 5 to 9 mph
Bicycling: >10 mph or uphill
Water aerobics
Aerobic dancing Step aerobics Water jogging
Calisthenics: light Yoga Gymnastics Stair climbing machine: light-to-moderate pace Rowing: moderate effort
Calisthenics: vigorous Martial arts Jumping rope Jumping jacks Rowing: vigorous
Weight training and bodybuilding
Circuit weight training
Data from Ainsworth BE, Haskell WL, Leon AS, et al. Compendium of physical activities: classification of energy costs of human physical activities. Medicine and Science in Sports and Exercise 1993;25(1):71–80.
loading on skeletal tissue can stimulate an increase in bone formation in young adults and slow bone loss in middle age.6 This can lead to a lower risk for osteopenia, osteoporosis, and bone fracture. So, why is exercise so important? In the United States less than 50% of the total population exercises on a regular basis. Exercise improves the functional capacity of the cardiovascular system and reduces myocardial oxygen demand at any level of physical activity in healthy individuals and in most persons who have cardiovascular disease.7 As discussed later, regular exercise contributes to enhanced health and sense of well-being.7,8 It can help control conditions such as blood lipid abnormalities, diabetes, and obesity. This article uses an evidence-based approach to see how exercise affects health, mental health, disease prevention, and productivity.
EXERCISE AND OBESITY
In America, obesity is a serious problem. Of American adults over age 20, 65% are overweight or obese, with 26% defined as obese, having a body mass index (BMI) greater than 30.9 This problem is secondary to causes, such as overeating, genetic factors, environment, and a lack of physical activity. The latest data collected by the Centers for Disease Control and Prevention (CDC) show a significant upward trend in obesity. CDC data from 1960–2004 show that although the percentage of overweight Americans (BMI 26 to 29) aged 20 to74 years remained steady at 32% to 34%, obesity rates in the same group increased from 13% to 34%.4,7 Looking at these figures, it is obvious that measures need to be taken to combat this problem. An important question to ask is, Does exercise alone produce weight loss? The answer is yes. An expert panel on the identification, evaluation, and treatment of overweight and obesity in adults helps answer this question.10
Exercise
The expert panel selected randomized controlled trials that involved 4 or months or more of treatment regardless of sample size. Thirteen articles compared exercise versus no treatment, and 15 articles compared diet plus exercise to diet alone. One study comparing exercise to control was excluded because the control group involved a diet condition. In the studies analyzing exercise alone, 10 of the 12 studies showed that the exercise group had larger weight losses than the control, with a mean difference of 2.4 kg in weight loss over a 4-month or greater time span.10 Six of 10 randomized studies found significantly greater weight loss in exercise alone versus no treatment controls. Their conclusion was that exercise alone produces modest weight losses. When comparing diet alone to diet and exercise, 12 of 13 articles showed a greater weight loss and a greater reduction in BMI (0.3–0.5) in the combined group than the diet group alone. Only 2 of 13 studies, however, showed a statistically significant difference in weight loss obtained in the combined group in comparison to the diet alone group. They concluded that exercise does not significantly increase initial weight loss over that obtained by diet alone. During 1990–2005, the Behavioral Risk Factor Surveillance System run by the CDC asked questions via a telephone survey that measured leisure-time physical activity, primarily exercise or sports-related activities. Survey respondents were classified as being active at the recommended level if they reported sufficient physical activities of moderate intensity (R30 minutes per day, R5 days per week) or of vigorous intensity (R20 minutes per day, R3 days per week). In 2005, 23.5% of adults surveyed reported no leisure-time activity, whereas 49.1% of adults met the American College of Sports Medicine (ACSM)/CDC recommendation for physical activity.4,11,12 Age played a factor in rates of exercise: 59.6% of people in the 18- to 24-year-old age group met the guidelines, whereas only 39.0% of individuals in the 65 and older age group met the recommendations.4,11,12 In summary, the majority (50.9%) of adults in the United States are not physically active on a regular basis. Another point is that nearly 50% of adolescents aged 12 to 21 years old are not vigorously active on a regular basis.13 The trend shows that physical activity decreases during adolescence. Elementary school and middle school students are more likely to participate in regular physical education classes than high school students.11 An alarming statistic is reflected in the 1996 surgeon general’s report, which stated that enrollment in daily physical education classes declined among high school students from 42% in 1991 to 27% in 1997.13 The 1998 youth risk behavior surveillance administered by the CDC obtained more recent data that showed only 48.8% of students in ninth through twelfth grades are enrolled in physical education classes and only 27.4% attend those classes daily. From this information alone, steps need to be taken by parents, schools, and the government to increase regular physical activity and combat the growing obesity epidemic. RECOMMENDED DAILY ACTIVITY
In 2001, the United States Department of Health and Human Services developed a list of objectives for adults of all ages in regard to cardiorespiratory fitness. Their guidelines include reducing the proportion of adults who engage in no leisure time physical activity; increasing the proportion of adults who engage regularly, preferably daily, in moderate physical activity for at least 30 minutes per day; and increasing the proportion of adults who engage in vigorous physical activity that promotes the development and maintenance of cardiorespiratory fitness 3 or more days per week for 20 or more minutes per occasion.14,15
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More recently, the ACSM and the American Heart Association published updated recommendations on physical activity from their initial consensus statement created in 1995. The organizations recommend that all healthy adults from the ages of 18 to 65 need moderate-intensity aerobic physical activity for a minimum of 30 minutes 5 days a week or vigorous-intensity aerobic activity for a minimum of 20 minutes on 3 days each week.4 These recommendations were developed by an expert panel of scientists (epidemiologists, physicians, public health specialists, and exercise scientists) using an evidence-based approach to determine the effects of participating in regular activity.1,4 By doing so, they were able to formulate the frequency, duration, intensity, and types of activity that would be effective. Currently, they are the only published exercise guidelines based on the best scientific knowledge. Examples of moderate- and vigorous-intensity exercise can be reviewed in Table 1. EXERCISE AND CARDIOVASCULAR DISEASE
Cardiovascular disease is the leading cause of death in the United States (Table 2). Cardiovascular disease includes coronary heart disease, hypertension, stroke, and other forms of heart disease. Based on a 2001 CDC survey, heart disease accounts for 29% of all deaths in the United States. Exercise plays an role in preventing cardiovascular disease. A 2003 systematic review showed a decrease of 3 mm Hg for systolic blood pressure (BP) and 2 mm Hg for diastolic BP particularly in relation to moderate levels of physical activity.16 The reduction in BP was most significant in those involved with moderate levels of physical activity, including walking. Decreases in systolic BP by 2 mm Hg reduces the risk for stroke by 14% and coronary artery disease by 6%, whereas a decrease in diastolic BP by 2 mm Hg reduces the risk for stroke and coronary artery disease by 17% and 6% in the general population.17 Another recent review of the literature identifies that regular physical exercise of the lower extremities decreases systolic and diastolic BP by 5 to 7 mm Hg, not including other factors, such as salt or alcohol intake or weight loss.3 Physical activity also is associated with a significant reduction of cardiovascular disease and stroke among women in a dose-response relation.18 It was observed that walking 1 hour per week was associated clinically with a statistically significant reduction of coronary vascular disease risk among women.18 Lower fitness levels
Table 2 Most common causes of death, United States, 2001 Cause of Death
Number of Deaths (InThousands)
Percent
Diseases of the heart
700
29.0
All cancers
554
22.9
Stroke
164
6.8
Chronic lower respiratory disease
123
5.1
Diabetes Top five chronic disease killers Others Total
71
3.0
1612
66.7
805
33.3
2416
100.0
Data from National Center for Chronic Disease Prevention and Health Promotion; the burden of chronic diseases as causes of death, United States 2001. Available at: http://www.cdc.gov/ nccdphp/burdenbook2004/Section01/tables.htm. Accessed March 1, 2008.
Exercise
are associated with a 4.7-fold increased risk for cardiovascular disease.19 A 2000 to 2003 review shows a median reduction of 31% in cardiovascular disease in individuals who exercise regularly. The average amount of activity was half an hour per day of moderate intensity on most days of the week.16 Another review of the literature reinforces the positive effects of physical fitness on mortality from cardiovascular disease (hypertension, coronary heart disease, and stroke). It showed that physical activity coincides with reduced morbidity and mortality from coronary diseases independent of age.20 Exercise also is a proved tool in the secondary prevention of cardiac disease. A recent systematic review researched the effectiveness of exercise-based cardiac rehabilitation worldwide. The data showed a 26% reduction in cardiac mortality over a range of 6 to 72 months in cardiac rehabilitation individuals in comparison to usual care patients.21 Another review investigating exercise training’s role on patients who had heart failure found exercise caused significant increase in maximal oxygen consumption, which is believed beneficial.22 Maximal oxygen consumption helps assess functional capacity in individuals who have heart failure. A review assessing the effects of exercise training on heart failure patients revealed a 13% improvement peak oxygen consumption and a 17% increase in exercise duration.23 A typical exercise routine consisted of a cycle ergometer with calisthenic exercises for 20 minutes 4 to 5 days per week over a duration of 6 to 16 weeks. The INTERHEART study analyzed the effect of physical activity on CHD risk factors (smoking, hypertension, diabetes, obesity, and hyperlipidemia) in 14,820 controls and 15,152 cases from 52 countries.24 They found that subjects regularly involved in moderate activities, such as walking, cycling, or swimming for 4 hours or more per week, had significantly decreased risk for developing coronary heart disease than those who were inactive. They also found a reduction in risk for myocardial infarction in women (from 14% to 4%) who exercised regularly (average 4 hours per week) and consumed fruit and vegetables daily.24 The risk factors that were examined (smoking, hypertension, diabetes, obesity, and so forth) were associated with greater than 90% of the risk for an acute myocardial infarction in the study. This landmark study showed that regular vigorous physical activity is inversely correlated with cardiovascular disease regardless of sex, age, and region. EXERCISE AND BLOOD GLUCOSE
Physical activity improves insulin sensitivity, which in turn lowers blood glucose levels.25–27 Regular physical activity (30 minutes per day, 5 or more days per week) is associated with a decrease in blood glucose levels in individuals who have type 2 diabetes mellitus, with an average decrease of Hg A1c levels of 0.5% to 1%.1,28 A 1997 randomized controlled trial of 577 people who had impaired glucose tolerance (plasma glucose of 140–199 2 hours after 75-g glucose load) tested the effects of diet and exercise on diabetes incidence.25 Diabetes incidence was reduced in exercise and diet groups, but a greater risk reduction effect was attributed more to exercise than diet. Another randomized controlled trial done in Finland involved 522 people who had impaired glucose tolerance. The study tested the effects of intensive nutritional counseling and endurance exercise advice on diabetes incidence. Diabetes incidence was reduced 58% more in the intervention group than the control group. The conclusion of the study was that for every 22 patients who received the intervention, one case of diabetes could be prevented.26 The 2002 Diabetes Prevention Project compared lifestyle modifications to medication use in individuals with impaired glucose tolerance. The 3234 participants were
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randomized into three groups: intensive lifestyle intervention (curriculum teaching diet and behavior modifications along with moderate-intensity physical activity 150 minutes per week), metformin, or a usual care protocol. Although there was a 31% reduction in the incidence of diabetes in the metformin group, there was a 58% reduction in the intensive lifestyle intervention group. The study was stopped early because the lifestyle intervention treatment was significantly more effective than pharmacologic treatment in preventing the onset of overt diabetes in patients with glucose intolerance.27 These trials show that diabetes can be prevented in high-risk individuals who undergo an intensive exercise and behavioral modification program. EXERCISE AND CANCER
A majority of epidemiologic studies show an inverse relationship between physical activity and cancer risk.29–33 There are multiple factors that play a role in the development of cancer, including diet, alcohol and tobacco use, physical activity, and environmental factors.33 Regarding exercise, the strongest evidence is seen in the research on prevention of colon and breast cancer. This is important because breast cancer makes up 10.4% of all cases of cancer, whereas colorectal cancer contributes to 9.4% of all cases in the United States.31,33,34 Increased BMI and decreased physical activity are associated with an increased risk for breast and colon cancer.35 One third of cases of breast, colon, and kidney cancer are attributed to obesity and lack of physical activity.33,35 Study participants who were involved in moderate to vigorous recreational/leisure-time activities or who had jobs that involved a moderate degree of physical exertion were found to have a decreased risk for colon cancer.30,36 A survey of 1993 cases of colon cancer and 2410 control subjects demonstrated that physical activity is an independent predictor for the risk for colon cancer. The risk for developing colon cancer was reduced significantly in those who had high levels of physical activity.36 A systematic review of physical activity and cancer showed a convincing relationship between physical activity and breast cancer.30 Forty-five of the 64 studies analyzed demonstrated that women who were most active in occupational or recreational activities had an overall lower percentage of breast cancer than those who were inactive. Twenty worldwide studies have recorded an average 30% to 40% risk reduction in active participants in comparison to sedentary participants.30 So, how much exercise is considered effective to reduce the risk? A Japanese case control study evaluated this in 2003. There was a 19% risk reduction of breast cancer in women who exercised regularly twice a week independent of menopausal status.37 The optimal level of exercise in the prevention of breast and colon cancer is unknown based on the available literature, but expert opinion currently recommends at least 30 to 60 minutes of daily exercise of moderate to vigorous intensity.34,37–39 EXERCISE AND OSTEOARTHRITIS
Arthritis affects more than 70 million Americans, making it the leading case of physical disability in older individuals.40,41 The most common form of arthritis is osteoarthritis, which can lead to muscle weakness, balance and mobility problems, and, at its worst, physical disability.42,43 Although the development of osteoarthritis is multifactorial, obesity is a primary risk factor.15 The Framingham Knee Osteoarthritis Observational Study found that in women who had a BMI greater than 25, losing at least 5.1 kg of weight decreases the risk for developing knee osteoarthritis by 50%.15 A 2006 study randomized obese adults over the age of 60 who had symptomatic knee osteoarthritis into a control or weight loss group over a 6-month period.44 The results showed an
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8.7% decrease in body weight, greater 6-minute walk distance, faster stair climb, and decreased symptoms in the weight loss group in comparison to the weight stable group. These data support exercise training in the improvement of physical function in obese adults with knee osteoarthritis. The Osteoarthritis Research Society International recently created a consensus statement for the management of knee osteoarthritis. Sixteen experts worldwide formed guidelines based on a systematic review of existing guidelines published between 1945 and 2006. They recommend that all patients who have osteoarthritis be given education about the importance of changes in lifestyle, exercise, weight reduction to unload the damaged joint.45 Other recommendations include regular aerobic and muscle strengthening exercises and weight loss with maintenance at a lower level. EXERCISE AND MENOPAUSE
Exercise is shown to have a positive effect on the overall health in women. Two disease states in women that are important to examine are menopause and osteoporosis. Vasomotor symptoms occur within the first 3 months of menopause in 70% of women, with 50% experiencing persistent symptoms during the first 5 years.46 These symptoms include hot flashes, skin flushing, perspiration, and chills.47 They can be from mild to intolerable, lasting seconds to minutes. Several studies in the current medical literature demonstrate that women who exercise regularly have a lower rate of hot flashes.48–51 One study showed that 5% of highly active women (participated in >2 hours per week of intense exercise [eg, swimming or running]) experienced severe hot flashes in comparison to 14% to 16% of women who had little to none weekly exercise. Another study looking at the effects of exercise on hot flashes showed that the exercise group had a significantly smaller number of moderate to severe hot flashes compared with the control group.50 The group of women who did not have hot flashes averaged 3.5 hours of exercise per week, whereas women who had moderate to severe hot flashes averaged 2.6 hours per week. A study from Japan evaluated the effects of a 12-week exercise program on climacteric symptoms. The exercise group participated in three 30-minute aerobic activity sessions (walking or aerobics) per week. The results showed that the exercise group had a statistically significant decrease in climacteric symptoms compared with the group that did not exercise.50 Overall, the literature supports that fact that regular physical activity decreases vasomotor symptom frequency and severity. EXERCISE AND OSTEOPOROSIS
Regular physical activity has a positive influence on bone mineral density and strength secondary to bone turnover caused by skeletal muscle activity.52,53 A systematic review of the literature from 1966 to 1997 examining the effect of impact and nonimpact exercise on bone mass in pre- and postmenopausal women showed that both types of exercise have a positive effect on bone mass at the lumbar spine. The data demonstrated that exercise slowed the rate of spine bone mass in postmenopausal women.54 There was no difference in effectiveness of exercise when comparing pre- to postmenopausal women. Another 4-year prospective study of 40 early postmenopausal women analyzed the effect of regular physical activity on menopausal risk factors.55 The treatment group (aerobic and resistance exercise) maintained their bone mineral density at the lumbar spine and femoral neck for more than 50 months, but the control group had a significant decrease in those measurements. Exercise has positive effects on the prevention of postmenopausal bone loss.6,55
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EXERCISE AND COGNITION
Animal studies have showed that physical activity has a positive effect on neuronal growth and on the systems involved with learning and memory.56 A study done by Booth and Lees57 demonstrated that exercise leads to changes in brain structure and function in humans. A meta-analysis of school-age children (from age 4–18) demonstrated a positive relationship between physical activity and cognitive performance measuring categories, such as intelligence quotient, achievement, verbal and mathematic tests, perceptual skills, and so forth.58 There was no significant relationship between physical activity and memory improvement, however. The data were stronger for the younger children in the study (4–7 years) versus the older age group (14–18 years). This data suggest that physical activity is beneficial at all ages, but an early start in activity may be helpful in improving cognitive function throughout adulthood. EXERCISE AND DEPRESSION
The literature shows that exercise plays a part in reducing symptoms of depression.59,60 This is an important fact because mild to moderate major depressive disorder is second behind ischemic heart disease for years lost secondary to disability or premature death.61 Another worrisome statistic is that only 23% of patients who have depression seek treatment and only 10% receive acceptable treatment because of the negative opinions associated with treatment.62–64 Therefore, exercise is a viable alternative for patients who have mild depressive disorder and who are reluctant to be treated with medications. A study of 156 adults who had major depressive disorder examined the effects of exercise on the subjects’ depression scale.65 They were randomly assigned to a 4-month course of medical therapy, aerobic exercise, or a combination of aerobic exercise and medical treatment. The exercise program consisted of three 45-minute sessions per week walking or jogging at 70% to 85% of each individual’s heart rate reserve. After 4 months of treatment, all three groups had significant improvement in symptoms with similar remission rates of major depressive disorder in all three groups. At 10 months’ follow-up, individuals who had remitted had lower relapse rates in the exercise group than the medication group. Subjects who exercised on their own in the follow-up period had a decreased probability of depression at 10 months. This study shows that exercise if continued over time shows a therapeutic benefit. It is difficult to make a general recommendation on the amount of exercise needed for a beneficial effect because there is only one published study that has examined the effects of varying duration, intensity, and frequency of exercise on depression.66 The DOSE trial took 80 previously sedentary adults who had major depressive disorder and randomized them into one of five aerobic exercise training groups over a span of 12 weeks.67 The treatment conditions were low energy expenditure 3 days per week, high energy expenditure 3 days per week, low energy expenditure 5 days per week, high energy expenditure 5 days per week, or stretching/flexibility control. Results showed that the high energy expenditure group exercising 5 days per week was effective in reducing depressive symptoms over the 12-week period. The low-energy group had some reduction in depressive symptoms, but they did not respond significantly better than the control group. Therefore, it is recommended that individuals who have depression be counseled to exercise at or above the minimum recommended levels. EXERCISE AND ANXIETY
The literature supports the beneficial effects of exercise on psychologic well-being.64 One component in maintaining mental well-being is controlling stress and anxiety.
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Anxiety disorders are one of the most common mental health conditions with a yearly prevalence estimated at 17%.68 Regular physical activity brings benefits to individuals who have anxiety symptoms.66,69 A survey conducted in the United States and Canada looked for a relationship between physical activity and symptoms of depression and anxiety. The investigators found that higher levels of physical activity were associated with minimal or no symptoms of anxiety or depression.70 Further support of the beneficial effects on exercise can be seen in a randomized controlled trial of patients diagnosed with panic disorder, generalized anxiety disorder, or social phobia. Individuals were randomized to one of two groups: standard group cognitive behavioral therapy with a home-based exercise program or therapy with three educational meetings.71 Both groups had a reduction in depression, anxiety, and stress scores. The exercise group, however, had a significantly greater decline in all scores in comparison to the control group. Overall, there seems to be a positive relationship in regards to exercise and decreasing anxiety. EXERCISE AND PRODUCTIVITY
There are companies that provide exercise programs for employees to improve overall health and well-being to keep their staff healthy, with an ultimate goal of improving work productivity. Obesity is linked to an increased risk for physical limitations and a worsening of existent medical conditions. Tunceli and coworkers72 reviewed longterm effects of obesity on employment and work limitations on adults from 1986 and 1999. Data were analyzed from a longitudinal cohort study, named the Panel Study of Income Dynamics. Participants were classified in underweight, normal weight, overweight, or obese categories. The investigators assessed the relationships between obesity and work disability and employment. Obesity was found associated with a reduced employment rate of 4.8% in men. Overweight or obese women had a statistically significant increase in self-reported work limitations in comparison to normal weight individuals. The investigators concluded that obesity results in future productivity losses through reduced workforce participation and increased work limitations. A 2007 study tested the impact of a self-paced exercise program on productivity and health outcomes of 32 adult workers in a large federal office complex over a 3-month period. Productivity (using the Endicott Work Productivity Scale), walking distance, and health outcomes (BP, weight, pulse rate, and body fat percentage) were measured weekly. Results showed that the exercise program had no significant impact on productivity.73 It did show, however, that participants lost weight and had reduced their BP measurements. A 2002 systematic review analyzed the efficacy of physical activity programs at worksites with respect to work-related outcomes. The review looked at eight studies measuring absenteeism, job satisfaction, job stress, and employee turnover. The results showed that exercise had a nonsignificant effect for absenteeism, inconclusive for job satisfaction, job stress, and employee turnover, and no effect on productivity.74 Overall, there are limited data in the literature correlating productivity with exercise programs implemented at work. Regarding the data available, the trend is that the exercise programs help the overall health of employees, but they have not demonstrated improved work productivity. SUMMARY
Exercise is beneficial in improving an individual’s overall health. Evidence shows that it reduces the incidence of chronic diseases, such as diabetes, obesity, osteoporosis,
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cancers, and cardiovascular disease. There are limited data correlating physical activity to reduction of morbidity from chronic diseases due to the lack of adequate randomized trials. Among the data available, however, there is strong evidence to support the positive effects of exercise on cardiovascular disease, osteoarthritis, and depression. Individuals who are physically active on a regular basis are less likely to develop health problems than sedentary individuals.75 There is well-defined evidence of an inverse dose-response relationship between amount of physical activity done and all-cause mortality rates in men and women of all ages.8 The maximum risk reduction in prevention of chronic disease found in people who exercise are 22% for colorectal cancer, 35% for diabetes, 49% for cardiovascular and heart diseases, and 75% for breast cancer.29 Exercise also plays an role in physical and psychologic well-being. Although the majority of studies show the positive effects of exercise of these different diseases, there needs to be more randomized controlled trials and larger prospective observational studies to examine the dose and type of activity required to better determine its effects. As summarized in this article, regular physical activity treats a multitude of medical illnesses ranging from hypertension to depression. By seeing the clear benefits of exercise on general health and prevention of chronic diseases, it is an topic that health care providers should address with all patients encountered. Specific guidelines should be outlined for every individual, starting from the ACSM and CDC physical activity recommendations, taking into consideration factors, such as time commitment, interests, and resources. It is a safe and effective modality to implement in everyday life for all individuals. REFERENCES
1. Danforth E, Jenseen M, Kopelman P, et al. Dose-response issues concerning physical activity and health: an evidence-based symposium. Med Sci Sports Exerc 2001;33:S351–8. 2. In: National institutes of health consensus statement: physical activity and cardiovascular health, vol. 13. Bethesda (MD): NIH; 1995. roux J, Feldman R, Petrella R. Recommendations on physical exercise train3. Cle ing. CMAJ 1999;160:S21–8. 4. Haskell W, Lee I, Pate R, et al. Physical activity and public health. Updated recommendation for adults from the ACSM and the AHA. Circulation 2007;116: 1081–93. 5. O’Connor F, Sallis R, Wilder R, et al. Sports medicine: just the facts. New York: McGraw-Hill; 2005. 6. Kemmler W, Engelke K. A critical review of exercise training on effects on bone mineral density in early-postmenopausal women. Int Jour Sports Med 2004;5: 67–77. 7. Fletcher G, Balady G, Blair SN, et al. Statement on exercise: benefits and recommendations for physical activity programs for all Americans. A statement for health professionals by the committee on exercise and cardiac rehabilitation of the council on clinical cardiology, American Heart Association. Circulation 1996;94:857–62. 8. Lee I, Skerrett P. Physical activity and all-cause mortality: what is the doseresponse relation? Med Sci Sports Exerc 2001;33:S459–71. 9. Prevalence of overweight and obesity among adults: United States 1999–2002. National Center for Health Statistics. Available at: www.cdc.gov/nchs. Accessed March 2008.
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10. Wing R. Physical activity in the treatment of the adulthood overweight and obesity: current evidence and research issues. Med Sci Sports Exerc 1999;31: S547–52. 11. The President’s council on fitness and sports. Available at: www.fitness.gov. Accessed April 1, 2008. 12. Prevalence of physical activity, including lifestyle activities among adults-United States, 2000–2001. Available at: www.cdc.gov. Accessed April 1, 2008. 13. United States Department of Health and Human Services. Physical Activity and Health: A Report of the Surgeon General. Atlanta, GA. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, The President’s Council on Physical Fitness and Sports. 1996. Available at: http://www.cdc.gov/ nccdphp/sgr/pdf/execsumm.pdf. Accessed September 10, 2008. 14. US Department of Health and Human Services Health People 2010. US Department of Health and Human Services, Washington, DC 2001. Available at: http://www.health.gov/healthypeople/Document/HTML/Volume1. Accessed April 1, 2008. 15. US Department of Health and Human Services. Exercise: a guide from the national institute on aging. Bethesda (MD): NIA, NIH; 1999. Available at: http:// www.nih.gov/nia. [page 6]. Accessed April 1, 2008. 16. Bauman A. Updating the evidence that physical activity is good for health: an epidemiological review 2000–2003. J Sci Med Sport 2004;7:6–19. 17. Pescatello L, Franklin B, Fagard R, et al. Exercise and hypertension. Available at: www.acsm-msse.org. 2004. Accessed April 1, 2008. 18. Oguma Y, Shinoda-Tagawa T. Physical activity decreases cardiovascular disease risk in women. Am J Prev Med 2004;26:407–18. 19. Blair S, Kohl H, Paffenbarger R, et al. Physical fitness and all cause mortality: a prospective study of healthy men and women. JAMA 1989;262:2395–401. 20. Faff J. Physical activity, physical fitness, and longevity. Biol Sport 2004;21:3–24. 21. Taylor R, Brown A, Ebrahim S, et al. Exercise-based rehabilitation for patients with coronary heart disease: systematic review and meta-analysis of randomized controlled trials. Am J Med 2004;116:682–92. 22. Smart N, Marwick T. Exercise training for patients with heart failure. A systematic review of factors that improve mortality and morbidity. Am J Med 2004;116: 693–706. 23. European Heart Failure Training Group. Experience from controlled trials of physical training in chronic heart failure. Protocol and patient factors in effectiveness in the improvement in exercise tolerance. Eur Heart J 1998;19: 466–75. 24. Yusuf S, Hawken S, Ounpuu S. Effect of potential modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case control study. Lancet 2004;364:937–95. 25. Pan X, Li G, Hu Y, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance: the Da Qing IGT and diabetes study. Diabetes Care 1997;20:537–44. 26. Tuomilehto J, Lindstrom J, Eriksson J, et al. Prevention of Type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001;344:1343–50. 27. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention of metformin. N Engl J Med 2002;346: 393–403.
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28. Wallberg-Henriksson H, Rincon J, Zierath J. Exercise in the management of noninsulin-dependent diabetes mellitus. Sports Med 1998;25:25–35. 29. Kruk J. Physical activity in the prevention of the most frequent chronic diseases: an analysis of the recent evidence. Asian Pac J Cancer Prev 2007;8:325–38. 30. Kruk J, Hassan A. Physical activity in the prevention of cancer. Asian Pac J Cancer Prev 2006;7:11–21. 31. Murthy N, Mathew A. Cancer epidemiology, prevention and control. Curr Sci 2004;86:518–27. 32. International Agency for Research on Cancer Press Release. Overweight and lack of exercise linked to increased cancer risk a growing problem. Available at: www.iarc.fr/WCR. 2002. Accessed April 1, 2008. 33. Slattery M. Physical activity and colorectal cancer. Sports Med 2004;34:239–52. 34. World Health Organization. World cancer report. Lyon: IARC Press; 2003. 35. Vainio H, Kaaks R, Bianchini F. Weight control and physical activity in cancer prevention: international evaluation of the evidence. Eur J Cancer Prev 2002; 11(Suppl 2):S94–100. 36. Slattery M, Potter J. Physical activity and colon cancer: confounding or interaction? Med Sci Sports Exerc 2002;34:913–9. 37. Hirose K, Hamajima N, Takezaki T, et al. Physical exercise reduces risk of breast cancer in Japanese women. Cancer Sci 2003;94:193–9. 38. Freidenrich C, Orenstein M. Physical activity and cancer prevention: etiologic evidence and biological mechanism. J Nutr 2002;132:3464S–5S. 39. Lee I. Physical activity and cancer prevention-data from epidemiologic studies. Med Sci Sports Exerc 2003;11:1823–7. 40. Davis M. Epidemiology of osteoarthritis. Clin Geriatr Med 1988;4:241–55. 41. Jokl P. Prevention of disuse muscle atrophy in chronic arthritides. Rheum Dis Clin North Am 1990;16:837–44. 42. Lawrence R, Helmick C, Arnett F. Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum 1998; 41:778–99. 43. Bolen J, Helmick C, Sacks J. Prevalence of self reported arthritis or chronic joint symptoms among adults: United States 2001. MMWR Morb Mortal Wkly Rep 2002;51:948–50. 44. Miller G, Nicklas B, Davis C, et al. Intensive weight loss program improves physical function in older obese adults with knee osteoarthritis. Obesity (Silver Spring) 2006;14:1219–30. 45. Zhang W, Moskowitz R, Nuki G, et al. OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage 2008;16:137–62. 46. Shanafelt T, Barton D, Adjei A, et al. Pathophysiology and treatment of hot flashes. Mayo Clin Proc 2002;77:1207–18. 47. Fugate S, Church CO. Nonestrogen treatment modalities for vasomotor symptoms associated with menopause. Ann Pharmacother 2004;38:1482–99. 48. Ivarsson T, Spetz A, Hammar M. Physical exercise and vasomotor symptoms in postmenopausal women. Maturitas 1998;29:139–46. 49. Hammar M, Berg G, Lindgren R. Does physical exercise influence the frequency of postmenopausal hot flushes? Acta Obstet Gynecol Scand 1990;69:408–12. 50. Ueda M. A 12-week structured education and exercise program improved climacteric symptoms in middle-aged women. J Physiol Anthropol Appl Human Sci 2004;23:143–8.
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51. Kronenberg F. Hot flashes: phenomenology, quality of life, and search for treatment options. Exp Gerontol 1994;29:319–36. 52. Chien M, Wu Y, Hsu AT, et al. Efficacy of a 24-week aerobic exercise program for osteopenic postmenopausal women. Calcif Tissue Int 2000;67:443–8. 53. Langberg H, Skovgaard D, Asp S, et al. Time pattern of exercise-induced changes in Type I collagen turnover after prolonged endurance exercise in humans. Calcif Tissue Int 2000;67:41–4. 54. Wallace B, Cumming R. Systematic review of randomized trials of effect of exercise on bone mass in pre and postmenopausal women. Calcif Tissue Int 2000;67:10–8. 55. Kemmler W, Engleke K, Von Stengel S, et al. Long-term four-year exercise has a positive effect on menopausal risk factors: the Erlangen Fitness Osteoporosis Prevention Study. J Strength Cond Res 2007;21:232–9. 56. Vaynman S, Gomez-Pinilla F. Revenge of the ‘‘sit’’: how lifestyle impacts neuronal and cognitive health through molecular systems that interface energy metabolism with neuronal plasticity. J Neurosci Res 2006;84:699–715. 57. Booth F, Lees S. Physically active subjects should be the control group. Med Sci Sports Exerc 2006;38:405–6. 58. Sibley B, Etnier J. The relationship between physical activity and cognition in children: a meta-analysis. Pediatr Exerc Sci 2003;15:243–56. 59. Dunn A, Trivedi M, Kampert JB, et al. Exercise treatment for depression. Am J Prev Med 2005;28:1–8. 60. Blumenthal J, Babyak M, Doraiswamy PM, et al. Exercise and pharmacotherapy in the treatment of major depressive disorder. Psychosom Med 2007;69:587–96. 61. Robins L, Regier D. Psychiatric disorders in America: the epidemiologic catchment area study. New York: Free Press; 1991. 62. Paluska S, Schwenk T. Physical activity and mental health. current concepts. Sports Med 2000;29:167–80. 63. Byrne A, Byrne D. The effects of exercise on depression, anxiety and other mood states: a review. J Psychosom Res 1993;37:565–74. 64. DiLorenzo T, Bargman E, Stucky-Ropp R, et al. Long-term effects of aerobic exercise on psychological outcomes. Prev Med 1999;28:75–85. 65. Blumenthal J, Babyak M, Moore KA, et al. Effects of exercise training on older patients with major depression. Arch Intern Med 1999;159:2349–56. 66. Dunn A, Trivedi M, O’Neal H. Physical activity dose-response effects on outcomes of depression and anxiety. Med Sci Sports Exerc 2001;33:S587–97. 67. Dunn AL, Trivedi MH, Kampert JB, et al. Exercise treatment for depression: efficacy and dose response. Am J Prev Med 2005;28:1–8. 68. Kessler R, McGonagle K, Zhao S, et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the national comorbidity survey. Arch Gen Psychiatry 1994;51:8–19. 69. Sexton H, Maere A, Dahl N. Exercise intensity and reduction of neurotic symptoms: a controlled follow-up study. Acta Psychiatr Scand 1989;80:231–5. 70. Stephens T. Physical activity and mental health in the United States and Canada: evidence from four population surveys. Prev Med 1988;17:35–47. 71. Merom D, Phongsavan P, Wagner R, et al. Promoting walking as an adjunct intervention to group cognitive behavioral therapy for anxiety disorders—a pilot group randomized trial. J Anxiety Disord 2007;22(6):959–68. 72. Tunceli K, Li K, Williams L. Long-term effects of obesity on employment and work limitations among U.S. adults, 1986–1999. Obesity 2006;14:1637–46.
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73. Low D, Gramlich M, Engram B. Self-paced exercise program for office workers. AAOHN J 2007;55:99–105. 74. Proper K, Staal B, Hildebrandt V, et al. Effectiveness of physical activity programs at worksites with respect to work-related outcomes. Scand J Work Environ Health 2002;28:75–84. 75. Blair S, Cheng Y, Holder J. Is physical activity or physical fitness more important in defining health benefits? Med Sci Sports Exerc 2001;33:S379–99.
Sle ep Disorder s : Ca uses, Effe cts, and Solutions G. MichaelTibbitts, MDa,b KEYWORDS Sleep function and benefits Sleep deprivation Sleep disorders Sleep medication
Sleep is something that allows humans to feel good, even refreshed, both mentally and physically. This article first explores the nature and function of ‘‘good sleep’’ with its benefits. This topic leads to the undesired effects of sleep deprivation. AN EXPLANATION AND DEFINITION OF SLEEP
Thomas Bailey Aldrich’s poem, ‘‘Human Ignorance,’’ ponders a question that was common in the nineteenth century: ‘‘What probing deep/Has ever solved the mystery of sleep?’’1 Today we know that sleep is a natural vital process that most animals need to maintain health and well being. Without sleep, animal life would become disordered, and death would ensue. Most people experience episodes of sleepiness. Excessive daytime sleepiness affects about 20% of the adult population, and 16% of those affected experience impairment in daily function.2 Disordered sleep commonly is related to medical or psychiatric conditions. Also, young children and elderly adults experience sleep disruption more commonly than persons of other ages. What is sleep and how much does a person need each day? Sleep is an active process. While the body is at rest, the brain actively prepares for the next period of wakefulness. The American Academy of Sleep Medicine’s International Classification of Sleep Disorders defines more than 80 different disorders of sleep. Also, research produces thousands of articles each year. Sleepiness is classified as mild, moderate, or severe when excessive sleepiness is ‘‘a complaint or difficulty in maintaining desired wakefulness or a complaint of excessive amount of sleep.’’3 Types of Sleep
The circadian rhythm or sleep-wake cycle is composed of alternating stages of sleep, which, along with the architecture of those stages, provide a healthy or disordered a
Family Medicine, Sanford School of Medicine of The University of South Dakota, 1400 West 22nd Street, Sioux Falls, SD 57105, USA b Sanford USD Physicians, Medical Bldg 1, 1200 S. Euclid Ave, Ste 104, Sioux Falls, SD 57105, USA E-mail address:
[email protected] Prim Care Clin Office Pract 35 (2008) 817–837 doi:10.1016/j.pop.2008.07.006 primarycare.theclinics.com 0095-4543/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.
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period of rest. The sleeping period is divided into two main states. Rapid eye movement (REM) sleep and non–rapid eye movement (NREM) sleep progress in a common pattern throughout the period of sleep. NREM sleep has four stages. In healthy younger adults, sleep onset usually occurs less than 30 minutes after lying down. Sleep progresses through stages 1 to 4 of NREM sleep and then into REM sleep. Sleep tends to deepen with progression into the next stage. Stage 1 NREM is considered a transition into sleep. When aroused from this stage, an individual may not realize that he or she was asleep. Stage 2 NREM sleep is considered intermediate sleep and accounts for 40% to 50% of sleep. Stages 3 and 4 of NREM sleep are deep sleep and usually occupy 20% of sleep time. These two stages combined are called ‘‘slow-wave sleep’’ because the electroencephalographic pattern shows deep delta slow-wave patterns. These stages are associated with restoration of alertness and energy. Arousal also is more difficult. REM sleep function is more complex and is less well understood. Bursts of rapid eye movements are common in REM sleep along with loss of voluntary skeletal muscle tone. Dreams and memory consolidation seem to take place during this time. The amount of time spent in REM sleep rebounds when REM sleep has been diminished during previous sleep periods. The architecture of the sleep pattern shows four or five sleep cycles per night. These sleep cycles last 90 to 120 minutes and move up and down the stages of sleep. In an early sleep cycle, wakefulness may occur when passing into stage 1. In later sleep cycles, stage 2 NREM and REM sleep alternate. As the sleep time progresses, REM sleep increases in length at the expense of slow-wave sleep. Abnormalities in the sleep architecture may suggest sleep disorders such as narcolepsy, depression, or medication withdrawal. Also, in the elderly, slow-wave sleep declines, and light sleep increases with more frequent sleep arousals. The net effect is increased wakefulness.4 Function of Sleep
The function of sleep is still debated. Sleeping well for about 8 hours per day is needed to maintain mental and physical health. The outcomes of inadequate or dysfunctional sleep are well documented. Those consequences affect general health, metabolism, memory, immune functions, and the safety of the individual and of others. The restorative theory of sleep proposes that sleep renews the body in preparation for the next day. The feeling of being refreshed upon awakening from normal sleep is common. Growth hormone production is increased during sleep. In youth, other proteins for development are produced in the brain during REM sleep.5 The effect of sleep loss on the next day’s performance and well being seems obvious. In a similar theory, a role for sleep in memory reinforcement and consolidation is proposed. REM sleep seems to improve memory function.6 The adaptive theory suggests that sleep during the night has a survival benefit: in the jungle daytime activity is safer than activity at night with dangerous, dark-adapted animals. The energy conservation theory proposes the importance of saving energy by lowering metabolism during sleep at night and reducing the amount of the time spent in active energy use each day. Thermoregulation also is impaired with sleep deprivation. The relationship between REM and NREM sleep on brain development in neonates has been noted. The function of this interrelationship for normal awakening patterns in adults is being studied also.7 Optimal Sleep and its Benefits
Optimal sleep is related to the quality of sleep that an individual enjoys. The quality of sleep is affected by the duration and architecture of the sleep period. Frequent arousals with short periods in deep sleep reduce sleep quality and the experience
Sleep Disorders: Causes, Effects, and Solutions
of restfulness the following day. In their editorial in the issue of the Archives of Internal Medicine devoted to the relationship of sleep and health, Phyllis Zee and Fred Turek state, ‘‘Sleep is an indicator of health, and sufficient sleep quantity and good quality should be considered as an essential component of a healthy lifestyle, as much as exercise and nutrition.’’8 The benefits of sleep are understood by most people when they contrast their physical, mental, and emotional feelings after a good night’s sleep with their experience after a night of little or interrupted sleep. Sleep at night clarifies mental and emotional states and motor skill activities undertaken during the day and even can improve the performance of those tasks the next day.9 It also is well known that the body seeks to regain the sleep that has been lost in previous sleepless periods. These long-term benefits are understood by describing the effects of sleep deprivation on health and well being.10 Effects of Sleep Deprivation
Many studies have shown that humans require about 8 hours of sleep per night. Varying from this ‘‘ideal’’ are individuals who sleep only 4 to 6 hours per night, but fewer than 4 hours or more than 10 hours of sleep have been shown to result in increased rates of mortality. Sleepiness can be confused with, accompany, or cause tiredness, fatigue, weariness, or loss of energy.10 The close relationships among these conditions can complicate survey measurements of daytime sleepiness. Such studies, however, show that about one in five adults suffers from daytime sleepiness.2 The physical effects of excessive daytime sleepiness involve numerous areas of human function from mild short-term cognitive losses to increased mortality in longitudinal studies. One study in healthy adults restricted sleep to 4, 6, or 8 hours of sleep per night for 2 weeks. Participants restricted to 6 hours or more of sleep per night showed cognitive losses in attention, motor skills, and information processing. Sleepiness ratings showed the subjects were largely unaware of their cognitive losses.10 In addition, sleep-deprived rats showed impaired immune function and reduced host defenses. In this study, complete sleep deprivation resulted in septicemia and death.11 Healthy young adults, who were deprived of sleep for 40 hours showed increased circulating pro- and anti-inflammatory factors.12 Persons who had insufficient sleep also showed significantly increased plasma interleukin-6 levels and increased self-rated pain levels over a 10-day period. The association of sleep deprivation, pain, and inflammatory processes is seen in a variety of medical disorders and conditions.13 Apnea spells with episodes of oxygen desaturation have been linked to sleep deprivation and sleep fragmentation. This association is particularly important during anesthesia and surgery, because both can affect sleep architecture adversely. Patients who have unrecognized obstructive sleep apnea seem to be at increased risk for adverse outcomes during and following surgery.14 Studies suggest that sleep loss may be related to increased eating and obesity. The percent of adults in the United States sleeping less than 7 hours at night more than doubled in the last 40 years (from 16% to 37%).15 Similarly, in this country from 1960 to 1994 the prevalence of obesity nearly doubled (from 12.8% to 22.5%).16 Sleep studies in healthy young men have shown that sleep restriction lowers levels of glucagon and the appetite-suppressing hormone leptin and elevates the appetiteincreasing factor ghrelin. Increased hunger and consumption of calorie-dense foods with a high carbohydrate content was noted. It is postulated that sleep deprivation produces increased hunger and appetite. This effect may be related to the loss of slow-wave sleep with resulting glucose intolerance and risk of diabetes.17,18
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Emotional and psychiatric effects
Sleep deprivation is interrelated with emotional and psychiatric conditions. Sleep loss may induce adverse conditions such as depression. The problem also may flow in the other direction, with depression inducing sleep disorders.8,19 The relationship is strong either way. Sleep loss is associated with loss of vigilance and executive function, emotional and mood dysregulation, and even increased risk for adolescent suicidal behavior.20 A study of 53 healthy adults compared their rested responses with those they gave after 53 hours of wakefulness. These sleep-deprived subjects showed impairment in the emotional and cognitive-integration abilities needed in making moral judgments.21 Societal and financial costs
The direct and indirect costs for untreated insomnia in a group of more than 200,000 adult patients who had health insurance in the United States were 25% higher for persons who had insomnia than for the controls.22 A larger study in Australia estimated that all costs for all sleep disorders in their health system (with a population of 20.1 million people) was $7.5 billion. The equivalent expense for to the population of the United States (293 million people in 2004) would have been $109 billion. This projection included the cost of work injuries, motor vehicle accidents, and other sleeprelated illnesses and problems. At that time, the expense for sleep disorders was figured to be among the 10 highest health conditions in Australia.23 Excessive daytime sleepiness is a major cause of traffic accidents, of work injuries, and potentially of medical errors by sleep-deprived resident physicians.24 COMMON SLEEP IMPAIRMENTS Insomnia
A simple definition of insomnia is ‘‘unsatisfactory sleep with a loss of daytime functioning.’’ The poor quality of sleep is related to difficulty initiating sleep, frequent nighttime or morning awakenings, and the feeling of an insufficient duration of sleep in the morning. Incidence
Insomnia is the most common type of sleep disturbance. Surveys show 30% to 50% of people experience isolated episodes of insomnia, with 9% to 15% of this group experiencing significant chronic daytime loss of well being. Etiology
Primary insomnia has no identifiable etiology except increased autonomic hyperarousal. Secondary or comorbid insomnia has an underlying etiology that often results from psychiatric or medical conditions.25 Insomnia is a symptom rather than a disease. This condition has a variety of associated factors and causes. Studies have shown that the risk of insomnia is increased in elderly people, women, individuals of lower socioeconomic status, and those who have limited education. Surveys, however, can use flawed study methods.26 Employment requirements for shift work or excessive hours of work are associated with increased insomnia. Factors that cause transient or short-term insomnia include stressful events, acute illness, changes in sleep timing (jet lag and shift work), environmental problems (room temperature or noise), and stimulant use. Symptoms and signs
Insomnia is a symptom that most people experience at one time or another. Insomnia may lead to feelings of fatigue, inattention, irritability, lack of energy, or anxiety the
Sleep Disorders: Causes, Effects, and Solutions
next morning. Insomnia may be transient, short-term, or chronic. Chronic insomnia may lead to problems with depression, learning difficulties, and poor job or school performance.27 Insomnia is graded as mild, moderate, or severe based on the degree of social and occupational impairment that it causes and the severity of associated daytime symptoms.3 Conditions that may make insomnia worse include a stressful lifestyle, physical inactivity, and lack of uniform bedtime pattern. Heavy caffeine use, regular alcohol use, and cigarette smoking are apparent risk factors for insomnia.25 Medical causes of insomnia include heart disease (ischemic heart disease, nocturnal angina, and congestive heart failure), chronic obstructive pulmonary disease, asthma, peptic ulcer disease, reflux esophagitis, fibromyalgia, and other painful medical conditions. Common neurologic conditions associated with insomnia are Alzheimer’s disease, Parkinson’s disease, cerebrovascular infarction, sleep-related headaches, and traumatic brain injury.27 Many psychiatric disorders are associated with sleep disorders as well. Evaluation
With 9% to15% of the members of society living with moderate to severe insomnia disorders and with the condition lasting for more than 5 years in 40% of those afflicted, the need for evaluation and treatment is obvious. Also, surveys show that 70% of patients who have chronic insomnia never discuss the problem with their physician.28 In other surveys, physicians were unaware that severe insomnia existed in 60% to 66% in those reporting the problem.28 Screening for insomnia is the first step in the evaluation process. The focus should be on those at highest risk: persons who have depression, stressed lives, emotional distress, medical or psychiatric illness, prescribed or illicit drug use, night-shift employment, and those who frequently travel across time zones.27 A comprehensive sleep history would focus on the associated features of the sleep problem: the hour of bedtime, the time needed to fall asleep, problems with staying asleep, early morning arousal, wakeup time, the amount of sleep, sleep quality, and daytime fatigue. The seriousness of the problem could be rated on a scale of 1 to 10 with 1 as mild and 10 as severe. It is important to know the number of nights each week the problem is experienced. These questions need to be answered: ‘‘Is the problem getting worse?’’ and ‘‘Is the condition acute, short term, or chronic in nature?’’ Pre-bedtime activities that might impair sleep include watching television or reading in bed; having a meal, working, or engaging in physical activity shortly before bedtime, and consuming caffeine or alcohol within several hours before sleep. It is helpful to know what the patient has tried or is trying for treatment, such as prescription drugs, over-the-counter medications, or behavioral therapies.28 The physical examination should look for possible disorders that are related to insomnia. Only occasionally are laboratory studies and formal sleep studies indicated for this clinical disorder.27 In some situations, other methods of evaluating sleep quality might be helpful. Patients can use sleep logs or diaries to self report bedtime, sleep latency, arousals, time of arising, sleep duration, and sleep quality. Reporting also might include daytime naps, daytime functioning, and the use of sleep aids. Sleep questionnaires, psychologic assessment, and actigraphs (a wrist watch-like device that measures movement) also can be useful in defining the type of insomnia.28 Treatment
Therapy should begin by applying the behaviors of good sleep hygiene: establishing stable bed and rising times; a sleep time of 7 to 8 hours with not more than 8 hours
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in bed; regular exposure to light during the daytime but not before bedtime; a quiet, dark sleeping space; avoiding hunger at bedtime but not eating a meal before sleeping; no consumption of caffeine, alcohol, or nicotine for several hours before bedtime; regular exercise but not within 2 hours of bedtime; avoiding watching the clock; and using relaxation procedures before sleep. A self-help educational intervention in adults who had insomnia showed modest but significant improvement in subjective sleep parameters when compared with control patients.29 A list of resources for health care providers and patients is provided in the Appendix. Cognitive behavioral therapies include relaxation techniques and stimulus control. Sleep restriction and behavioral therapy are more active forms of treatment for insomnia. These treatments promote relaxation of the mind and body, reduced time awake in bed, reduced learned wakefulness in the bedroom, and the correction of misconceptions about sleep. Studies have shown cognitive-behavioral therapies to be more effective than pharmacologic therapy in the short-term treatment of insomnia and in the maintenance of sleep improvement in young, middle-aged, and older adults.30,31 In summary, as mentioned earlier, the treatment of insomnia requires diagnosing and treating other sleep disorders and medical and psychiatric conditions. The sleep environment, bedtime routines, and medications (both prescribed and over the counter) should be adjusted to promote restful sleep. A randomized, placebocontrolled trial of 72 elderly adults (mean age, 65 years) who had primary insomnia was performed for 8 weeks with a 24-month follow-up. The four trial arms included cognitive-behavioral therapy (stimulus control, sleep restriction, sleep hygiene, and cognitive therapy), pharmacotherapy (temazepam), both interventions, or placebo. The time awake after sleep onset was reduced by 63.5% with the combined therapy, by 55% with cognitive-behavior therapy, by 46.5% with the pharmacotherapy, and by 16.9% with the placebo control. In this study, the long-term outcomes of patient satisfaction were higher and more sustained with the behavioral approach.30 Other studies have shown similar results.27,31 Randomized, controlled studies of elderly community-dwelling adults who had moderate sleep complaints demonstrated significant improvement in self-rated sleep quality, latency, and duration though a 16-week program of moderate-intensity exercise compared with control participants and through a 24-week program of tai chi compared with low-impact exercise.32,33 Diphenhydramine and doxylamine are used for night-time sedation by individuals who have insomnia. A cross-over study of driving performance in 40 licensed 25- to 44-year-olds performed 1 hour after ingestion of 50 mg of diphenhydramine, 60 mg of fexofenadine, a, amount of alcohol calculated to produce a blood level 0.1%, or placebo showed the poorest performance in those taking diphenhydramine. Another study showed that extended use of diphenhydramine impaired older individuals’ scores on the Mini Mental Status Examination. The risk–benefit ratio of these antihistamines fails to support their use in the treatment of insomnia.27 The efficacy and safety of nonprescription agents such as melatonin, valerian, kava, and St. John’s wart have not been well studied for use in insomnia. For this reason their use generally is discouraged.27 Small studies of the short-term use of melatonin indicate that it may be safe, but its benefit is not certain. Again, melatonin is not recommended for the treatment of insomnia.27 Table 1 shows the benefits and adverse effects of prescription medications for the treatment of insomnia and other sleep disorders. Benzodiazepines commonly used to treat insomnia include estazolam, flurazepam, quazepam, temazepam, and triazolam. They generally shorten sleep latency and unscheduled waking. They are associated with lingering daytime effects of cognitive and psychomotor impairment and some
Sleep Disorders: Causes, Effects, and Solutions
hangover effect, however. Discontinuance of these medications is associated with rebound insomnia, anxiety, and irritability. Therefore, the use of minimal effective doses for short periods (1 month) and tapering the dose at discontinuance are recommended.27 The nonbenzodiazepine drugs include zolpidem, zaleplon, and eszopiclone. They are selective agonists of the of the benzodiazepine receptor complex and produce sleep benefits that are similar to those of the benzodiazepines but have fewer side effects. Each of these drugs has a distinct clinical profile. Table 1 provides many of those details.34 Remelteon is a melatonin receptor agonist that acts more specifically than melatonin on the pineal gland receptors for sleep induction. Studies in adults, including the elderly, have shown significant reduction in sleep latency and increases in total sleep time. Next-day residual effects, withdrawal, and rebound insomnia were not noted. This drug should be avoided in patients who have severe liver disease.34,35 In 2007 the Food and Drug Administration issued a warning that all these hypnotics have a risk of serious allergic reactions and complex sleep behaviors, including driving while asleep.27 Although studies show that 10% to 15% of patients use hypnotics for longer than 1 year, the benefit of long-term use is not supported by well-controlled studies.27 Patient referral should be considered if the diagnosis of the sleep disorder remains uncertain, the patient has ongoing daytime sleepiness, or another underlying medical or psychiatric disorder is suspected. Circadian Rhythm Disorders: Jet-Lag and Shift-Work Disorders Incidence and etiology
Circadian rhythm sleep disorders (CURDs) are divided by the International Classification of Sleep Disorders-2 into six distinct types with ‘‘a persistent or recurrent pattern of sleep disturbance due primarily to alterations in the circadian timekeeping system or a misalignment between the endogenous circadian rhythm and exogenous factors that affect the timing of sleep.’’3 Sleep is driven by the burden of an individual’s sleep debt that normally is lowest in the morning daylight at 9 AM and highest at 9 PM in the dark of night. Light is the stimulus in the exogenous system. Light passing through the neuropathways of the eyes promotes wakefulness. The circadian clock or endogenous system is the other method for control of sleepiness. Here, the highest alerting drive for wakefulness is at 9 PM, and the nadir of the drive for wakefulness is at 8 AM. These CURD types are referred to as ‘‘syndromes’’ or ‘‘disorders’’ in other sleep classifications. These disorders can produce social and occupational impairments and other limitations. At times, other conditions such as obstructive sleep apnea may be better explanations for sleepiness than a CURD.36 The best-known and probably the most common CURDs are the jet-lag type and the shift-work type. These two types of CURDs are related to changes in the exogenous external factors that interfere with the normal function of the internal circadian clock (central pacemaker). The other types of this disorder involve malfunction of the internal endogenous circadian system. Thus the demand for sleep or wakefulness by the central sleep pacemaker is placed at odds with societal or environmental signals for the opposite action of wakefulness or sleep.37 Although the incidence of CURDs is not known, hundreds of thousands of people are undertake jet travel on any given day. Many of those people probably experience jet lag. Also, 20% of the work force in modern societies is engaged in shift work. Not all but a large percent of those individuals experience temporary or chronic sleep disturbance.36 Signs and symptoms
Shift work sleep disorder (SWSD) is suspected when excessive sleepiness, hypersomnia, or unrefreshed feelings upon awakening are associated with a work shift.
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Table 1 Pearls and perils regarding medications used to treat insomnia* Drug Class
Pearls
Perils
Medications approved by the Food and Drug Administration (FDA) Melatonin receptor agonists Rapidly absorbed. Specific action on sleep-onset process. Four metabolites also are active for sleep induction with their half-life of 1–3 h. Multiple studies showed reduced sleep latency, improved sleep time, and no rebound, withdrawal, or next-day residual effects.
2% bioavailability because of rapid liver metabolism. Elimination mainly by the urine, a concern in elderly patients. Reduced absorption after high-fat meal. 5% discontinuation rate because of adverse effects versus 2% rate for placebo. Most common side effect is headache (7% with drug and with placebo)
Zaleplon (Sonata) Dose: 5–10 mg/d per day; 5 mg/d in elderly or patients who have hepatic disease. Take immediately at bedtime or at least 4 h before awakening. Half-life: 1 h
Rapid absorption with peak level at about 1 h. Inactive metabolites. Improved sleep onset. No morning memory impairment, rebound insomnia, withdrawal,or tolerance noted in elderly.
Half-life about 1 h. High-fat meal interferes with absorption. Increased awakenings. Questioned sleep time improvement.
Zolpidem (Ambien) Dose: 5–10 mg (Zolpidem, 5 mg in elderly; Ambien CR, 6.25 mg in elderly) Half-life: 1.2–4 h Extended-release zolpidem should be taken whole, not divided, and should be ingested only at bedtime. Dose: 6.25–12.5 mg Half-life: 1.6–4 h
Rapid absorption and onset in 30 minutes. Reduced sleep latency and increased total sleep time. Inactive metabolites. Improved sleep quality and quality of life. No decrease in performance the next day.
Headache, drowsiness, fatigue, and dizziness reported (14%–28%). Impaired memory in sleep. Reduced sleep quality. Elderly rebound sleep noted on discontinuation. Rapid discontinuation may result in withdrawal symptoms and rebound sleep.
Ramelteon (Rozerem) Dose: usual dose 8 mg taken 30 minutes before bedtime. Do not take after high-fat meal. Half-life: 1.2 h
Benzodiazepine receptor agonists
Eszopiclone (Lunesta) Dose: 1–3 mg/d with starting dose of 2 mg (3 mg. if needed) 1 mg for patients who have severe liver disease, taking potent CYP3A4 inhibitorsa, or elderly Half-life: 6 h
Improved sleep onset, sleep quality, sleep time, next-day alertness, function, and well being. 12 months of nightly use was well tolerated and without withdrawal symptoms.
Adverse effects of medication versus placebo: unpleasant taste (34% versus 3%), headache (17% versus 13%) and dizziness (7% versus 4%).
For the benzodiazepines, as a group, the lowest dose for the shortest time period needed for effective therapy is recommended. Treatment of insomnia with this class of drugs is generally considered safe and effective.
Group adverse effects: Daytime sedation, altered sleep architecture (less deep sleep), cognitive and psychomotor impairment. Headache, dizziness with discontinuation, withdrawal symptoms, and rebound insomnia. Tolerance and dependence noted with long-term use. Elderly patients with slower drug metabolism are at potential increased risk for side effects and falls. Patients who have a history of seizure may be at more risk of a seizure with rapid discontinuation of medication.
Benzodiazepines
(continued on next page)
Sleep Disorders: Causes, Effects, and Solutions
Triazolam (Halcion) Dose: 0.125–0.25 mg Half-life: 1.5–5.5 h Temazepam (Restoril) Dose: 7.5–30 mg Half-life: 11 6 h. Greatest effect on sleep latency and sleep time. Estazolam (Prosom) Dose: 1–2 mg Half-life: 10–24 h Good effect on sleep time. Quazepam Dose 7.5–15 mg Half-life: 24 h Better effect on sleep time than sleep latency. Flurazepam (Dalmane) Dose: 15–30 mg Half-life: 74 24 h Improved sleep onset and maintenance in short term treatment.
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Table 1 (continued) Drug Class
Pearls
Perils
Medications not approved by the FDA for the treatment of insomnia Trazodone Commonly used dose of 25–50 mg at bedtime is much lower than FDA recommended dose for depression. Other sedating antidepressants show similar results and effects. Half-life: 6.4 h in adults and 11.6 h in the elderly
Absorbed well on empty stomach. Small studies showed minimal benefits compared with controls. Low cost of these medications is a potential reason for their use.
Common side effects: headache, somnolence, dry mouth, dizziness, constipation, difficulty awakening, blurred vision. Cardiovascular complications are possible. Longer half-life in elderly is a concern.
Diphenhydramine Common dose: 12.5–50 mg at night Other sedating antihistamines show similar results and effects.
Few controlled studies. One study showed improved sleep quality and sleep duration but not improved sleep interruption or severity of insomnia.
Morning sedation in 10%–25% of patients. Dry mouth and eyes, constipation, urinary retention, blurred vision and delirium are reported. Dizziness is common and may affect driving. Seizure threshold may be lowered.
Melatonin Dose: 0.3–5 mg taken 30–120 min before bedtime. Safety in those < 18 years is unknown, and drug is not recommended. For jet-lag sleep disturbance: Melatonin 1.0 mg before desired sleep may help but not studied well enough to recommend. Half-life: less than 60 min with uncommon morning effects
Benefit for insomnia and jet-lag sleep improvement is suggested but not backed by rigorous study. Long-term use for up to 2 years of doses up to 5 mg/d is considered safe.
Few rigorous treatment studies performed. Common adverse effects: fatigue, drowsiness, headache, dizziness and irritability. Mood changes, gastrointestinal distress, hyperglycemia, and hypotension noted. High doses have effects on fertility. There are case reports of coagulation disorders, seizures, and psychotic symptoms.
Valerian (valerian root): commonly used for anxiety and insomnia. Dose: 1.5–3 mg of the root, 400–900 mg of extract, or tea prepared with 1.5–3 mg of root; taken at bedtime.
FDA recognition: ‘‘generally regarded as safe.’’ Reported randomized clinical trials show short-term reduction in sleep latency, improved sleep maintenance, and sleep satisfaction. No clinical trials on tolerance, dependence, rebound, or withdrawal with discontinued use.
Mild effects of dizziness, hangover, and headache noted but not more frequent than with placebo. Withdrawal tachycardia and possible hepatotoxic effect. Additive sedation with other products unknown. No FDA control on preparation. Not recommended for those younger than 18 years of age.
Sleep Disorders: Causes, Effects, and Solutions
* Barbiturates such as chloral hydrate, methaqualone, qlutethimide, and others are seldom used because of a lack of effectiveness, loss of cognition, abuse potential, overdose toxicity, and even risk of death. L-tryptophan and kava (kava kava) have some sedative qualities, but there are major health concerns with their use. Kava is considered unsafe because of reported cases of hepatotoxicity at suggested bedtime doses. L-tryptophan should be used with caution because of associated eosinophilic-myalgia syndrome. Other herbal products (chamomile, passion flower, coenzyme Q10, hops, lemon balm, lavender, and skullcap) are used for sleep but have not been studied sufficiently for effect and safety. a Medicines that are potent CYP3A4 inhibitors are ketoconazole, clarithromycin, and nelfinavir. Data from Morin AK, Jarvis CI, Lynch AM. Therapeutic options for sleep-maintenance and sleep-onset insomnia. Pharmacotherapy 2007;27(1):89–110; Pagel JF. Medications and their effects on sleep. Prim Care Clin Office Pract 2005;32:491–509.
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Variations in coping ability influence an individual’s sleeping difficulty with the shiftwork or jet-lag disorders. Additional factors that may make these disorders more serious include advanced age, domestic responsibilities, diurnal sleep preference, and the type of work schedule.38 Jet-lag disorder is a temporary circadian clock misalignment of the sleep/awake cycle caused by moving too rapidly across several time zones. Eastward flight increases the deepness of the sleepiness and the difficulty in adapting to the new time zone. Eastward travel results in trouble in falling asleep, and westward travel causes trouble in maintaining sleep. Jet-lag symptoms usually are temporary and include insomnia, excessive daytime sleepiness, malaise, and impaired performance. Gastrointestinal and urinary demands may become problematic. Other causes of sleepiness, such as primary sleep disorders and drug or alcohol dependence, need to be considered.37 Evaluation and treatment
To evaluate SWSD, sleep logs or diaries are kept for 2 to 4 weeks to evaluate the timing, quality, and quantity of sleep. Actigraphy (as discussed previously) may supplement the diary findings. This information helps with development of the sleep plan. Occasionally other, less commonly used tools may be clinically helpful. These tools include phase markers of circadian/sleep misalignment such as core body temperature and melatonin rhythm studies.36 The treatment of SWSD involves multiple modalities. The treatment needs to be tailored to the individual patient’s situation. Specific considerations include the patient’s need and desire for treatment, the patient’s support system, and the type of shift schedule.34 Planned napping before shifts and short naps during shifts improve alertness during work, reduce accidents, and improve sleep after work.36 Realigning the circadian rhythm to the shift with bright light treatment during work has been shown to be helpful. Wearing dark goggles when returning from work may help the patient adjust to the desired sleep phase by avoiding exposure to bright light.38 Melatonin or even melatonin agonists are available and are used for phase-shifting benefits to improve daytime sleep for night workers. Research is still in progress to determine the appropriate dose and timing for benefit in these conditions. Studies have shown benefit with melatonin use particularly when combined with light therapy.36,37 Melatonin is marketed as a nutritional supplement. Concerns have been raised about the purity of available melatonin preparations and the reliability of the stated doses.36 Hypnotic drugs promote daytime sleep but may affect performance and safety adversely during the following night at work.36 The evaluation of jet-lag disorder is related to the symptoms of the mismatch between the biological clock’s drive for sleep or wakefulness and the environmental light/dark cycle at the new destination. Symptoms usually are short lived, but occasional errors in judgment may have serious effects. Older individuals may have less difficulty than younger people. Gender differences are not known. With the possible exception of sleep logs, assessment methods have proved useful only in the laboratory setting at this time.36 Treatment is intended to speed the re-entrainment of the circadian pacemaker to the new time zone. For short trips, one level 2 study showed a benefit in remaining on the home sleep schedule at the new destination, but one third of the participants preferred to adopt the destination sleep schedule to be in synch with local activities. A sleep-simulation study of altering the sleep schedule to an eastward destination time zone before travel showed some small benefits.36 A level 2 simulation experiment with bright light exposure for 3 days before travel to an eastward destination showed
Sleep Disorders: Causes, Effects, and Solutions
significant benefit compared with dim light exposure but required strict compliance with the dark-light schedule. One field trial with artificial light exposure after westward travel failed to show improved measures of sleep or performance.36 Twelve doubleblinded, placebo-controlled field trials studied treatment with melatonin for jet lag following travel across multiple time zones. Five reports were level 1 studies, and seven were level 2 studies. Two studies produced negative results; the others showed melatonin treatment improved sleep and reduced jet-lag symptoms. Immediate-release formulations with doses of 0.5 to 5 mg were effective and were better than sustained-released formulations. Only a few studies monitored and reported side effects. Those that reported side effects showed no increased adverse effects compared with placebo. Strategically timed melatonin administration also has been shown to reduce jet-lag symptoms and to improve sleep following long flights.36 Only two small level 2 studies of the effects of caffeine on jet lag have been reported. Daytime sleepiness was less with caffeine use than with melatonin or placebo. Entrainment of the circadian rhythm with caffeine was similar to melatonin and better than placebo. Sleep onset was longer, however, and awakenings were more frequent with the caffeine.36 Three level 1 and six level 2 studies show that hypnotics improved short-term insomnia, but their effect on daytime jet-lag symptoms is not known. Also, when concomitant alcohol use is expected, safety during daytime activities makes the value of hypnotic use uncertain.36 In conclusion, treatment for jet-lag disorder could include the use of immediaterelease melatonin at bedtime. Smaller doses seem to be as effective as larger doses. Caffeine helps with daytime sleepiness but may interfere with restful sleep. In new environments hypnotics should be used only with care. Entrainment of the circadian pacemaker with light therapy may be helpful but is cumbersome to achieve.
Other Sleep Problems Medical conditions and sleep
Sleep disorders are related to poor health outcomes, increased risk of anxiety, depression, cardiovascular disease, and respiratory disorders, and amplification of pain.7,39 On the other hand, psychiatric disorders including psychosis, mood disorders, anxiety disorders, panic disorders, and alcoholism/drug abuse commonly cause sleep disturbances. Dementia produces poor sleep efficiency, frequent awakenings, and possible wanderings at night. A common presenting complaint in Parkinson’s disease is insomnia.40 Sleep quality is bad in patients who have coronary artery disease, sleep apnea, chronic obstructive pulmonary disease, asthma, and allergic rhinitis. Multiple sclerosis, uncontrolled seizures, and chronic pain interfere with sleep and produce daytime sleepiness.7,40 Obstructive sleep apnea is associated with a number of medical disorders including an increased risk for hypertension, transient ischemic attacks, stroke, and other cardiovascular diseases.41 Sleep disorders are interrelated with psychiatric and medical diseases, so the assessment of medical and psychiatric disease is necessary in patients who have sleep difficulties, and vise versa.7,42 Medications may disrupt sleep and cause physical side effects. Their relationship with these problems needs to be considered; dose adjustment or discontinuation of medication may be indicated. The treatment of insomnia or sleep apnea may improve sleep and thereby improve associated medical or psychiatric conditions. Similarly, the treatment of pain or anxiety might solve the sleep problem.
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The effect of medications on sleep
Medications are prescribed to improve and control many medical conditions. In addition, patients buy over-the-counter substances hoping to improve function and treat minor ailments. Many patients also use alcohol, tobacco, and caffeine for social and personal reasons. Substance abuse is common and has increased lifetime prevalence in individuals who have mental disorders.43 Many of these compounds have the potential to interfere with sleep efficiency, resulting in difficulty sleeping and excessive sleepiness the following day. Common medications that effect sleep are discussed later. Polypharmacy (taking more than five medications daily) is more common in the elderly, as would be expected. Surveys have shown that 46% of persons more than 65 years old take five or more medications, and 39% take more than 10 medications. The likelihood of drug-to-drug and drug-to-disease adverse interactions on sleep is more common in older adults.43 (Common drug–drug interactions are listed in Table 2). Medications affect each of the three major types of sleep disorders: insomnia (difficulty in falling or staying asleep with nonrestorative feelings the next day), disorders in which the primary symptom is daytime sleepiness, and disorders involving arousal-disruptive sleep behaviors. Although medications to treat these conditions are available, the mediation may have ‘‘limited efficacy, serious side effects, addiction, and lethal toxicity in overdose.’’44 In treatment it is important to limit side effects and the potential for addiction or overdose. It also is prudent to avoid writing sleeping prescriptions for conditions resulting from the adverse effects of other medications. Excessive daytime sleepiness is a common sleep complaint and may be described by the patient as sleepiness, drowsiness, fatigue, sluggishness, or a similar state.44 According to The Physician’s Desk Reference,43 drowsiness is a commonly reported side effect of almost 600 medications. This problem is noted commonly with the anticholinergic medications and certain antihistaminergic medications such as diphenhydramine. These drugs have soporific effects and also have the potential to interfere with the regulatory neurotransmitters for wakefulness. This interference may result in waking drowsiness and cognitive impairment. Similar effects are seen with antipsychotic, antispasmodic, antiemetic, and antiparkinsonian drugs.43 Ethanol also is widely used to help induce sleep, but diminished sleep quality, development of tolerance, dependence, and overdose are possible. Opiate pain medications may interfere with sleep efficiency and produce daytime sleepiness. Other medications interfere with sleep by activating the brain. This effect is particularly problematic if the medication is taken before bedtime or when the long half-life of the drug continues the alerting effect into the sleep period. Other over-the-counter medications that interfere with sleep are caffeine, ephedrine, and pseudoephedrine, which are common in cold/flu and pain medications. b-Agonists, corticosteroids, and theophylline are used to treat chronic lung conditions but can interfere with sleep maintenance. Activating antidepressants such as buproprion, desipramine, reboxetine, venlafaxine, and most selective serotonin reuptake inhibitors can interfere with the initiation and maintenance of sleep. Other activating medications include dextroamphetamine (Dexedrine), methylphenidate, modafinil, and selegiline. If the use of troubling medications cannot be stopped, they should be taken as far from the time of sleep as possible.43 Some medications may worsen medical and psychiatric conditions, thereby interfering with sleep. Anti-inflammatory medications may worsen heart failure, potentially producing central sleep apnea and nocturia. Lipophilic b-blockers (metoprolol, pindolol, and propranolol) are associated with insomnia and daytime sleepiness. Nocturnal gastroesophageal reflux may be caused by calcium-channel blockers and nitrates. Confusion, urinary retention, and nocturia may be caused by anticholinergic
Sleep Disorders: Causes, Effects, and Solutions
Table 2 Drug^drug interactions Drug
Possible Interacting Drugs
Digoxin
Amiodarone, cyclosporine, loop diuretics, propafenone, quinidine, verapamil
Warfarin
Amiodarone, aspirin, barbiturates, capecitabine, cimetidine, dipyridamole, erythromycin, fluconazole, metronidazole, nonsteroidal anti-inflammatory drugs (NSAIDs), quinidine, sulfonamides, ticlopidine, thyroid products, zafirlukast, 17-akyl androgens,
3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HMG CoAs)
Gemfibrozil
Verapamil
Beta-blockers, carbamazepine, quinidine
Potassium-sparing diuretics
Potassium
Clonidine
Beta-blockers
Macrolide antibiotics
HMG CoAs
Sumatriptan
Selective serotonin reuptake inhibitors (SSRIs)
Methotrexate
NSAIDs, sulfonamides, salicylates/aspirin
Lithium
NSAIDs
Theophylline
Cimetidine, fluoroquinolones, macrolide antibiotics
Tricyclic antidepressants
Clonidine
Sildenafil
Nitrates
Sibutramine
SSRIs
Carbamazepine
Macrolide antibiotics
Allopurinol
Azathioprine
Cyclosporine
Phenytoin
Rifampin
Oral corticosteroids
Ketoconazole
Histamine-2 receptor antagonists
Amiodarone
Quinidine
Selegiline
Venlafaxine
Lovastatin
Cyclosporine
Rifampin
Oral contraceptives
Ergot alkaloids
Macrolide antibiotics
Monoamine oxidase inhibitors
Amphetamines, SSRIs, sumatriptan, tricyclic antidepressants
Data from Zhan C, Correa-de-Araujo R, Bierman AS, et al. Suboptimal prescribing in elderly outpatients: potentially harmful drug-drug and drug disease combinations. J Am Geriatr Soc 2005;53(2):262–7; and Peng CC, Glassman PA, Marks IR, et al. Retrospective drug utilization review: incidence of clinically relevant potential drug-drug interactions in a large ambulatory population. J Manag Care Pharm 2003;9(6):513–22.
medications such as amitriptyline. Diuretics given too close to bedtime are associated with nocturia. Diabetic medications may cause hypoglycemic episodes with resulting nocturnal arousals. Primary sleep disorders such as restless legs syndrome and periodic limb movement disorder may be made worse by certain antidepressant medications, alcohol, benzodiazepines, caffeine, antihistamine withdrawal, and antipsychotic therapies. Cigarette smoking also is associated with sleep disturbances.45 Other medications
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are associated with worsened sleep architecture and interfere with sleep. High-dose niacin, some antibiotics, oral contraceptives, L-thyroxine, and the chronic use of some sedative/hypnotic drugs have been associated with insomnia. The patient’s medical history should include a complete listing of prescribed and over-the-counter medications that are taken. When the patient is taking more than five medications regularly, the difficulty of polypharmacy should be considered. It should be remembered that both prescribed and over-the-counter medications can interfere with normal restful sleep with resulting daytime sleepiness. Patient complaints of excessive daytime sleepiness or the report of such difficulties from family members should begin an investigation into the cause of the problem. It should be remembered that sleepiness or insomnia are symptoms with a diagnosis waiting to be made and an appropriate treatment instituted. An early review of the medications taken is easy to perform and may provide a potential solution to the problem. If a suspected medication is needed to treat another problem, one should consider changing the timing of administration of the drug. Also, the dose might be modified, or replacement medication might be given. Nonpharmacologic treatments for insomnia are available and might reduce the mediation burden. As with most medical treatment, pharmacology for sleep disorders should be approached with caution, and the smallest effective dose should be used for the shortest duration needed. These principles are particularly important in the elderly, many of whom already have an underlying loss of sleep efficiency, an increased burden of disease, and the likelihood of increased numbers of medications. WOMEN AND SLEEP The Problem
In the National Sleep Foundation 2007 Sleep in America Poll, 1003 women, including women who were pregnant or had given birth within the last 6 months, were interviewed.46 In women aged 18 to 64 years, 67% experienced a sleep problem. Women under the age of 45 years were more likely than older women in the survey to be too sleepy for exercise (48%) or to run out of time to sleep (52%). Other activities that also were negatively affected were spending time with friends (39%), leisure activities (38%), eating a healthy meal (37%), and having sex (33%). Loss of daytime alertness was common, and 27% of those surveyed reported driving while drowsy. Working mothers (72%), single working mothers (68%), and stay-at-home mothers (74%) reported symptoms of insomnia. Poor mood was associated with sleep loss. Pregnant women spent more time in bed (8.25 hours), but 84% of this group still reported symptoms of insomnia. Menstruating women spent 7.45 hours in bed, but 67% experienced insomnia a few nights a week. Postpartum women spent 7.45 hours in bed, but 84% had frequent symptoms of insomnia. This survey showed a national trend for women at all ages and in varied life situations to have sleep that is inadequate for normal refreshment the next morning. To treat daytime sleepiness, women coped by just keeping going (80%), increasing their caffeine intake (65%), eating high-carbohydrate foods (46%), taking a nap (39%), and/or smoking a cigarette (21%). The 2005 National Sleep Foundation Sleep in America poll showed that women experience more sleep problems than men. Common Conditions
The central circadian clock with its associated sleep/wake rhythm seems to be influenced by the estrogen and progesterone receptors near suprachiasmatic nucleus, home of the ‘‘central pacemaker.’’ This hormonal relationship may make the female shift worker more susceptible to additional heath disorders in addition to findings
Sleep Disorders: Causes, Effects, and Solutions
noted earlier. Fifty-three percent of nurses during shift work reported dysmenorrhea or changes in menstrual flow and in the length and duration of menstrual flow. Another survey of 2264 women working a shift schedule found an increase in dysmenorrhea and menstrual irregularity. Increased levels of progesterone associated with the postovulatory phase of the cycle influence the circadian rhythm, sleep, and mood. These effects may contribute to maladaptation to shift work. The association of night shift work with the change in the menstrual phase results in a reduced subjective quality of good sleep with increased irritability and decreased alertness. When compared with day workers, young women working shift schedules had greater risks of firsttrimester miscarriage and of babies born with reduced birth weight and at an earlier gestational age.47 Such associated clinical findings, although important, may be related as much to individual adaptation to shift work as to hormonal changes that also are taking place. The relationship of the menstrual cycle physiology with shiftwork difficulties should be considered when women present with such difficulties. A potential aid for a female night-shift worker to improve nighttime function and sleep the next morning is the use of bright light exposure during the night shift. Epidemiologic studies have shown a larger-than-expected increase in breast cancer in women working various types of shift schedules. It is proposed that melatonin may have an oncostatic function in the suppression of such cancer, and melatonin is suppressed by the bright light therapy. Although this association is interesting, shift work also is associated with nutritional deficits, weight gain, and other changes. The association of bright light therapy and breast cancer is still being investigated. Additional studies are in progress at this time.48 Shift workers have altered meal times, and they have been reported to eat fewer meals than those who work day hours. The methods they use to stay awake include increased snacking, eating unhealthy sweets and high-energy foods, drinking more caffeinated drinks, and smoking. Weight gain, higher body mass index, and lower participation in exercise are noted also. Female shift workers have a reported increased risk of hypertension, diabetes mellitus, elevated cholesterol, coronary artery disease, and myocardial infarction. Gastrointestinal symptoms and disorders are increased in shift workers.47 Female shift work also has significant negative effects on personal psychologic health and on domestic and family life. Sleep time is reduced because of the additional domestic responsibilities following the night shift. Family and spousal relationships are affected. A survey comparing shift and nonshift workers (84% of those surveyed were female) showed although ‘‘overall happiness and life satisfaction’’ was maintained, other quality indices were affected. The shift workers reported less opportunity to improve their psychologic health and personal growth. They also reported lower scores in their ‘‘spiritual being’’ (personal values, standards, and spiritual beliefs) and fewer opportunities to become involved in domestic, school, or volunteer activities.49 Low back pain, temporomandibular joint disorder, and tension headaches are more common in women than in men and may interfere with restorative sleep. Perhaps of greater concern, women have a higher incidence for a group of chronic pain conditions that likewise interfere with sleep. These conditions are grouped together as the functional somatic syndromes (FSSs), which include fibromyalgia (1%–3% of women), irritable bowel (3%–20% of women), and chronic pelvic pain (7% to 8% of women). The close relationship between nonrestorative, fragmented sleep and the perpetuated central processing of pain and the activation of immune/inflammatory regulation are not well defined. This problem needs further research. In the FSSs, the chronic persistence of the symptoms of dysphoria, profound fatigue, and cognitive impairment place a heavy burden on many women.50
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As discussed earlier, insomnia, with a reported prevalence between 2% and 11%, is more common in women. A positive family history, particularly in the patient’s mother, is a significant risk factor for insomnia. Female hormones (pregnancy, menstruation, and menopause) and care of a child at night or eldercare may increase the rate of insomnia in women. A sleepless young child and the late return of an adolescent son or daughter typically increase maternal vigilance and sleep impairment. Treatment
A woman’s lifestyle with multiple roles can make sleep more difficult. Setting up a routine for good sleep will help with general sleep maintenance. The routine should include relaxing activities before sleep (avoiding television, strenuous exercise, or late meals); a dark, quiet, cool sleep environment; avoiding caffeine drinks, alcohol, or nicotine for several hours before sleep; and initial help with the care of a new baby. Twenty-one percent of women snore at night, and 19% have symptoms of restless leg syndrome. If these symptoms persist, interfere with sleep, or cause daytime sleepiness, the cause for the symptom should be brought to the physician’s attention. Women who sleep with a child (9%) or a pet (14%) in bed may have sleep disruptions and should find another place for the child or pet to sleep.48 The FFSs (e.g., fibromyalgia) still are not well understood. Whether early treatment of the pain or sleep disturbance would modulate the development of immune inflammatory mediators is not known, but such treatment may be helpful. Each of the FSS disorders has evaluation and treatment recommendations that ameliorate the condition. General medical and specialist care may be needed to maximize the treatment plan.50 Future research probably will provide a better understanding of FSSs and improved treatment options. Studies of medical and sleep disorders related to SWSD are complex, and additional information is in development. The use of light exposure during shift work and naps before work or during the work period can align the central circadian clock to extend the sleep period. These measures improve alertness, performance, and safety at work and improve next-day sleep efficiency. Efforts to reduce sleep debt in shift work may be healthy. Naps are a method to counteract the effect of sleep loss and improve work vigilance. Improved sleep may reduce the effects of abbreviated shift work, such as obesity, hypertension, and endocrine changes. The short-term use of hypnotics or melatonin may improve sleep time. Caffeine and other stimulants such as modafinil may increase workers’ attention during the work shift.47 Better understanding of the effects of shift work on women is needed for development of public policy for such work and the development of new treatment options. Insomnia can be treated with pharmacologic and psychologic interventions. Both types of intervention can be beneficial. A combination of the two types has been tried. Nonpharmacologic treatments such as cognitive-behavioral therapy are time consuming to initiate but have long-term benefits when compared with medication prescription. In some places trained therapists may be difficult to find.35 Table 1 presents pharmacologic and herbal products used for treatment of sleep loss. The table shows the benefits of those medications and concerns regarding their use. In conclusion, this article has discussed briefly the function and benefits of sleep. The consequences of sleep impairment with a few associated sleep disorders were noted. Importantly, it has addressed insomnia, the most common sleep disorder, and has discussed the current approach to this common and debilitating problem. A listing of additional resources for continued study by health professionals and patients is provided in the Appendix. By ‘‘probing deep,’’1 one finds that excellent treatments for sleep disorders do exist. Much has yet to be learned, but improved care is being developed for patients who have those disorders.
Sleep Disorders: Causes, Effects, and Solutions
APPENDIX Resources for Providers
National Heart Lung and Blood Institute. Problem sleepiness in your patient (free PDF downloadable version). Available at: http://www.nhlbi.nih.gov/health/prof/ sleep/index.htm; Accessed March 27, 2008. Guide to selected publicly available sleep-related data resources. National Center on Sleep Disorders Research, July, 2006. Available at: http://www.nhlbi.nih.gov/ about/ncsdr/research/sleep-datasets-july-06.pdf. Accessed March 27, 2008. The American Academy of Sleep Medicine offers on-line resources for CME, current journal articles, training, and practice standards. Available at: http:// www.aasmnet.org/ProfDev.aspx. Accessed April 1, 2008. Resources for Patients
National Sleep Foundation (English and Spanish versions) sleep information, sleep logs, learning tools, and much more. Available at: http://www.sleepfoundation. org. Accessed March 10, 2008. National Heart, Lung and Blood Institute. Your guide to healthy sleep (60-page publication: free downloadable PDF or purchase for $3.50). Available at: http:// www.nhlbi.nih.gov/health/public/sleep/healthy_sleep.pdf. Accessed March 27, 2008. National Heart Lung and Blood Institute. Star sleeper for kids (interactive website for kids, parents, and teachers). Available at: http://www.nhlbi.nih.gov/health/ public/sleep/starslp/index.htm Accessed March 27, 2008. Sleep disorders from Medline Plus health topics. U.S. National Library of Medicine and the National Institutes of Health. Available at: http://www.nlm.nih.gov/ medlineplus/sleepdisorders.html#cat64; Accessed March 25, 2008.
REFERENCES
1. Aldrich TB. Human ignorance. Harper’s New Monthly Magazine 1876; June:48. Available at: http://www.gigausa.com/quotes/authors/thomas_bailey_aldrich_ a001.htm. Accessed February 24, 2008. 2. Young TB. Epidemiology of daytime sleepiness: definitions, symptomatology, and prevalence. J Clin Psychiatry 2004;65(Suppl 16):12–6. 3. International classification of sleep disorders: diagnostic and coding manual. 2nd edition. Westchester (IL): American Academy of Sleep Medicine; 2005. 4. Hirshkowitz M, Moore CA, Hamilton CR, et al. Polysomnography of adults and elderly: sleep architecture, respiration and leg movements. J Clin Neurophysiol 1992;9(1):56–62. 5. Markov D, Goldman M. Normal sleep and circadian rhythms: neurobiologic mechanisms underlying sleep and wakefulness. Psychiatr Clin North Am 2006; 29:841–53. 6. Swick TJ. The neurology of sleep. Neurol Clin 2005;23:967–89. 7. Siegel JM. Clues to the functions of mammalian sleep. Nature 2005;437:1264–71. 8. Zee PC, Turek FW. Health and sleep everywhere and in both directions. Arch Intern Med 2006;166:1686–8. 9. Lambert C. Deep in sleep. Harvard Magazine 2005;July-August. Available at: http://harvardmagazine.com/2005/07/deep-into-sleep.html. Accessed February 24, 2008; 25–33.
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10. Van Dongen HP, Maislin G, Mullington JM, et al. The cumulative cost of additional wakefulness: dose-response effects on neurobehavioral functions and sleep physiology from chronic sleep restriction and total sleep deprivation. Sleep 2003;26(2):117–26. 11. Rechtschaffen A, Bergmann BM, Everson CA. Sleep deprivation in the rat: X. Integration and discussion of the findings 1989. Sleep 2002;25:68–87. 12. Frey DJ, Fleshner M, Wright KP Jr. The effects of 40 hours of total sleep deprivation on inflammatory markers in health young adults. Brain Behav Immun 2007; 21(8):1050–7. 13. Haack M, Sanchez E, Mullington JM. Elevated inflammatory markers in response to prolonged sleep restriction are associated with increased pain experience in healthy volunteers. Sleep 2007;30(9):1145–52. 14. Kaw R, Michota F, Jaffer A, et al. Unrecognized sleep apnea in the surgical patient: implications for the perioperative setting. Chest 2006;129:198–205. 15. National Sleep Foundation. Sleep in America poll. Washington, DC: National Sleep Foundation; 2002. 16. Flegal KM, Carroll MD, Kuczmarski RJ, et al. Overweight and obesity in the United States: prevalence and trends, 1960–1994. Int J Obes 1998;22:39–47. 17. Tasali E, Leproult R. Ehrmann DA, et al. Slow-wave sleep and the risk of type 2 diabetes in humans. PNAS early edition 2008:1–6. Available at: www.pnas.org/ cgi/doi/10.1073/pnas.0706446105. Accessed February 24, 2008. 18. Schmid SM, Hallschmid M, Jauch-Chara K, et al. Sleep loss alters basal metabolic hormone secretion and modulates the dynamic counterregulatory response to hypoglycemia. J Clin Endocrinol Metab 2007;92:3044–51. 19. Van Moffaert MM. Sleep disorders and depression: the ‘chicken and egg’ situation. J Psychosom Res 1994;38(Suppl 1):9–13. 20. Franzen PL, Siegle GJ, Buysse DJ. Relationships between affect, vigilance, and sleepiness following sleep deprivation. J Sleep Res 2008;17:34–41. 21. Killgore WDS, Killgore DB, Day LM, et al. The effects of 53 hours of sleep deprivation on moral judgment. Sleep 2007;30(3):345–52. 22. Ozminkowski RJ, Wang S, Walsh JK. The direct and indirect costs of untreated insomnia in adults in the United States. Sleep 2007;30(3):263–73. 23. Hillman DR, Murphy AS, Antic R, et al. The economic cost of sleep disorders. Sleep 2006;29(3):299–305. 24. Sigurdson K, Ayas NT. The public health and safety consequences of sleep disorders. Can J Physiol Pharmacol 2007;85:179–83. 25. Edinger JD, Means MK. Overview of insomnia: definitions, epidemiology, differential diagnosis and assessment. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine. 4th edition. Philadelphia: Elsevier Saunders; 2005. p. 702–13. 26. Taylor DJ, Mallory LJ, Lichstein KL, et al. Comorbidity of chronic insomnia with medical problems. Sleep 2007;30(2):213–8. 27. Wilson JF. In the clinic. Insomnia. Ann Intern Med 2008;148(1):ITC13-1–16. 28. Sateia MJ, Doghramji K, Hauri PJ, et al. Evaluation of chronic insomnia. Sleep 2000;23(2):1–66. 29. Morin CM, Beaulieu-Bonneau S, LeBlanc M, et al. Self-help treatment for insomnia: a randomized controlled trial. Sleep 2005;28(10):1319–27. 30. Morin CM, Colecchi C, Stone J, et al. Behavioral and pharmacological therapies for late-life insomnia: a randomized controlled trial. JAMA 1999; 281(11):991–9.
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31. Jacobs GD, Pace-Schott EF, Strickgold R, et al. Cognitive behavior therapy and pharmacotherapy for insomnia: a randomized controlled trial and direct comparison. Arch Intern Med 2004;164:1888–96. 32. King AC, Oman RF, Brassington GS, et al. Moderate-intensity exercise and selfrated quality of sleep in older adults: A ramdomized controlled trial. JAMA 1997; 277(1):32–7. 33. Li F, Fisher KJ, Harmer P, et al. Tai chi and self-rated quality and daytime sleepiness in older adults: a randomized controlled trial. J Am Geriatr Soc 2004;52: 892–900. 34. Morin AK, Jarvis CI, Lynch AM. Therapeutic options for sleep-maintenance and sleep-onset insomnia. Pharmacotherapy 2007;27(1):89–110. 35. Davidson JR. Insomnia: therapeutic options for women. Sleep Med Clin 2008;3: 109–19. 36. Sack RL, Auckley D, Auger R, et al. Circadian rhythm sleep disorders: part I, basic principles, shift work and jet lag disorders. Sleep 2007;30(11):1460–83. 37. Reid KJ, Chang AM, Zee PC. Circadian rhythm sleep disorders. Med Clin North Am 2004;88:631–51. 38. Reid KJ, Zee PC. Circadian rhythm disorders. Semin Neurol 2004;24(3):315–25. 39. Banks S, Dinges DF. Behavioral and physiological consequences of sleep restriction. J Clin Sleep Med 2007;3(5):519–28. 40. Dozier J. Psychiatric and neurologic disorders that affect sleep. Respir Care Clin N Am 2006;12:71–80. 41. Parish JM, Somers VK. Obstructive sleep apnea and cardiovascular disease. Mayo Clin Proc 2004;79(8):1036–46. 42. Peterson MJ, Benca RM. Sleep in mood disorders. Psychiatr Clin North Am 2006; 29:1009–32. 43. Barczi SR, Juergens TM. Comorbidities: psychiatric, medical, medications and substances. Sleep Med Clin 2006;1:232–45. 44. Pagel JF. Medications and their effects on sleep. Prim Care 2005;32(2):491–509. 45. Zhang L, Samet J, Caffo B, et al. Cigarette smoking and nocturnal sleep architecture. Am J Epidemiol 2006;164:529–37. 46. National Sleep Foundation. Sleep in America poll. 2007. Available at: http://www. sleepfoundation.org/site/c.huIXKjM0IxF/b.2574229/k.14DA/2007_Sleep_in_America_ Poll.htm. Accessed March 15, 2008. 47. Shechter A, James FO, Boivin DB. Circadian rhythms and shift working women. Sleep Med Clin 2008;3:13–24. 48. Davis S, Mirick DK. Circadian disruption, shift work and the risk of cancer: a summary of the evidence and studies in Seattle. Cancer Causes Control 2006;17: 539–45. 49. Lipovcan K, Larsen Z, Zganec N. Quality of life, life satisfaction and happiness in shift- and non-shiftworkers. Rev Saude Publica 2004;38(Suppl):3–10. 50. Shaver LF. Sleep disturbed by chronic pain in fibromyalgia, irritable bowel and chronic pelvic pain syndromes. Sleep 2008;3:47–60.
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Stress a nd Health Michele M. Larzelere, PhDa,*, Glenn N. Jones, PhDb KEYWORDS Stress Stress reduction Meditation
Stress is any situation in which environmental or perceived demands force significant psychologic or biological change upon an organism, to preserve homeostasis or ensure survival. Stress results from physical or psychosocial disequilibrium. Stress responses are those behavioral, psychologic, or physiologic efforts to compensate for situational demands. Stress responses sometimes lead to increased disease risk. It often can be useful to conceptualize an individual’s reaction to stress in accordance with the general adaptation syndrome, as proposed by Selye.1 Upon being presented with a physical or emotional stressor, the individual recognizes (alarm reaction) and initially mounts a strong physiologic (or psychologic or behavioral) reaction to the stressor (stage of resistance) until such time as the challenge is met, the stressor has passed, or the organism’s ability to mount the response is depleted (stage of exhaustion). This model is understood easily by patients and allows one to draw explicit attention to the physiologic and psychologic costs of fighting a stressor. This paradigm easily adapts to situations in which multiple stressors, chronic stressors, or personal or environmental factors decrease an individual’s coping abilities. Stress can be categorized in several ways, including by duration (acute/chronic), domain (physical/psychologic), and severity (traumaticy/daily hassles). Although physical strain often is documented and quantified, psychologic stress can be more difficult to define. Psychologic models of stress rely on the concept of perceived stress (eg, events or situations are only stressful to the degree that the individual defines them as straining his or her ability to cope). The appraisal of the situation as threatening brings about the physiologic and behavioral changes defined
a
Department of Family Medicine, Louisiana State University Health Sciences Center–New Orleans, 200 West Esplanade Avenue, Suite 412, Kenner, LA 70065, USA b Department of Family Medicine, Louisiana State University Health Sciences Center, Earl K. Long Medical Center, 5825 Airline Highway, Baton Rouge, LA 70805, USA * Corresponding author. Department of Family Medicine, Louisiana State University Health Sciences Center–New Orleans, 200 West Esplanade Avenue, Suite 412, Kenner, LA 70065. E-mail address:
[email protected] (M.M. Larzelere). y A full description of the nature and treatment of post-traumatic stress disorder (PTSD) is beyond the scope of this article, so the remainder of this discussion will be devoted to the health implications and coping challenges inherent to stress of a nontraumatic nature. Readers interested in a comprehensive treatment of PTSD are referred to Handbook of PTSD: Science and Practice, edited by MJ Friedman, TM Keane, and PA Resick. New York: Guilford; 2007. Prim Care Clin Office Pract 35 (2008) 839–856 doi:10.1016/j.pop.2008.07.011 primarycare.theclinics.com 0095-4543/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.
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as the stress response. The controllability of a stressor also significantly impacts its potential for long-term psychologic detriment. Stress-causing situations do not necessarily have to be negative. Selye1 chose the term adaptation, noting that both pleasant and unpleasant events can evoke the stress response. Similarly, Holmes and Rahe2 focused on change as a stress in their pioneering studies. Their Social Readjustment Rating Scale asks about several life changes, some of which might be pleasant (vacation) or positive (promotion). Across this variety of stressor types, research has documented the possibility of resultant negative emotional and physical impacts. THE IMPACT OF STRESS ON PHYSICAL FUNCTIONING
The fight-or-flight response to acute stress causes rapid changes in the nervous, cardiovascular, immune, and endocrine systems. Cortisol and catecholamines are produced to increase energy availability. Heart rate and stroke volume are increased. The immune system is activated to prepare for the possibility of injury. Less vital activities (eg, feeding, growth, reproduction) are suspended during the crisis. Many of these changes have physiologic costs that are minimized by a rapid return to homeostatic baseline following the cessation of the stressor. Acute stressors in healthy adults are unlikely to have negative impacts on health. Stressful situations often persist beyond the time period when these physiologic coping strategies are adaptive, however. Further, psychologic factors lead some individuals to turn acute stressors into chronic stressors because of their meanings or implications. In addition, physiologic response magnitude differs between individuals because of genetic influences and previous stress exposures, which cause some individuals to produce a sustained hyper-response to stress. Stress and the Endocrine System
The corticotropin-releasing factor system is the integrator of the brain’s (central nervous system [CNS]) response to stress and negative emotion. Under conditions of stress, cells of the hypothalamus control the secretion of corticotropin releasing hormone (CRH), which stimulates release of ACTH (adrenocorticotropic hormone). ACTH activity leads to the secretion of glucocorticoid hormones (cortisol) from the adrenal cortex. This constitutes the hypothalamic-pituitary-adrenal (HPA) axis. Glucocorticoids provide inhibitory feedback on the HPA that helps to limit the duration of the stress response. The sympathetic adrenal medullary (SAM) axis often acts in parallel with the HPA axis. CRH stimulation of sympathetic nervous system activity also leads to the release of epinephrine and noradrenaline. The interactions of adrenal system components under conditions of stress are nonlinear.3 Some of the stress-/cortisol-related changes include suppression of gonadotropin-releasing hormone and inhibition of thyroid-stimulating hormone (TSH) release. Although acute stress may increase plasma concentrations of growth hormone (GH), chronic activation of the HPA axis inhibits growth through suppression of GH secretion and inhibition of the action of GH on target tissues. Chronic glucocorticoid elevations may cause individuals to experience catabolic effects (visceral adiposity, decreased lean body mass) and increased insulin resistance. This can lead to increased difficulties achieving glycemic control in diabetic patients under stress. Cortisol also plays a role in memory formation by means of its role on the amygdala and hippocampus. Elevated cortisol levels, during conditions of stress, may aid the formation of emotionally valenced long-term memories, promoting enhanced response to similar future stressors. This sensitization of the amygdale to further
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stressors (ie, cortisol-increased stress reactivity)4 would be adaptive in allowing individuals previously exposed to stressful environments to react more quickly when faced with additional threat. Interestingly, increased cortisol levels may interfere with working memory and information processing, which suggests that individuals with decreased cortisol response to stress may evidence improved cognitive performance under trying conditions.5 Stress and the Gastrointestinal System
The activities of the brain and gut are highly inter-related, which accounts for the high prevalence of gastrointestinal (GI) symptoms reported by patients in response to stress.6 Digestive function can be influenced by psychologic state, and GI difficulty can impact mood, behavior, and pain responsiveness. These interrelationships are thought to be mediated by neural, immune, and endocrine mechanisms directed by the autonomic nervous system (ANS) and HPA axis. The limbic system, which is the seat of emotionality, also helps to control gut function, and is thought to modulate both visceral pain and perception. The hypothalamus controls the release of CRH, which, when released during stress, increases transit through the large bowel and delays gastric emptying. As noted previously, exposure to high levels of cortisol are believed to promote hyper-reactivity to subsequent psychologically stressful conditions. These factors may help to explain the frequently noted observation that irritable bowel syndrome (IBS) is associated with historical psychosocial stressors. The initial studies suggesting this linkage are bolstered by reports showing increased colonic motility in response to CRH by IBS patients when compared with individuals without IBS; suggesting hyper-responsivity to CRH in affected populations.7 Increased cytokine production, also a result of stress, can produce similar physiologic effects (delayed stomach emptying and increased colonic motility).8 Untreated psychologic symptoms increase GI distress in patients who have IBS, and both low-dose tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) have been shown to be useful in some patients who have these disorders. Peptic ulcers provide another interesting domain in which to examine the impact of stress on GI functioning. The discovery of Helicobacter pylori downgraded the longtheorized causal link between life stress and ulcers to a clear infectious cause with possible stress-related exacerbations. However, the presence of ulcers in H pylorinegative patients, and the high rate of infected patients who do not develop ulcers, argues for a more nuanced view of ulcer etiology. It has been estimated that high levels of life stress confer an age-adjusted odds ratio of 2.8% of developing an ulcer.9 Additional data suggest that up to 40% of the excess ulcer risk attributed to stress is mediated by stress-fueled negative health behaviors (tobacco use, skipping meals, alcohol (ETOH) use, poor sleep patterns). Stress also promotes physiologic alterations that may encourage ulcer development: increased acid secretion, decreased duodenal motility, hyperpepsinogenemia, and impaired mucosal defenses. Therefore, it has been suggested that the alteration in the duodenal acid load secondary to stressrelated (and behavior-related) changes may promote H pylori colonization, duodenitis, and ulcers. Psychologic stress has been highlighted as a possible risk factor for exacerbations in ulcerative colitis,10 although the research base supporting such a link is limited by confounds. Pathophysiologic mechanisms for stress-related exacerbations include the possibility of altered local intestinal and systemic immune activity and increased gut permeability. Additional routes of stress impact include a possible decrement in
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prophylactic medication adherence and other self-care behaviors by patients experiencing stress.11 Stress and the Immune System
Researchers have examined a range of stressors from acute, high-intensity events to chronic, moderate-level challenges, and found a consistent pattern of immune alterations. The acute stress response is adaptive in producing leukocytosis; however, longerterm stress can produce dysregulation of proinflammatory cytokines.12 Changes associated with this dysregulation suppress immunity and lead to deficits in wound healing,13 decreased antibody response to vaccination,14 reactivation of latent viruses,15 greater vulnerability to viral infections,16 and impaired functional immune responding in women at risk for cervical cancer.17 Increased life stress also has been associated with faster HIV to AIDS progression.18 Stress and the Cardiovascular System
Acute stress, with its catecholamine release, has numerous, well-known effects on the cardiovascular system, including increased heart rate, cardiac output, and peripheral vascular constriction, leading to a short-term increase in blood pressure. Chronic stress is thought to contribute to hypertension through persistent activation of the sympathetic nervous system and HPA axis.19 Further, the stress response can impact the risks for cardiovascular disease through several mechanisms. It has been suggested that, under conditions of prolonged stress, down-regulation in cortisol receptors can lead to deficits in proinflammatory cytokine regulation.20 Proinflammatory cytokines then would remain elevated, promoting C-reactive protein production, and helping to account for observed worsening of pathophysiology and symptomatology during extended periods of stress in individuals who have coronary artery disease (CAD) or autoimmune diseases such as multiple sclerosis or rheumatoid arthritis.21,22 Animal models suggest that stressful social environments can enhance atherosclerotic processes, and socially affiliative (social support) conditions can reduce atherogenesis.23,24 Brief mental stress can cause transient endothelial dysfunction in healthy individuals.25,26 In animal models, psychologic stress produces actual endothelial injury.27–29 Endothelial dysfunction and damage are potential steps toward atherosclerosis. Mental stress and its sympathetic activation can lead to platelet activation and deposition.30 Psychologic stress modifies macrophage activity,31 and emotional arousal keeps plasma lipid levels elevated.32 Chronic cardiovascular stimulation also can lead to vascular hypertrophy and chronically elevated blood pressure. These changes, if sustained, can produce left ventricular hypertrophy and increased plaque formation.33 Each of these is a potential mechanism through which stress may play a role in atherosclerosis development. The linkage between psychosocial factors such as stress and CAD has drawn significant attention. In the INTERHEART study,34 a composite measure of psychosocial stress was a strong predictor of myocardial infarction (MI), comparable to risk factors such as smoking and hypertension. Chronically stressful situations (such as work stress, marital stress, caregiver strain, low social support, low socioeconomic status) have been linked to increased risk of CAD and adverse cardiac events.35,36 There is also evidence that emotional stressors can act as triggers for acute cardiovascular events.37 Some of the best evidence for stress as a cardiovascular event trigger comes from studies using a case-crossover design (eg, Determinants of Myocardial Infarction Onset Study [ONSET]38 and Stockholm Heart Epidemiology Programme [SHEEP]),39,40 in which patients are matched to themselves to derive a hazard and control period. The ONSET study found elevated risk associated with
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anger and anxiety. Both studies also documented elevations in risk of acute coronary events associated with occupational stress in the form of high-pressure deadlines. In addition, the ONSET study found that the stress of having to fire an employee was associated with increased risk of MI. Stress and Psychiatric Health
Stress has long been thought to precipitate mental illness, especially in vulnerable individuals (eg, stress–diathesis model).41 Stress also has been associated with increased psychiatric morbidity and relapse risk in numerous psychiatric disorders.42 Stress activates the HPA axis and increases firing in the locus coeruleus, thereby dysregulating the noradrenergic system, which is thought to be a major cause of increased psychopathology.43 Chronic stress is thought to lead to hippocampal damage (decreased volume, dendritic atrophy in pyramidal neurons, decreased neuron generation) because of overstimulation of glucocorticoid receptors. The damage, which can impair memory and other cognitive capacities, may be enhanced by the increase in proinflammatory cytokines, nitric oxide, and prostaglandins also because of CRH activity. It has been proposed that antidepressant action may be primarily a function of returning the noradrenergic system to appropriate functioning (by limiting locus coeruleus activity) and by reducing the neurodegenerative changes in the noradrenergic system caused by glucocorticoids.44 The linkage of HPA axis functioning to mental state is bolstered by evidence that higher baseline cortisol values have been associated with anxiety, social impairment, psychotic depression, and psychosis in patients who have post-traumatic stress disorder (PTSD).45 Cytokines released during stress can produce behaviors that are adaptive during illness, such as decreased activity, increased sleep, and decreased interest in activities. It has not escaped notice that many of these symptoms of illness are similar to those witnessed in depression. There is currently much speculation that prolonged proinflammatory cytokine production may produce depression, and several studies have noted a correlation between depressive symptomatology and markers of inflammation (eg, C-reactive protein).46,47 It also has been observed that depression can be an adverse effect of proinflammatory cytokines (eg, interferon) given in the course of treatment for other illnesses.48 Social stress also has been implicated in alterations of the serotonergic system. It has been proposed that chronic stress, especially in early life, results in reduced serotonergic system functioning, which negatively impacts mood and behavior.49–51 Because serotonin plays an important role in both CNS and GI functioning, disruption of the serotonergic system by stress history may help to explain the frequent suggestion of a link between a history of abuse and IBS symptoms. IMPACT OF STRESS ON HEALTH BEHAVIORS
In addition to direct physiologic effects of stress, stress impacts health through changes in health behaviors (substance use, eating, sleep, exercise) that can both mitigate and enhance stress’ physiologic impacts. There is considerable evidence that individuals use health-impacting behaviors in an attempt to self-regulate mood (blunt negative mood, produce positive mood), and may use some typically inhibited behaviors to escape paying attention to stressors or problems.52 Stress is thought to impact diet in many ways. In general, it has been shown that stress often leads to increased food intake, and greater consumption of high-fat, high-salt, and high-sugar foods. Stress also may decrease motivation to adhere to prescribed diets that are felt to be overly restrictive. Exercise has been long investigated as a possible aid to stress
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coping. Research, however, has shown that stress often decreases the frequency of exercise.53 It has been established that stress increases the frequency and amount of substance use (ETOH, nicotine, illicit/illegal drugs) and is a predictor of relapse following cessation.53,54 Stress also has been implicated in promotion of sexual risk behaviors (although the relationship may be mediated by substance use) and decreasing adherence to medical regimens.55,56 Given the importance of these modifiable risk factors in health promotion and maintenance, methods of reliably reducing stress are vital. SCREENING FOR STRESS
Primary care physicians play a critical role in identifying the psychologic and health impacts stress may have upon patients. Several measures of stress exist. Questions about psychosocial stress, however, can be incorporated into the medical history/review of systems by screening in three areas: 1. Chronic stressors (‘‘How are things at home? At work? Has anything been troubling you lately?’’) 2. Coping strategies (‘‘When you are stressed, what do you do to cope? What do you do for fun?’’) 3. Social supports (‘‘Who can you turn to in times of stress? Do you feel like you have the help you need to cope?’’) Given the prevalence of daily hassles and life stage changes, and the possibility of traumatic stressors, it may be prudent to screen for stress regularly. After a patient is well-known, physicians should be alert to increases in day-to-day stresses, new chronic stressors, and major life events. Identifying psychosocial stress and psychologic distress as part of a primary care visit does have its challenges. Many symptoms (eg, palpitations) can be indicators of both medical and psychologic problems. When a physician has identified symptoms that appear to be stress-linked, it may be helpful to ask the patient to record his or her physical status and psychologic status (1 to 10 basis; 1 5 calm and relaxed; 10- 5 extreme stress) on a daily basis for several weeks. Physical status can be recorded either by functional ability (1 5 no impairment; 10 5 unable to participate in activities) or whatever physical symptom is most troubling to the patient (eg, 1 5 normal bowel functioning; 10 5 hourly diarrhea). Charting these processes together may provide chronologic clues to stress-related exacerbations of physical symptoms, or, conversely, to the psychologic impact of coping with illness exacerbations. For patients who have difficulty identifying the role stress may play in their illness, a modified stress biopsy57 may be useful. In a stress biopsy, patients are asked to close their eyes and think about a stressful situation (eg, deadline at work, aggravation by spouse, worry about the health of a parent or child) that frequently occurs in their lives. Then, they are asked to describe the physical sensations that would be prominent in this situation (eg, shortness of breath, heart palpitations, muscle tension, headache, urge to defecate). This opens a discussion of the patient’s stereotypic pattern of autonomic response to stress and easily lends itself to instructing the patient to monitor both psychologic and physical functioning to note their interrelationship. Such monitoring also can be expanded to track the impact of medical or psychosocial interventions that are attempted. MANAGEMENT OF STRESS
There is a growing recognition that developing skills to manage stress can be beneficial to patients. Many interventions for stress exist, each with varying levels of
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empirical support. Indeed, most stress management programs include a variety of components, many of which can be adapted to office practice. Physicians also should strive to develop a referral network of specialists in stress-related conditions. This network is likely to include mental health practitioners, but the possible role of massage therapists and community resources, such as meditation, yoga, and relaxation classes should not be overlooked. Follow-up is very important, as many patients never take advantage of the referral or initially may discount the physician’s investment in stress management as a health-related goal. For patients who seem to have difficulty with lifestyle balance, having a physician provide them with explicit permission to take time for relaxation or self-care can be very important. Patients (and professionals) can benefit from regularly re-evaluating the time they spend engaged in activities versus the value they ascribe to these activities, and re-adjusting their efforts accordingly. One mnemonic that can often serve as a starting point for exploring the domains in which individuals invest their time is the PRAISES model (Table 1). Although patients should be assured that balance may be sacrificed over the short term because of pressing needs, discussing a patient’s long-term efforts to balance life across these areas often can illuminate changes that would be beneficial in managing his or her stress. Pharmacotherapy for Stress
In the aftermath of significant stressors, anxiolytics and hypnotics frequently are prescribed in an understandable, humanitarian effort to do something for a patient in distress, especially one struggling with hyperarousal. The use of benzodiazepines, especially, can often set up a false benchmark for the effectiveness of other medications in decreasing the physiologic stress response, however. Their potential for psychologic and physical addiction is known, and their use decreases motivation to learn other adaptive means to cope with chronic stress. In addition, prolonged use of benzodiazepines after a traumatic stressor may predispose patients to ongoing stress syndromes.58 A robust literature attests to the utility of selective serotonin reuptake inhibitors (SSRIs) for treating PTSD.59 There is no scientific consensus supporting the utility of SSRIs in stress conditions that do not meet PTSD diagnostic criteria, however. Several preliminary investigations suggest that both short- and longer-term antidepressant administration may decrease sympathetic nervous system (SNS) reactivity in healthy
Table 1 PRAISES model of lifestyle balance Domain
Content
Physical
Time spent meeting basic physical needs and self care/health care activities
Recreational
Time spent in the pursuit of fun or relaxation
Artistic
Time engaging in creative pursuits, or enjoying the creativity of others (eg, listening to music, drawing, going to movies/plays)
Intellectual
Time spent expanding or engaging the mind by means of direct or indirect learning activities
Spiritual
Efforts made to connect with anything larger than the individual or family (eg, religion, community)
Employment
Time devoted to the pursuit of financial goals
Social
Time spent with important others (eg, parenting)
(Data from D Glaser, personal communication, July 1997.)
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subjects, which might hint toward benefit in counteracting the effects of stress.60,61 The cost–benefit analysis (especially in the areas of weight gain and sexual dysfunction) of using the SSRIs becomes more problematic when they are used to treat conditions of decreased severity, however. There is some biologic plausibility to the suggestion that medications that decrease locus coeruleus firing rate (eg, beta antagonists, alpha-2 adrenergic antagonists, alpha-1 agonists) may aid in resilience to stress and possibly decrease risk for the development of a mood or anxiety disorder.62,63 Few investigations, however, have addressed this question. Determining which patients would benefit, which pharmacologic agents would be most helpful, and at what point in the stress response administration would be indicated, are areas worthy of research. Physical Activity
Exercise often is recommended as part of a stress management intervention. It has been shown to decrease stress hormones64 and to decrease stress reactivity.65 Exercise has received support as a primary or adjunctive treatment for several psychiatric disorders,66 and improves stress and quality-of-life ratings.66,67 A written exercise prescription, adapted to the patient’s fitness level and level of motivation, is an excellent initial approach to managing psychologic distress. Physicians should be active in assisting patients to set concrete and attainable goals that promote regular movement, without initial focus on changing cardiovascular fitness. Being active (eg, walking) for 15 to 20 minutes three or more times a week is a reasonable place to start. Exercise duration of at least 20 minutes may provide stress reduction after only one session in situationally stressed individuals.68,69 Those patients who have stable tendencies toward increased anxiety may take a longer duration of exercise training (10 or more weeks) to achieve improvement. Relaxation Training
Effective approaches to relaxation training include progressive muscle relaxation, autogenic training, guided imagery, and diaphragmatic breathing. Relaxation training alone is effective for treating certain anxiety disorders70 and beneficial for insomnia.71 Relaxation training techniques often are incorporated into more general stress management programs that borrow from time management and cognitive–behavioral approaches. There is preliminary evidence that general stress management improves immune functioning among individuals who have HIV.72 Similarly, a stress reduction program reduced coronary events among cardiac patients.73,74 Stress management workbooks and recorded relaxation sessions are widely available, and their use can be prescribed for suitable patients. Intensity might be stepped up by referring the patient to a therapist skilled in these approaches. Cognitive–Behavioral Therapy
Cognitive–behavioral therapy (CBT) is based upon the hypothesis that thoughts drive emotions and behavior and that by changing unrealistic or irrational cognitions, behavior and emotion can be altered in positive ways. As previously noted, the psychologic component of the stress response depends on appraisals of the nature and impact of subjective and environmental events (threatening/benign, important/irrelevant). The link between negative thoughts and physiologic arousal long has been established. The goal of CBT is to change the negative/distorted cognitions that might fuel a patient’s stress, negative mood states, and maladaptive illness behaviors. The cognitive distortions most frequently associated with increased stress are listed in Table 2. CBT techniques have been found to be helpful for stress reduction and are useful in treating
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Table 2 Cognitive distortions often related to stress Cognitive Distortion
Stress Results Because
Ways to Counter this Thinking Pattern
All-or-nothing thinking
Person demands perfection or the effort is not acceptable
Focus on effort instead of outcome
Overgeneralization
Every negative event/occurrence predicts other negative similar events
Focus on counterexamples to the statement
Dwelling on negatives
Person disqualifies the positive attributes of any situation or event
Focus on positive elements within the situation
Catastrophizing
Person exaggerates the importance of minor negative events
Realistic reappraisal of the event’s long-term impact
More information can be found in Feeling Good by Burns.106
the psychologic distress associated with change in functional status or acute or longterm medical illness.75 Health status and quality of life in various medical conditions have been improved through the use of cognitive–behavioral interventions, most prominently those conditions with a substantial component of psychologic/stress overlay.76,77 For those patients willing to follow through with a therapy referral, cognitive–behavioral therapists are widely available. Many of the concepts of CBT, however, can be incorporated into the primary care setting. Patients often have unrealistic expectations (both positive and negative) about the progression of their condition and their functional abilities, which can be corrected through information provision and challenging their beliefs. Physicians also can help patients to set realistic positive health goals that might support stress management (eg, increasing physical activity, scheduling a pleasant activity). Finally, for those self-motivated patients without literacy limitations, a prescription to purchase a cognitive–behaviorally oriented self-help book can be efficient and cost-effective.
Social Support
It has been fairly well documented78 that social support is associated with both physical health benefit (decreased all-cause mortality) and mental health benefit. Social support is likely to promote a sense of stability and self worth, but more importantly, an individual’s social support network may act in ways that ameliorate the impact of stressors (eg, expressions of support, helpful advice, financial aid).79 The consistent positive association between social support and health has garnered interest in the health benefits of enhancing social support in patients (typically those who have serious illnesses). Hundreds of psychosocial support interventions have been attempted. Professional support
For those patients without an adequate naturally occurring support network, nurse interventions and educational contacts may provide similar, although reduced benefits. Increased contacts with professional supporters can reduce distress, improve disease coping, increase sense of control, and enhance adherence.80,81
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Peer group support
Matching patients to similar peers for purposes of support has received conflicting support in the literature.82–84 Peer support groups for various conditions improve psychologic well-being when established to provide frequent contacts, under conditions designed to foster equitable exchange of social support, and when emphasis is placed on friendship formation.80 In addition to health-related educational topics, useful components to include in a peer group setting may be discussions of disease-related coping strategies, problem-solving skills, stress management, and methods of enhancing support among patients’ natural support networks. Support from existing network members
Intervening to enhance individuals’ abilities to acquire support from their existing networks, involve a member of the support network in treatment, or improve the support provided by significant network members can provide positive psychosocial and health behavior change benefits.85 Physicians can encourage social support mobilization in their continuity relationships by exploring patients’ connections to others. Physicians should be mindful that negative aspects of relationships can harm well-being, so discussion of relationship quality should precede encouragement to increase contact with social supports. Additionally, physicians can encourage contacts with professional supports or positive supports of decreased connection if the patient’s primary relationships are strained. Social ties can cause a negative influence if one is integrated into a peer group with risky health behaviors (eg, smoking, substance abuse). Therefore, the existence of strong social ties cannot be assumed to be health protective. Recommendations to increase social support can be tailored to the patient’s interests (eg, political activism, joining a church) and hobbies, and can be combined with other stress management components (eg, recommending joining a neighborhood walking group). Positive Emotional Experience
Given the evidence that negative mood states compromise health, there has been interest in examining the possible buffering effect of positive emotions. Positive emotional style has been associated with resistance to illness, decreased symptom expression, and decreased symptom complaints during experimental exposure.86 Several other measures of physical health (eg, hospital readmission rates in cardiac patients, injury proneness, stroke rate in elderly individuals) and markers of perceived health (eg, pain and symptom reporting) also have been demonstrated to be inversely associated with positive emotional experience. Although conclusive intervention studies are lacking, preliminary associative studies suggest that enhancing positive mood (in addition to decreasing negative mood states, which are somewhat independent) may be beneficial for health.52,86 Possible means of achieving mood–state enhancement include encouraging patients to engage in regularly scheduled pleasant events, activities that provide success experiences, and prosocial activities (eg, volunteer work). Physicians also should refrain from challenging positive illusions that might support patients’ optimism (eg, enhanced self-perceptions, mildly exaggerated perceptions of self-control) that have been linked to increased display of health-positive behaviors and improved social relationships.87 Mindfulness Meditation
Mindfulness meditation as an adjunctive treatment for health conditions has generated significant interest because of its cost-effectiveness and applicability to a range of conditions. Meditation strategies have been demonstrated to be helpful for several
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psychiatric disorders in initial investigations.88–91 The interest in meditation as an adjunctive treatment for medical illness largely was spurred by the research and writings of Jon Kabat-Zinn, who has championed the cause of mindfulness meditation in clinical and hospital settings. Mindfulness is the quality of being acutely aware of the current moment without burdening that experience with judgments about, or emotional reactions to, the situation (which would render it positive or negative). Mindfulness was considered to be an ideal way to counteract the tendency of some patients to engage in negative mental rumination about physical or emotional states, and to improve the ability of patients to cope with the stress inherent in managing chronic disease. The practice of mindfulness meditation is thought to teach patients to view their thoughts and feelings with greater perspective (eg, thoughts are just mental events, thoughts may not be accurate). Although both Vipassana meditation and Zen Buddhist meditation include the concept of mindfulness, the Mindfulness Based Stress Reduction (MBSR) intervention developed by Kabat-Zinn is used most frequently in research because of its manualized techniques and disconnection from the spiritual/religious components inherent in some meditation practices. MBSR incorporates traditional meditation practices (sitting meditation, nonjudgment of thoughts, and body scan), with the teaching of more general stress management/coping skills, assertiveness strategies, diaphragmatic breathing, and Hatha yoga. MBSR typically is taught in an 8-week program of 2.5-hour weekly sessions, with one all-day retreat during the sixth week of training. Training encourages participants to develop seven core mindfulness attitudes: 1. 2. 3. 4. 5. 6. 7.
Nonjudgment of their daily experiences Patience Beginner’s mind (the ability to view things as if for the first time) Trust in self Nonstriving (releasing of goals other than the meditative practice) Acceptance of the status quo Noncensoring of one’s thoughts
Participants are taught to engage in a systematic focus on successive body parts (body scan) to observe bodily sensations. Hatha yoga postures also are taught in an attempt to enhance participants’ ability to increase awareness during movement. Participants are asked to practice mindfulness skills for 30 to 45 minutes per day (initially focused on performing body scan) during training. Mindfulness meditation has developed a research literature suggestive of significant benefit for enhancing coping with distress and improving indices of mental health and quality of life.92 Further, mindfulness meditation also may be beneficial in various chronic illnesses and conditions.92 Randomized wait list-controlled designs to examine the efficacy of MBSR have supported psychologic benefit in conditions including fibromyalgia,93,94 pregnancy,95 and cancer.96 Pilot studies without the benefit of control also suggest a benefit of MBSR on varied parameters including subjective health status,97 immune parameters of stress in patients who have cancer,98 and glycemic control in patients who have diabetes.99 The practice requirements required to master mindfulness techniques may be a barrier for some patients, and the need for long-term maintenance of mindfulness practice for sustained benefit has not yet been demonstrated empirically. The extant research, however, does support mindfulness as a promising adjunctive intervention to promote stress management and illness coping in distressed patients. For those patients without access to a center offering MBSR training, several books and CDs
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designed to teach the technique are also available.100 The benefits of individual mindfulness-based meditation practice, however, have not been investigated.
Emotional Expression
Emotional disclosure through writing about a trauma or stressful situation has received much empiric attention since Pennabaker and Beall101 first obtained a significant reduction in illness-related physician visits among college students asked to write about the facts and emotions surrounding a recent trauma. Writing expressively about traumas and stressful situations generally has been found to have a beneficial but small effect on distress, subjective well-being, anxiety, anger, and depression.102 The effects tend to be most pronounced on indices of emotional functioning (eg, reducing depression) and immune parameters (eg, viral load, liver function). Interestingly, perceived stress and stress-related parameters are not very amenable to reduction through expressive writing. Taken together, these findings suggest that expressive writing may not reduce stress, but rather, the impact of stress.102,103 The situation may still be seen as stressful, but the person may be able to handle the stress in a more productive, healthy way. Expressive writing has much appeal as an office-based intervention. It is inexpensive, readily available, and the parameters appear fairly straightforward. Typically, a person is instructed to write expressively about an upsetting topic, including both the facts and their emotional reactions. Optimum instructions and conditions remain under investigation, but some guidelines can be taken from a recent meta-analysis.102 More seems better; three or more writing sessions of at least 15 minutes appeared to be most useful. The comfort of the patient appears to improve the effectiveness, as participants did better when they wrote at home, in private settings, and the writings were not turned in to investigators. Instructions to write about more recent traumas or stressful events, and about previously undisclosed events also were associated with more benefit. The patient does not need to let anyone read the product, although if he or she wants to disclose to a trusted, appropriate person, that also might be beneficial.
Brief Interpersonal Counseling
Brief interpersonal counseling has a long, although largely informal, tradition of use for stress management in primary care settings. Most successful practitioners have developed strategies to allow patients to discuss psychosocial stressors that may be impacting their health status.104 A structured version of interpersonal counseling was tested in primary care settings. A series of up to six half-hour sessions were provided to patients who had elevated numbers of functional complaints (presumed to be stress-related). Patients were given the opportunity to discuss recent changes and psychosocial life stressors and were supported in their use of coping strategies to meet these stressors. This pilot study found both psychologic and physical benefits of the protocol.105 The widely familiar BATHE (Background, Affect, Trouble, Handling, Empathy) technique,104 combined with an active focus on problem solving strategies, interpersonal connections, and frequent supportive visits during stressful times would seem to offer an efficient way to incorporate most of the components of this intervention during shorter clinic visits. Interestingly, the tested intervention employed nurse practitioners to deliver the intervention, suggesting that support staff also can play a useful role in assisting patients with stress management needs.
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FURTHER READINGS Cognitive–behavioral therapy
Greenberger D, Padesky C. Mind over mood: change the way you feel by changing the way you think. New York: Guilford; 1995. Finding a qualified cognitive–behavioral therapist
Association for Behavioral and Cognitive Therapies. Available at: www.ABCT.org. Academy of Cognitive Therapy. Available at: www.academyofCT.org. Mindfulness meditation
Kabat-Zinn J. Full catastrophe living: using the wisdom of your body and mind to face stress, pain, and illness. New York: Delta; 1990. Kabat-Zinn J. Mindfulness for beginners (Audio CD). Louisville (CO): Sounds True; 2006. Kabat-Zinn J. Guided mindfulness meditation (Audio CD). Louisville (CO): Sounds True; 2005. Jon Kabat-Zinn books for patients and audio CDs can also be obtained at: http:// www.mindfulnesstapes.com. Relaxation skills
Davis M, Eshelman ER, McKay M. The relaxation and stress reduction workbook. 5th edition. Oakland (CA): New Harbinger; 2000. Catalano EM, Hardin KN. Chronic pain control workbook. Oakland (CA): New Harbinger; 1996. Weil A. Breathing. (Audio CD). Louisville (CO): Sounds True; 2006. REFERENCES
1. Selye H. The stress of life. New York: McGraw-Hill; 1956. 2. Holmes TH, Rahe RH. The social readjustment rating scale. J Psychosom Res 1967;11(2):213–8. 3. McEwen BS. Central effects of stress hormones in health and disease: understanding the protective and damaging effects of stress and stress mediators. Eur J Pharmacol 2008;583(2–3):174–85. 4. Lovallo WR. Stress and the endocrine system. In: Stress and health: biological and psychological interactions. 2nd edition. Thousand Oaks (CA): Sage; 2005. p. 113–32. 5. Al’Absi M, Hugdahl K, Lovallo WR. Adrenocortical stress response and altered working memory performance. Psychophysiology 2002;20:155–60. 6. Sternbach RA. Pain and hassles in the United States: findings of the Nuprin pain report. Pain 1986;27(1):69–80. 7. Fukudo S, Nomura T, Hongo M. Impact of corticotropin-releasing hormone on gastrointestinal motility and adrenocorticotropic hormone in normal controls and patients with irritable bowel syndrome. Gut 1998;42(6):845–9. 8. Tache’ Y, Bonaz B. Corticotropin-releasing factor receptors and stress-related alterations of gut motor function. J Clin Invest 2007;117(1):33–40. 9. Levenstein S. The very model of a modern etiology: a biopsychosocial view of peptic ulcer. Psychosom Med 2000;62(2):176–85. 10. Bitton A, Sewitch MJ, Peppercon MA, et al. Psychosocial determinants of relapse in ulcerative colitis: a longitudinal study. Am J Gastroenterol 2003; 98(10):2203–8.
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11. Nigro G, Angelini G, Grosso S, et al. Psychiatric predictors of noncompliance in inflammatory bowel disease: psychiatry and compliance. J Clin Gastroenterol 2001;32(1):66–8. 12. Glaser R, MacCallum RC, Laskowski BF, et al. Evidence for a shift in the Th-1 to Th-2 cytokine response associated with chronic stress and aging. J Gerontol A Biol Sci Med Sci 2001;56(8):477–82. 13. Marucha PT, Kiecolt-Glaser JK, Favagehi M. Mucosal wound healing is impaired by examination stress. Psychosom Med 1998;60(3):362–5. 14. Glaser R, Kiecolt-Glaser JK, Bonneau RH, et al. Stress-induced modulation of the immune response to recombinant hepatitis B vaccine. Psychosom Med 1992;54(1):22–9. 15. Cacioppo JT, Kiecolt-Glaser JK, Malarkey WB, et al. Autonomic and glucocorticoid associations with the steady-state expression of latent Epstein-Barr virus. Horm Behav 2002;42(1):32–41. 16. Cohen S, Frank E, Doyle WJ, et al. Types of stressors that increase susceptibility to the common cold in healthy adults. Health Psychol 1998;17(3):214–23. 17. Fang CY, Miller SM, Bovbjerg DH, et al. Perceived stress is associated with impaired T-cell response to HPV16 in women with cervical dysplasia. Ann Behav Med 2008;35(1):87–96. 18. Leserman J. HIV disease progression: depression, stress, and possible mechanisms. Biol Psychiatry 2003;54(3):295–306. 19. McEwen BS. Protective and damaging effects of stress mediators: central role of the brain. Dialogues Clin Neurosci 2006;8(4):367–81. 20. Miller GE, Cohen S, Ritchey AK. Chronic psychological stress and the regulation of proinflammatory cytokines: a glucocorticoid-resistance model. Health Psychol 2002;21(6):531–41. 21. Miller GE, Blackwell E. Turning up the heat: inflammation as a mechanism linking chronic stress, depression, and heart disease. Curr Dir Psychol Sci 2006;15(6): 269–72. 22. Robles TF, Glaser R, Kiecolt-Glaser JK. Out of balance. A new look at chronic stress and immunity. Curr Dir Psychol Sci 2005;14(2):111–5. 23. Kaplan JR, Manuck SB, Clarkson TB, et al. Social status, environment, and atherosclerosis in cynomolgus monkeys. Arteriosclerosis 1982;2(5):359–68. 24. McCabe PM, Gonzales JA, Zaias J, et al. Social environment influences the progression of atherosclerosis in the Watanabe heritable hyperlipidemic rabbit. Circulation 2002;105(3):354–9. 25. Ghiadoni L, Donald AE, Cropley M, et al. Mental stress induces transient endothelial dysfunction in humans. Circulation 2000;102(20):2473–8. 26. Spieker LE, Hurlimann D, Ruschitzka F, et al. Mental stress induces prolonged endothelial dysfunction via endothelin-A receptors. Circulation 2002;105(24):2817–20. 27. Henry JP, Ely DL, Stephens PM, et al. The role of psychosocial factors in the development of arteriosclerosis in CBA mice. Observations on the heart, kidney, and aorta. Atherosclerosis 1971;14(2):203–18. 28. Strawn WB, Bondjers G, Kaplan JR, et al. Endothelial dysfunction in response to psychosocial stress in monkeys. Circ Res 1991;68(5):1270–9. 29. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993;362(6423):801–9. 30. Roux SP, Sakariassen KS, Turitto VT, et al. Effect of aspirin and epinephrine on experimentally induced thrombogenesis in dogs. A parallelism between in vivo and ex vivo thrombosis models. Arterioscler Thromb 1991;11(5):1182–91.
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31. Adams DO. Molecular biology of macrophage activation: a pathway whereby psychosocial factors can potentially affect health. Psychosom Med 1994; 56(4):316–27. 32. Dimsdale JE, Herd JA. Variability of plasma lipids in response to emotional arousal. Psychosom Med 1982;44(5):413–30. 33. Julius S. Corcoran Lecture. Sympathetic hyperactivity and coronary risk in hypertension. Hypertension 1993;21(6 Pt 2):886–93. 34. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case–control study. Lancet 2004;364(9438):937–52. 35. Blumenthal JA, Babyak MA, Moore KA, et al. Effects of exercise training on older patients with major depression. Arch Intern Med 1999;159(19):2349–56. 36. Rozanski A, Blumenthal JA, Davidson KW, et al. The epidemiology, pathophysiology, and management of psychosocial risk factors in cardiac practice: the emerging field of behavioral cardiology. J Am Coll Cardiol 2005;45(5):637–51. 37. Tofler GH, Muller JE. Triggering of acute cardiovascular disease and potential preventive strategies. Circulation 2006;114(17):1863–72. 38. Mittleman MA, Maclure M, Sherwood JB, et al. Triggering of acute myocardial infarction onset by episodes of anger. Circulation 1995;92(7):1720–5. 39. Moller J, Theorell T, de Faire U, et al. Work-related stressful life events and the risk of myocardial infarction. Case–control and case-crossover analyses within the Stockholm Heart Epidemiology Programme (SHEEP). J Epidemiol Community Health 2005;59(1):23–30. 40. Moller J, Hallquist J, Diderichsen F, et al. Do episodes of anger trigger myocardial infarction? A case-crossover analysis in the Stockholm Heart Epidemiology Programme (SHEEP). Psychosom Med 1999;61(6):842–9. 41. Goodyer IM, Herbert J, Tamplin A, et al. Recent life events, cortisol, dehydroepiandrosterone, and the onset of major depression in high-risk adolescents. Br J Psychiatry 2000;177:499–504. 42. Corcoran C, Gallitano A, Leitman D, et al. The neurobiology of the stress cascade and its potential relevance for schizophrenia. J Psychiatr Pract 2001; 7(1):3–14. 43. Morilak DA, Barrera G, Echevarria DJ, et al. Role of brain norepinephrine in the behavioral response to stress. Prog Neuropsychopharmacol Biol Psychiatry 2005;29(8):1214–24. 44. Leonard BE. Stress, norepinephrine and depression. Acta Neuropsychiatrica 2002;14:173–80. 45. Corcoran C, Walker E, Huot R, et al. The stress cascade and schizophrenia: etiology and onset. Schizophr Bull 2003;29(4):671–92. 46. Danner M, Kasl SV, Abramson JL, et al. Association between depression and elevated C-reactive protein. Psychosom Med 2003;65(3):347–56. 47. Fassbender K, Schmidt R, Mossner R, et al. Mood disorders and dysfunction of the hypothalamic-pituitary-adrenal axis in multiple sclerosis: associations with cerebral inflammation. Arch Neurol 1998;55(1):66–72. 48. Asnis GM, De La Garza R II. Interferon-induced depression in chronic hepatitis C: a review of its relevance, risk factors, biology, and treatment approaches. J Clin Gastroenterol 2006;40(4):322–35. 49. Higley JD, Suomi SJ, Linnoila M. A longitudinal assessment of CSF monoamine metabolite and plasma cortisol concentrations in young rhesus monkeys. Biol Psychiatry 1992;32(2):127–45.
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50. Arango V, Underwood MD, Mann JJ. Serotonin brain circuits involved in major depression and suicide. Prog Brain Res 2002;136:443–53. 51. Lopez JF, Chalmers DT, Little KY, et al. Regulation of serotonin 1A, glucocorticoid, and mineralocorticoid receptor in rat and human hippocampus: implications for the neurobiology of depression. Biol Psychiatry 1998;43: 547–73. 52. Salovey P, Rothman AJ, Detweiler JB, et al. Emotional states and physical health. Am Psychol 2000;55(1):110–21. 53. Steptoe A, Wardle J, Pollard TM, et al. Stress, social support, and health-related behavior: a study of smoking, alcohol consumption, and physical exercise. J Psychosom Res 1996;41(2):171–80. 54. Tate SR, Wu J, McQuaid JR, et al. Comorbidity of substance dependence and depression: role of life stress and self-efficacy in sustaining abstinence. Psychol Addict Behav 2008;22(1):47–57. 55. Molloy GJ, Perkins-Porras L, Strike PC, et al. Social networks and partner stress as predictors of adherence to medication, rehabilitation attendance, and quality of life following acute coronary syndrome. Health Psychol 2008;27(1):52–8. 56. O’ Cleirigh C, Ironson G, Smits JA. Does distress tolerance moderate the impact of major life events on psychosocial variables and behaviors important in the management of HIV? Behav Ther 2007;38(3):314–23. 57. Blackwell B, DeMorgan NP. The primary care of patients who have bodily concerns. Arch Fam Med 1996;5:457–63. 58. Gelpin E, Bonne O, Peri T, et al. Treatment of recent trauma survivors with benzodiazepines: a prospective study. J Clin Psychiatry 1996;57(9):390–4. 59. Stein DJ, Ipser JC, Seedat S. Pharmacotherapy for post-traumatic stress disorder (PTSD). Cochrane Database Syst Rev 2006;(1):CD002795. 60. Shores MM, Pascauly M, Lewis NL, et al. Short-term sertraline treatment suppresses sympathetic nervous system activity in healthy human subjects. Psychoneuroendocrinology 2001;26(4):433–9. 61. Veith RC, Lewis N, Linares OA, et al. Sympathetic nervous system activity in major depression. Arch Gen Psychiatry 1994;51:411–22. 62. Pittman R, Sanders KM, Zusman RM, et al. Pilot study of secondary prevention of post-traumatic stress disorder with propranolol. Biol Psychiatry 2002;51:189–92. 63. Schelling G, Briegel J, Roozendaal B, et al. The effect of stress doses of hydrocortisone during septic shock on post-traumatic stress disorder in survivors. Biol Psychiatry 2001;50:978–85. 64. Knox S, Theorell T, Malmberg BG, et al. Stress management in the treatment of essential hypertension in primary health care. Scand J Prim Health Care 1986; 4(3):175–81. 65. Georgiades A, Sherwood A, Gullette EC, et al. Effects of exercise and weight loss on mental stress-induced cardiovascular responses in individuals with high blood pressure. Hypertension 2000;36(2):171–6. 66. Barbour KA, Edenfield TM, Blumenthal JA. Exercise as a treatment for depression and other psychiatric disorders: a review. J Cardiopulm Rehabil Prev 2007; 27(6):359–67. 67. Atlantis E, Chow CM, Kirby A, et al. An effective evidence-based intervention for improving mental health and quality-of-life measures: a randomized–controlled trial. Prev Med 2004;39:424–34. 68. Hale BS, Raglin JS. State anxiety responses to acute resistance training and step aerobic exercise across eight weeks of training. J Sports Med Phys Fitness 2002;42(1):108–12.
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69. Petruzzello SJ, Landers DM, Hatfield BD, et al. A meta-analysis on the anxietyreducing effects of acute and chronic exercise. Outcomes and mechanisms. Sports Med 1991;11(3):143–82. 70. Siev J, Chambless DL. Specificity of treatment effects: cognitive therapy and relaxation for generalized anxiety and panic disorders. J Consult Clin Psychol 2007;75(4):513–22. 71. Irwin MR, Cole JC, Nicassio PM. Comparative meta-analysis of behavioral interventions for insomnia and their efficacy in middle-aged adults and in older adults 551 years of age. Health Psychol 2006;25(1):3–14. n RE, et al. Randomized clinical trial of cognitive 72. Antoni MH, Carrico AW, Dura behavioral stress management on human immunodeficiency virus viral load in gay men treated with highly active antiretroviral therapy. Psychosom Med 2006;68(1):143–51. 73. Frasure-Smith N, Prince R. The ischemic heart disease life stress monitoring program: impact on mortality. Psychosom Med 1985;47:431–45. 74. Cossette S, Frasure-Smith N, Lesperance F. Clinical implications of a reduction in psychological distress on cardiac prognosis in patients participating in a psychosocial intervention program. Psychosom Med 2001;63:257–66. 75. Butler AC, Chapman JE, Forman EM, et al. The empirical status of cognitive–behavioral therapy: a review of the meta-analyses. Clin Psychol Rev 2006;26(1): 17–31. 76. Tirch D, Radnitz CL. Cognitive–behavioral treatment of irritable bowel syndrome. Clin Psychol 1997;50:18–20. 77. Morley S, Eccleston C, Williams A. Systematic review and meta-analysis of randomized–controlled trials of cognitive–behavior therapy and behavior therapy for chronic pain in adults, excluding headache. Pain 1999;80:1–13. 78. Cohen S, Underwood LG, Gottlieb BH. Social support measurement and intervention. New York: Oxford; 2000. 79. Cohen S, Willis TA. Stress, social support, and the buffering hypothesis. Psychol Bull 1985;98:310–57. 80. Hogan BE, Linden W, Najarian B. Social support interventions: do they work? Clin Psychol Rev 2002;22:381–440. 81. Helgeson VS, Cohen S. Social support and adjustment to cancer: reconciling descriptive, correlational, and intervention research. Health Psychol 1996;15:135–48. 82. Heller K, Thompson MG, Trueba PE, et al. Peer support telephone dyads for elderly women: was this the wrong intervention? Am J Community Psychol 1991;19:53–74. 83. Thoits PA, Hohmann AA, Harvey MR, et al. Similar–other support for men undergoing coronary artery bypass surgery. Health Psychol 2000;19:264–73. 84. Harris T, Brown GW, Robinson R. Befriending as an intervention for chronic depression among women in an inner city. I. Randomised controlled trial. Br J Psychiatry 1999;174:219–24. 85. Cutrona CE, Cole V. Optimizing support in the natural network. In: Cohen S, Underwood LG, Gottlieb BH, editors. Social support measurement and intervention: a guide for health and social scientists. New York: Oxford Press; 2000. p. 278–308. 86. Cohen S, Alper CM, Doyle WJ, et al. Positive emotional style predicts resistance to illness after experimental exposure to rhinovirus or influenza A virus. Psychosom Med 2006;68:809–15. 87. Taylor SE, Kemeny ME, Reed GM, et al. Psychological resources, positive illusions, and health. Am Psychol 2000;55(1):99–109.
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88. Teasdale JD, Segal ZV, Williams JMG, et al. Prevention of relapse/recurrence in major depression by mindfulness-based cognitive therapy. J Consult Clin Psychol 2000;68:615–23. 89. Kabat-Zinn J, Massion AO, Kristeller J, et al. Effectiveness of a meditation-based stress reduction program in the treatment of anxiety disorders. Am J Psychiatry 1992;19:936–43. 90. Kristeller JL, Hallett CB. An exploratory study of meditation-based intervention for binge eating disorder. J Health Psychol 1999;4:357–63. 91. Davis JM, Fleming MF, Bonus KA, et al. A pilot study on mindfulness-based stress reduction for smokers. BMC Complement Altern Med 2007;7:2. 92. Grossman P, Niemann L, Schmidt S, et al. Mindfulness-based stress reduction and health benefits: a meta-analysis. J Psychosom Res 2004;57:35–43. 93. Sephton SE, Salmon P, Weissbecker I, et al. Mindfulness meditation alleviates depressive symptoms in women with fibromyalgia: results of a randomized clinical trial. Arthritis Rheum 2007;57(1):77–85. 94. Grossman P, Tiefenthaler-Gilmer U, Raysz A, et al. Mindfulness training as an intervention for fibromyalgia: evidence of postintervention and 3-year follow-up benefits in well-being. Psychother Psychosom 2007;76(4):226–33. 95. Vieten C, Astin J. Effects of a mindfulness-based intervention during pregnancy on prenatal stress and mood: results of a pilot study. Arch Womens Ment Health 2008;11(1):67–74. 96. Speca M, Carlson ME, Goodey E, et al. A randomized wait list-controlled clinical trial: the effect of a mindfulness meditation-based stress reduction program on mood and symptoms of stress in cancer patients. Psychosom Med 2000;62: 613–22. 97. Majumdar M, Grossman P, Dietz-Waschkowsi B, et al. Does mindfulness meditation contribute to health? Outcome evaluation of a German sample. J Altern Complement Med 2002;8(6):719–30. 98. Carlson LE, Speca M, Faris P, et al. One year pre-/postintervention follow-up of psychological, immune, endocrine, and blood pressure outcomes of mindfulness-based stress reduction (MBSR) in breast and prostate cancer outpatients. Brain Behav Immun 2007;21:1038–49. 99. Rosenzweig S, Reibel DK, Greeson JM, et al. Mindfulness-based stress reduction is associated with improved glycemic control in type 2 diabetes mellitus: a pilot study. Altern Ther Health Med 2007;13(5):36–8. 100. Kabat-Zinn J. Mindfulness meditation practice CDs and tapes. Available at: http://www.mindfulnesstapes.com/books.html. Accessed August 12, 2008. 101. Pennebaker JW, Beall SK. Confronting a traumatic event: toward an understanding of inhibition and disease. J Abnorm Psychol 1986;95:274–81. 102. Frattaroli J. Experimental disclosure and its moderators: a meta-analysis. Psychol Bull 2006;132(6):823–65. 103. Lepore SJ. Expressive writing moderates the relation between intrusive thoughts and depressive symptoms. J Pers Soc Psychol 1997;73:1030–7. 104. Stuart MR, Lieberman JA. The fifteen minute hour: applied psychotherapy for the primary care physician. 2nd edition. Westport (CT): Praeger; 1993. 105. Klerman GL, Budman S, Berwick D. Efficacy of a brief psychosocial intervention for symptoms of stress and distress among patients in primary care. Med Care 1987;25(11):1078–87. 106. Burns DD. Feeling good: the new mood therapy (revised and updated). New York: HarperCollins; 1999.
Role of the Soc ial Milieu in Health a nd Wellness Robert Mallin, MDa,*, Sharon K. Hull, MD, MPHb KEYWORDS Social milieu Spirituality Health Wellness Education Economics Political systems Health systems
The impact of the social milieu on health and wellness is not a new concept. Connections of this type are found in the literature as far back as Hippocrates.1Before the invention of an effective pharmacopeia, manipulation of the social environment was one of the few tools available to physicians. In the eighteenth and nineteenth centuries, the architecture of hospitals and asylums was influenced by the concept of controlling the social milieu to improve the mental and physical health of patients. Although today the evidence for the importance of social support in the health and wellness of the population is clearly present, modern medicine continues to focus on individual rather than community efforts at risk reduction.2 To understand health and wellness in patients, physicians must look not only at their bodies and illnesses but also at their communities and social structure. The impact of the social milieu on health is far more than the sum of its parts. The Public Health Agency of Canada has listed several key ‘‘determinants of health (Box 1).3 Several of these determinants are considered in this article, including the impact of spirituality and religion, education, economics, and politics on health and wellness. The impact of any single determinant is influenced by all the others. The interactions of these complex dynamics on health and wellness defy simplistic causative explanations. Taken together, however, it is the authors’ belief that the net impact of these issues on health is of such significance that it will drive system-level change in global health care for much of the next century. SPIRITUALITY, HEALTH, AND WELLNESS
The impact of religion or spirituality on health has been discussed for many years. The first modern look at this relationship perhaps can be traced to Williams James’ book, a
Family Medicine, Psychiatry and Behavioral Medicine, Medical University of South Carolina, Box 250592, 295 Calhoun Street, Charleston, SC 29425, USA b Department of Community Health Sciences, Northeastern Ohio Universities College of Medicine and Pharmacy, 4209 State Route 44, PO Box 95, Rootstown, OH 44272, USA * Corresponding author. E-mail address:
[email protected] (R. Mallin). Prim Care Clin Office Pract 35 (2008) 857–866 doi:10.1016/j.pop.2008.07.003 primarycare.theclinics.com 0095-4543/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.
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Box 1 The key determinants of health according to the Public Health Agency of Canada Income and social status Social support networks Education and literacy Employment/working conditions Social environments Physical environments Personal health practices and coping skills Healthy child development Biology and genetic endowment Health services Gender Culture Data from Population health approach: what determines health? 2003. Available at: http:// www.phac-aspc.gc.ca/ph-sp/determinants/index-eng.php. Accessed April 27, 2008.
Varieties of Religious Experience, in which he makes an academic connection between psychology and spirituality.4 By 2000, nearly 1200 scientific studies had been published on the relationship between health and religion or spirituality. Most of these studies have found a positive association between religion and spiritual and mental health.5 Many of these studies are cross-sectional in design; consequently, although associations are present, cause and effect cannot be inferred. More recent studies have included prospective cohort and clinical trials and have supported the earlier claims.6 Prospective investigation reveals that attending weekly religious services improve the risk of mortality, especially in women, and is a good predictor of better health behaviors, increased social connections, and improved mental health.7–9 One study of 21,000 adults showed that persons who never attended religious services had a 19 times higher risk for death from all causes over an 8-year period than those who attend more than once weekly.10 For those who attended a religious service more than once weekly from age 20, life expectancy was on average 7.5 years longer than those who never attended. For African Americans, the difference was greater, resulting in a 13.7-year difference in life expectancy.10 Higher levels of religious involvement are shown to reduce adolescent drug and alcohol use, smoking, early sexual activity, and depression and suicide risk.11 A review of 35 studies revealed that religious practices from Judeo-Christian and Eastern traditions resulted in decreased levels of stress hormones and lipids and improved health in patient populations.12 Alternatively there have been studies that have shown negative health effects of religious activity.11,13–16 Although generally religious activity is believed to improve social relationships, it also may increase stress by the criticism that may come from failing to conform to religious expectations.13 More straightforward negative outcomes, such as death of children whose parents relied on faith healing in lieu of standard medical care, are documented.14
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There are those who argue that there is little empiric evidence to support claims of a link between religious or spiritual involvement and health outcomes and that investigation into this relationship should be left out of clinical medicine.17 Despite this, however, there seems to be mounting scientific evidence that there is a positive association between religious or spiritual activity and multiple indicators of health and wellness.2,5–11 Health practices and social relationships are important ways that religion or spirituality can affect health. If one accepts that there may be a relationship between spirituality and health, it is reasonable to question how such a relationship exists. There are neurobiologic explanations that do not require the inclusion of supernatural forces to explain these relationships.17 Meditation produces increases in g-aminobutyric acid, melatonin, and serotonin levels in the brain.18 Dopamine is an important neurotransmitter found in the prefrontal cortex that is significantly involved in reinforcement and reward. Changes in dopamine levels in the prefrontal cortex are associated with religious activity. Significant loss of religiosity is noted in patients who have Parkinson’s disease.18 Religiosity is associated with better acquisition of executive cognitive functions through stimulation of the frontal lobes. Decreased activity in the frontal lobes can lead to poor decision making and poor impulse control, which are associated with relapse in drug addicts.18 A straightforward explanation of religion’s health effects might be as simple as religious participation encouraging better health habits, social support, selfesteem, and self-efficacy.18 Spirituality is negatively correlated with drug use.19 Stress or, more accurately, an individual perception of stress has a significant impact on health through modulation of cardiovascular and immune system primarily through alteration of the sympathetic nervous system. Religious or spiritual beliefs and practices are related to well-being, hope, optimism, purpose, meaning, and social support.20–22 Through reduction in stress perception, spiritual practices result in reduction in heart disease, hypertension, morbidity, and mortality and improve immune and endocrine function.5 Areas that will benefit from further research include clarification of the different types of religious and spiritual activity and the variables that affect health. The majority of research in this area has focused on United States populations with strong JudeoChristian religious affiliations. Defining and differentiating religious from spiritual activity presents a challenge. Further work is needed regarding identification of the mechanisms that result in the observed health differences in those who participate in spiritual activity. Understanding the temporal relationship of specific religious and spiritual activities to their health effects will be challenging but important in the design of future studies.20 EDUCATION, HEALTH, AND WELLNESS
Health is distributed unevenly following a gradient that is a function of social and economic advantage. This gradient is steepest in countries, such as the United States, in which there are wide differences in income, housing, and education. Beyond genetics, social position is the most powerful determinant of health.23 Education often is the key to where persons find themselves in the hierarchy of social position. Bettereducated people are healthier and have lower levels of disability, morbidity, and mortality.24 There is an inverse relationship between all-cause mortality and years of education for men and women in the United States.25 Further, research has shown that the quality of education and the environment in which it is received adds to the health protective effects of education.26 Illiteracy, as a marker of poor education, is associated with worse health outcomes. In addition, patients who have low literacy
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rates have higher health costs.27 Even when corrected for income, those less well educated have worse health than those better educated.28 In a racially diverse lower income population of diabetics, a tight relationship was found between glucose control (measured by HbA1c) and literacy.1 Although the relationship between health and education is well studied, the mechanisms by which health is affected by education are not clear. Education is believed to influence economic conditions through work, enhance social and psychologic resources, and support healthy lifestyle and behaviors. Those who have more education tend to have more supportive associations with family friends and others in their communities and there is ample evidence for the positive impact that social support has on health.29 Well-educated people are more likely to have higher incomes and are less likely to become unemployed or experience financial difficulty. The higher personal or household income, the longer life expectancy.30 In the National Longitudinal Mortality Study those who have more than 12 years of education can expect to live to 82; for those who have 12 or fewer years of education, life expectancy is 75.31 There is some suggestion, however, that this holds true best in high population areas, because in low population or rural areas, income inequality may not be as strong a measure of the scale of social stratification or social hierarchy.29 Better-educated people are more likely to use the health care system effectively and less likely to engage in negative health behaviors, such as smoking, excessive alcohol consumption, drug use, and sedentary living. This effect of education on health behaviors begins as early as eighth grade and is a function of the amount of education received.30 Although education improves health, other factors also may be involved. In the United States, collegeeducated women of African American descent have better health than non– college-educated African American women. When compared with college-educated European American women, however, the college-educated African American women had poorer health, had higher body mass index, and were more likely to smoke.32 The association between education and health is robust. Mechanisms for this association have been postulated, although more research is needed to further identify and support the potential causal relationships. It seems clear, however, that although health and education are considered important values in the United States, public policy has failed to provide resources to further the development of these values. It seems prudent for the advocates for education and health to cooperate rather than compete for resources that will benefit each. ECONOMICS, HEALTH, AND WELLNESS
The discussion of the impact of education on health, outlined previously, sets the stage for a discussion of the role of economic issues on the health and well-being of individuals and populations. It is impossible to separate education, racial and ethnic disparities, income inequality, and social class structure as contributing factors to the social milieu, so they are considered together as elements of the discussion of economic impact on health and wellness. In a study of census data from Harlem, an economically deprived neighborhood in New York City, black men were found less likely to reach the age of 65 than men living in Bangladesh. The overall mortality rate from this neighborhood was at least twice the expected rate compared with the white population in the United States and 50% higher than all blacks in the United States. This excess mortality rate was most likely to be found in areas of high populations of blacks and Hispanics.33 Blacks, Hispanics, and Native Americans in the United States are disproportionately represented among those in poverty and are more likely to self-report their health as ‘‘fair or poor’’ and
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blacks and Native Americans have the highest rates of infant mortality.34 People at the lowest end of the income spectrum ($15,000 or less in annual income) in the United States have an odds ratio for death three times those in the highest income bracket ($70,000 or more in annual income).35 Causal relationships with regard to mortality are not as simple as those implied by these differences, however. The classic Whitehall studies by Marmot and colleagues indicate a gradient relating social class and hierarchy to health outcomes.36,37 It is tempting to attribute higher mortality rates to lifestyle factors that are more prevalent among those who have lower income and who are lower in the social class structure. Native Americans, Hispanics, and African Americans have the highest rates of death from heart disease and the highest prevalence of chronic conditions, such as obesity and type 2 diabetes mellitus.34 A study of American men, which controlled for behavioral risk factors, including smoking, found that even when controlling for these behaviors, those earning less than $10,000 annually were significantly more likely to die prematurely than those who earned more.38 The Whitehall studies of British civil servants also found that differences in health-related behaviors were associated with differences in social hierarchy more than they were associated with income.37 Despite these clear and widely accepted associations, poverty, disadvantage, and inequality are complex phenomena and ones that cannot easily be explained in causal models related to health. In a recent editorial, Marmot pointed out that ‘‘poor people in the United States are rich by world standards, but they have worse health than the average in some poor countries. Poverty is more complex than simply a lack of money.’’ He goes on to suggest that it is possible that poor health outcomes themselves may lead to lower socioeconomic status and that higher burdens of disease among certain racial, ethnic, income, or class groups may represent a contributor to lower socioeconomic status rather than an outcome of such status.39 Recent investigators have focused on the relationship between inequalities in income, rather than income itself, as a key determinant of health status. Income inequality essentially describes the variation in income between the highest-income group in a geographic region and the lowest-income group and also might be thought of as what colloquially is known as the difference between the ‘‘haves and have-nots.’’ One study found a correlation between income inequality and variation in death rates across the United States and between income inequality and a variety of indicators, such as low birth weight, homicides, violent crimes, disability, sedentary lifestyle, smoking behavior, and total medical care expenditures.40 A more recent and detailed follow-up to this study found that 40% of mortality rate differences among US states, for those under age 65, was related to income inequality.41 International researchers have found that more than 3.5 billion human beings worldwide live on the equivalent of $10 (US) per day in terms of income and that income inequality had the highest impact on those between the ages of 15 and 29 years in wealthiest countries, whereas its impact was believed the most on those between the ages of 25 and 39 worldwide.42 Another recent study pointed to relative income equality in Japan as significantly accounting for good quality health status in that country since World War II.43 The interrelationships between economic status, race, income inequality, and other socioeconomic factors is complex. An emerging focus of research in this area is directed toward community-level interventions. Some have written of the concept of ‘‘opportunity neighborhoods,’’ defined as ‘‘neighborhoods that support healthy development’’ and that ‘‘include availability of sustainable employment, high-performing schools, healthy environments, access to high-quality health care, adequate transportation, high-quality child care, neighborhood safety, and institutions that facilitate civic
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engagement.’’44 Marmot suggests that efforts be directed toward ‘‘enhancing the social and psychologic resources of individual people, and improving the quality of neighborhoods and communal life.’’39 This is an apt description of the types of system-level interventions that will be necessary to untangle the complicated web of socioeconomics and health status. POLITICAL SYSTEMS, HEALTH, AND WELLNESS
Politics may be defined as, ‘‘The art or science of government or governing, especially the governing of a political entity, such as a nation, and the administration and control of its internal and external affairs.’’45 Government may be defined as that ‘‘political organization comprising the individuals and institutions authorized to formulate public policies and conduct affairs of state.’’46 The authors suggest considering a functional definition of politics and government that consists of those decisions and policies by which a society organizes itself and determines allocation of common resources. Political systems may be categorized as monarchies (with hereditary and lifelong rulers) or republics (with elected heads of state). Other classifications may be based on the extent to which democracy and constitutional rule of law are incorporated into the governance structure and by the methods in which economic distribution of resources is accomplished (socialism versus capitalism). Imperialism or colonialism may be thought of as the ‘‘extension of capital[ism] beyond national boundaries, and the social, political and economic effects of this expansion.’’47 Politics and economics are intricately linked, and separating the effects of one from the other may be difficult. Several methods have been used to describe links between the type of political system and the health of individuals and populations. It might be assumed that wealthier countries should have better health outcomes, but the example of the United States belies this theory. The United States has the highest annual per capita spending on health care in the world ($6401 per person per year),48 yet, in 2006, ranked last among developed countries for overall health care performance.49 This finding, surprising to many, may be related to the choice in the United States to have an entirely market-driven health care system. There is some evidence that those countries that choose to implement universal health care (a nominally socialist choice but not one enacted exclusively by socialist governments) have better health care outcomes;50 every other developed country in the world except the United States has made this choice. The World Bank Institute has developed a set of World Governance Indicators,51 which include six broad categories: (1) voice and accountability, (2) political stability and absence of violence, (3) governmental effectiveness, (4) regulatory quality, (5) rule of law, and (6) control of corruption. These indicators together measure the overall quality of governance and have been found to have significant relevance to several health indicators. An increase in the aggregate measure of these indicators by 1 SD results in a two-thirds decline in infant mortality.51 Higher scores from these indicators are associated with lower rates of HIV prevalence,52 and corruption as a stand-alone measure has been implicated in diversion of funds from public health infrastructure, with resultant negative implications for health outcomes.53 Developing countries often make the choice to implement universal health care, and those that are in postcolonial or postimperial periods of development often choose to allocate significant resources to this effort. As these countries encounter efforts to solicit global development funds, structural limitations on financial and governance practices often limit the amount of funds available to them and may pose serious limits to the allocation of resources to health care issues.54,55
Role of the Social Milieu in Health and Wellness
Secrecy, denial of health issues, failure to allocate resources to health infrastructure, and failure to prevent the deleterious impact of corruption on access to health care all are issues related to governance. These issues have influenced illicit drug use in Turkmenistan,56 life expectancy and mortality in Latin America,57 differences in morbidity and health use between rural and urban populations,58 overall health care cost inflation59 in China, and access to care in the United States. These examples delineate several complex ways in which governmental systems can influence health, health care spending, access to care, and health systems functionality. The concept of a ‘‘medical commons,’’ essentially an understanding that health care is a common good for which all are accountable and to which all contribute, has been posited as an ethical framework for approaching health system reform.60 Another suggestion is that ‘‘without good germ governance a country does not have good governance.’’61 Those who take a different approach, focusing on a market-driven system for creating health system reform, believe that the forces of the capitalist market system eventually will provide the best and most economically efficient health care system. Such an approach holds that ‘‘Reform should be undertaken in ‘incremental steps’ that ‘promote greater competition, improve quality and make care more affordable.’’62 No matter which side of this argument is considered, governmental systems are an important factor in the greater social milieu that has an impact on health. Appropriate allocation of scarce health care resources in a setting where all are assumed to have a basic right to fundamental health at the maximum capacity they can attain may be one of the most basic human rights that governments around the world have yet to adequately address. The idea that provision of adequate health care is a core responsibility of government (see the functional definition of government suggested by the authors above) is a core tenet of the global public health community, as evidenced by the preamble to the Constitution of the World Health Organization,63 which includes the following key principles: 1. The enjoyment of the highest attainable standard of health is one of the fundamental rights of every human being without distinction of race, religion, political belief, and economic or social condition. 2. The health of all peoples is fundamental to the attainment of peace and security and is dependent on the fullest cooperation of individuals and states. 3. The achievement of any state in the promotion and protection of health is of value to all. 4. Governments have a responsibility for the health of their peoples, which can be fulfilled only by the provision of adequate health and social measures. Only those governments that embrace full responsibility for health will maximize economic productivity and fulfill their ethical obligations to the people they govern. SUMMARY
This article describes the impact of the social milieu on health and wellness by looking at the literature in areas of spirituality/religion, education, economics, and politics. The evidence supports a robust relationship between health and each of these areas in the social milieu. Further, it is clear that none of these areas has an impact on health in a vacuum. Rather, each area interacts with the others in a dynamic fashion, ultimately having a profound impact on the health of populations. Although it seems clear that enhanced education, better economic conditions, good governance, and spiritual growth will result in improved health for those who achieve these goals, determining which changes to make in the social milieu to allow these to develop is another matter.
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Even if further research can determine what needs to change in the social milieu, the ability to effect these changes is yet another challenge. A broad view of responsibility for society in the area of health and wellness needs to be embraced to see progress in this area. This is a task that crosses professional boundaries and training. It requires health care professionals to come out of hospitals, clinics, and research laboratories and into the community to work for change. REFERENCES
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