Gastroenterol Clin N Am 36 (2007) xiii–xiv
GASTROENTEROLOGY CLINICS OF NORTH AMERICA
Preface
Henry P. Parkman, MD Guest Editor
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his issue of Gastroenterology Clinics of North America focuses on an important area in gastroenterology for both clinicians and researchers: neurogastroenterology and gastrointestinal (GI) motility disorders. GI motility and functional GI disorders are common reasons for patients to see physicians. Knowledge of GI motility disorders, including the evaluation and treatment of these disorders, is important for gastroenterologists, clinicians, and health care providers to appropriately care for these frequently seen patients in clinical practice. Gastrointestinal motility can be defined as motor activity in the digestive tract that mixes ingested food with digestive juices and moves luminal contents of the gastrointestinal tract in an aboral direction from the mouth toward the anus. A better understanding of the pathophysiology of GI motility disorders has revealed a crucial role of the enteric, autonomic, and central nervous system. In fact, the term neurogastroenterology was introduced in the early 1990s to account for the study of these processes. As with any new term, there was resistance to its introduction. The breakthrough came when the editorial board of the Journal of Gastrointestinal Motility changed its name to Neurogastroenterology and Motility in 1994. The European Society changed its name in 1996; recently, the American Society became the American Neurogastroenterology and Motility Society, and the International Group became the International Society of Neurogastroenterology. Neurogastroenterology emphasizes clinical and experimental gastroenterology embracing the concept of brain–gut interactions and refers to motor disorders of the gastrointestinal tract attributable to neural control mechanisms, including the psychophysiology of clinical disorders of visceral perception and motor function. As defined in the free online encyclopedia Wikipedia, ‘‘neurogastroenterology is a research area in the field of 0889-8553/07/$ – see front matter doi:10.1016/j.gtc.2007.07.011
ª 2007 Elsevier Inc. All rights reserved. gastro.theclinics.com
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PREFACE
gastroenterology which regards interactions of the central nervous system (brain) and the gut—the so-called brain–gut axis. Important research focuses upon upward (sensory) and downward (motor and regulatory) neural connections and upon endocrine influences on gut function and the enteric nervous system in itself. Clinical research deals on many levels involving GI motility disorders and functional bowel disorders.’’ The articles in this issue discuss key aspects of GI motility disorders, focusing on how they relate to practicing gastroenterologists, clinical investigators, and other health care providers. Current knowledge in the area as well as evolving concepts from clinical investigations and translational research from basic sciences is discussed. The rapid explosion of new technology used in the evaluation of patients is also addressed. Most of the articles in this issue were written by members of the American Neurogastroenterology and Motility Society, formerly known as the American Motility Society. The mission of the American Neurogastroenterology and Motility Society (ANMS) is to advance the study of neurogastroenterology, GI motility, and related enteric sciences; to promote the training of basic scientists and clinician investigators; to translate the scientific advances to patient care; and to disseminate the knowledge to patients and caregivers to improve the diagnosis and treatment of patients with GI motility and functional GI disorders. I hope you enjoy this edition of the Gastroenterology Clinics of North America! It was a pleasure putting it together. Henry P. Parkman, MD Gastroenterology Section Department of Medicine Temple University Hospital 3401 North Broad Street Philadelphia, PA 19104, USA E-mail address:
[email protected]
Gastroenterol Clin N Am 36 (2007) 485–498
GASTROENTEROLOGY CLINICS OF NORTH AMERICA
Overview of NeurogastroenterologyGastrointestinal Motility and Functional GI Disorders: Classification, Prevalence, and Epidemiology Ann Ouyang, MDa, G. Richard Locke III, MDb,* a
Division of Gastroenterology and Hepatology, Hershey Medical Center, 500 University Drive, Hershey, PA 17033, USA b Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA
‘‘
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he times they are a-changing.’’ This famous title from a Bob Dylan track and album sums up state of the understanding of functional gastrointestinal disorders and motility disorders. Advancing technology, the increased application of pharmacogenomics, and an expansion of an integrative approach to understanding disease pathophysiology has led to significant changes in how clinicians view the conditions that are encompassed by the term ‘‘neurogastroenterology and motility disorders,’’ which is being increasingly applied to these conditions. Classically, these conditions have been described as functional gastrointestinal disorders (FGIDs) if patients complain of symptoms related to the gastrointestinal tract in the absence of anatomic and biochemical abnormalities [1] or motility disorders when a distinct and measurable alteration of motor function occurs (eg, achalasia, scleroderma, gastroparesis). The overlap between these two groups of conditions has caused significant confusion in both nomenclature and in the literature. The rationale and genesis of the Rome classification resulted from a need to change the focus from a group of conditions serving as a catch-all diagnosis after exclusion of organic conditions to ones with a positive diagnosis [1,2] and has been helpful toward achieving this goal. This classification has been a useful tool for clinical studies to decrease the heterogeneity of subjects recruited and to improve general acceptance that these conditions are clustered in a manner that suggests that there is a common pathophysiology that can be determined with time and appropriate study. The last decade has resulted in tremendous advances in understanding the pathophysiology related to these conditions. It is
*Corresponding author. E-mail address:
[email protected] (G.R. Locke III). 0889-8553/07/$ – see front matter doi:10.1016/j.gtc.2007.07.009
ª 2007 Elsevier Inc. All rights reserved. gastro.theclinics.com
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anticipated that the next decade will move these conditions from being symptom based to pathophysiology based. The term ‘‘neurogastroenterology’’ was introduced to include the processing of information between the viscera and the brain [3]. Research in the ensuing decade has shown overlap between conditions affecting the end organ and the brain-gut axis. The term ‘‘neurogastroenterology and motility disorders’’ encompasses the organ systems that contribute to the symptom constellation that are experienced by patients with these disorders: the central nervous system (CNS), contributing to the sensory and motor control of the gastrointestinal tract; and the gastrointestinal functional unit, which includes the enteric nerves and smooth muscle. Most of the motor and sensory function of the gut occurs subconsciously and cerebral cortical activity is a key to the perception of gastrointestinal activity. The patient’s experience of visceral activity is influenced by psychologic context, which can affect both the severity of the sensation and the degree of unpleasantness of the sensations. This issue highlights some of the advances in the understanding of these conditions and how to translate this knowledge into the diagnosis and management of patients. This article focuses on the classification and epidemiology of these conditions. CLASSIFICATION OF NEUROGASTROENTEROLOGY DISORDERS The Rome III classification of FGID is outlined below [4]. In comparison with the Rome II criteria, the current classification has expanded the pediatric categories and provided more restrictive criteria for functional disorders of the gallbladder and sphincter of Oddi. In addition, functional abdominal pain was separated from functional bowel disorders and placed into its own category as recognition that this was primarily related to disorders of CNS functioning, which results in a perceived sensation of pain in the presence of normal visceral signals. These changes in the classification imply an acceptance that the classification will eventually change to one based on pathophysiology rather than symptom complexes. A. Functional esophageal disorders A1. Functional heartburn A2. Functional chest pain of presumed esophageal origin A3. Functional dysphagia A4. Globus B. Functional gastroduodenal disorders B1. Functional dyspepsia B1a. Postprandial distress syndrome B1b. Epigastric pain syndrome B2. Belching disorders B2a. Aerophagia B2b. Unspecified excessive belching B3. Nausea and vomiting syndromes
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B3a. Chronic idiopathic nausea B3b. Functional vomiting B3c. Cyclic vomiting syndrome C. Functional bowel disorders C1. Irritable bowel syndrome C2. Functional bloating C3. Functional constipation C4. Functional diarrhea C5. Unspecified functional bowel disorder D. Functional abdominal pain syndrome E. Functional gallbladder and sphincter of Oddi disorders E1. Functional gallbladder dysfunction E2. Functional biliary sphincter of Oddi disorder E3. Functional pancreatic sphincter of Oddi disorder F. Functional anorectal disorders F1. Functional fecal incontinence F2. Functional anorectal pain F2a. Chronic proctalgia F2a1. Levator ani syndrome F2a2. Unspecified functional anorectal pain F3. Functional defecation disorders F3a. Dyssynergic defecation F3b. Inadequate defecatory propulsion G. Functional disorders: neonates and toddlers G1. Infant regurgitation G2. Infant rumination syndrome G3. Cyclic vomiting syndrome G4. Infant colic G5. Functional diarrhea G6. Infant dyschezia G7. Functional constipation H. Functional disorders: children and adolescents H1. Vomiting and aerophagia H1a. Adolescent rumination syndrome H1b. Cyclic vomiting syndrome H1c. Aerophagia H2. Abdominal pain-related functional gastrointestinal disorders H2a. Functional dyspepsia H2b. Irritable bowel syndrome H2c. Abdominal migraine H2d. Childhood functional abdominal pain H2d1. Childhood functional abdominal pain syndrome H3. Constipation and incontinence H3a. Functional constipation H3b. Nonretentive fecal incontinence
Table 1 provides a classification of the conditions that are considered neurogastroenterology and motility disorders based on the current understanding of the neuroanatomic level at which dysfunction can be recognized. This includes
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Table 1 Neurogastroenterology and motility disorders: classification based on brain-gut axis model Location
Evidence for GI dysmotility
Both motor and sensory dysfunction
Primarily sensory
Primarily CNS processing
Esophagus
Achalasia
Diffuse esophageal spasm Nutcracker esophagus Hypertensive LES
Functional heartburn Functional dysphagia
Globus
Scleroderma Hypotensive LES-GERD Stomach
Gastroparesis Tachygastria Scleroderma
Biliary tract
Intestine and colon
Gallbladder dysmotility Sphincter of Oddi dysfunction Chronic idiopathic intestinal pseudoobstruction Colonic inertia Scleroderma
Anorectal
Hirschsprung’s disease Pelvic floor dyssynergia
GERD-normal LES Dumping syndrome Cyclic vomiting syndrome Rumination syndrome Belching disorders
Irritable bowel syndrome
Bacterial overgrowth Functional diarrhea Functional constipation Functional constipation Functional anorectal pain Functional defecation disorders
Functional dyspepsia Functional nausea
Functional bloating
Functional abdominal pain
Functional proctalgia
Abbreviations: CNS, central nervous system; GERD, gastroesophageal reflux disease; GI, gastrointestinal; LES, lower esophageal sphincter.
the end organ (at the gut level, which includes the enteric nerves, interstitial cells of Cajal, and smooth muscle); sensory dysfunction alone (including the afferent pathway from the gut and CNS processing); and disorders in which there is a combined sensory and motor dysfunction. This classification is possible because of the development of technologies to assess these pathways separately. Examples of these technologies include the electrogastrogram, which allows an assessment of motor activity in the stomach; advances in interpretation of videofluoroscopy and measurements of motor activity [5]; the barostat,
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which allows a measurement of the sensory pathway [6] particularly if used in conjunction with pharmacologic blockade of motor activity; and a variety of CNS imaging modalities including positron emission tomography scans and functional MRI [7]. In the future, the next level of classification will be based on the underlying pathophysiology, which might include a combination of factors including prior inflammatory conditions with peripheral sensitization of the visceral pain pathway. Such a classification will necessarily depend on the ability to detect such alterations in the immune and cytokine pathways and assessment of the neurotransmitter function in the brain and gut [8–11]. One Disease or Many Although a classification system based on physiology is the goal for the future, the Rome criteria are the accepted classification scheme of the present for FGID. Still, the question remains as to whether 27 separate adult and 13 separate pediatric disorders exist. Some of these disorders are symptom complexes, whereas others are single symptoms. One might argue whether or not a single symptom should qualify as a unique disorder. The hope was that homogeneity would lead to better studies of pathogenesis and therapy. These disorders occur within the human body, however, and many similarities exist from esophagus to stomach to small and large intestine. Patients often present with multiple symptoms from different regions of the body. Disorders of sensorimotor function might affect multiple sites along the gastrointestinal tract. For example, half of people with irritable bowel syndrome (IBS) also have symptoms of reflux [12]. Symptoms may change over time and a patient may have IBS symptoms one year and then dyspepsia symptoms the next year [13]. One approach is to split these into separate conditions and manage them separately. An alternative, however, is to think of the patient as having one ‘‘pan-gut’’ or systemic disorder and manage the patient accordingly. In the future, much will be learned about the prevalence and epidemiology of these pathophysiologic abnormalities. This will shed light on the appropriate classification scheme. At present clinicians must continue to rely on symptoms to define many of the neurogastroenterology and motility disorders. These symptom-based diagnoses have been used extensively over the past 20 years to understand the epidemiology of these conditions. EPIDEMIOLOGY Neurogastroenterology and motility disorders include the currently accepted FGIDs and other primarily motor disorders, such as achalasia. FGIDs are extremely common conditions [14,15]. Studies have shown that many people with FGIDs do not seek care. The decision to seek care introduces bias in clinic-based research [16]. For this reason, population-based research has been used to evaluate fully the epidemiology and clinical symptoms in individuals with FGIDs. Many gender- and age-related issues arise related to the
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FGIDs. Extensive epidemiologic data exist for IBS, dyspepsia, heartburn, constipation, and fecal incontinence, but less is known about the other neurogastroenterology conditions. For many FGIDs, such as globus, rumination, and sphincter of Oddi dysfunction, the only data on prevalence by age come from a single study [14]. Similarly, other motility disorders, such as achalasia and gastroparesis, which are defined by physiologic or anatomic criteria, do not lend themselves to epidemiologic studies except in small, very well characterized populations [17,18]. To date, the epidemiologic studies have been conducted primarily in western populations; data from other areas of the world are limited but growing [19]. Esophageal Disorders The functional esophageal disorders include globus, rumination syndrome, functional chest pain, functional heartburn, and functional dysphagia. Studies have shown that these functional esophageal disorders are all quite common [14,20]. Globus sensation is reported by 7% to 12.5% of the population [14,20] and is more common in women. Rumination syndrome is reported by 10.9% of the population [14]. No difference in gender has been reported. The prevalence estimates of functional chest pain have varied between 12.5% and 23.1% [14,20,21]. These population-based estimates have relied on the person’s self-report of not having cardiac disease. Still, noncardiac chest pain and functional chest pain of esophageal origin are not synonymous. People with noncardiac chest pain can have many underlying causes [22]. In the community, noncardiac chest pain has an equal gender prevalence [14,20,21], but a higher female-to-male ratio in tertiary care referral centers [23]. The prevalence of most of these disorders decreases with age. Specifically, globus, rumination syndrome, and self-reported functional chest pain are all more common in younger people [14,20,21]. Many of the symptoms of functional esophageal disorders are experienced by people with gastroesophageal reflux disease [20]. Estimating the true prevalence of functional heartburn in the community is quite difficult. In population-based studies, pH monitoring is not a real option because invasive studies greatly reduce response rates [24]. The data are on symptoms rather than a diagnosis. The prevalence of heartburn does not vary by gender and is similar among people ages 25 to 74 [20]. Dysphagia is reported by 7% to 13% of the population [14,20]. Whether dysphagia is associated with gender is not clear. One study found that a difference of 6.3% in men and 8.5% in women was statistically significant [14], whereas in another study, the difference between 12.4% of men and 14.6% of women was not statistically significant [18]. A gender effect may exist but it is small. The prevalence of dysphagia increases with age, most notably in participants in the 65- to 74-year category [18]. The proportion of these people who have functional dysphagia versus another esophageal disorder (eg, esophageal obstruction or a motility disorder) is not known. Many conditions that affect motor function of the oropharynx and esophagus, such as stroke and Parkinson’s disease, are more prevalent in the elderly [25].
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Esophageal motility disorders, which primarily involve the end organ (eg, achalasia), are defined by the abnormal motility pattern of aperistalsis and impaired lower esophageal relaxation. Clearly, a population-based study that involves an invasive diagnostic test is not feasible. Studies of the prevalence of achalasia have often relied on hospital admissions and are retrospective. Studies from Iceland and Great Britain indicate an incidence of about 0.55 cases per 100,000 population per year [17,18]. Gastroduodenal Disorders Dyspepsia is not a condition; it is a symptom complex. Dyspepsia can be defined as persistent or recurrent abdominal pain or abdominal discomfort centered in the upper abdomen [26]. The term ‘‘discomfort’’ includes symptoms of nausea, vomiting, early satiety, postprandial fullness, and upper abdominal bloating. Symptoms are typically associated with eating but not with bowel movements. In early studies, the symptoms of heartburn and acid regurgitation were often included as symptoms of dyspepsia. Yet, if these symptoms are the main symptoms, the patient should be considered to have reflux rather than dyspepsia. Right upper quadrant pain or epigastric pain radiating to the back should not be included in the dyspepsia definition. Functional dyspepsia can then be defined as dyspepsia symptoms of more than 3 months’ duration without an anatomic or biochemical abnormality [26]. Typically, this means negative blood tests and a negative evaluation of the upper gastrointestinal tract with either an endoscopy or barium radiograph. Defining a negative endoscopy, however, can be difficult. Does this include biopsies of the esophagus for esophagitis or biopsies of the stomach for gastritis or Helicobacter pylori? Are erythema, erosions, or histologic inflammation meaningful findings? These are somewhat controversial issues. What about other tests like ultrasounds, CT scans, gastric emptying studies, or ambulatory pH monitoring? Do these have to be done before making a diagnosis of functional dyspepsia? These are issues that still need to be resolved. Many surveys have evaluated how many people experience symptoms of dyspepsia in the community. The rates vary in large part because of the definitions used. The surveys that include the symptom of heartburn in the definition of dyspepsia report a prevalence of 40% [27]. Other surveys exclude subjects with symptoms of heartburn or IBS and report prevalence rates below 5% [14]. Nonetheless, it is reasonable to say that 15% (about one in seven) of the adult population has dyspepsia [28]. Not all these people with dyspepsia have functional dyspepsia. In one study, a random sample of the population with dyspepsia underwent endoscopy [29]. Only 53% had a normal endoscopy. The abnormal findings were esophagitis, peptic ulcer disease, duodenitis, and duodenogastric reflux. Only 66% of the asymptomatic controls in this study, however, had normal endoscopy. Peptic ulcer disease and duodenitis were more common in the dyspepsia cases than the controls, but the other findings, such as gastritis, were seen in similar numbers of cases and asymptomatic controls.
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The prevalence of dyspepsia does not vary by gender [14,30]. Distinct subgroups of dyspepsia have been defined: ulcer-like dyspepsia, dysmotility-like dyspepsia, and unspecified dyspepsia [26]. The prevalence of the ulcer-like and dysmotility-like dyspepsia subgroups also do not vary by gender. Some studies have suggested that the prevalence of dyspepsia decreases with age [31–33]. The distribution of subtypes (ulcer-like and dysmotility-like), however, does not vary by age. The prevalence of aerophagia has been estimated to be 23.4% to 29% [14,34]. Men are slightly more likely to report aerophagia than women. Young people are slightly more likely to report aerophagia than older people. The overall prevalence of functional vomiting is 2.3%, but there is no association with gender. In general, more men than women reported vomiting, but this is not a statistically significant difference [30,31]. Vomiting decreases with age. The prevalence of gastroparesis, as defined by delayed gastric emptying, is unclear. Although delayed gastric emptying has been recognized as a consequence of systemic conditions, such as diabetes mellitus and systemic sclerosis, it is also reported in functional dyspepsia and gastroesophageal reflux [35]. The true prevalence is unknown because, in its strictest sense, the diagnosis depends on a study that, although relatively noninvasive, is not applicable to a large population. The issues related to gastroparesis are discussed elsewhere in this issue. Bowel Disorders Affecting Small Intestine and Colon IBS is the best studied of all the FGIDs and can be defined as a constellation of recurrent or chronic abdominal pain that is associated with defecation and a chronically altered bowel habit [2]. How common is IBS? The answer depends greatly on the definition used. In an early study, a representative random sample of the United States population was asked if they had active symptoms of spastic colon or mucous colitis. The prevalence varied by age and gender but overall was roughly 20 per thousand [36]. This study, however, required that the patient needed to know if they in fact had one of these diagnoses. Because not everyone with IBS goes to the doctor and receives a diagnosis, an alternative strategy to determining prevalence was required. Many population-based surveys have assessed the individual symptoms of IBS. The survey responses are then used to make a diagnosis of IBS. The prevalence rates in these studies have varied between 8 and 22 per hundred [14,15,37–39]. Note the 10-fold difference in prevalence rates between asking about a diagnosis and asking about the symptoms of IBS. Why do the prevalence rates from the IBS-specific symptom surveys vary threefold? Although this may represent true differences in populations, it more likely reflects differences in the IBS definition. Higher prevalence rates are identified using a threshold of two of six Manning criteria [40]. Lower prevalence rates are identified using more specific criteria, whether by increasing the threshold of Manning criteria necessary to make the diagnosis or using the Rome criteria. In a direct comparison, prevalence using standard
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Rome criteria is comparable with using a threshold of three of six Manning criteria [40]. In clinic-based studies, IBS is strongly associated with gender. Of interest, however, the female to male ratio in the community is approximately 2:1. Gender may have a role in the onset of IBS but also has a role in health care seeking behavior [16]. Gender may also play a role in symptom severity. In a study of patients having general examinations in a health maintenance organization, overall 68% of those with IBS symptoms were female. In those with mild symptoms (<3 Manning criteria), 65% were female, and in those with more severe symptoms (3 Manning criteria), 80% were female [41]. In another study, symptom severity was compared in IBS patients from primary care clinics with those from university internal medicine outpatient clinics [42]. Women attending the outpatient clinics had a higher severity score than did men attending the same clinics, but women and men attending the primary care clinics had the same severity. The prevalence rates for pain-related symptoms in IBS are similar by gender [43], but a greater female predominance is seen in non– pain-associated symptoms of constipation, bloating, and extraintestinal manifestations. In contrast, men reported higher levels of diarrhea [44,45]. The prevalence of IBS does decrease slightly with age. New-onset symptoms may occur in the elderly [14,46]. Among the elderly, however, the prevalence of IBS was found to increase with age from 8% among those 65 to 74 years to over 12% for those over 85 [46]. Data regarding racial differences are increasing with studies now available from around the globe [17]. The prevalence of IBS seems to be lower in non-Western countries. This difference may reflect a true cultural or biologic phenomenon or stem from methodologic differences, such as the difficulties in performing population studies in some of these countries [17]. In contrast to IBS, much less is known about the epidemiology of functional abdominal bloating. One study found that women were more likely than men to report bloating or abdominal distention. The prevalence in women was 19% versus 10% in men [47]. Another study, however, found that men were more likely than women to report bloating (34% versus 27%) [14]. The existing literature is also discordant in regard to the changes in the estimates of bloating by age [14,47]. Studies evaluating gender differences in the prevalence of functional constipation and functional diarrhea have reported a female predominance in functional constipation but similar rates in men and women with functional diarrhea [14,31,48–50]. Chronic constipation is a common condition that has been self-reported in 20.8% of women and 8% of men [49]. A more recent study of more than 10,000 individuals reported the prevalence of constipation in 16% of women and 12% of men [50]. The female-to-male ratio was elevated for both the outlet type and the combined IBS-outlet type of functional constipation. In one study, women with functional constipation were more likely to seek medical care compared with men (36% versus 19.5%) at all ages except for 50 to 64 years where probability rates were similar [51]. The prevalence of
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constipation clearly increases with advancing age [52–54]. Pathophysiologic studies in patients with constipation classify patients based on underlying conditions, which include medication-related constipation; constipation related to a systemic disorder; and neurogastroenterology conditions, which include colonic inertia and pelvic floor dyssynergy. These disorders are discussed elsewhere in this issue. The prevalence estimates of self-reported diarrhea vary from 1.6% to 27% [14,31,55]. Some people with diarrhea may be alternating, however, and individual diarrhea symptoms do not correlate well to an overall self-report of diarrhea. One study identified decreasing rates of diarrhea with age [36]. The prevalence of functional abdominal pain has been estimated to be 1.7% [14]. The rate was higher in women and decreased slightly with age. Disorders of the Biliary Tract and Pancreas As opposed to studies of IBS, which allow for symptoms to be assessed by questionnaire, the diagnosis of sphincter of Oddi dysfunction requires invasive testing. Very little epidemiologic data exist. One study estimated the prevalence of sphincter of Oddi dyskinesia to be 0.8%. The rate was much higher in women (2.3% versus 0.6%) and increased with age [14]. Anorectal Disorders Prevalence rates of fecal incontinence have varied from 3% to 11% [14,52,56,57]. The role of gender in fecal incontinence has varied by study. Among nursing home residents, incontinence has been reported to be more common in men [58], whereas among older people living at home, the reported rates are higher in women [59,60]. Men are more likely to report soiling of underclothes [56]. Fecal incontinence clearly increases with age [14,52,56,57]. Relatively little data exist on the epidemiology of functional anorectal pain. The estimated prevalence is 11.3% with no difference in gender, but decreasing rates with age [14]. Pelvic floor dysfunction is a recognized cause of constipation. The prevalence of outlet delay has varied from 4.6% [47] and 11% [61] and was more common in women. In the one study that attempted to estimate the prevalence of dyschezia, the rate was 13% with higher rates in women [14]. The prevalence of rectal outlet delay does not vary by age [61]. Outlet delay is more common in women. Finally, prevalence of dyschezia has been reported to be similar by age. SUMMARY Symptoms of neurogastroenterologic and motility disorders are quite prevalent in the community. The epidemiologic data for FGIDs are summarized in Table 2. In general, women report these symptoms more than men. Women are more likely to report globus, IBS, bloating, constipation, chronic functional abdominal pain, sphincter of Oddi dysfunction, fecal incontinence, and pelvic floor dysfunction. In contrast, women and men report similar rates of functional esophageal symptoms and dyspepsia. Most of the high-quality epidemiologic
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Table 2 Prevalence by gender and change with age for the functional GI disorders FGID Esophageal Globus Rumination Functional chest pain Functional heartburn Dysphagia Gastroduodenal Dyspepsia Aerophagia Functional vomiting Biliary tract Lower GI tract IBS Functional constipation Functional diarrhea Functional bloating CFAP Fecal incontinence Functional anorectal pain Outlet delay
Prevalence by gender
Change with age
F F F F F
>M ¼M ¼M ¼M >M
# # # ¼ "
F¼M M >F ¼ F
# # # "
F F M >F Discordant studies F >M F >M (at home) M >F (nursing homes) F >M F
# " # Discordant studies # " # ¼
Of note, some of the data in this table are based on single studies or multiple small-scale studies and should be interpreted with caution. Abbreviations: CFAP, chronic functional abdominal pain; FGID, functional gastrointestinal disorder; GI, gastrointestinal; IBS, irritable bowel syndrome.
studies have been conducted in Western populations with IBS, constipation, heartburn, and dyspepsia but not the other FGID. Some FGID increase with age, whereas others decrease. The challenge is that these studies do not include diagnostic tests and they measure symptom reporting rather than being true estimates of the prevalence of the FGIDs. Exclusions are often done based on self-report but this is not entirely accurate. Any shift in classification to a pathophysiologic basis requires different approaches to determine the prevalence. Most of the studies have been of middle-aged populations. More recently studies have been more focused on patients at the two extremes of age, children and the elderly. The presence of FGIDs in children is well recognized [62]. Only recently, however, have studies begun to examine the relationship between gastrointestinal symptoms in children and adults. The exact age of onset of FGIDs remains to be determined. The classification of FGID and motility disorders is in a state of transition. Over time, the emphasis will likely shift from symptoms to pathophysiology. Nonetheless, the epidemiology of these conditions is based on symptom surveys. This article reviewed the epidemiology of these common disorders from the esophagus to the anorectum.
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References [1] Thompson WG. The road to Rome. Gastroenterology 2006;130:1552–6. [2] Rome III: the functional gastroenterology disorders. In: Drossman DA, editor. McLean (VA): Publ. Degnon Associates; USA; 2000. p. 2–9. [3] Enck P, Frieling T. Neurogastroenterology: information processing from the viscera to the brain in humans. Dtsch Tierarztl Wochenschr 1998;105:468–71. [4] Drossman DA. The functional gastrointestinal disorders and the Rome III process. Gastroenterology 2006;130:1377–90. [5] Pandolfino JE, Zhang QG, Ghosh SK, et al. Transient lower esophageal sphincter relaxations and reflux: mechanistic analysis using concurrent fluoroscopy and high-resolution manometry. Gastroenterology 2006;131:1725–33. [6] Sarnelli G, Vos R, Cuomo R, et al. Reproducibility of gastric barostat studies in healthy controls and in dyspeptic patients. Am J Gastroenterol 2001;96:1047–53. [7] Mayer EA, Naliboff BD, Craig AD. Neuroimaging of the brain-gut axis: from basic understanding to treatment of functional GI disorders. Gastroenterology 2006;131:1925–42. [8] Akiho H, Deng Y, Blennerhassett P, et al. Mechanisms underlying the maintenance of muscle hypercontractility in a model of postinfective gut dysfunction. Gastroenterology 2005; 129(1):131–41. [9] Grundy D, Al-Chaer ED, Aziz Q, et al. Fundamentals of neurogastroenterology: basic science. Gastroenterology 2006;130(5):1391–411. [10] O’Mahony L, McCarthy J, Kelly P, et al. Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles. Gastroenterology 2005;128:541–51. [11] Gershon MD, Tack J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology 2007;132:397–414. [12] Locke GR III, Zinsmeister AR, Fett SL, et al. Overlap of gastrointestinal symptom complexes in a US community. Neurogastroenterol Motil 2005;17(1):29–34. [13] Agreus L,, Svardsudd K, Nyren O, et al. Irritable bowel syndrome and dyspepsia in the general population: overlap and lack of stability over time. Gastroenterology 1995;109(3): 671–80. [14] Drossman DA, Li Z, Andruzzi E, et al. US householder survey of functional gastrointestinal disorders: prevalence, sociodemography, and health impact. Dig Dis Sci 1993;38: 1569–80. [15] Locke GR III. The epidemiology of functional gastrointestinal disorders in North America. Gastroenterol Clin North Am 1996;25:1–19. [16] Koloski NA, Talley NJ, Boyce PM. Does psychological distress modulate functional gastrointestinal symptoms and health care seeking? A prospective, community cohort study. Am J Gastroenterol 2003;98:789–97. [17] Birgisson S, Richter JE. Achalasia in Iceland, 1952–2002: an epidemiologic study. Dig Dis Sci 2007; [epub April 10]. [18] Mayberry JF, Atkinson M. Variation in the prevalence of achalasia in Great Britain and Ireland: an epidemiological study based on hospital admissions. Q J Med 1987;62:67–74. [19] Chang L, Toner BB, Fukudo S, et al. Gender, age, society, culture, and the patient’s perspective in the functional gastrointestinal disorders. Gastroenterology 2006;130(5): 1435–46. [20] Locke GR III, Talley NJ, Fett SL, et al. Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmsted County, Minnesota. Gastroenterology 1997;112:1448–56. [21] Eslick GD, Jones MP, Talley NJ. Non-cardiac chest pain: prevalence, risk factors, impact and consulting–a population-based study. Aliment Pharmacol Ther 2003;17:1115–24. [22] Prina LD, Decker WW, Weaver AL, et al. Outcome of patients with a final diagnosis of chest pain of undetermined origin admitted under the suspicion of acute coronary syndrome: a report from the Rochester epidemiology project. Ann Emerg Med 2004;43(1):59–67.
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[23] Cormier LE, Katon W, Russo J, et al. Chest pain with negative cardiac diagnostic studies: relationship to psychiatric illness. J Nerv Ment Dis 1988;176:351–8. [24] Andersen LI, Jensen G. Prevalence of benign oesophageal disease in the Danish population with special reference to pulmonary disease. J Intern Med 1989;225:393–401. [25] Achem S, DeVault KR. Dysphagia in the elderly [review]. J Clin Gastroenterol 2005;39: 357–71. [26] Talley NJ, Stanghellini V, Heading RC, et al. Functional gastroduodenal disorders. Gut 1999;45(Suppl 2):II37–42. [27] Jones R, Lydeard S. Prevalence of symptoms of dyspepsia in the community. BMJ 1989;298(6665):30–2. [28] Locke GR. Prevalence, incidence and natural history of dyspepsia and functional dyspepsia. Baillieres Clin Gastroenterol 1998;12(3):435–42. [29] Johnsen R, Bernersen B, Straume B. Prevalences of endoscopic and histologic findings in subjects with and without dyspepsia. BMJ 1991;302:749–52. [30] Talley NJ, Zinsmeister AR, Schleck CD, et al. Dyspepsia and dyspepsia subgroups: a population-based study. Gastroenterology 1992;102:1259–68. [31] Agreus L, Svardsudd K, Nyren O, et al. The epidemiology of abdominal symptoms: prevalence and demographic characteristics in a Swedish adult population. A report from the Abdominal Symptom Study. Scand J Gastroenterol 1994;29:102–9. [32] Kay L. Prevalence, incidence and prognosis of gastrointestinal symptoms in a random sample of an elderly population. Age Ageing 1994;23(2):146–9. [33] Kay L, Jorgensen T. Epidemiology of upper dyspepsia in a random population: prevalence, incidence, natural history, and risk factors. Scand J Gastroenterol 1994;29:2–6. [34] Frexinos J, Denis P, Allemand H, et al. [Descriptive study of digestive functional symptoms in the French general population]. Gastroenterol Clin Biol 1998;22:785–91 [in French]. [35] Horowitz M, Su YC, Rayner CK, et al. Gastroparesis: prevalence, clinical significance and treatment. Can J Gastroenterol 2001;15(12):805–13. [36] Sandler RS. Epidemiology of irritable bowel syndrome in the United States. Gastroenterology 1990;99:409–15. [37] Talley NJ, Zinsmeister AR, Van Dyke C, et al. Epidemiology of colonic symptoms and the irritable bowel syndrome. Gastroenterology 1991;101:927–34. [38] Jones R, Lydeard S. Irritable bowel syndrome in the general population. BMJ 1992;304: 87–90. [39] Kay L, Jorgensen T, Jensen KH. The epidemiology of irritable bowel syndrome in a random population: prevalence, incidence, natural history and risk factors. J Intern Med 1994;236: 23–30. [40] Saito YA, Talley NJ, Melton J, et al. The effect of new diagnostic criteria for irritable bowel syndrome on community prevalence estimates. Neurogastroenterol Motil 2003;15: 687–94. [41] Longstreth GF, Wolde-Tsadik G. Irritable bowel-type symptoms in HMO examinees: prevalence, demographics, and clinical correlates. Dig Dis Sci 1993;38:1581–9. [42] van der Horst HE, van Dulmen AM, Schellevis FG, et al. Do patients with irritable bowel syndrome in primary care really differ from outpatients with irritable bowel syndrome? Gut 1997;41:669–74. [43] Taub E, Cuevas JL, Cook EW III, et al. Irritable bowel syndrome defined by factor analysis: gender and race comparisons. Dig Dis Sci 1995;40:2647–55. [44] Simren M, Abrahamsson H, Svedlund J, et al. Quality of life in patients with irritable bowel syndrome seen in referral centers versus primary care: the impact of gender and predominant bowel pattern. Scand J Gastroenterol 2001;36:545–52. [45] Talley NJ, Boyce P, Jones M. Identification of distinct upper and lower gastrointestinal symptom groupings in an urban population. Gut 1998;42:690–5. [46] Talley NJ, O’Keefe EA, Zinsmeister AR, et al. Prevalence of gastrointestinal symptoms in the elderly: a population-based study. Gastroenterology 1992;102(3):895–901.
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[47] Sandler RS, Stewart WF, Liberman JN, et al. Abdominal pain, bloating, and diarrhea in the United States: prevalence and impact. Dig Dis Sci 2000;45:1166–71. [48] Talley NJ. Diagnosing an irritable bowel: does sex matter? Gastroenterology 1991;100: 834–7. [49] Everhart JE, Go VL, Johannes RS, et al. A longitudinal survey of self-reported bowel habits in the United States. Dig Dis Sci 1989;34:1153–62. [50] Stewart WF, Liberman JN, Sandler RS, et al. Epidemiology of constipation (EPOC) study in the United States: relation of clinical subtypes to sociodemographic features. Am J Gastroenterol 1999;94:3530–40. [51] Pare P, Ferrazzi S, Thompson WG, et al. An epidemiological survey of constipation in Canada: definitions, rates, demographics, and predictors of health care seeking. Am J Gastroenterol 2001;96:3130–7. [52] Chen GD, Hu SW, Chen YC, et al. Prevalence and correlations of anal incontinence and constipation in Taiwanese women. Neurourol Urodyn 2003;22:664–9. [53] Wong ML, Wee S, Pin CH, et al. Sociodemographic and lifestyle factors associated with constipation in an elderly Asian community. Am J Gastroenterol 1999;94:1283–91. [54] Wei X, Chen M, Wang J. [The epidemiology of irritable bowel syndrome and functional constipation of Guangzhou residents]. Zhonghua Nei Ke Za Zhi 2001;40:517–20 [in Chinese]. [55] Talley NJ, Weaver AL, Zinsmeister AR, et al. Self-reported diarrhea: what does it mean? Am J Gastroenterol 1994;89(8):1160–4. [56] Lynch AC, Dobbs BR, Keating J, et al. The prevalence of faecal incontinence and constipation in a general New Zealand population; a postal survey. N Z Med J 2001;114:474–7. [57] Rizk DE, Hassan MY, Shaheen H, et al. The prevalence and determinants of health careseeking behavior for fecal incontinence in multiparous United Arab Emirates females. Dis Colon Rectum 2001;44:1850–6. [58] Nelson R, Furner S, Jesudason V. Fecal incontinence in Wisconsin nursing homes: prevalence and associations. Dis Colon Rectum 1998;41:1226–9. [59] Edwards NI, Jones D. The prevalence of faecal incontinence in older people living at home. Age Ageing 2001;30:503–7. [60] Walter S, Hallbook O, Gotthard R, et al. A population-based study on bowel habits in a Swedish community: prevalence of faecal incontinence and constipation. Scand J Gastroenterol 2002;37:911–6. [61] Talley NJ, Weaver AL, Zinsmeister AR, et al. Functional constipation and outlet delay: a population-based study. Gastroenterology 1993;105:781–90. [62] Hyman PE,, Milla PJ, Benninga MA, et al. Childhood functional gastrointestinal disorders: neonate/toddler. Gastroenterology 2006;130(5):1519–26.
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Evolving Concepts in the Cellular Control of Gastrointestinal Motility: Neurogastroenterology and Enteric Sciences Amelia Mazzone, PhDa,b, Gianrico Farrugia, MDa,b,* a
Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA b Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA
T
he function of the gastrointestinal tract is controlled by a dynamic interaction between different cell types that interact directly, or through a large number of signaling molecules. Enteric neural integrity is essential for normal gastrointestinal motility, as is a constant communication between the enteric and the central nervous system (CNS). Smooth muscle cells form an electrical syncytium within the gut and are innervated, directly or indirectly, by neurons. Not only are smooth muscle cells the final effector cells that result in gastrointestinal motility, but recently they have been found also to have an active role in the control of motility. The basic electrical rhythm of the gut, the slow waves, originates from a complex network of cells known as ‘‘interstitial cells of Cajal’’ (ICC). ICC not only generates the slow wave but is also involved in effective neurotransmission and in the control of smooth muscle membrane potential. Other cellular elements, such as the immune system and enteric glia, are now increasingly understood actively to be involved in the modulation of intestinal functions. The study of the complex interaction of different kind of cells is known as ‘‘neurogastroenterology,’’ a subspecialty of gastroenterology that focuses on understanding the control of the sensory and motor function of the gastrointestinal tract in health and disease. ENTERIC NERVOUS SYSTEM The enteric nervous system (ENS) regulates most of the physiologic and pathophysiologic processes in the gastrointestinal tract. These include control of This work was supported by grants DK17238, 57061, and 68055 from the National Institutes of Health.
*Corresponding author. Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905. E-mail address: farrugia.
[email protected] (G. Farrugia). 0889-8553/07/$ – see front matter doi:10.1016/j.gtc.2007.07.003
ª 2007 Elsevier Inc. All rights reserved. gastro.theclinics.com
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motor functions for the transport of luminal content, regulation of blood flow and of secretion and absorption, and modulation of the immune response against pathogens. The ENS consists of a network of enteric neurons organized in ganglia interconnected by nerve fiber bundles surrounded by support cells. These neural circuits are able to exchange and integrate information in a way similar to the CNS, including generation of reflexes; the ENS often is referred to as the ‘‘little brain.’’ The ENS is made up of two major components. The submucosal plexus is located between the inner layer of the circular muscle and the submucosa and is more developed in the small and large intestine. Its role is mainly in the regulation of mucosal and vascular functions in responses to nutrients. In large mammals, submucosal ganglia form two distinct, but interconnected, plexuses that are defined as inner and outer submucosal plexus [1]. The myenteric plexus lies between the inner circular and outer longitudinal smooth muscle layers along the entire gastrointestinal tract and it is mainly involved in the coordination of the activity of the muscle layers. In the small intestine a deep muscular plexus is also present, made up of nerve bundles (without cell bodies). The deep muscular plexus lies between the most inner circular smooth muscle cells and the rest of the circular muscle layer. Work on identification and classification of enteric neurons has been performed mostly in the guinea pig small intestine [2], but the overall organization and function of neurons is applicable to larger mammals, including humans. Based on morphology, electrophysiologic properties, function, and neurochemistry, enteric neurons can be classified in intrinsic primary afferent neurons (IPANs), interneurons, motor neurons, and intestinofugal neurons (Fig. 1). IPANs respond to mechanical and chemical stimuli and regulate the physiologic function of the gastrointestinal tract by transmitting information to other neurons. IPANs initiate intestinal reflexes. The somewhat laborious name given to these neurons rather than the more commonly used term ‘‘sensory neurons’’ is because of the fact that IPANS do not usually convey sensation from the intestine, as demonstrated by Kirchgessner and colleagues [3]. There are no nerve endings that directly reach the lumen of the gut; sensation occurs through enterochromaffin cells, located in the enteric epithelium, which work as sensory transducers [4]. IPANS are found in both plexi [5] and are cholinergic neurons [6]. Motor neurons are either excitatory or inhibitory and innervate the muscle layers of the digestive tract and blood vessels and glands. The cell bodies of motor neurons that supply the muscle layers are located in the myenteric ganglia, but there is evidence that there are a few cell bodies that innervate the muscle layers in submucosal ganglia [7]. The primary transmitters of the excitatory motor neurons are acetylcholine and tachykinins, such as substance P and neurokinin A. Inhibitory neurons use a larger spectrum of transmitters including nitric oxide, vasoactive intestinal polypeptide, c-aminobutyric acid, ATP, carbon monoxide, and pituitary adenyl cyclase–activating polypeptide [8]. Regulation of secretion of water and electrolytes and of blood flow in
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Fig. 1. Types of neurons in the enteric nervous system. 1. interneuron; 2. excitatory longitudinal muscle motor neuron; 3. myenteric intrinsic primary afferent neuron; 4. inhibitory longitudinal muscle motor neuron; 5. intestinofugal neuron; 6. myenteric plexus interstitial cell of Cajal; 7. excitatory circular muscle motor neuron; 8. inhibitory circular muscle motor neuron; 9. circular muscle interstitial cell of Cajal; 10. cholinergic secretomotor (nonvasodilator) neuron; 11. cholinergic secretomotor neuron; 12. noncholinergic vasomotor neuron; 13. submucosal intrinsic primary afferent neuron; 14. mucosal cell; 15. enterochromaffin cell. PVG, prevertebral ganglia. (Adapted from Furness JB. The enteric nervous system. Blackwell Publishing: Oxford, UK; 2006; p. 30; with permission.)
the gut occurs by secretomotor and vasomotor neurons, respectively. The cell bodies of these neurons reside in the submucosal plexus [9]. Interneurons are defined as ascending or descending based on whether their processes run orally or anally. They integrate information from IPANs and, in general, relay the information to enteric motor neurons. At least one type of ascending and three types of descending interneurons have been described in the small intestine of guinea pig [10]. Ascending interneurons are mainly cholinergic, whereas descending motor neurons have a varied and complex neurochemistry [11]. Ascending interneurons and the three types of the descending ones participate in local motility reflexes. A fourth type of descending interneuron conducts the migrating myenteric complexes (MMC). Ascending interneurons project to other myenteric neurons, whereas descending interneurons also innervate the submucosal plexus. A fourth class of enteric neurons, intestinofugal afferent neurons (IFANs), have their cell bodies within the myenteric plexus but send their processes out of the gut wall to form synapses with the inferior and superior mesenteric ganglia and the celiac ganglion (collectively known as ‘‘prevertebral ganglia’’) [12]. IFANs carry efferent signals from the gut and they work as mechanoreceptors that detect changes in gut volume [12]. Primary IFANs transmit directly to the prevertebral ganglia without synaptic interruption, whereas another
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population of intestinofugal neurons receives information arising from other enteric neurons [13]. MOTOR PATTERNS Coordinated activation of enteric neuronal circuits is responsible for the rhythmic and regular contraction of the gastrointestinal muscle and the aboral transport of the luminal content. Control of gastrointestinal motor function requires the coordinated function of several cell types. Four fundamental patterns of motility are present in the small intestine: (1) peristalsis, (2) segmentation, (3) the migratory motor complex, and (4) the postprandial motor pattern. Peristalsis consists of contraction waves that propagate along the gastrointestinal tract that mix and propel content distally. Peristalsis is initiated by mechanical and chemical stimuli triggered by the presence of a bolus in the gut lumen. These stimuli activate IPANs, which then activate ascending and descending interneurons, which activate excitatory and inhibitory motor neurons. Activation of excitatory motor neurons above the bolus results in contraction of smooth muscle above the bolus. Activation of inhibitory motor neurons results in relaxation of smooth muscle below the bolus. Shortening of the muscle immediately below the bolus also occurs as a result of descending excitation [14]. The rhythmicity of peristalsis is determined by the electrical activity of the ICC. Peristalsis is not affected by vagotomy or sympathetectomy, indicating it is mediated exclusively by the ENS. The ENS also initiates clusters of contractions that are nonpropulsive. These segmental contractions have the purpose of mixing chyme with digestive juices exposing it to the mucosa for absorption [15]. The MMC is a specific pattern of motor activity identified in the stomach and small intestine smooth muscle during fasting in most mammalian species, including human. The MMC clears the stomach and intestine of residual food and mucosal debris and prevents microorganism overgrowth [16]. The MMC is a periodic activity with a cycle time of about 1.5 to 2 hours in humans; it can be divided into four phases. Phase I is a quiescent phase of about 45 to 60 minutes during which there are only rare action potentials and contractions that progressively increase in frequency, followed by an irregular phase II of 30 minutes characterized by random activity. In phase III, also called the activity front, each slow wave is associated with spike potentials and resulting contractions, which consist of bands of quickly moving, evenly spaced contractions. This phase lasts for about 5 to 15 minutes. In contrast to the digestive period, the pylorus remains open during these peristaltic contractions, allowing many indigestible materials to pass into the small intestine. Phase IV is a brief cycle of irregular activity in between phase III and phase I. Extrinsic stimuli can modulate the MMC but are not required for its initiation or propagation. The progression of the activity front is a result of sequential activation of a specialized class of descending interneurons. Following the ingestion of a meal, the MMC is replaced by an irregular activity, similar to phase II, which in humans lasts for 1 to 2 hours.
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Colon motility is irregular and complex and the neuronal control of colonic patterns of motility is not yet well delineated. There are several distinct colonic motor patterns. The baseline pattern is one of seemingly chaotic, irregular contractile activity. Another pattern consists of high-amplitude propagated contractions. These often, but not always, propagate colonic content over long segments of the colon and can be associated with the urge to defecate [17]. The occurrence of these contractions is not regulated by slow waves and their duration in dogs is approximately 18 to 20 seconds [18]. Electrical activity that underlies motor activity in the colon is also not as well delineated as in the stomach and small bowel. Electrical activity recorded from the colonic myenteric plexus region is not in the form of electrical slow waves as in the small intestine and stomach but is in the form of frequent oscillations in membrane potential that originate near the myenteric border or within longitudinal muscle, and conduct through most of the circular muscle [18], defined as myenteric potential oscillations. Electrical slow waves do originate from submucosal plexus ICC but their role in regulating smooth muscle contractile activity is not yet established. EXTRINSIC CONTROL OF ENTERIC NERVOUS SYSTEM There is a close functional relationship between the ENS and the CNS in the control of gut function. Extrinsic afferent and efferent pathways transfer stimuli to and from the gut, respectively, providing a constant exchange of information between CNS and ENS. Afferent neurons signal information to the CNS about the chemical content of the gut lumen; about the mechanical status (tension or relaxation) of the gut wall; and about the condition of tissues (inflammation, pH, heat, cold). Efferent neurons transmit information from the CNS to the ENS. CNS neurons do not directly innervate smooth muscle cells. Both afferent and efferent nerves follow two major pathways (spinal and vagal) (see [19] for a review). Extrinsic Efferents The primary transmitter of sympathetic postganglionic neurons that supply the gastrointestinal tract is norepinephrine. Efferent neurons innervating the gut originate from prevertebral or paravertebral ganglia. Most cell bodies of sympathetic postganglionic neurons, located in paravertebral ganglia, control gastrointestinal blood vessels. Three other classes of neurons, whose cell bodies reside in the prevertebral ganglia, control motility and secretion. Several important roles of the upper gastrointestinal tract, such as gastric fundic relaxation and gastric and pancreatic secretion, are mediated through vagal neurons whose cell bodies lie within the brainstem. In contrast to the upper gut, the distal colon and rectum are innervated by pelvic nerves, not the vagus. In general, vagal stimulation causes inhibition of gastrointestinal secretion and motor activity, and contraction of gastrointestinal sphincters and blood vessels. Conversely, spinal stimuli typically stimulate these digestive activities.
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Extrinsic Primary Afferents Afferent innervation conveys sensory information from the gut to the CNS activating spinal and vagal-pelvic reflexes. Extrinsic primary afferent neurons (EPANs) are classified in vagal and spinal based on the physical location of their cell bodies. Vagal primary afferent neurons have cell bodies in the nodose and jugular ganglia and project centrally to the brainstem, whereas the cell bodies of the spinal EPANs are located in the dorsal root ganglia. Vagal afferent pathways carry information about the physiologic state of the digestive organs (eg, satiety and nausea) and regulate inflammatory responses, whereas spinal afferents primarily mediate pain impulses [20]. Similar to vagal efferents, vagal afferents are concentrated mainly in the upper gastrointestinal tract, whereas pelvic afferents innervate mostly the lower bowel; spinal afferents are distributed throughout the gut by splanchnic nerves [21]. SENSATION OF THE GUT Humans are usually not aware of the ongoing functions of the gastrointestinal tract, such as contractile activity, digestion, and absorption. In health, physiologic stimuli from the gut induce motor reflexes, but these remain largely unperceived, with the exception of those related to ingestion and excretion. Although these processes generally do not reach a level of sensation unless they go awry, they are closely monitored by specialized neurons in both the enteric and extrinsic nervous systems of the gastrointestinal tract. Food intake, contractile activity, and metabolic products of the enteric flora regulate digestive motility through the brain-gut axis mediated by extrinsic nerves, intrinsic neurons, and gastrointestinal hormones. These processes are also influenced by the environment and emotions. Disturbed digestive motility often contributes to the generation of gastrointestinal symptoms in various diseases. Two types of primary afferent neurons are involved in the detection of changes in the gastrointestinal environment: IPANs (whose cell bodies and processes never leave the gut) and vagal and spinal EPANs (whose cell bodies reside outside the gut). A third cell type, IFANs (whose cell body is within the gut but whose processes leave the gut), also participates in detecting gut stimuli. No nerve cell processes reach the enteric lumen. Sensation must be accomplished transepithelially by means of specialized cells, enteroendocrine cells. The best characterized of these sensory transducers are enterochromaffin cells that have been demonstrated to respond not only to mechanical pressure [22] but also to nutrients (eg, glucose or fatty acids) present in the intestinal lumen, by releasing chemical mediators into the wall of the gut and initiating responses [23,24]. Mechanosensation Mechanosensitivity, in particular that mediated by spinal afferents, can be transduced by a wide range of chemical mediators released following detection of mechanical stimuli inside the lumen of the gut. Paracrine mediators of distention include serotonin, cholecystokinin, gastrin, somatostatin, and peptide YY. Release of peptides activates intrinsic and extrinsic afferent neurons
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present in the submucosal plexus. The intrinsic afferents provide the basis for local reflexes that control and coordinate gastrointestinal function. Stretchsensitive IPANs also respond to tension in the muscle and to direct distortion of their processes [25] and communicate the information by the discharge of action potentials, through gating of mechanosensitive ion channels that are expressed in neurons [26]. Mechanical stimuli are also detected by EPANs and transferred to the CNS, to be processed and to evoke a reaction, through the combined action of vagal and spinal pathways. Vagal mechanosensitive EPANs are activated by low-intensity mechanical stimuli and can be classified based on localization of the terminal ending receiving the stimulus. Mucosal stroking, but not distention, stimulates one class of EPANs whose terminals innervate the gut mucosa. A second class responds to food intake by reacting to gut wall tension within the physiologic range (<10 mm Hg). These EPANs have endings in the muscle and mediate satiety [27]. The third class of vagal nerves is in close association with ICC, suggesting that ICC may be involved in afferent neural transduction [28]. Spinal afferents convey to the CNS discomfort and pain through nerve endings that reside in the muscle wall. In contrast to vagal afferents, spinal afferents also respond to intense stimuli that go beyond the physiologic range. A subclass of spinal afferents responds to distending pressures that exceed 30 mm Hg (high threshold mechanoreceptors) and are considered as mechanonocireceptors. They encode both physiologic and noxious levels of stimulation [20]. Intestinofugal processes, whose cell bodies are in the myenteric plexus, project to the prevertebral ganglia. Mechanosensory IFANs function as volume detectors, and unlike most vagal and spinal mechanosensitive afferent nerves, are arranged ‘‘in parallel’’ with the circular muscle layer [12]. This arrangement results in a decrease in synaptic input with a decrease of the colon circumference. Chemosensation Chemosensation is also mediated by enteroendocrine cells, which act as the sensory mediator between the mucosal epithelial cells and the neuronal system. Immune cells also seem to play a role in the process of chemosensation in the gut. Direct innervation of mast cells has been shown and also a functional connection between mast cells and extrinsic afferent nerves by the release of mediators, such as histamine and serotonin (see [29] for a review). Data generated from functional experiments that measured inhibition of gastric motility or acid secretion as a measure of activation of sensors have yielded useful information about the mechanism by which nutrients are perceived by the intestinal wall. Chemosensation is a separate process from osmotic or mechanical effects. Also, the different nutrient groups activate distinct pathways and mechanisms. Vagal and spinal EPANs are involved in the response to chemical stimulation of the gastrointestinal tract wall and mediate inhibition of gastric emptying and secretion by generating satiety, nausea, and vomiting sensations. Chemical mediators can also directly trigger the response of mechanosensitive afferent
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nerves [30]. A subset of spinal chemosensitive receptors have been identified that can only be activated after high threshold stimulations, such as inflammation. These receptors are considered silent nociceptors because they do not normally respond to physiologic stimuli. Activators include inflammatory mediators and a variety of neuronal released factors including nerve growth factor [30]. INTERSTITIAL CELL OF CAJAL ICC were tentatively identified in the 1890s by histochemical techniques using methylene blue and silver staining [31]. They are mesenchymal cells, interposed between enteric nerves and smooth muscle cells (Fig. 2), with small cell bodies and several elongated processes and are classified based on their distribution. In most regions of the gastrointestinal tract, there is a network of ICC cells lying between the longitudinal and circular layers in the myenteric region (ICC-MY). This subclass of ICC is largest in the corpus and antrum of the stomach and in the small intestine [32]. A second group of ICC has an intramuscular location (ICC-IM), with individual ICC being distributed among the smooth muscle cells in the muscle layers. Intramuscular ICC are found in all levels of the human gut, unlike smaller animals. In the small intestine, ICC also form a second network between the innermost and outer circular muscle cells, known as the ‘‘deep muscular plexus’’ (ICC-DMP). In the gastric antrum, ICC-IM are widely distributed throughout the circular layer and only very few are found in the longitudinal layer (see [33] for a review). In the fundus, a myenteric network of ICC is absent, but ICC-IM are widely distributed through both the circular and longitudinal muscle layers [32]. In the colon,
Fig. 2. Innervation of smooth muscle cells. Two mechanisms for neuronal innervation of gastrointestinal smooth muscle exist. Most innervation occurs through interstitial cells of Cajal. Neurons can also directly innervate intestinal smooth muscle cells. ICC, interstitial cells of Cajal.
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there is also a population of ICC located at the submucosal surface of the circular muscle (ICC-SMP) but no ICC-DMP present. The close association between ICC and enteric neurons suggested since the beginning of the 1900s that ICC could mediate neurotransmission in peripheral tissues [34] and their ability to work as pacemakers of the gut had been suggested a few decades ago [35,36]. Direct evidence for the importance of ICC in the generation of slow waves came from experiments on the small intestines of W/WV mutant mice, in which the development of myenteric ICC is impaired. In the homozygote all ICC are absent and the mutation is lethal. In the heterozygote strain, ICC-MY are absent and mice are unable to generate slow waves [37,38]. The pacemaker function of ICC has since been confirmed by several studies, although the pacemaker channel has yet to be elucidated. These pacemaker ICC generate the electrical slow wave, a regular depolarization that consists of a rapid upstroke and a longer plateau phase followed by a repolarization. This slow wave is passively transmitted to smooth muscle and controls chronotropicity and ionotropicity. Not all the classes of ICC work as pacemakers. In the stomach, pacemaker activity is a function of both ICC-MP and ICC-IM, in the small intestine by ICC-MP [39,40], and in the colon likely by ICC-SMP [41]. ICC activity is influenced by motor neurons of the ENS through the release of neurotransmitters. In general, cholinergic stimulation increases the slow wave frequency [42], or decreases the frequency but increases the slow wave duration [43]. Noradrenaline, however, has an inhibitory effect in the colon [44], whereas it increases slow wave frequency in the stomach [45]. It has been demonstrated that ICC can form synapse-like junctions with nerves and gap junctions with smooth muscle cells [46], although the role of these gap junctions is not established. ICC also mediate neurotransmission. Both ICC-IM and ICC-DMP are required for effective cholinergic and nitrergic neurotransmission [37,47,48] but not for all forms of neurotransmission. There are two ways by which enteric nerves regulate smooth muscle activity. One is by direct contact with smooth muscle; the other is through the ICC. An additional role for ICC is to hyperpolarize intestinal smooth muscle by generating carbon monoxide [49]. Carbon monoxide regulates gastrointestinal contractile activity because it is a hyperpolarizing factor and also because it helps set the intestinal smooth muscle membrane potential gradient. In the gut there is a membrane potential gradient that allows a graded contractile response to a stimulus, with a weak stimulus recruiting only the more depolarized smooth muscle and a stronger stimulus recruiting more hyperpolarized smooth muscle [39]. This gradient is a function of ICC and occurs through the generation of carbon monoxide [49]. ICC also function as mechanosensors. ICC and smooth muscle are in close contact through peg and socket junctions [50]. It has recently been shown that both human ICC and smooth muscle express the mechanosensitive Na channel Nav1.5. Mechanical activation of this channel results in changes in membrane potential and slow wave frequency [51].
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SMOOTH MUSCLE Smooth muscle represents the final end point in the regulation of gut motility and is the contractile unit. Smooth muscle in the gut has a large variability in contractile properties. Phasic smooth muscles, such as those found in the gastrointestinal tract, can undergo rhythmic rapid contraction cycles, whereas tonic smooth muscles, such as those found in blood vessels and sphincters, have slower shortening velocities and assist in blood pressure regulation by their ability to maintain prolonged contractions with little energy expenditure. For example, in the esophagus the lower esophageal sphincter maintains a sustained pressure and relaxes to allow the passage of a bolus, whereas the body of the esophagus is normally relaxed and contracts only briefly when required to propel food. To carry out their mechanical function effectively, smooth muscle cells are organized into bundles and the contractile apparatus of smooth muscle should be viewed as a structure that transcends cell boundaries. Smooth muscle cells within individual bundles are connected to one another with longitudinal axes of the cells lying parallel to the direction of force transmission through the bundle [52]. The functional variation in the mechanical properties of smooth muscle may be correlated with the myosin heavy chain content and isoform expression that account for some of these functional phenotypes [53]. The major determinant of gut smooth muscle contractility is Ca2þ entry through L-type Ca2þ channels. Smooth muscle cells are depolarized by the ICC-generated slow wave, which results in activation of L-type Ca2þ channels and Ca2þ entry. This also then leads to activation of Ca2þ release channels expressed in the membrane of the sarcoplasmic reticulum. The L-type Ca2þ channel is mechanosensitive, suggesting that smooth muscle cells are not only motor organs but also sensory organs, able to sense stretch and respond by modulating Ca2þ entry and subsequently contractility [54,55]. Until recently, voltage-gated Naþ channels, the primary molecules responsible for generating the action potentials in most electrically excitable cells, were not identified in gastrointestinal smooth muscle cells. Action potential in gastrointestinal smooth muscle is predominantly carried by Ca2þ not Naþ. In the past 10 years or so, sodium channels have also been identified in smooth muscle cells throughout the gastrointestinal tract [56–60]. In particular, a sodium channel identified as Nav1.5 is expressed in human gastrointestinal smooth muscle cells and ICC [51]. This channel allows sufficient Naþ entry to modulate resting membrane potential of the cells [61]. The channel is also mechanosensitive [51], resulting in mechanical regulation of the membrane potential and slow wave. The finding of Nav1.5 in the human gut is of interest because a recent study showed that subjects with mutations in the gene encoding for the Nav1.5 sodium channel were much more likely to have abdominal pain and other gastrointestinal symptoms than controls. This observation raises the possibility that, in a subset of patients, ionchannelopathies occur in the gastrointestinal tract and may contribute to motility and functional bowel disorders [62].
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IMMUNE CELLS Motility of the gut is also affected by the immune system. Communication between nerves and immune and inflammatory cells of the intestine result in modulation of several intestinal functions, including motility, ion transport, and mucosal permeability. The role of the immune system is to recognize foreign and potentially harmful organisms or substances in the gut lumen, to contain and limit their access to the intestinal milieu, and to promote the eviction of these agents from the gut. The effect of the immune system on intestinal motility was demonstrated by experiments showing that intraluminal exposure of the animal to a sensitizing antigen causes diarrhea and marked changes in intestinal myoelectric activity [63]. The ENS may, under certain conditions, act as an extension of the immune system to defend the host from pathogens. Gastrointestinal motility is normally determined by myogenic, ICC, efferent, and afferent neural and hormonal control mechanisms. Each of these mechanisms is subject to modulation by the immune system, whose products have been shown to influence the excitability of smooth muscle, peripheral, enteric, and central nerves. Discrimination between beneficial commensal organisms and potentially harmful pathogens is a central role of immune cells to maintain the balance between immune activation and tolerance. Immune action against nonpathogenic materials, besides being wasteful, can also lead to inflammatory disorders (see review [64]). Neuroimmune interactions are associated with the pathophysiology of infectious and enterotoxinmediated diarrhea and intestinal inflammation, including inflammatory bowel disease and more recently irritable bowel syndrome [65]. In the small intestine, gut-associated lymphoid tissues consist of organized lymphoid structures (mesenteric lymph nodes and aggregated lymphoid follicles defined Peyer’s patches) and diffusely distributed populations of B and T lymphocytes. Foreign antigens in the gut lumen are transported to the Peyer’s patches were they are sampled by antigen-presenting cells. Peyer’s patch contains antigen-presenting cells of all major types including dendritic cells, macrophages, and B cells for initiation of mucosal responses. The status of antigen-presenting cells determines whether an antigen induces tolerance or protective immunity. Dendritic cells are the antigen-presenting cells, which seem to be the most important in these events. Under physiologic conditions, antigens (eg, food, proteins, or commensal bacteria) are recognized by quiescent dendritic cells, resulting in tolerance. When inflammatory stimulus are present, however, local dendritic cells become activated and stimulate production of T cells and the initiation of the immune response. Humoral immune responses at mucosal surfaces, including the intestinal epithelium, are characterized by production of immunoglobulins. IgA is the most abundant immunoglobulin isotype in mucosal secretions and its transport to the luminal side across the epithelium represents a first line of defense against pathogens. Peyer’s patches are considered to be the major inductive site of IgA in response to antigens in the lumen of the gastrointestinal tract. Part of the intestinal IgA produced against cell wall antigens and proteins of
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commensal bacteria is specifically induced in response to their presence within the microflora to control their numbers [66]. Mast cells are also important mediators of neuroimmune interactions. They are present in the lamina propria throughout the colon. In the ileocecal region in particular, there is an increase in the degree of mast cell infiltration during inflammation. Mast cells are in close proximity to nerves in both health and in disease. There is cross-talk between mast cells and nerves in the gut wall. Mast cells release mediators in response to certain neuropeptides and are ideally placed to mediate neuroimmune interactions [29,67]. Communication between immune system, nerves, ICC, and smooth muscle cells occurs through a myriad of mediators released in response to inflammation or sensitizing antigens. These include such molecules as histamine, somatostatin, adenosine, interleukin-6, nitric oxide, and prostaglandins (see [68] for a review). Enteric glial cells were, until recently, largely overlooked. Glial cells were thought to be only support cells for enteric nerves. It is now increasingly known that glia plays an important additional role in mucosal protection, in the inflammatory response, and in signal transduction [69]. SUMMARY The ENS is an independent nervous system with a complexity comparable with the CNS. This complex system is integrated into several other complex systems, such as ICC networks and immune cells. The result of these interactions is effective coordination of motility, secretion, and blood flow in the gastrointestinal tract. Much progress has been made in recent years on the understanding of these complex interacting networks. Loss of subsets of enteric nerves, loss of ICC, malfunction of smooth muscle, and alteration in immune cells have been identified as the basis of many motility disorders. Clinicians now need to understand the initial factors triggering these changes and how to intervene to prevent, halt, and reverse them. References [1] Timmermans JP, Hens J, Adriaensen D. Outer submucous plexus: an intrinsic nerve network involved in both secretory and motility processes in the intestine of large mammals and humans. Anat Rec 2001;262(1):71–8. [2] Costa M, Brookes SJ, Steele PA, et al. Neurochemical classification of myenteric neurons in the guinea-pig ileum. Neuroscience 1996;75(3):949–67. [3] Kirchgessner AL, Tamir H, Gershon MD. Identification and stimulation by serotonin of intrinsic sensory neurons of the submucosal plexus of the guinea pig gut: activity-induced expression of Fos immunoreactivity. J Neurosci 1992;12(1):235–48. [4] Gershon MD. Plasticity in serotonin control mechanisms in the gut. Curr Opin Pharmacol 2003;3(6):600–7. [5] Kirchgessner AL, Gershon MD. Projections of submucosal neurons to the myenteric plexus of the guinea pig intestine: in vitro tracing of microcircuits by retrograde and anterograde transport. J Comp Neurol 1988;277(4):487–98. [6] Li ZS, Furness JB. Immunohistochemical localisation of cholinergic markers in putative intrinsic primary afferent neurons of the guinea-pig small intestine. Cell Tissue Res 1998;294(1): 35–43.
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[7] Furness JB, Lloyd KC, Sternini C, et al. Projections of substance P, vasoactive intestinal peptide and tyrosine hydroxylase immunoreactive nerve fibres in the canine intestine, with special reference to the innervation of the circular muscle. Arch Histol Cytol 1990;53(2):129–40. [8] Lecci A, Santicioli P, Maggi CA. Pharmacology of transmission to gastrointestinal muscle. Curr Opin Pharmacol 2002;2(6):630–41. [9] Furness JB. Types of neurons in the enteric nervous system. J Auton Nerv Syst 2000;81(1–3): 87–96. [10] Brookes SJ. Classes of enteric nerve cells in the guinea-pig small intestine. Anat Rec 2001;262(1):58–70. [11] Bornstein JC, Costa M, Grider JR. Enteric motor and interneuronal circuits controlling motility. Neurogastroenterol Motil 2004;16(Suppl 1):34–8. [12] Szurszewski JH, Ermilov LG, Miller SM. Prevertebral ganglia and intestinofugal afferent neurones. Gut 2002;51(Suppl 1):i6–10. [13] Szurszewski JH, Miller SM. Physiology of prevertebral sympathetic ganglia. In: Johnson LR, editor. Physiology of the gastrointestinal tract. 4th edition. Amsterdam: Academic Press; 2006. p. 603–27. [14] Bayliss WM, Starling EH. The movements and innervation of the small intestine. J Physiol 1899;24(2):99–143. [15] Ehrlein HJ, Schemann M, Siegle ML. Motor patterns of small intestine determined by closely spaced extraluminal transducers and videofluoroscopy. Am J Physiol 1987;253(3 Pt 1): G259–67. [16] Szurszewski JH. A migrating electric complex of canine small intestine. Am J Physiol 1969;217(6):1757–63. [17] Narducci F, Bassotti G, Gaburri M, et al. Twenty four hour manometric recording of colonic motor activity in healthy man. Gut 1987;28(1):17–25. [18] Sarna SK. Giant migrating contractions and their myoelectric correlates in the small intestine. Am J Physiol 1987;253(5 Pt 1):G697–705. [19] Aziz Q, Thompson DG. Brain-gut axis in health and disease. Gastroenterology 1998; 114(3):559–78. [20] Grundy D. Neuroanatomy of visceral nociception: vagal and splanchnic afferent. Gut 2002;51(Suppl 1):i2–5. [21] Berthoud HR, Blackshaw LA, Brookes SJ, et al. Neuroanatomy of extrinsic afferents supplying the gastrointestinal tract. Neurogastroenterol Motil 2004;16(Suppl 1): 28–33. [22] Bulbring E, Crema A. The release of 5-hydroxytryptamine in relation to pressure exerted on the intestinal mucosa. J Physiol 1959;146(1):18–28. [23] Raybould HE, Glatzle J, Robin C, et al. Expression of 5-HT3 receptors by extrinsic duodenal afferents contribute to intestinal inhibition of gastric emptying. Am J Physiol Gastrointest Liver Physiol 2003;284(3):G367–72. [24] Fukumoto S, Tatewaki M, Yamada T, et al. Short-chain fatty acids stimulate colonic transit via intraluminal 5-HT release in rats. Am J Physiol Regul Integr Comp Physiol 2003;284(5): R1269–76. [25] Kunze WA, Furness JB, Bertrand PP, et al. Intracellular recording from myenteric neurons of the guinea-pig ileum that respond to stretch. J Physiol 1998;506(Pt 3):827–42. [26] Kunze WA, Clerc N, Furness JB, et al. The soma and neurites of primary afferent neurons in the guinea-pig intestine respond differentially to deformation. J Physiol 2000;526(Pt 2): 375–85. [27] Blackshaw LA, Gebhart GF. The pharmacology of gastrointestinal nociceptive pathways. Curr Opin Pharmacol 2002;2(6):642–9. [28] Fox EA, Phillips RJ, Martinson FA, et al. C-Kit mutant mice have a selective loss of vagal intramuscular mechanoreceptors in the forestomach. Anat Embryol (Berl) 2001;204(1): 11–26.
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[29] Stead RH, Colley EC, Wang B, et al. Vagal influences over mast cells. Auton Neurosci 2006;125(1–2):53–61. [30] Bueno L, Fioramonti J. Visceral perception: inflammatory and non-inflammatory mediators. Gut 2002;51(Suppl 1):i19–23. [31] Cajal SR. El Plexo De Auerbach De Los Batracios. Nota Sobre El Plexo De Auerbach De La Rana. Barcelona (Spain): Impreso de la Casa Provincial de Caridad; 1892. p. 23–8. [32] Burns AJ, Herbert TM, Ward SM, et al. Interstitial cells of Cajal in the guinea-pig gastrointestinal tract as revealed by c-Kit immunohistochemistry. Cell Tissue Res 1997;290(1): 11–20. [33] Komuro T. Structure and organization of interstitial cells of Cajal in the gastrointestinal tract. J Physiol 2006;576(Pt 3):653–8. [34] Cajal S. Histologie du systeme nerveux de l’homme et desvertebres, vol. 2. Paris: Maloine; 1911. [35] Faussone Pellegrini MS, Cortesini C, Romagnoli P. [Ultrastructure of the tunica muscularis of the cardial portion of the human esophagus and stomach, with special reference to the so-called Cajal’s interstitial cells]. Arch Ital Anat Embriol 1977;82(2):157–77 [in Italian]. [36] Thuneberg L. Interstitial cells of Cajal: intestinal pacemaker cells? Adv Anat Embryol Cell Biol 1982;71:1–130. [37] Ward SM, Burns AJ, Torihashi S, et al. Mutation of the proto-oncogene c-kit blocks development of interstitial cells and electrical rhythmicity in murine intestine. J Physiol 1994;480 (Pt 1):91–7. [38] Huizinga JD, Thuneberg L, Kluppel M, et al. W/kit gene required for interstitial cells of Cajal and for intestinal pacemaker activity. Nature 1995;373(6512):347–9. [39] Hara Y, Kubota M, Szurszewski JH. Electrophysiology of smooth muscle of the small intestine of some mammals. J Physiol 1986;372:501–20. [40] Dickens EJ, Hirst GD, Tomita T. Identification of rhythmically active cells in guinea-pig stomach. J Physiol 1999;514(Pt 2):515–31. [41] Smith TK, Reed JB, Sanders KM. Origin and propagation of electrical slow waves in circular muscle of canine proximal colon. Am J Physiol 1987;252(2 Pt 1):C215–24. [42] Sanders KM, Smith TK. Enteric neural regulation of slow waves in circular muscle of the canine proximal colon. J Physiol 1986;377:297–313. [43] Huizinga JD, Chang G, Diamant NE, et al. Electrophysiological basis of excitation of canine colonic circular muscle by cholinergic agents and substance P. J Pharmacol Exp Ther 1984;231(3):692–9. [44] Huizinga JD, Diamant NE, El-Sharkawy TY. Electrical basis of contractions in the muscle layers of the pig colon. Am J Physiol 1983;245(4):G482–91. [45] el-Sharkawy TY, Szurszewski JH. Modulation of canine antral circular smooth muscle by acetylcholine, noradrenaline and pentagastrin. J Physiol 1978;279:309–20. [46] Hanani M, Farrugia G, Komuro T. Intercellular coupling of interstitial cells of Cajal in the digestive tract. Int Rev Cytol 2005;242:249–82. [47] Burns AJ, Lomax AE, Torihashi S, et al. Interstitial cells of Cajal mediate inhibitory neurotransmission in the stomach. Proc Natl Acad Sci U S A 1996;93(21):12008–13. [48] Torihashi S, Ward SM, Nishikawa S, et al. c-kit-dependent development of interstitial cells and electrical activity in the murine gastrointestinal tract. Cell Tissue Res 1995;280(1): 97–111. [49] Farrugia G, Lei S, Lin X, et al. A major role for carbon monoxide as an endogenous hyperpolarizing factor in the gastrointestinal tract. Proc Natl Acad Sci U S A 2003;100(14): 8567–70. [50] Thuneberg L, Peters S. Toward a concept of stretch-coupling in smooth muscle. I. Anatomy of intestinal segmentation and sleeve contractions. Anat Rec 2001;262(1):110–24. [51] Strege PR, Ou Y, Sha L, et al. Sodium current in human intestinal interstitial cells of Cajal. Am J Physiol Gastrointest Liver Physiol 2003;285(6):G1111–21.
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[52] Kuo KH, Seow CY. Contractile filament architecture and force transmission in swine airway smooth muscle. J Cell Sci 2004;117(Pt 8):1503–11. [53] Rovner AS, Thompson MM, Murphy RA. Two different heavy chains are found in smooth muscle myosin. Am J Physiol 1986;250(6 Pt 1):C861–70. [54] Farrugia G, Holm AN, Rich A, et al. A mechanosensitive calcium channel in human intestinal smooth muscle cells. Gastroenterology 1999;117(4):900–5. [55] Holm AN, Rich A, Sarr MG, et al. Whole cell current and membrane potential regulation by a human smooth muscle mechanosensitive calcium channel. Am J Physiol Gastrointest Liver Physiol 2000;279(6):G1155–61. [56] Muraki K, Imaizumi Y, Watanabe M. Sodium currents in smooth muscle cells freshly isolated from stomach fundus of the rat and ureter of the guinea-pig. J Physiol 1991;442:351–75. [57] Yamamoto Y, Fukuta H, Suzuki H. Blockade of sodium channels by divalent cations in rat gastric smooth muscle. Jpn J Physiol 1993;43(6):785–96. [58] Smirnov SV, Zholos AV, Shuba MF. Potential-dependent inward currents in single isolated smooth muscle cells of the rat ileum. J Physiol 1992;454:549–71. [59] Xiong Z, Sperelakis N, Noffsinger A, et al. Fast Naþ current in circular smooth muscle cells of the large intestine. Pflugers Arch 1993;423(5–6):485–91. [60] Holm AN, Rich A, Miller SM, et al. Sodium current in human jejunal circular smooth muscle cells. Gastroenterology 2002;122(1):178–87. [61] Ou Y, Strege P, Miller SM, et al. Syntrophin gamma 2 regulates SCN5A gating by a PDZ domain-mediated interaction. J Biol Chem 2003;278(3):1915–23. [62] Locke GR III, Ackerman MJ, Zinsmeister AR, et al. Gastrointestinal symptoms in families of patients with an SCN5A-encoded cardiac channelopathy: evidence of an intestinal channelopathy. Am J Gastroenterol 2006;101(6):1299–304. [63] Scott RB, Diamant SC, Gall DG. Motility effects of intestinal anaphylaxis in the rat. Am J Physiol 1988;255(4 Pt 1):G505–11. [64] Neuman MG. Immune dysfunction in inflammatory bowel disease. Transl Res 2007;149(4): 173–86. [65] Pimentel M, Chatterjee S, Chow EJ, et al. Neomycin improves constipation-predominant irritable bowel syndrome in a fashion that is dependent on the presence of methane gas: subanalysis of a double-blind randomized controlled study. Dig Dis Sci 2006;51(8): 1297–301. [66] Macpherson AJ, Gatto D, Sainsbury E, et al. A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria. Science 2000;288(5474): 2222–6. [67] Schemann M, Michel K, Ceregrzyn M, et al. Human mast cell mediator cocktail excites neurons in human and guinea-pig enteric nervous system. Neurogastroenterol Motil 2005;17(2):281–9. [68] Wood JD. Enteric neuroimmunophysiology and pathophysiology. Gastroenterology 2004;127(2):635–57. [69] Ruhl A, Nasser Y, Sharkey KA. Enteric glia. Neurogastroenterol Motil 2004;16(Suppl 1): 44–9.
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GASTROENTEROLOGY CLINICS OF NORTH AMERICA
The Gastrointestinal Motility Laboratory Henry P. Parkman, MDa,*, William C. Orr, PhDb a
Gastroenterology Section, Department of Medicine, Temple University School of Medicine, Parkinson Pavilion, 8th Floor, 3401 North Broad Street, Philadelphia, PA 19140, USA b Lynn Health Science Institute, University of Oklahoma Health Sciences Center, 5300 N. Independence, Suite 130, Oklahoma City, OK 73112, USA
G
astrointestinal (GI) motility and functional GI disorders are common and often perplexing problems encountered by the gastroenterologist (Table 1). GI and functional GI disorders affect up to 25% of the American population [1], comprise about 40% of GI problems for which patients seek health care [2], and are common reasons for patients to see gastroenterologists. For the patients, they cause symptoms and pose a heavy burden of illness, decreasing quality of life and work productivity [3–5]. Proper evaluation of these disorders is important to care for these patients appropriately in clinical practice. The GI motility laboratory can provide useful, if not definitive, information about the diagnosis and management of some of the most common problems confronted by gastroenterologists. These include heartburn, dysphagia, chest pain, chronic cough, chronic constipation, and fecal incontinence. Less common disorders, such as achalasia and scleroderma, have esophageal motor abnormalities that can also be diagnosed and managed more effectively by way of esophageal motility and 24-hour esophageal pH studies. Proper evaluation of patients who have suspected GI motility disorders is important to diagnose the patient’s condition correctly and to treat the patient in an appropriate manner. Tests of GI motility allow the assessment and identification of abnormal patterns and physiology. Symptom-based definitions are often used to make a positive diagnosis for functional bowel disorders [6]. A GI motility procedure is often used for further evaluation to detect some specific physiologic dysfunction [7]. Usually, these procedures are performed after upper endoscopy or colonoscopy is performed to rule out an obstructive lesion. For instance, for esophageal symptoms, esophageal manometry and esophageal pH monitoring are used to determine the presence of gastroesophageal reflux disease (GERD) and to assess esophageal motor function. For other symptoms
*Corresponding author. E-mail address:
[email protected] (H.P. Parkman). 0889-8553/07/$ – see front matter doi:10.1016/j.gtc.2007.07.010
ª 2007 Elsevier Inc. All rights reserved. gastro.theclinics.com
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Table 1 An anatomic classification of gastrointestinal motility and functional gastrointestinal disorders Organ
GI motility disorders
Functional GI disorders
Esophagus
Achalasia Diffuse esophageal spasm Gastroesophageal reflux disease Gastroparesis Dumping syndrome Chronic intestinal pseudoobstruction Small intestinal bacterial overgrowth Gallbladder hypomotility Sphincter of Oddi dysfunction Colonic inertia Pelvic floor dyssynergia Hirschsprung’s disease
Functional dysphagia Functional chest pain Functional heartburn
Stomach Small intestine
Biliary tract
Colon
Functional dyspepsia Cyclic vomiting syndrome Irritable bowel syndrome
Irritable bowel syndrome Functional constipation Functional incontinence Functional diarrhea
such as heartburn, motility tests are used to evaluate patients who have refractory or atypical symptoms that do not respond to medications. As the pathogenesis of GI motility disorders and functional bowel disorders becomes better understood, the ability to conduct studies in GI motility becomes increasingly relevant. Motility disorders also play an increasingly recognized role in issues outside of traditional gastroenterology, such as nutrition, obesity, and drug delivery. The ability to measure intestinal motor function in the GI motility laboratory enhances the understanding of abnormal functioning of the luminal GI tract, and also allows the establishment of a relationship between symptoms and identifiable motor abnormalities. This article addresses important concepts in setting up and running an efficient and practical GI motility laboratory. GENERAL COMMENTS ON THE GASTROINTESTINAL MOTILITY LABORATORY The goals of GI motility testing are to allow the assessment of GI physiology and to identify patterns of abnormal physiology, which can provide the correct diagnosis of GI motility disorders, guide the treatment of patients, and provide prognostic information for patients. Some examples of the importance of motility testing in the diagnosis and guidance of treatment are readily apparent in clinical practice. For example, esophageal pH monitoring can evaluate patients for GERD. Esophageal manometry can specifically diagnose achalasia and provide the rationale for effective treatments. Anal manometry can determine if the cause of constipation is dyssynergic defecation or evacuation disorders for which biofeedback may be recommended. Anorectal manometry is
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also helpful for evaluating fecal incontinence to determine any sensory or motor dysfunction. Advances in technology have greatly improved the ability to measure intestinal motility and to measure these functions in an ambulatory setting, thereby greatly improving the understanding of the relationship between symptoms and motor abnormalities, which, in time, can be better linked by way of prolonged ambulatory monitoring. Another advantage of having a comprehensive GI motility laboratory is the opportunity to conduct research and study the pathophysiology of various neurogastroenterology and GI motility disorders. For example, it is difficult to investigate the pathogenesis of GERD in any sophisticated manner without the availability of esophageal motility and 24-hour esophageal pH recordings, especially in a patient who has unexplained heartburn or chest pain after a negative endoscopy or failure to respond to proton pump inhibitor therapy. Similarly, the proper study of constipation and its pathophysiology cannot be accomplished without the ability to assess anorectal function. Academic practitioners and research-oriented individuals in clinical practice also have a substantial advantage. By keeping careful records of studies over the years, a rich database can be acquired, which allows research queries to occur that can serve as the basis of a clinical research project. Thus, a GI motility laboratory is an ideal opportunity to meld clinical practice and clinical research. Unfortunately, experts in GI motility are relatively scarce. It is likely that the comprehensive digestive disease center will have greater access to experts in endoscopic ultrasound than GI motility. Thus, having expertise in GI motility should be a valuable asset as the development of comprehensive digestive centers proliferates. Specialized laboratories in other areas of medicine have been shown recently to be useful and financially feasible, even in smaller hospitals. Perhaps the best example is the development of sleep laboratories. Ten years ago, sleep laboratories were located almost exclusively in academic or tertiary hospitals. With the widespread dissemination of information on the prevalence of sleep disorders, particularly sleep apnea, most hospitals in even smaller communities now have a sleep laboratory. Similarly, the burgeoning of advertising and continuing medical education courses regarding heartburn and acid reflux disease has stimulated the growth of esophageal laboratories not only in hospitals but also in the offices of gastroenterologists. Based on these observations, it would seem that the GI motility laboratory is poised to grow as the level of diagnostic sophistication in gastroenterology continues to advance. The recent analysis of the future practice of gastroenterology suggests that disorders of GI motility and functional GI disorders will comprise a larger percentage of the GI practice in the future, further increasing the importance of the GI motility laboratory [8]. THE GASTROINTESTINAL MOTILITY LABORATORY Several items need to be considered carefully in setting up a practical and efficient GI motility laboratory, including the room, the equipment, the procedures to be performed, the personnel to run the laboratory, billing and coding, and patients.
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The Gastrointestinal Motility Laboratory Room A comprehensive GI laboratory does not require a great deal of space, or even specially configured space. The procedure unit should be readily accessible to inpatients and outpatients [9]. In most centers, the GI motility laboratory is one room, or perhaps two rooms, in the endoscopy suite. This location readily affords easy access to physicians and nurses. Often, the patient may be having endoscopic procedures with manometric procedures, making the GI endoscopy suite location practical. In some instances, the manometric tubes need to be placed with the endoscopic or fluoroscopic guidance. A few basics are required for the motility room (Box 1). The room needs to be a minimum of 14 ft 16 ft, which should accommodate the necessary equipment and a comfortable bed that can be raised or lowered easily. Ideally, the layout of the room should allow the patient to be accommodated comfortably, and equipment and instruments should be out of view. Electric outlets need to be plentiful. Having the room decorated with some nice landscape pictures is helpful in creating a more comfortable and visually appealing environment. Running water and a large sink are required. A double-basin sink allows cleaning of the equipment and use of running water for other chores. An adequate number of storage cabinets are needed because many supplies, probes, and catheters must be stored. A bed that can be elevated is highly recommended. Suction and oxygen are desirable, but not essential. Bins for regular and
Box 1: The gastrointestinal motility laboratory room Adequate space for conducting tests: 14 16 feet Sink with running water and drain (double basin preferred) Plenty of electric outlets Cabinets for storage Storage rack for catheters Container for biohazards or sharp disposables Suction, oxygen Blood pressure and pulse oximeter machines Computers and equipment Desk Chairs Telephone Clock with second hand Elevatable bed Crash cart availability Nearby restroom Nearby laundry bin
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biohazard disposable trash must be available in the laboratory space. Near the motility laboratory should be a private bathroom for the patients. An emergency crash cart should be in the vicinity, if not in the actual laboratory space. Equipment The equipment for a GI motility laboratory depends on the procedures performed and the types of patients seen in the center (Box 2). The comprehensive GI motility laboratory includes the ability to measure luminal GI functioning from mouth to anus. Realistically, however, very few laboratories have a level of comprehensive diagnostic capability that covers this range. Depending on the interest of the specific laboratory director and the types of patients seen,
Box 2: Evaluations in gastrointestinal practice for gastrointestinal motility and functional gastrointestinal disorders Esophageal symptoms Esophageal manometry Esophageal impedance Esophageal pH monitoring Esophageal sensory testing with balloon distension Dyspeptic symptoms Gastric emptying test SmartPill pH and pressure capsule Electrogastrography Antroduodenal and jejunal manometry Satiety testing with water or nutrient load Gastric barostat Irritable bowel syndrome symptoms Breath testing Bacterial overgrowth Lactose intolerance Fructose intolerance Constipation/fecal incontinence Anal manometry Anorectal electromyography Pudendal nerve latency Balloon expulsion Colonic transit with sitzmarkers SmartPill pH and pressure capsule
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some laboratories may specialize in upper GI motility studies and others in lower GI motility studies (see Box 2). However, a GI motility laboratory should have the expertise to perform certain minimum tests, including esophageal manometry, esophageal pH monitoring, and anorectal manometry (Box 3). Recently, hydrogen breath testing for bacterial overgrowth and lactose intolerance has become popular. More specialized centers allow referral of patients who may require more sophisticated procedures, such as antroduodenal manometry and luminal balloon distention. In the comprehensive digestive disease center, the GI laboratory covers other sophisticated diagnostic services, such as breath testing, capsule endoscopy, and SmartPill transit studies. Different types and brands of equipment are used for each procedure performed in the GI motility laboratory. Different equipment may perform slightly different tests that assess different functions and provide different types of information (see Box 3). The performance characteristics and extent of recording
Box 3: Equipment and procedures for the gastrointestinal motility laboratory First level Esophageal manometry Esophageal pH monitoring Second level Anal manometry Balloon expulsion Anal electromyography Third level Breath testing Bacterial overgrowth Helicobacter pylori Lactose intolerance Fructose intolerance Specialized procedures SmartPill Antroduodenal manometry Electrogastrography Colonic manometry Barostat studies of stomach and rectum Biofeedback therapy for constipation and fecal incontinence
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ability of these devices differ and need to be considered, depending on the need of the individual laboratory [10]. For instance, for esophageal manometry, the test can be performed with water-perfused catheters or with solid-state catheters, using conventional spacing of the recording channels or high-resolution systems. In addition, manometry can be combined with impedance to measure esophageal transit and more subtle esophageal motor disorders. For esophageal pH monitoring, one can use a catheter pH probe with one to three pH recording sites, a catheter probe with pH and impedance measurements, or capsule pH monitoring (Bravo pH). Equipment in the laboratory should be Food and Drug Administration– approved with high fidelity. Maintenance of the equipment is important, and cleaning and sterilization between procedures, and regular bioengineering inspection and service, are essential. The laboratory should demonstrate appropriate data acquisition and storage capabilities (archival storage and so forth). The report should include patient data, specific parameters, professional interpretation, and letters to referring physicians. In today’s environment of computerized motility studies, data storage is not an issue, but data should be kept for at least 5 years. Advances in current monitoring techniques allow relatively noninvasive recording of GI motility under physiologic conditions. Novel technologies to evaluate GI motility are being evaluated on a continuing basis. Gastric emptying measurements may shortly enter the GI motility laboratory with the use of SmartPill or breath testing with octanoic acid. Colonic manometry and rectal barostat studies have been added to some laboratories for patient evaluation. Motility laboratories now also function therapeutically, with the performing of anorectal biofeedback for the treatment of constipation and fecal incontinence. Procedures Proper performance of GI motility tests is critically important in the evaluation of patients. The Clinical Practice Committee of the American Motility Society has defined standards of practice for a number of clinical motility tests (Box 4). These guidelines help to standardize GI motility procedures better and are useful not only for motility laboratories but also for trainees in learning to appreciate the value of GI motility testing. Technical and Professional Staff Director The director of the laboratory should be an MD or PhD with training and experience in GI motility testing. Because no specific certifications or board examinations certify motility expertise, it must be assessed based on the training and the curriculum vitae of the director. Non-MD professional staff will be expected to have a PhD in one of the related medical sciences (ie, physiology, neurobiology, pharmacology, and so forth) [11]. If the director is a PhD, then proper medical oversight must be provided. Expertise in GI motility evaluations should include training in a recognized motility laboratory.
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Box 4: Documents on minimal standards for gastrointestinal motility testing Esophagus Murray JA, Clouse RE, Conklin JL. Components of the standard esophageal manometry. Neurogastroent Motil 2003;15(6):591–606. Stomach Camilleri M, Hasler W, Parkman HP, et al. Measurement of gastroduodenal motility in the GI laboratory. Gastroenterology 1998;115:747–62. Parkman HP, Hasler WL, Barnett JL, et al. Electrogastrography: a document prepared by the gastric section of the American Motility Society Clinical GI Motility Testing Task Force. Neurogastroent Motil 2003;75:89–102. Lin HC, Prather C, Fisher RS, et al. AMS Task Force Committee on Gastrointestinal Transit. Measurement of gastrointestinal transit. Dig Dis Sci 2005;50(6): 989–1004. Colon/rectum Rao SS, Azpiroz F, Diamant N, et al. Minimum standards of anorectal manometry. Neurogastroent Motil 2002;14(5):553–9. Biliary tract Hogan WJ, Sherman S, Pasricha P, et al. Sphincter of Oddi manometry. Gastrointest Endosc 1997;45(3):342–8. Pediatrics Di Lorenzo C, Hillemeier C, Hyman P, et al. Manometry studies in children: minimum standards for procedures. Neurogastroent Motil 2002;14(4):411–20. Billing and coding Botoman VA, Rao S, Dunlap P, et al. Bill Coding and RVS Committee of the American Motility Society. Motility and GI function studies billing and coding guidelines: a position paper of the American Motility Society. Am J Gastroenterol 2003;98(6):1228–36.
The director of a GI laboratory is most often a gastroenterologist interested in GI motility and functional bowel disorders. Training during gastroenterology fellowship can provide some of the foundation for performing and interpreting GI motility tests [12]. The gastroenterology core curriculum for the training of gastroenterology fellows recommends two training levels in GI motility [13]: Level 1 Training in GI Motility: Level 1 is basic training in GI motility expected of all GI fellows. GI fellows should understand the pathophysiology of GI motility and functional GI disorders, learn to manage patients with these disorders, and understand the usefulness of the various GI motility tests available to evaluate patients. Trainees should have an appropriate clinical outpatient experience in which to see and manage patients with
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possible motility disorders. GI fellows should learn about the various GI motility tests including the appropriate indications, interpretation of test results, and appropriate treatment of patients. Trainees should have the opportunity for hands-on experience with GI motility studies, including 24 hour esophageal pH monitoring. Level 2 Training in GI Motility: Level 2 training is for trainees who wish to have a subspecialty in GI motility and perform motility studies as consultants to other physicians. All directors of GI motility laboratories should have at least this level 2 training. These subspecialty trainees should become familiar with performance and interpretation of a number of different types of GI motility tests. The recommended numbers of studies to achieve expertise was suggested to be 50 esophageal manometry studies, 25 esophageal pH recordings, and 30 anorectal manometry studies. These trainees should also spend at least three months in a GI motility laboratory under the preceptorship of experienced clinicians in the performance of these studies.
The American Neurogastroenterology and Motility Society (ANMS) has developed teaching opportunities for those interested in learning more on GI motility and for those interested in directing a GI motility laboratory. ANMS course in GI motility: The ANMS gives courses on GI motility in clinical practice for individuals at each level of interest in learning about GI motility (GI fellows, practicing physicians, and nurses/technicians who perform the GI motility procedures). These courses are held every 2 years. The instructors are national experts who are actively practicing in the field of gastrointestinal motility. The goal of these courses is to familiarize participants with, and update them on, the current indications, methodology, and interpretation of clinical GI motility tests. In addition, the courses provide an in-depth and up-to-date discussion of the physiology and pathophysiology and treatment of GI motility and functional bowel disorders. ANMS clinical training program: Recently, the ANMS has started a clinical training program for fellows and junior faculty in gastrointestinal motility and neurogastroenterology. This program is an apprenticeship-based 1-month training in GI motility and neurogastroenterology for GI fellows and junior faculty in a dedicated GI motility center of excellence. The goal of this training period is to enable participants to learn first hand the various GI motility procedures used to evaluate patients.
Gastrointestinal motility nurse or technician A dedicated nurse or technician is needed for the GI motility laboratory, to perform the appropriate testing. This person should work full time in the GI motility laboratory. Finding technical staff is challenging. Most nurses and medical assistants have no experience in motility measurements. In most circumstances, staff needs to be trained from scratch. It is advantageous if a nurse can be recruited from the endoscopy laboratory or if he/she has had some GI nursing experience. Specific GI anatomy and disease states will be familiar, making training easier because it can be focused on learning procedures. Training
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technical staff is largely done in the laboratory as on-the-job training. Some additional training may be obtained from courses sponsored by industry or the ANMS, and these can be very helpful because a great deal of information is concentrated in a short period of time (usually 2 to 3 days). However, the bulk of training is obtained in the local laboratory. Depending on how many procedures are done in the laboratory, effective training of a technician can take between 3 and 6 months. The involvement of the director varies from laboratory to laboratory. Typically, nurses/technicians can be trained to do the standard laboratory procedures, with the director performing the study interpretation. Some directors have more involvement in procedures, depending on the comfort level and particular desires of the director to supervise the conduct of studies. In general, the more involvement and interaction between the director and nurse/technician, the better the clinical care. In most laboratories, the technician conducts all the esophageal studies, whereas a physician and the technician conduct the anorectal procedures together. Typically, studies are interpreted at the end of the day, or the day after the study, and they are sent by fax or mail to the referring physician’s office. Constant communication between the laboratory technician and the director is essential. Reviewing tracings and discussing cases should occur on a regular basis to ensure that the technician and director remain in close agreement on procedure protocol and the recognition of abnormalities that need to be identified during the conduct of the study. An example of this would be proper identification of lower esophageal sphincter pressure and the relaxation of this pressure with swallows, which needs to be recognized on line during a procedure. In patients who have suspected achalasia, it is imperative that this be done properly, which can only be accomplished by constant surveillance of the conduct of the studies by the director, and interaction with the technician. It is important that the technician be knowledgeable about referrals from different specialists and the specific questions that should be addressed. For example, a referral from a surgeon would need to focus on assessment of peristalsis, especially the magnitude of specific amplitudes of the peristaltic waves, because these may determine how or whether a Nissen fundoplication is done. The technician must be able to recognize that more swallows should be obtained in some circumstances to obtain a reliable assessment of true esophageal function. Similarly, referrals from otolaryngologists often dictate a more thorough assessment of the pharynx and upper esophageal sphincter. The technician must communicate effectively with the director about the nature of the referral and any special requests that may have accompanied the specific referral. Referrals for evaluation of rectal pain, as opposed to constipation, may dictate a somewhat different focus on the interpretation by the director and the technician, and director must be knowledgeable about the nature of the referral to perform a proper study and interpretation for the referring physician.
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Scheduling coordinator Different GI motility laboratories handle scheduling differently. Scheduling is usually performed in the office when the patient sees the physician, when the technician is busy performing other GI motility procedures, which often necessitates a medical assistant to schedule the tests. It is important for the scheduling coordinator (eg, medical assistant) to understand the essentials of the test (preparation [eg, fasting], medications the patient should stop for the test [eg, proton pump inhibitors], the duration of the test, and the order that the test should be performed with others, in case multiple tests are performed the same day). In some centers, the GI motility technician is involved in scheduling the procedures directly with the patient, or at least in having a conversation with the patient ahead of time, which allows the technician to establish some rapport with the patient and to answer any questions the patient may have concerning the procedure. In addition, the technician can determine and schedule to allow for the most efficient use of time available.
PATIENTS Patients need to be advised about the preparation for the test and given this in writing. Information should include the preparation for the test (generally fasting after midnight), the need to stop certain medications, and the date, time, and location of the test. Patients also need to understand beforehand what the test will entail. Patient information sheets have been developed for several GI motility procedures (Box 5), available through the ANMS website at www.motilitysociety.org. Many patients are apprehensive because, unlike endoscopic procedures, motility studies are usually performed without sedation. Hence, a detailed explanation and repeated reassurance from a compassionate nurse or technician is important for a successful motility laboratory. Laboratories differ as to whether signed informed consent of patients is needed before performing these tests. Approximately one half of the laboratories have the patient sign an informed consent for the procedure, whereas about one half do not. In general, GI motility tests are low-risk procedures. Esophageal manometry is similar to inserting a nasogastric tube, for which consent is not usually obtained. Others feel that proper informed consent should be obtained for GI motility procedures. Most hospitals have an adequate consent for procedures, which has had appropriate legal review. Useful information on the disorders may be needed for patients who undergo GI motility tests. Patient information has been developed for several GI motility procedures, located and available for downloading on the ANMS web site at www.motilitysociety.org. These can be used for distribution to patients who are undergoing a GI motility procedure. It is important that a standard format be used for reporting the results of GI motility tests. The ANMS, together with the European Neurogastroenterology and Motility Society, has developed consensus minimum guidelines for testing and reporting of GI motility procedures (see Box 4).
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Box 5: Patient information sheets on the American Neurogastroenterology and Motility Society website (www.motilitysociety.org) Gastrointestinal motility tests and procedures Anal manometry Esophageal manometry Esophageal pH monitoring Gastric emptying scintigraphy Defecography Breath hydrogen testing Small bowel manometry Gastrointestinal motility disorders Achalasia Diffuse esophageal spasm Chronic intestinal pseudoobstruction Dumping syndrome diet Gastroparesis Gastroparesis diet Hirschsprung’s disease
BILLING AND CODING Billing is performed using established Current Procedural Terminology (CPT) codes. Virtually all GI motility procedures have codes for the facility fee and interpretation (Box 6). Billing and coding are best decided by the individual practitioner, in consultation with respective payers in his/her location [14]. The ANMS, with the American Gastroenterology Association, American Society for Gastrointestinal Endoscopy, and American College of Gastroenterology, has been striving for improved coding and reimbursement for procedures performed in the GI motility laboratory. Proper reimbursement and constant monitoring of payments is necessary to ensure maximal reimbursement. Insurance companies vary significantly with regard to the reimbursement of GI motility procedures, and inadequate reimbursement should be monitored and periodically addressed by the billing specialists. Proper coding and billing to get allowable reimbursement is an ongoing learning process and needs to be monitored. When esophageal manometry, pH studies, or endoscopy are performed on the same day, the 51 modifier for multiple procedures on the same day should not be needed because manometry and pH testing are separate diagnostic procedures. A modifier is also not needed when endoscopy and manometry are performed on the same day. This point, however, may have variable responses, depending on the specific payer source. If manometry and prolonged pH studies are
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performed on day 1, manometry should be billed on day 1 and the pH study should be billed on the day the procedure is terminated. If studies are billed for the same day, it is also best to use separate International Classification of Diseases, Ninth Revision (ICD-9) diagnostic codes. An outline of a method for coding and billing for the esophageal motility laboratory is as follows: 1. Choose the correct procedure code (CPT) for the test performed. 2. Chose a clinical diagnosis code (ICD-9) that is appropriate for the CPT code. The ICD-9 code should be as specific as possible. Often, the ICD-9 code is the indication for the test. However, one should try to bill using the appropriate ICD-9 code for the final, related diagnosis and not for the reason the test was performed. For example, if the esophageal manometry is abnormal, bill for the specific abnormality (eg, 530.0 for achalasia); if the manometry is normal, bill for the indication (eg, 787.1 for heartburn, 787.2 for dysphagia, 786.50 for chest pain). 3. Letters of necessity are occasionally needed to send in with the bill. A template letter of necessity is often valuable. 4. Use electronic software ‘‘scrubbers’’ for reviewing claims and identifying billing or coding errors before submission to insurance company. 5. Monitor the payments and denials. 6. If needed, appeal denials. Have template denial letters for procedures.
REGISTRY OF GASTROINTESTINAL MOTILITY LABORATORIES Proper evaluation of patients who have a possible GI motility disorder is important to provide the proper diagnosis and for the patient to receive optimal care. To provide a meaningful service to physicians and patients, laboratories involved in the conduct of clinical motility studies should meet a set of specified standards that are recognized as appropriate (see Box 4). Individuals performing clinical motility studies should be appropriately trained, have sufficient experience in the areas in which they are performing studies, and have appropriate space and equipment to conduct clinical studies. The Clinical Practice Committee of the ANMS has developed a registry of GI motility laboratories that have experience in performing high-quality GI motility procedures commonly used for the evaluation of patients. The purpose of this registry is to have a listing of GI motility laboratories that perform good-quality GI motility testing that can be relied on by other physicians, which will help physicians who want to refer patients, and patients who might need to find a local laboratory that does a particular procedure. The registry also serves several other purposes: (1) identifies GI motility laboratories that perform procedures using appropriate standard methodology; (2) raises awareness of these centers for health care providers who do not have direct access to a GI motility laboratory; (3) raises awareness for patients who are either seeking such centers or wish to be evaluated for their condition. The procedures tracked in the registry are the standard motility procedures, such as esophageal manometry, esophageal pH monitoring, and anorectal manometry. Other procedures tracked include more specialized
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Box 6: Billing and coding for the gastrointestinal motility laboratory Esophageal testing
91010: Esophageal manometry 91011: Esophageal manometry with stimulant (edrophonium) 91012: Esophageal manometry with acid perfusion (Bernstein testing) 91034: Esophageal pH monitoring using nasal catheter pH electrode 91035: Esophageal pH monitoring using mucosal attached telemetry pH probe (Bravo pH system) 91037: Esophageal function testing using gastroesophageal impedance for up to 1 hour 91038: Prolonged gastroesophageal impedance testing for more than 1 hour and up to 24 hours 91040: Esophageal balloon distension provocation testing to evaluate patients who have atypical chest pain Anorectal testing
91122: Anorectal manometry 90911: Biofeedback training during anal manometry or electromyography 91120: Rectal balloon provocation to measure sensory, motor, and biochemical function of rectum. 45391: Flexible sigmoidoscopy with endoscopic ultrasound Breath testing
91065: Breath hydrogen testing for lactose intolerance, fructose intolerance, bacterial overgrowth, or evaluation of orocecal transit time Electrogastrography
91132: Electrogastrography 91133: Electrogastrography with provocative testing (meals, stimulants) Antroduodenal manometry
91022: Duodenal motility study with the placement of a motility probe into the duodenum 91020: Gastric motility (can both be billed with 91020) if the test is measuring both If an endoscopy is performed for tube placement, 43235 should be used, and if fluoroscopy is performed, 76000 should be used with 91022 Sphincter of Oddi manometry
43263: Endoscopic retrograde cholangiopancreatography with sphincter of Oddi manometry Miscellaneous
91299: Unlisted diagnostic gastroenterologic procedure Note: The 26 modifier is for the professional services component. The technical component modifier is for the technical component.
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procedures, such as electrogastrography and antroduodenal manometry. This registry is available at the ANMS website at www.motilitysociety.org. SUMMARY Abnormalities of GI motor function contribute directly or indirectly to a number of common clinical problems and account for significant health care–related expenditure [15]. Proper evaluation of patients who have suspected GI motility disorders is important to ensure a correct diagnosis and to embark on an appropriate plan of treatment. The GI motility laboratory serves as an important station for patient evaluation and treatment in gastroenterology and is an essential element in any comprehensive digestive disease program. Acknowledgments The authors would like to acknowledge the suggestions made for this article by Dr. Satish Rao and Dr. Joel Richter. References [1] Drossman DA, Li Z, Andruzzi E, et al. U.S. householder survey of functional gastrointestinal disorders: prevalence, sociodemography, and health impact. Dig Dis Sci 1993;38: 1569–80. [2] Russo MW, Wei JT, Thiny MT, et al. Digestive and liver diseases statistics, 2004. Gastroenterology 2004;126:1448–53. [3] Parkman HP, Doma S. The importance of gastrointestinal motility disorders. Pract Gastroenterol 2006;30(9):23–40. [4] Chang L. Epidemiology and quality of life in functional gastrointestinal disorders. Aliment Pharmacol Ther 2004;20(Suppl 7):31–9. [5] Camilleri M, Dubois D, Coulie B, et al. Prevalence and societal impact of upper gastrointestinal disorders in the United States. Clin Gastroenterol Hepatol 2005;3:543–62. [6] Drossman DA, Corazziari E, Delvaux M, et al, editors. The functional gastrointestinal disorders. 3rd edition. McLean (VA): Degnon Associates; 2006. [7] Galmiche JP, Clouse RE, Balint A, et al. Functional esophageal disorders. Gastroenterology 2006;130:1459–65. [8] AGA Institute Future Trends Committee. Will screening colonoscopy disappear and transform gastroenterology practice? Threats to clinical practice and recommendations to reduce their impact: report of a consensus conference conducted by the AGA Institute Future Trends Committee. Gastroenterology 2006;131:1287–312. [9] Drossman DA. Manual of gastroenterologic procedures. 2nd edition. New York: Raven Press; 1987. [10] Shaker R, Hofmann C. How to set up and manage a motility laboratory. Goyal & Shaker GI Motility online. Available at: http://www.nature.com/gimo/contents/pt1/full/ gimo96.html. Accessed March 25, 2007. [11] Orr WC. Evaluation of laboratory standards for GI motility laboratories. New Wave 2001;1(3). Available at: http://www.giphysiology.org/. Accessed March 25, 2007. [12] Parkman HP. Training in GI motility. Dig Dis 2006;24(3–4):221–7. [13] AASLD, ACG, AGA, et al. Training the gastroenterologists of the future: the gastroenterology core curriculum. Gastroenterology 2003;124:1055–104. [14] Botoman VA, Rao S, Dunlap P, et al. Bill Coding and RVS Committee of the American Motility Society. Motility and GI function studies billing and coding guidelines: a position paper of the American Motility Society. Am J Gastroenterol 2003;98(6):1228–36. [15] Wiley JW, Nostrant TT, Owyang C. Evaluation of gastrointestinal motility: methodlogic considerations. In: Yamada T, editor. Textbook of gastroenterology. 4th edition. Philadelphia: Lippincott Williams & Wilkins; 2003. p. 3057–73 [chapter 150].
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New Technologies for the Evaluation of Esophageal Motility Disorders: Impedance, High-resolution Manometry, and Intraluminal Ultrasound Ikuo Hirano, MD*, John Pandolfino, MD, MSCI Division of Gastroenterology, Department of Medicine, Northwestern University Feinberg School of Medicine, 676 North St. Clair Street, Suite 1400, Chicago, IL 60611, USA
O
ver the past decade, new technologies have been introduced for studying esophageal function, including intraluminal impedance and ultrasound, whereas conventional techniques, such as manometry, have undergone substantial upgrades because of advances in transducer technology, computerization, and graphic data presentation. Although these techniques provide both novel and more detailed information regarding esophageal function, it is still unclear whether they have improved the ability to diagnose and treat patients more effectively. Regardless, they are excellent research tools and they have added substantially to the understanding of the pathophysiology of dysphagia and esophageal motor dysfunction. This article describes the technical aspects of each of these technologies and the potential benefits they offer over conventional techniques for the evaluation of esophageal motor diseases. APPROACH TO THE PATIENT PRESENTING WITH DYSPHAGIA The approach to a patient with dysphagia begins with a careful evaluation of mechanical or anatomic causes for obstruction, such as webs, rings, strictures, and mass lesions. Once these entities are ruled out using endoscopy or fluoroscopy, the focus shifts to the consideration of disorders of esophageal motor function and bolus transit. Although fluoroscopy can provide information on bolus transit and limited information regarding esophageal motor function, it requires radiation exposure and provides only qualitative information. Currently, only manometry can define the pressure profile of both peristalsis and lower esophageal sphincter (LES) relaxation; however, in its current form it does not provide information on bolus transit and emptying. In
*Corresponding author. E-mail address:
[email protected] (I. Hirano). 0889-8553/07/$ – see front matter doi:10.1016/j.gtc.2007.07.005
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addition, conventional manometry is also limited in that it only provides information on circular muscle contraction and ignores the important contribution of the longitudinal muscle in bolus clearance and symptoms. New technologies have been developed that have the potential to improve the management of dysphagia and chest pain: intraluminal impedance, highresolution manometry (HRM), and intraluminal ultrasound. Although HRM is an evolution of current manometric technique, impedance monitoring is a new technology that complements manometric data by providing information on bolus transit without the need for radiation exposure. Intraluminal ultrasound is a technology that can detect changes in muscle thickness, and can assess the contribution of longitudinal muscle in peristalsis and symptom generation. Although these techniques have advanced the understanding of esophageal motility and function, there are growing data to support their potential clinical use in the evaluation of esophageal motility disorders and chest pain. MULTICHANNEL INTRALUMINAL IMPEDANCE Technical Aspects Fluoroscopic evaluation of the esophagus is an excellent method to assess the intraluminal anatomy of the esophagus and bolus transit in the esophageal body. Unfortunately, it requires radiation and also lacks sensitivity in diagnosing esophageal motor function. Intraluminal impedance was created to circumvent the requirement of radiation by using changes in resistance to current flow between two metal rings as a surrogate marker of bolus transit (Fig. 1) [1]. Impedance monitoring works by using an alternating current generator to apply an electrical potential between two metal electrode rings separated by an isolator. The electrical current can only be closed through the conduction of electrical charges through the surrounding material bridging the two metal electrode rings. Air, liquid (saline-refluxate), and the esophageal mucosa each have unique impedance characteristics, thereby allowing definition of which material resides between each pair of electrodes. Air is highly resistant to current flow and has a high impedance value, whereas saline and gastric juice have low resistance to flow and have a low impedance value. Esophageal mucosa has an intermediate impedance range and serves as a baseline during monitoring. By dispersing the impedance electrodes along a catheter and defining impedance changes over adjacent pairs of rings one can determine the direction of bolus transit within the esophagus and also document whether complete bolus clearance has occurred [2–4]. Studies using combined fluoroscopy and impedance have validated the convention that liquid bolus entry is signaled by a 50% drop in impedance at the recording site, whereas bolus exit is signaled by a return to at least 50% of baseline (see Fig. 1) [5,6]. Using healthy controls, Simren and colleagues [5] also reported that there is a strong correlation between videofluoroscopy and intraluminal impedance in determining esophageal emptying time (r2 ¼ 0.79). Recently, Imam and colleagues [7] reported excellent agreement between barium esophagram and impedance during swallowing. Concordance between the two techniques for determining normal bolus transit,
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Fig. 1. Concurrent videofluoroscopic imaging and multichannel intraluminal impedance recordings of a 5-mL renograffin swallow that was completely cleared by one peristaltic sequence. Representative tracings from the videofluoroscopic sequence are overlayed on the impedance tracing showing the distribution of the bolus at the times indicated by the vertical yellow arrows. At each recording site, the line intersecting the impedance scale in ohms (X) on the right represents the impedance recording tracing. Bolus entry at each impedance recording site is signaled by a greater than 50% decrease in impedance. In this example, the bolus propagates past recording sites 1, 2, 3, and 4 rapidly as indicated by an abrupt reduction in impedance at time 1.5 seconds. Luminal closure and hence the tail of the barium bolus is evident at each recording site by the 50% increase in recorded impedance. Hence, at 5 seconds, the peristaltic contraction was beginning at recording site 3, corresponding to a 50% increase in impedance and the tail of the barium bolus at the same esophageal locus. Finally, after completion of the peristaltic contraction (time 8.5 seconds), all renograffin was passing from the distal esophagus into the stomach.
stasis, or retrograde escape was 97% (83 of 86) (Fig. 2). This technique does provide direct qualitative evidence of esophageal emptying; however, it does not provide any quantitative data regarding volume. Role in Studying Esophageal Function Although esophageal manometry has been considered the gold standard for defining esophageal motor function and classifying various disease states, it can only provide indirect evidence of bolus transit by extrapolating from previous studies using combined videofluoroscopy and manometry. These studies suggested that the efficacy of distal esophageal emptying is inversely related to peristaltic amplitude such that emptying becomes progressively impaired with peristaltic amplitudes less than or equal to 30 mm Hg [8]. Recently,
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Fig. 2. Example of retrograde escape and proximal stasis on simultaneous multichannel intraluminal impedance and fluoroscopy. The fluoroscopic bolus is represented by the gray bolus at each time interval. The bottom panel is a single impedance tracing at the proximal location. The bolus is present at the proximal impedance site until 2.6 seconds where the bolus tails moves distal to the two rings at that level and the impedance tracing returns to baseline. At 3.6 seconds, the bolus re-enters the recording site and once again the impedance drops consistent with bolus retention. (Modified from Imam H, Shay S, Ali A, et al. Bolus transit patterns in healthy subjects: a study using simultaneous impedance monitoring, videoesophagram, and esophageal manometry. Am J Physiol Gastrointest Liver Physiol 2005;288:G1000–6; with permission.)
multichannel intraluminal impedance has been used to assess the efficacy of esophageal emptying as a function of peristaltic amplitude in a much greater number of swallows and subjects [9]. Receiver operating characteristic curve analysis of combined manometric-impedance data revealed that a 30 mm Hg cutoff for distal esophageal peristaltic amplitude had a sensitivity of 85% and a specificity of 66% for identifying incomplete bolus transit. With diminishing peristaltic amplitudes, the sensitivity progressively decreased and the specificity progressively increased. This analysis illustrates the complementary nature of manometry and impedance testing and also highlights the fact that bolus transit may be normal in the context of peristaltic failure. Although initially this technology was used primarily for research as an alternative to fluoroscopy for assessing esophageal transit and emptying, its clinical use as an esophageal function test is currently being investigated. The clinical protocol for impedance is very similar to standard conventional manometric protocol with the exception that normal saline is used for the 10 liquid swallows and there is an additional portion of the study that uses viscous swallows. Saline is required so that a contrast in impedance is noted between the
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liquid bolus and the esophageal wall, whereas the viscous bolus is typically a gel provided by the manufacturer or another food, such as yogurt. Normal values for both liquid and viscous swallows have been reported by various groups using different techniques. Tutuian and colleagues [10] performed combined impedance-manometry on 43 normal healthy subjects and analyzed 10 liquid and 10 viscous swallows to determine normative ranges for total bolus transit time and the percent of swallows associated with complete bolus transit. Their results revealed that total bolus transit time for both liquid and viscous swallows was 12.5 seconds, and greater than 90% of individuals had more than 80% of the liquid swallows associated with complete bolus transit and more than 70% of the viscous swallows associated with complete bolus transit. Two other studies in normal controls revealed similar bolus transit parameters, and it seems that this technology is reproducible in normal subjects [11,12]. In addition to establishing normative data, impedance has been used to describe bolus transit patterns in various patient groups. Using their criteria for normal percent swallows associated with complete bolus transit, Tutuian and colleagues [13] assessed the percentage of patients with normal bolus transit in a prospective cohort of 350 patients. The patients were categorized into conventional manometric diagnoses and then assessed based on the presence or absence of complete bolus transit. Their results revealed that all patients fulfilling criteria for achalasia and scleroderma had abnormal bolus transit. In contrast, only half of the patients with ineffective esophageal motility and half of the patients with spasm had abnormal bolus transit, whereas most patients with intact peristalsis and various LES abnormalities have normal bolus transit. The findings in the ineffective esophageal motility patients were consistent with their previous study assessing the manometric cutoff for impaired bolus transit because the 30 mm Hg value did not have perfect specificity for predicting poor bolus transit. In a smaller study that assessed 40 patients with undiagnosed dysphagia not related to mechanical obstruction, Conchillo and coworkers [14] also reported heterogeneity among the various manometric diagnoses and also noted that approximately 35% of subjects with normal motility have abnormal bolus transit. These studies once again highlight the fact that normal motility is not a marker for normal bolus transit. One interesting question regarding the clinical use of impedance in evaluating esophageal motor diseases is whether or not the information provided by impedance regarding bolus transit is clinically relevant. Certainly, incomplete bolus transit is a marker for abnormal esophageal function; however, there are no data directly to link impaired bolus transit to symptoms of dysphagia or chest pain. Looking to provide more focused information regarding a clinical role for impedance, Tutuian and coworkers [15] analyzed 71 subjects with distal esophageal spasm and characterized them based on both their motor function and ability to obtain complete bolus transit. Their findings revealed that distal esophageal spasm patients with dysphagia were more likely to have abnormal bolus transit than their counterparts that presented with predominant chest pain. Furthermore, they also noted that distal esophageal spasm patients
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presenting with chest pain were not only more likely to have normal bolus transit, but also exhibited higher contraction amplitudes. These observations are intriguing because it seems that impedance may help define treatment strategies for various patient groups: spasm patients with poor bolus transit and normal or low contractile amplitudes are not likely to respond to therapy focused on relaxing the smooth muscle esophagus, whereas chest pain patients with extremely high contractile amplitudes may be a subpopulation with a good response to nitrates and calcium channel blockers. The stage is set for defining patient subtypes and performing prospective interventional outcome trials. In contrast to studying antegrade bolus transit, intraluminal impedance has also been adapted to study other esophageal motor diseases that focus on retrograde bolus transit, such as gastroesophageal reflux disease (GERD), rumination, and belching. Multichannel intraluminal impedance combined with manometry can be helpful in distinguishing rumination from regurgitation related to an incompetent antireflux barrier or another esophageal motor disease. The classic findings of regurgitation of ingested food and remastication and swallowing can be easily documented with combined impedance manometry by documenting the chain of events starting with an increased intragastric pressure noted on manometry with subsequent impedance changes consistent with regurgitation of food and reswallowing [16]. Similarly, this technique can also be used to differentiate the various causes of belching. Recently, Bredenoord and coworkers [17] used impedance to describe a group of patients with belching that originates from air being sucked into the esophagus with immediate expulsion termed a ‘‘supragastric belch.’’ This phenomenon is not related to an increase in gastric belching similar to that seen with transient LES relaxations. Multichannel intraluminal impedance has also been combined with conventional catheter-based pH monitoring to assess the role of weakly acidic and weakly alkaline reflux in patients not responding to proton pump inhibitor therapy. Intraluminal impedance detects changes in resistance to electrical currents across electrodes and has the ability to differentiate mucosa from both air and liquid. By placing multiple impedance electrodes along the axial length of a catheter, impedance can be modified to determine both the direction of the refluxate and the proximal extent. Although impedance alone cannot determine the pH of the refluxate, this technology has been combined with pH electrodes (MII-pH) so that all types of reflux can be described. A recent study examined the impedance characteristics of reflux events in 60 healthy subjects during a 24-hour recording period [18]. Their results revealed that one third of the total reflux events were nonacid and would have been missed using conventional pH monitoring. Although there is no doubt that nonacid reflux exists, the main question concerns its clinical importance in symptom generation. It is biologically plausible that weakly acidic reflux could activate symptoms of heartburn through chemosensitive pathways set at lower thresholds for hydrogen ion exposure. In addition, it is also possible that distention or perception of volume could also stimulate symptoms through mechanoreceptors in the esophageal wall. Data
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to support this causal relationship were reported by Vela and colleagues[19] in a study using simultaneous impedance-pH monitoring in GERD patients in the postprandial state. Their results revealed that heartburn and regurgitation were temporally associated with nonacid reflux in patients taking proton pump inhibitor therapy. It should be emphasized that almost 90% of the symptoms associated with nonacid reflux on proton pump inhibitor therapy were regurgitation and only 10% heartburn. In a recent study of GERD patients off acid suppression, Bredenoord and coworkers [20] reported that although most symptoms were associated with acid reflux, a small proportion (15%) of symptoms were associated with weakly acidic reflux. These same investigators also reported that combined MII-pH increased the yield for obtaining a positive symptom association probability by almost 10% [20]. Although the significance of finding this small group of patients with nonacid reflux can be questioned, MII-pH does improve the ability to characterize patients and may be helpful in defining functional heartburn and dyspepsia. This can be extremely important in the evaluation of patients not responding to proton pump inhibitor therapy, because this represents one of the most common indications for prolonged esophageal monitoring [21]. This was highlighted in recent studies by Zerbib and coworkers [22] and Mainie and coworkers [23] in which they reported that over half the subjects studied on acid suppression had a negative symptom index for all types of reflux events. This supports that reflux was not the cause of their continued symptoms and that these patients would likely benefit from therapy focused on reducing functional symptoms. Future Directions in Impedance A major evolution of impedance technology has been the application of highresolution impedance for studying flow dynamics of esophageal transit and mechanical properties of the esophagus. The authors’ group recently applied high-resolution impedance to study esophagogastric opening patterns during swallowing and transient LES relaxations [24]. By converting the raw data into color isocontour plots, flow through the esophagogastric junction (EGJ) was depicted as a two-dimensional image that defined flow of liquid and air in both a spatial and time domain (Fig. 3) [25]. This provided detailed information regarding the opening dynamics of the EGJ and allowed the distinction between EGJ relaxation and EGJ opening to be clearly defined. A further evolution of this two-dimensional high-resolution impedance has been the creation of techniques that provide a three-dimensional reconstruction of the esophageal lumen. By applying high-resolution to impedance planimetry, Gregersen and colleagues created the functional lumen imaging probe [26,27]. This device can measure cross-sectional area of the esophagus at extremely small intervals and can generate a computer animation that recreates the geometry of the anatomic zone (Fig. 4). In addition, a pressure-distention relationship can be measured to define elasticity and compliance of the lumen wall and represents the first dynamic technique to profile both anatomy and function of the esophagus in a single device. Although these devices are currently only available for
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Fig. 3. High-resolution impedance with color isocontour plots. Example of manometric evidence of flow confirmed with simultaneous high-resolution impedance during a tLESR. Manometric data are converted into spatial pressure variation plots (bottom) and are plotted along the same time-line with simultaneous isocontour impedance data (top). The impedance color scale is on the right. During the prolonged transient LES relaxation there is intermittent transit of liquid through the EGJ highlighted by a sudden decrease in impedance along each 1 cm segment of the EGJ into the esophagus (blue color). During this 7-second time frame there is manometric evidence of flow (pressure equalization gradient from high [gastric] to low [esophagus]) at the exact instance that liquid is moving through the EGJ into the proximal esophagus (orange shading on the spatial pressure variation plot). Note the sequential rise in pressure in the distal esophagus from 2 to 1 mm Hg corresponding to liquid reflux. (From Pandolfino JE, Zhang QG, Ghosh SK, et al. Transient lower esophageal sphincter relaxations and reflux: mechanistic analysis using concurrent fluoroscopy and high-resolution manometry. Gastroenterology 2006;131:1725–33; with permission.)
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Fig. 4. Functional lumen image probe incorporating high-resolution impedance planimetry. Multidimensional reconstruction of the EGJ CSA through eight recording sites using functional lumen imaging probe. The arrow shows location of narrowest EGJ constriction. Each axis is in millimeters (x,y,z) and the color scale represents pressure. (Courtesy of H. Gregersen, MD and B. McMahon, MD, Dublin, Ireland.)
research purposes, it is likely that conventional impedance will move toward incorporating high-resolution because volume is an important variable that until now could only be inferred indirectly from fluoroscopy or ultrasound. HIGH-RESOLUTION MANOMETRY Technical Aspects Esophageal manometry is considered the gold standard for assessing esophageal motor function. This is evidenced because the current diagnostic classification of esophageal motor disorders is based almost entirely on manometric patterns of abnormal peristalsis and LES function defined by this technique. Conventional manometry uses three to eight pressure sensors positioned within the esophageal lumen to assess the contractile pattern during water swallows. A variety of sensor technologies exist including solid-state transducers, circumferentially sensitive transducers, perfused ports, and the Dentsleeve device (Dentsleeve, Ontario, Canada), each optimized to study the contractile activity of a particular area of interest, be that the upper esophageal sphincter, esophageal body, or EGJ. Unfortunately, the heterogeneity of the sensor types and lack of consensus regarding the optimal array of sensor spacing have led to
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problems with reproducibility and diagnostic accuracy. Direct evidence of this predicament can be found in a recent publication highlighting the poor interobserver agreement in the analysis of clinical manometry even among expert practitioners [28]. Refinements in manometry are needed to improve reproducibility and accuracy. By definition, HRM is not a new technology. Instead, it represents a refinement in methodology that can provide greater detail with the added benefit of simplifying data interpretation. The concept behind high-resolution is that by vastly increasing the number of sensors and reducing the space in between the sensors it provides representation of the entire pressure profile of the esophagus. The vastly increased quantity of data and the unfriendly presentation of multiple overlapping tracings spaced closely together presents new challenges. New algorithms have been devised to provide a seamless dynamic representation of pressure at every axial position. Probably the most important refinement of HRM has been the conversion of the waveform data into a topographic display that reconstructs the deglutitive motor events into a space-time continuum. Clouse and Staiano [29] were the first to describe this technique in the esophagus and described their methodology to interpolate and convert this information into topographic plots. Fig. 5 illustrates this process where the individual data points are displayed in a curvilinear interpolation between adjacent sites along the entire length of the catheter at a given time (t). Plotting multiple time points one generates a spatial pressure variation plot initially described by Li and colleagues [30]. These graphs are excellent for determining pressure gradients along the esophagus; however, they do not portray time and space as a continuum. To accomplish this, the magnitude of pressure can be plotted at a specific locus (x ¼ time, y ¼ position) using a z term that converts pressure amplitude into a color scale. These data generate the standard color isocontour plot, which is more akin to an imaging technique as opposed to the conventional waveforms (see Fig. 5). The immediate advantages of this topographic approach are that it eliminates the problems of movement- (shortening) related artifacts and alterations in anatomy (short esophagus, hiatus hernia) in the assessment of sphincter relaxation. It also permits an easier way to illustrate and analyze the data. HRM can be adapted to work with any transducer technology, as long as the recording fidelity of the sensor is adequate and the number of sensors along the catheter can accurately reflect the appropriate spatial resolution. The frequency response required to reproduce esophageal pressure waves with 98% accuracy is 0 to 4 Hz, whereas that required for reproducing pharyngeal pressure waves is 0 to 56 Hz [31]. Expressed in terms of maximal recordable DP/Dt, 300 mm Hg/s is sufficient for studying the esophageal body, whereas the pharynx requires a DP/Dt of 4000 mm Hg/s for the pharynx. Early studies incorporating HRM used water-perfused systems because of the cost of solid-state pressure sensors. Unfortunately, the response characteristics of the water-perfused sensors were technically limited for studying the pharynx and also measuring detailed pressure gradients through both the upper and lower esophageal sphincters.
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Fig. 5. Isocontour manometric plots of the EGJ of a patient with normal anatomy using the high-resolution manometry system from Sierra Scientific (Los Angeles, California). The isocontour representation provides an overview of regional differences in intraluminal pressure integrated over time. The on-screen pressure scale is color coded. High-pressure zones, such as the LES or the separated components of the EGJ, are easily recognized by sharp transitions in pressure. The exact pressure at any point on this spatial-temporal grid can be ascertained either using the isobaric contour tool or the point-and-click smart mouse tool of the ManoView software. The isobaric contour tool was used to make measurements of basal LES pressure. This tool allows delineation of anatomic-temporal boundaries of a pressure domain of user-designated magnitude. In this example the isobaric contour tool is set at a pressure of 4 mm Hg to determine the nadir pressure. The automated E-sleeve analysis gives the lowest mean LES relaxation pressure over a 3-second interval and in this example is recording a value of 8.2 mm Hg over the time interval depicted by the black box.
Recently, a 36-channel high-resolution solid-state manometric assembly that uses 1-cm spacing has become available that spans the entire esophagus and has a temporal frequency response adequate for studying all anatomic zones extending from the pharynx into the stomach (Sierra Scientific, Los Angeles, California). As technology advances, other solid-state systems may become available that reduce spacing even further or new technologies, such as fiberoptic manometry, may also be introduced into high-resolution manometric assemblies. It is important to emphasize, however, that the principles of HRM and topographic analysis are device independent and will likely become and remain the convention for manometric analysis of esophageal motor function. Role in Studying Esophageal Function Topographic analysis of HRM data has clearly advanced the knowledge of esophageal motor function. The recent application of topographic analysis to
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esophageal peristalsis demonstrated that progression through the esophageal body is not seamless. Rather, it is comprised of a sequence of contractile events occurring in four discrete pressure segments (Fig. 5C). The first segment represents the striated muscle component of the proximal esophagus and extends from the upper esophageal sphincter to the first pressure trough in the region of the aortic arch. This trough represents the transition zone and is usually easily identified. The distal portion of the esophagus is considered the smooth muscle dominant portion of the esophagus and can be separated into two overlapping neuromuscular segments. The fourth contractile segment encompasses the LES. This segmental configuration was not appreciated by conventional manometry and underscores the strength of topographic analysis of manometric data [29,32,33]. Topographic analysis of HRM data has also allowed a more accurate analysis of EGJ function. In the basal period the various components of the EGJ high-pressure zone can be identified and the authors’ group recently applied this technology to define various EGJ pressure morphology subtypes and study their relationship to GERD (Pandolfino and colleagues [34]). The authors’ results revealed that reduced inspiratory EGJ pressure augmentation, an indicator of crural functional integrity, was a common finding in GERD patients and that this was not entirely dependent on axial separation of the LES and crural diaphragm. In addition, the authors also devised a classification system based on the relationship between the two sphincters and the location of the respiratory inversion point (Fig. 6) [34]. HRM technique is a major evolution over conventional manometry. These systems simplify procedural setup and reduce the duration of studies by removing the positional issues of localizing the LES and also by providing a clearer representation of esophageal function similar to an imaging modality. The use of solid-state HRM also improves accuracy by allowing HRM to be referenced to atmospheric pressure, providing superior recording characteristics and removing any movement artifact. Although these attributes make this a better system for describing and identifying abnormal esophageal motor function, it is unclear whether this technique impacts patient management. Future Directions in High-Resolution Manometry Researchers in esophageal physiology have almost uniformly adopted HRM in research studies and currently this tool is rapidly evolving into a widely available diagnostic tool. This being a relatively new technique, however, there is currently no uniform scheme to analyze HRM data. Recently, the authors’ group performed a comprehensive characterization of esophageal HRM data in 75 normal subjects to fill this void [35,36]. The first objective was to characterize EGJ pressure dynamics during swallowing because this is possibly the most important measurement made during esophageal manometry. They developed an automated analysis that could capture the entire space-time history of EGJ relaxation during a swallow (Figs. 7–9). This technique allowed one to define the maximal obstructive pressure in a continuum across the entire length
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Fig. 6. Examples of EGJ pressure morphology subtypes primarily distinguished by the extent of LES crural diaphragm (LES-CD) separation. The upper plot in each panel is isobaric contour representation of the spatiotemporal pressure changes spanning from the distal esophagus, across the EGJ, and into the proximal stomach during several respiratory cycles. The pressure magnitude corresponding to spectral colors is shown at the bottom of the figure. The lower plot in each panel illustrates a series of spatial pressure variation plots at the instants of peak inspiration (dark gray) and expiration (light gray) corresponding to the times marked I and E on the upper panels. Pressure magnitude is plotted along the x-axis and the axial location along the esophagus on the y-axis. The location of the respiratory inversion point (RIP) is shown by the horizontal dashed line. (A) Example of complete overlap of the CD and the LES with a single pressure peak in the spatial pressure variation plots during both inspiration and expiration (type I). The RIP lies at the proximal margin of the EGJ. (B) Example of EGJ type II characterized by minimal, but discernible, LES-CD separation making for a double peaked spatial pressure variation plot, but the nadir pressure between the peaks was still greater than gastric pressure. (C, D) The RIP is within the EGJ at the proximal margin of the CD. EGJ type III was defined when LES-CD separation was >2 cm at inspiration. This is the HRM signature of hiatus hernia. Two subtypes were discernible, IIIa and IIIb, with the distinction being that the respiratory inversion point was proximal to the CD with IIIa (C) and proximal to the LES in IIIb (D). Minimal pressure increase reflecting CD contraction is observed during inspiration in type IIIb. (From Pandolfino JE, Kim H, Ghosh SK, et al. High-resolution manometry of the EGJ: an analysis of crural diaphragm function in GERD. Am J Gastroenterol, 2007;102(5):1056-63; with permission.)
of the EGJ and quantify the amount of time that the pressure across the EGJ was flow permissible. Although the paradigms described in these studies were the result of an iterative process of programming and then testing potential analytic algorithms unique to their institution, analogous measures can be made with the current commercially available Manoview software (Sierra Scientific). For instance, the isobaric contour tool on the Manoview analysis software can be set at various pressure values and the time at each pressure
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Fig. 7. An isobaric contour and a spatial pressure variation plot representation of a typical normal swallow. (A) Isobaric contour representation of the swallow. The upper esophageal sphincter (UES) briefly relaxes (at 0 seconds) to let the bolus through into the esophagus, which is then propelled in the antegrade direction by the peristaltic contraction wave. The proximal esophagus, the distal esophagus, and the transition zone that separated the striated from the smooth muscle esophagus are shown. (B) A series of spatial pressure variation plots of the swallow at 0.4-second intervals. The darkened plots show pressure scaling at 1.6 seconds. This provides a convenient method to visualize intraluminal pressure gradients responsible for esophageal emptying or retrograde escape. These plots allow a simultaneous illustration of peristaltic contraction, intrabolus pressure, and EGJ resistance pressure, and the pressure gradients for flow can be assessed. (Courtesy of S. Ghosh, MD and P. Kahrilas, MD, Chicago, IL.)
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Fig. 8. High-frequency, intraluminal ultrasonographic images of the LES and esophageal body in normal subjects; patients with high-amplitude esophageal contractions (nutcracker esophagus); diffuse esophageal spasm; and achalasia. Increased muscular thickness is appreciated in each of the spastic esophageal motility disorders. DES, diffuse esophageal spasm; HAEC, high-amplitude esophageal contractions.
can be calculated manually to provide a plot of the time in which the pressure is below the set relaxation pressure. The nadir pressure is easily determined for the entire deglutitive time period and the total time for a specific residual pressure can be calculated. Although this analysis can provide detailed information regarding EGJ relaxation and resistance through the EGJ, it is unclear whether these new measurements improve on existing technique. HRM does provide an opportunity, however, to explore the true physiologic pressure relationship underlying bolus transport by simultaneously measuring the relationship between intrabolus pressure and EGJ resistance. The authors have developed various paradigms to quantify this relationship and recently validated these techniques against fluoroscopy for predicting the time period were bolus transit is likely to occur [36]. Once again, it is unclear whether these techniques improve clinical management of patients with dysphagia and vigorous validation using objective end points is required. INTRALUMINAL ESOPHAGEAL ULTRASOUND Technical Aspects Although manometry is the primary tool available for the study of gastrointestinal motility disorders, conventional manometry only measures contractions of the circular muscle layer and ignores the activity of the longitudinal muscle and muscularis mucosa. In vitro studies using longitudinal muscle strips obtained from animals have demonstrated significant differences in the motor responses of the longitudinal muscle and circular muscle layers to enteric neurotransmitters. Additional physiologic studies in animals have used the relative
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Fig. 9. (A) Sustained esophageal contraction lasting for 2 minutes and associated with chest pain in the absence of either a corresponding significant perturbation on esophageal manometry or significant drop in esophageal pH. (B, C) Two phasic esophageal pressure waves are seen of normal amplitude [53].
movement of metal markers attached to the esophagus or strain gauges oriented along the longitudinal axis of the esophagus [37,38]. Human studies have used metal clips attached to esophageal mucosa with longitudinal contractions indirectly measured by relative clip movement under fluoroscopy and shown attenuated esophageal shortening in patients with hiatal hernias providing a possible mechanism for impaired bolus clearance [39,40]. Miller and Liu were the first to apply high-frequency, intraluminal ultrasonographic (HFIUS) probes to study esophageal motility [41,42]. The technology and images are similar to those obtained during endoscopic ultrasonography. Higher frequencies (20–30 MHz), however, are used to obtain detailed visualization of the muscularis layers and the probe size allows for transnasal
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intubation in unsedated patients and combination catheter assemblies that incorporate manometric sensors, impedance electrodes, and pH detection. An increase in thickness of the muscularis propria serves as a marker for longitudinal muscle contraction. Currently, the technique has been studied in two centers for investigative purposes. The analysis of images is very labor intensive and significant artifacts are created by the orientation of the HFIUS probe and the esophageal wall and even minute volumes of swallowed or refluxed air. Role in Studying Esophageal Function Early studies of longitudinal muscle function using fluoroscopic displacement of radiopaque markers on the esophagus and strain gauges in animal models concluded that the longitudinal muscle of the esophagus contracts before the circular muscle [37,40,43]. Using HFIUS, both Miller and Mittal demonstrated that longitudinal muscle precedes circular muscle contraction, whereas the maximum contractions of both muscle layers occurs simultaneously in healthy subjects [44–46]. The importance of the esophageal longitudinal muscle in disease has received little attention, largely because of technical difficulties in measurements of its function and the strong symptom correlation with circular muscle dysfunction in patients with achalasia, scleroderma, and esophageal spasm. The advent of ultrasonography has allowed novel insights into the pathogenesis of esophageal motility disorders. Several investigators using conventional endosonography and HFIUS have reported significant hypertrophy of both the circular and longitudinal muscular layers of the esophagus in achalasia and diffuse esophageal spasm, confirming earlier pathologic studies [47–49]. In patients with reflux esophagitis and scleroderma, increased echogenicity and thinning of muscular layers have been demonstrated [50,51]. It remains unclear whether these observations are primary to the disease pathogenesis or secondary phenomena. The opposing findings may reflect the neurogenic defect of achalasia and myogenic defect of scleroderma. Alternatively, Dogan and colleagues [52] hypothesized that the greater muscle thickness is a marker for esophageal outflow obstruction. An increase in muscle wall thickness was also noted in high-amplitude esophageal contractions or nutcracker esophagus patients [49]. Furthermore, the peak increase in muscle wall thickness occurred significantly earlier than the peak circular muscle contraction in contrast to the simultaneous circular and longitudinal muscle contractions measured in control subjects [44]. The investigators speculated that this asynchrony could lead to increased esophageal wall stress that could be responsible for the formation of esophageal diverticula. An increase in muscle thickness was also seen in subsets of patients with nonspecific esophageal motility disorders including hypertensive LES, impaired LES relaxation, and ineffective motility and patients with esophageal symptoms and normal manometry [52]. Although this suggests the potential use of HFIUS in defining clinically significant subgroups of patients with nonspecific disorders, it also implies a lack of specificity of the HFIUS characteristics. Further studies measuring intrabolus pressures or esophageal impedance will help substantiate this application of HFIUS.
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HFIUS has been applied to patients with noncardiac chest pain in a study of 20 subjects using prolonged HFIUS combined with manometry and pH monitoring [53]. Sustained esophageal contractions with increased thickness of both the circular and longitudinal muscle lasting a mean of 68 seconds were detected by HFIUS and associated with 75% of the episodes of chest pain. Of note, these episodes of chest pain did not generate simultaneous changes in intraluminal pressure that could be detected by simultaneous esophageal manometry. The study proposed a novel mechanism whereby the esophageal chest pain is induced by the sustained esophageal contractions. It should be noted, however, that 50% of the sustained esophageal contractions were associated with an acid reflux episode that typically preceded the contraction. This raises the important question as to whether the sustained esophageal contraction is a marker for transient LES relaxation with the pain generated by acid reflux or esophageal distention rather than the contraction itself. Further studies are needed to validate this important observation. SUMMARY The new technologies described in this article represent modifications of existing techniques and new methodologies that can improve accuracy and detail in describing esophageal function. These technologies should not be viewed as competing technologies because each method provides a valuable improvement over the existing technology. Instead, efforts should be focused on combining these techniques because they are largely complementary. For instance, wireless esophageal monitoring is less cumbersome, more comfortable, and allows for prolonged monitoring when compared with catheter-based systems. Efforts should be made to devise a wireless capsule system that can also measure impedance so that information on nonacid reflux can be obtained in a more comfortable and less restricting fashion. Similarly, HRM is the best method to analyze the pressure profile and certainly it should be combined with impedance and intraluminal ultrasound to provide a complete functional assessment of bolus transit and mechanics. Acknowledgments The authors acknowledge Dr. Sudip Ghosh for developing the HRM software programs and figures. References [1] Pandolfino JE, Kahrilas PJ. AGA technical review on the clinical use of esophageal manometry. Gastroenterology 2005;128:209–24. [2] Fass J, Silny J, Braun J, et al. Measuring esophageal motility with a new intraluminal impedance device: first clinical results in reflux patients. Scand J Gastroenterol 1994;29: 693–702. [3] Nguyen HN, Silny J, Albers D, et al. Dynamics of esophageal bolus transport in healthy subjects studied using multiple intraluminal impedancometry. Am J Physiol 1997;273: G958–64. [4] Srinivasan R, Vela MF, Katz PO, et al. Esophageal function testing using multichannel intraluminal impedance. Am J Physiol Gastrointest Liver Physiol 2001;280:G457–62.
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[5] Simren M, Silny J, Holloway R, et al. Relevance of ineffective oesophageal motility during oesophageal acid clearance. Gut 2003;52:784–90. [6] Sifrim D, Castell D, Dent J, et al. Gastro-oesophageal reflux monitoring: review and consensus report on detection and definitions of acid, non-acid, and gas reflux. Gut 2004;53: 1024–31. [7] Imam H, Shay S, Ali A, et al. Bolus transit patterns in healthy subjects: a study using simultaneous impedance monitoring, videoesophagram, and esophageal manometry. Am J Physiol Gastrointest Liver Physiol 2005;288:G1000–6. [8] Kahrilas PJ, Dodds WJ, Hogan WJ. Effect of peristaltic dysfunction on esophageal volume clearance. Gastroenterology 1988;94:73–80. [9] Tutuian R, Castell DO. Clarification of the esophageal function defect in patients with manometric ineffective esophageal motility: studies using combined impedance-manometry. Clin Gastroenterol Hepatol 2004;2:230–6. [10] Tutuian R, Vela MF, Balaji NS, et al. Esophageal function testing with combined multichannel intraluminal impedance and manometry: multicenter study in healthy volunteers. Clin Gastroenterol Hepatol 2003;1(3):174–82. [11] Nguyen HN, Domingues GR, Winograd R, et al. Impedance characteristics of normal oesophageal motor function. Eur J Gastroenterol Hepatol 2003;15:773–80. [12] Nguyen NQ, Rigda R, Tippett M, et al. Assessment of oesophageal motor function using combined perfusion manometry and multi-channel intra-luminal impedance measurement in normal subjects. Neurogastroenterol Motil 2005;17:458–65. [13] Tutuian R, Castell DO. Combined multichannel intraluminal impedance and manometry clarifies esophageal function abnormalities: study in 350 patients. Am J Gastroenterol 2004;99:1011–9. [14] Conchillo JM, Selimah M, Bredenoord AJ, et al. Assessment of oesophageal emptying in achalasia patients by intraluminal impedance monitoring. Neurogastroenterol Motil 2006;18:971–7. [15] Tutuian R, Mainie I, Agrawal A, et al. Symptom and function heterogenicity among patients with distal esophageal spasm: studies using combined impedance-manometry. Am J Gastroenterol 2006;101:464–9. [16] Tutuian R, Castell DO. Rumination documented by using combined multichannel intraluminal impedance and manometry. Clin Gastroenterol Hepatol 2004;2:340–3. [17] Bredenoord AJ, Weusten BL, Sifrim D, et al. Aerophagia, gastric, and supragastric belching: a study using intraluminal electrical impedance monitoring. Gut 2004;53:1561–5. [18] Shay S, Tutuian R, Sifrim D, et al. Twenty-four hour ambulatory simultaneous impedance and pH monitoring: a multicenter report of normal values from 60 healthy volunteers. Am J Gastroenterol 2004;99:1037–43. [19] Vela MF, Camacho-Lobato L, Srinivasan R, et al. Simultaneous intraesophageal impedance and pH measurement of acid and nonacid astroesophageal reflux: effect of omeprazole. Gastroenterology 2001;120(7):1599–606. [20] Bredenoord AJ, Weusten BL, Timmer R, et al. Addition of esophageal impedance monitoring to pH monitoring increases the yield of symptom association analysis in patients off PPI therapy. Am J Gastroenterol 2006;101:453–9. [21] Kahrilas PJ, Quigley EM. Clinical esophageal pH recording: a technical review for practice guideline development. Gastroenterology 1996;110:1982–96. [22] Zerbib F, Roman S, Ropert A, et al. Esophageal pH-impedance monitoring and symptom analysis in GERD: a study in patients off and on therapy. Am J Gastroenterol 2006;101: 1956–63. [23] Mainie I, Tutuian R, Shay S, et al. Acid and non-acid reflux in patients with persistent symptoms despite acid suppressive therapy: a multicentre study using combined ambulatory impedance-pH monitoring. Gut 2006;55:1398–402. [24] Pandolfino JE, Shi G, Zhang Q, et al. Measuring EGJ opening patterns using high resolution intraluminal impedance. Neurogastroenterol Motil 2005;17:200–6.
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[25] Pandolfino JE, Zhang QG, Ghosh SK, et al. Transient lower esophageal sphincter relaxations and reflux: mechanistic analysis using concurrent fluoroscopy and high-resolution manometry. Gastroenterology 2006;131:1725–33. [26] McMahon BP, Frokaer JB, Drewes AM, et al. A new measurement of oesophago-gastric junction competence. Neurogastroenterol Motil 2004;16:543–6. [27] McMahon BP, Frokjaer JB, Liao D, et al. A new technique for evaluating sphincter function in visceral organs: application of the functional lumen imaging probe (FLIP) for the evaluation of the oesophago-gastric junction. Physiol Meas 2005;26:823–36. [28] Nayer DS, Khandwhalla F, Achkar EA, et al. Esophageal manometry: assessment of interpreter consistency. Clin Gastroenterol Hepatol 2005;3:218–24. [29] Clouse RE, Staiano A. Topography of the esophageal peristaltic pressure wave. Am J Physiol 1991;261:G677–84. [30] Li M, Brasseur JG, Dodds WJ. Analyses of normal and abnormal esophageal transport using computer simulations. Am J Physiol 1994;266:G525–43. [31] Orlowski J, Dodds WJ, Linehan JH, et al. Requirements for accurate manometric recording of pharyngeal and esophageal peristaltic pressure waves. Invest Radiol 1982;17: 567–72. [32] Clouse RE, Staiano A. Topography of normal and high-amplitude esophageal peristalsis. Am J Physiol 1993;265:G1098–107. [33] Clouse RE, Prakash C. Topographic esophageal manometry: an emerging clinical and investigative approach. Dig Dis 2000;18:64–74. [34] Pandolfino JE, Kim H, Ghosh SK, et al. High-resolution manometry of the EGJ: an analysis of crural diaphragm function in GERD. Am J Gastroenterol 2007;12(5):1056–63. [35] Pandolfino JE, Ghosh SK, Zhang Q, et al. Quantifying EGJ morphology and relaxation with high-resolution manometry: a study of 75 asymptomatic volunteers. Am J Physiol Gastrointest Liver Physiol 2006;290(5):1033–40. [36] Ghosh SK, Pandolfino JE, Zhang Q, et al. Quantifying esophageal peristalsis with highresolution manometry: a study of 75 asymptomatic volunteers. Am J Physiol Gastrointest Liver Physiol 2006;290:G988–97. [37] Dodds WJ, Stewart ET, Hodges D, et al. Movement of the feline esophagus associated with respiration and peristalsis: an evaluation using tantalum markers. J Clin Invest 1973;52: 1–13. [38] Sugarbaker DJ, Rattan S, Goyal RK. Swallowing induces sequential activation of esophageal longitudinal smooth muscle. Am J Physiol 1984;247:G515–9. [39] Kahrilas PJ, Wu S, Lin S, et al. Attenuation of esophageal shortening during peristalsis with hiatus hernia. Gastroenterology 1995;109:1818–25. [40] Pouderoux P, Lin S, Kahrilas PJ. Timing, propagation, coordination, and effect of esophageal shortening during peristalsis. Gastroenterology 1997;112:1147–54. [41] Liu JB, Miller LS, Goldberg BB, et al. Transnasal US of the esophagus: preliminary morphologic and function studies. Radiology 1992;184:721–7. [42] Miller LS, Liu JB, Klenn PJ, et al. High-frequency endoluminal ultrasonography of the esophagus in human autopsy specimens. J Ultrasound Med 1993;12:563–6. [43] Sugarbaker DJ, Rattan S, Goyal RK. Mechanical and electrical activity of esophageal smooth muscle during peristalsis. Am J Physiol 1984;246:G145–50. [44] Jung HY, Puckett JL, Bhalla V, et al. Asynchrony between the circular and the longitudinal muscle contraction in patients with nutcracker esophagus. Gastroenterology 2005;128: 1179–86. [45] Miller LS, Liu JB, Colizzo FP, et al. Correlation of high-frequency esophageal ultrasonography and manometry in the study of esophageal motility. Gastroenterology 1995;109: 832–7. [46] Nicosia MA, Brasseur JG, Liu JB, et al. Local longitudinal muscle shortening of the human esophagus from high-frequency ultrasonography. Am J Physiol Gastrointest Liver Physiol 2001;281:G1022–33.
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[47] Deviere J, Dunham F, Rickaert F, et al. Endoscopic ultrasonography in achalasia. Gastroenterology 1989;96:1210–3. [48] Miller LS, Liu JB, Barbarevech CA, et al. High-resolution endoluminal sonography in achalasia. Gastrointest Endosc 1995;42:545–9. [49] Mittal RK, Kassab G, Puckett JL, et al. Hypertrophy of the muscularis propria of the lower esophageal sphincter and the body of the esophagus in patients with primary motility disorders of the esophagus. Am J Gastroenterol 2003;98:1705–12. [50] Manabe N, Haruma K, Hata J, et al. Evaluation of esophageal motility by endosonography using a miniature ultrasonographic probe in patients with reflux esophagitis. Scand J Gastroenterol 2002;37:674–8. [51] Miller LS, Liu JB, Klenn PJ, et al. Endoluminal ultrasonography of the distal esophagus in systemic sclerosis. Gastroenterology 1993;105:31–9. [52] Dogan I, Puckett JL, Padda BS, et al. Prevalence of increased esophageal muscle thickness in patients with esophageal symptoms. Am J Gastroenterol 2007;102:137–45. [53] Balaban DH, Yamamoto Y, Liu J, et al. Sustained esophageal contraction: a marker of esophageal chest pain identified by intraluminal ultrasonography. Gastroenterology 1999;116: 29–37.
Gastroenterol Clin N Am 36 (2007) 553–575
GASTROENTEROLOGY CLINICS OF NORTH AMERICA
Esophageal Motor and Sensory Disorders: Presentation, Evaluation, and Treatment Benson T. Massey, MD, FACP GI Manometry Laboratory, Division of Gastroenterology and Hepatology, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, USA
D
isorders of esophageal motility and sensation are relatively rare in the general population. Because their prevalence generally increases with age [1,2], more patients are expected to present with these disorders as the average age of the population increases. The rarity of these disorders, combined with the lack of specificity in their clinical presentation, makes early diagnosis a challenge. All of the currently available treatments are at best palliative, and their benefit may be offset by side effects and complications that require additional therapy. Despite treatment, progression of the underlying disorder occurs frequently, so that ongoing follow-up is necessary to manage symptom relapse and complications. Although rarely life-threatening, these disorders have substantial effects on the quality of life experienced by afflicted patients [3,4]. The magnitude of anxiety and suffering that these disorders engender is readily evident from Internet postings by members of disease-specific patient support groups. Quality care of these patients requires technical and cognitive mastery of the various diagnostic and treatment modalities, along with clinical acumen and compassion in helping patients cope with a chronic illness. This article develops an algorithmic approach to the evaluation of idiopathic and secondary esophageal motor and sensory disorders, with the exception of those related to gastroesophageal reflux disease (GERD). Readers are strongly encouraged to review the article on GERD elsewhere in this issue. This article also does not cover sensory and motor disorders of the oropharynx. Although the article title suggests that sensory and motor disorders are separate entities, a common clinical scenario is the conjoint manifestation of these problems in any single patient. Indeed, it is often hard to determine whether the sensory or the motor disturbance is the dominant agent for symptoms. A final introductory caveat is that although sensory and motor disorders comprise a wide
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spectrum, the condition with the greatest body of information and consensus on clinical approach is esophageal achalasia. Evaluation and management of achalasia of necessity dominates the article, as does the use of achalasia to exemplify important concepts in the general approach to all such disorders. ARE SYMPTOMS PRESENT THAT SUGGEST AN ESOPHAGEAL MOTOR OR SENSORY DISORDER? The first step in diagnosing an esophageal sensorimotor disorder is to recognize that the patient’s presentation is consistent with such a disorder (Fig. 1). The repertoire of presenting symptoms for esophageal sensorimotor disturbances is relatively limited. Symptomatic presentation of esophageal sensory and motor disorders is as follows: Primary symptoms of disorder Dysphagia for solids and liquids Chest pain or heartburn Regurgitation or vomiting Coughing or choking Hiccups, eructation Halitosis Globus Altered diet or eating behavior Secondary symptoms from complications Weight loss Fever Respiratory symptoms Hematemesis
Individual symptoms or constellations of symptoms are inconsistently present. For example, although the classic hallmark of motor disorders is dysphagia for both solids and liquids, dysphagia is an initial symptom in less than half of achalasia patients [5]. Certain features of the symptoms suggest the presence of a sensorimotor disorder. More difficulty is reported with cold or carbonated beverages, whereas warm drinks may improve symptoms. Patients may get up from the meal to walk around or arch their neck to move the swallowed material into the stomach [5]. Belching is not a spontaneous event that relieves a sense of gastric distention; instead, it is an event induced by air swallowing to try to remove air trapped in the top of the esophagus. Regurgitated food is not sour and has a taste similar to that when originally swallowed. Regurgitation of such food often occurs hours after it was consumed. Rather than food, the patient may bring up a bland foam-laden liquid, essentially the saliva that was swallowed throughout the day. Food particles are found on the bedclothes in the morning. Elicitation of these features often requires pointed questioning of the patient or family and at times direct observation of patient behavior during a challenge of eating and drinking. The symptoms typically begin insidiously and progress gradually over the course of weeks-to-months. The course of symptom progression is not always
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Are symptoms present that suggest an esophageal sensorimotor disorder?
Have more common caus for these symptoms been excluded?
Do test findings support the diagnosis of an esophageal sensorimotor disorder?
Is the sensorimotor disorder idiopathic, or does it result from another condition?
Are there additional disorders present to cause or modulate symptoms?
Are symptoms the result of complications from the disorder?
For secondary disorders, are symptoms manifestations of the underlying disorder?
Are significant psychosocial disorders or stressors present that are modulating the symptom presentation?
Fig. 1. Algorithm for the evaluation of patients with possible esophageal sensorimotor disorders.
relentless. For milder disorders, symptoms may only appear intermittently (but, to the patient’s consternation, often not predictably). Patient modification of eating habits and diet can give a false semblance of remission or reversal of the disorder. The dominant symptom can also change as the disorder progresses. For example, a common history in achalasia is that the major symptom early in the course is chest discomfort, to be replaced by dysphagia and eventually regurgitation, as the esophagus progressively dilates. Rarely, the patient has no primary symptom. This is more likely to be the case in patients with cognitive disturbances or developmental disorders, as with achalasia in patients
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with Down syndrome [6]. In such cases, presence of the disorder becomes recognized during the evaluation of a complication (eg, aspiration pneumonia), or by chance during evaluation of another condition (eg, dilated esophagus seen on a CT scan performed to rule out pulmonary embolism). Symptoms in patients may reflect complications of the disease. Respiratory symptoms can result from aspiration pneumonia or a piece of regurgitated food lodged in a bronchus. Rarely, achalasia presents with life-threatening acute respiratory distress from occlusion of the airway by the distended esophagus [7]. Hematemesis may be from a Mallory-Weiss tear from retching or a bleeding esophageal cancer. Weight loss would seem to be an obvious symptom of a condition that makes eating a challenge. As the prevalence of obesity has increased in the United States population, however, more patients with achalasia have been encountered who continue to gain weight despite the disorder to the point of warranting bariatric surgery [8]. One should not conclude that the patient with weight gain cannot have a major esophageal sensorimotor disorder. The standard physical examination is essentially unhelpful in determining the presence of a sensorimotor disorder per se. Physical findings may offer a clue to the presence of conditions causing secondary sensorimotor disturbances or the presence of complications from such disturbances. HAVE MORE COMMON CAUSES FOR THESE SYMPTOMS BEEN EXCLUDED? Two fundamental problems interact to impede attempts at making a presumptive diagnosis of an esophageal sensorimotor disorder based on symptoms. First, none of the individual symptoms are pathognomonic for a specific disorder or the general category of sensorimotor disorders. All of the primary and secondary symptoms listed previously have been reported in some fashion by patients with GERD. For example, in one series of patients studied manometrically for mixed solid-liquid dysphagia, GERD was over twice as prevalent as achalasia [9]. Second, sensorimotor disorders of the esophagus are extremely rare, especially when compared with the presence of GERD. As an example, the annual incidence of achalasia is about 1 per 200,000 population [10]. Given that about 1 out of 20 adults has daily symptoms caused by GERD, any given patient presenting with esophageal symptoms is about 10,000 times more likely to have GERD than achalasia. Even in a patient with multiple classic symptom features, the probability is still overwhelming that the patient has atypical GERD, not typical achalasia. More problematic still are the patients who initially have GERD and subsequently develop a separate disorder, such as achalasia [11,12]. The combination of rarity and symptom nonspecificity causes considerable delay between the onset of symptoms and the diagnosis of esophageal sensorimotor disorders. For achalasia, this diagnostic delay averages about 5 years [13,14]. Although it is frustrating for patients to be mistakenly diagnosed and treated initially as having GERD, most patients with similar symptoms are
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going to have GERD and are likely to respond to treatment. Even patients who fail to respond to such treatment are more likely to be patients with GERD who need a different treatment regimen than patients with a separate sensorimotor disorder. For patients with alarm symptoms, such as progressive dysphagia, the standard diagnostic test (endoscopy) can be nondiagnostic for both conditions. Most patients undergo endoscopy and unsuccessful courses of treatment for GERD before the diagnosis of an esophageal sensorimotor disorder is considered. GERD is the most common of a diverse range of other conditions that must be considered in the differential diagnosis of esophageal sensorimotor disorders, listed as follows: Structural esophageal disorders Rings, webs, caustic and inflammatory strictures Eosinophilic esophagitis Intrinsic neoplasm Extrinsic compression (neoplasm, vascular, inflammatory) Congenital atresia or fistula Inflammatory esophageal disorders Reflux esophagitis Infection (fungal, viral) Radiation Medication (pill injury) Nonesophageal functional and motor disorders Oropharyngeal motor disorders Bulimia Cyclic vomiting syndrome Rumination Gastroparesis Hyperemesis gravidarum Disorders of other organ systems Cardiovascular disease Pulmonary disease Musculoskeletal disorders of the chest Postherpetic and other sensory neuropathies Iatrogenic complications Dysfunctional antireflux procedure
The presence of many of these as the cause for symptoms becomes readily apparent after a careful history, physical examination, and evaluation by standard tests, such as endoscopy, barium esophagrams, and CT imaging of the chest and abdomen. Among this broad list, several conditions warrant specific discussion. In the patient whose dominant symptoms are chest discomfort rather than altered bolus transit, great care should be taken to ensure that the symptoms are not a result of underlying cardiovascular disease. Although a delay in the accurate diagnosis of an esophageal sensorimotor disorder can affect quality of life, a delay in the diagnosis of coronary artery disease can be fatal. Eosinophilic esophagitis is being diagnosed with increasing frequency
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[15]. Although certain characteristic features have been identified, these are not universally present, nor are the endoscopic, radiographic, and pathologic features always recognized when they are present. To avoid missing this diagnosis, the endoscopist needs to obtain esophageal biopsies from multiple sites and the pathologist needs to quantify the number of eosinophils per high-powered field. Patients with a tight fundoplication wrap may have a normal endoscopic and radiographic evaluation. The standard esophagram misses oropharyngeal motor disorders; if these are in the differential diagnosis, a videotaped fluoroscopic swallow study with a speech pathologist should be performed. DO TEST FINDINGS SUPPORT THE DIAGNOSIS OF AN ESOPHAGEAL SENSORIMOTOR DISORDER? Because the symptoms of esophageal sensorimotor disorders are nonspecific, once likely alternative causes for the symptoms are excluded, additional testing is required to support the clinical hypothesis that such a disorder is present. Testing for these disorders is imperfect and should serve as adjuncts to, not substitutes for, diagnostic reasoning. Testing for Esophageal Motor Disorders Testing for esophageal motor disorders is fraught with several conceptual and methodologic difficulties. First, the tests currently clinically available only provide information on the phenotype of the disorder. That is, they delineate alterations in esophageal morphology, muscle activity, and bolus transit without elucidating the underlying pathophysiologic disturbances contributing to the phenotype. Different disease processes may manifest an indistinguishable phenotype on a given test, the classic example being the similar manometric findings of idiopathic achalasia and pseudoachalasia from adenocarcinoma of the cardia [16]. Second, because the underlying pathophysiology is unknown, constellations of findings on the diagnostic test have been used as the gold standard for deciding that the disorder is present. Such gold standards have commonly been determined by expert consensus or statistical parameters (ie, a value on a given measurement that is outside the 95% confidence interval of a control group). In many cases, these gold standards lack rigorous evidence for validity (in terms of predicting natural disease course or response to therapy) or reproducibility. Diagnoses based on a finding being outside the normal range are particularly problematic because, by definition, 5% of normal subjects have this finding, and these normal ‘‘outliers’’ may be over 100 times more prevalent in the population than patients with true motor disorders who have similar outlying values. Because there can be considerable random variation in a parameter over time, a group of patients who are categorized as abnormal based on an outlier value on a single test have some members of that group revert to a normal value on repeat testing (regression to the mean), as has been demonstrated with hypertensive peristalsis [17]. Third, considerable functional variability can exist within a diagnosis. For example, by definition, diffuse esophageal spasm can range from a patient
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with infrequent (20%) normal amplitude simultaneous contractions but otherwise normal motility to a patient in whom nearly every swallow results in highamplitude, long-duration simultaneous contractions. Even in such a disorder as esophageal achalasia, which has considerable expert consensus about the diagnostic criteria, variant forms have been recognized [18]. Fourth, published diagnostic criteria for different disorders are inconsistently applied to manometric findings by different clinicians [19]. Fifth, there is little consensus for the testing apparatus used or the testing protocol followed among different motility centers. Normal values may vary greatly among manometry laboratories if they use different catheters and score pressure phenomena differently. Lack of uniformity in formatting of manometry data across different systems can make it nearly impossible for a person in one laboratory to interpret the raw data from a manometric study performed in another laboratory. Finally, one needs to distinguish between testing to document the presence of an esophageal sensorimotor disorder and testing to determine if the disorder is the cause of a particular symptom. This is especially true when motor disorders are identified, but the symptoms are more related to pain than abnormal bolus transport. Several tests are available to help establish the diagnosis of an esophageal motor disorder. Tests for motor dysfunction Endoscopy Barium radiography Esophageal scintigraphy Manometry Impedance testing Endosonography
Endoscopy is used more to exclude other causes for the symptoms than to diagnose a sensorimotor disorder. Certain findings on endoscopy can suggest the presence of some disorders. An obviously dilated esophageal lumen with substantial fluid retention and no obstructing structural lesion is highly suggestive of achalasia. Failure to observe peristaltic contractions with swallows on endoscopy, and abnormal opening patterns of the gastroesophageal junction with swallows, have been reported to be accurate in distinguishing the extreme motor disorders of achalasia and scleroderma esophagus from normal motility [20]. The use of endoscopy to detect more subtle motor disturbances remains untested. Both fluoroscopy and scintigraphy have been used in the evaluation of esophageal motor disorders. Both are excellent at detecting the gross disturbances in bolus transit through the esophagus that can be a consequence of some motor disorders. Abnormal temporal patterns of bolus deformation on radiology can suggest the presence of failed or weak contractions; simultaneous (spastic) contractions; or retrograde contractions. Neither modality can identify a contraction abnormality in a region of esophagus that has been cleared of bolus material, so that patients with hypertensive peristalsis are usually not detected by these
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techniques [21,22]. These tests are operator-dependent, and some radiologists fail to appreciate the characteristic features of even a standard motor disorder, such as achalasia [23]. Variant and early forms of achalasia are even less well recognized, so that the sensitivity for radiology and scintigraphy in the detection of achalasia is suboptimal [24]. This is becoming more of a problem as radiologists in training in the United States devote less time and enthusiasm to mastery of these techniques. This author’s clinical perception is that unseasoned radiologists are often overcalling motor disturbances, because of a failure to appreciate the effects of normal physiologic processes on bolus transport, such as deglutitive inhibition and refractory periods with closely spaced swallows, the normal degree of retrograde bolus escape seen in the transition zone region between the striated and smooth muscle in the proximal esophagus, and the normal inefficient clearance of solid boluses with single swallows [25,26]. The risks of radiation exposure limit the duration of these studies. Manometric studies of esophageal motor function have traditionally been used as the gold standard for determining the presence and classification of an esophageal motor disorder. Clear advantages for manometry over radiology and scintigraphy are the ability to perform prolonged studies and detect motor abnormalities in regions of the esophagus not occupied by a bolus at the time of observation. Methodologic limitations for manometry until recently have been a lack of adequate spatial resolution for most systems. This can result in two problems. One is the likelihood of missing focal abnormalities (uncoordinated or weak contractions) that occur between two widely spaced sensors. The other is the axial dislocation of a high-pressure zone off of a point sensor, resulting in the spurious finding of relaxation. The manometric sleeve device was developed to allow continuous recording of high-pressure zones, such as the lower esophageal sphincter (LES), during axial movement [27], identifying the failed relaxation of the LES with deglutition in achalasia. Accurate interpretation of sleeve findings requires careful positioning of the sleeve relative to the sphincter. If the sphincter is located too close to the proximal end of the sleeve, the sphincter moves off of the sleeve with deglutition, imparting a false sense of relaxation. Although the customary position of the top of the sleeve is 2 cm above the top of the sphincter high-pressure zone, it is clear that in some circumstances more vigorous axial displacement is possible [28]. Such displacement may well account for the unexpectedly frequent occurrence of LES relaxations in conjunction with vigorous esophageal body contractions during ambulatory sleeve recordings in achalasia patients [29]. As a practical rule, if the sleeve seems to record LES relaxations that are simultaneous with vigorous proximal esophageal body contractions, recordings should be repeated with the sleeve repositioned at least 2 cm more proximally. Like radiographic methods, esophageal manometry is exceedingly dependent on the expertise of the operator. Few trainees in gastroenterology devote sufficient time and concentration in the technique. Failure to appreciate the limitations of the manometric recording apparatus, and a lack of knowledge about esophageal anatomy and physiology, are the major reasons for the need to
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repeat studies performed elsewhere. In this author’s experience, the most common errors are a failure to identify incomplete LES relaxations because of use of a single point sensor, misdiagnosis of ineffective motility by recording from a hiatal hernia instead of the distal esophagus, misinterpretation of intrabolus pressures as esophageal contractions, and failure to appreciate the effect of dry swallows and upright body position on peristaltic amplitude and velocity [30–32]. Because atypical features are inconsistently interpreted and consensus criteria for diagnosis are not uniformly applied, diagnostic agreement on study interpretation, even at expert centers, can be poor for certain disorders [19]. Given these difficulties in assigning diagnostic labels to manometric findings, a reasonable approach may be instead to report the component abnormalities in sphincter and esophageal body motor function [33,34]. Newer techniques of high-resolution solid-state manometry, esophageal impedance, and endosonography may revolutionize the assessment of these patients in the future. The performance characteristics of these tests are covered in more detail elsewhere in this issue. Testing for Esophageal Sensory Disorders Positive diagnosis of esophageal sensory disorders remains problematic. Sensory disorders tend to be considered only after nonesophageal disorders (eg, cardiac disease), GERD, and esophageal motor disorders have been ruled-out by testing. Evidence against this approach comes from studies indicating that these different disorders may occur together in groups of patients with chest pain [35–37]. Ideally, a diagnostic test for esophageal sensory disturbances has reproducibility and clinical validity even when other disorders are present. Diagnostic tests for esophageal sensory and motor disorders include the following: Tests for sensory dysfunction Esophageal distension Esophageal electrical stimulation Pharmacologic provocation Esophageal acid perfusion
A variety of stimuli have been applied to the esophagus to demonstrate that selected groups of patients with chest symptoms have reduced thresholds for discomfort or higher perceptions of pain, when compared with normal subjects. Some of these stimuli could potentially cause symptomatic motor responses; however, response to noxious stimuli after blockade of motor responses supports the presence of visceral hypersensitivity [38]. Several factors have limited the clinical use of provocative sensory testing for diagnosing esophageal sensory disorders. First, the techniques for stimulus production vary considerably among laboratories, with accompanying variation in normal values. The manner in which the stimulus is applied can significantly affect the threshold for symptom induction [39]. Second, there is a high risk of response bias, requiring blinding of the test administrator and the patient to the stimulus [40]. Third, studies have shown significant age and gender differences in sensory thresholds [41,42].
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Fourth, although studies have shown significant differences between patients with chest symptoms and asymptomatic controls, the range of responses between the two groups often overlaps. Some otherwise normal subjects have been identified as having esophageal hypersensitivity, based on their outlier responses to testing [43]. For most tests, data on sensitivity and specificity are either not available or inadequate because of a lack of sufficient sample size or performance of a receiver operating characteristic curve analysis to determine the optimal test threshold for diagnosis. Fifth, patients may have a positive response to one stimulus but not another. Use of multiple stimuli is likely to improve sensitivity at the expense of specificity. Use of multiple sequential stimuli at the same test setting also runs the risk of inducing altered responses because of central sensitization [44]. From these considerations, it is evident that any laboratory proposing to perform a diagnostic test battery for abnormal esophageal sensitivity cannot assume that its protocol precisely matches those from published studies. This means that each laboratory needs to develop its own set of normal data for its specific protocol. Such a data set needs to include subjects rigorously tested for the presence of other symptomatic disorders and report normal value ranges adjusted for age and gender. Although the usual clinical emphasis is on hypersensitive disorders, some patients may have reduced esophageal sensitivity. Reduced sensitivity has been demonstrated in patients with achalasia [45] and Chagas’ disease [46]. Abnormal sensory pathways may result in a failure to elicit normal clearing peristaltic contractions in response to a retained esophageal bolus [47]. Despite its potential importance, testing for esophageal hyposensitivity is almost never performed clinically. IS THE SENSORIMOTOR DISORDER IDIOPATHIC, OR DOES IT RESULT FROM ANOTHER CONDITION? When esophageal sensorimotor abnormalities have been identified, the clinician needs to determine whether they are primary (idiopathic) or are a secondary manifestation of another disorder. Secondary etiologies for esophageal sensory and motor disorders include the following: Neoplastic Adenocarcinoma of the cardia Small cell carcinoma (anti-Hu) Amyloidosis Neurologic disorders Parkinson’s disease Multiple sclerosis Autonomic or sensory neuropathies Inflammatory or autoimmune disorders Chagas’ disease Connective tissue disorders Eosinophilic esophagitis
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Metabolic Diabetes mellitus Hypothyroidism Alcoholism Hereditary or genetic disorders Allgrove’s (AAAS) syndrome Down syndrome Fabry’s disease Neurofibromatosis Iatrogenic Anticholinergic medication Vagotomy Tight fundoplication wrap Myotomy Mediastinal radiation Miscellaneous Idiopathic intestinal pseudo-obstruction
For some conditions, the medical history, examination findings, and other laboratory tests may have already confirmed the presence of the underlying disorder, and the role of esophageal function testing is to confirm that this organ is also affected and causing symptoms. The esophageal manifestations, however, can sometimes be the presenting feature of the disease. An important example of this is the development of an achalasia phenotype as a paraneoplastic response months before the underlying small cell carcinoma can be detected [48]. In patients with Allgrove’s syndrome, the esophageal motor disturbance can develop before the life-threatening adrenal insufficiency [49]. The entity of pseudoachalasia arising from adenocarcinoma of the gastric cardia requires specific mention, because this condition can on manometry be indistinguishable from idiopathic achalasia. Although frequently identified at endoscopy, at times CT scanning or endosonography is required to identify the lesion. Pseudoachalasia should be suspected in patients presenting at an older age, with a rapid symptom course and substantial weight loss [50]. Rare cases of eosinophilic esophagitis presenting as secondary motor rather than mucosal disorders can be extremely difficult to diagnose [51]. ARE THERE ADDITIONAL DISORDERS PRESENT TO CAUSE OR MODULATE SYMPTOMS? At times, one is fortunate to identify an esophageal sensorimotor disorder relatively early in the presentation and diagnostic work-up. In such cases, one has to be cognizant of the potential for a more common disorder to be present also and contributing to the clinical picture. The 65-year-old hyperlipidemic smoker with dysphagia and chest pain may have both achalasia and unstable angina. Abnormal esophageal acid exposure is a common finding in hypertensive peristalsis. Symptoms may result from a complication of the disorder, rather than the inherent pathophysiology of the disorder. An example is odynophagia from an ulcer caused by a retained caustic medication. For secondary
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disorders, symptoms may be another manifestation of the underlying disorder, such as chest pain resulting from diabetic sensory neuropathy. Since the classic studies of Wolf and Almy [52], it has been known that psychologic stressors can modulate esophageal sensorimotor disorders. Psychiatric disorders are common among patients with esophageal motor disorders referred for diagnostic testing [53], although patients with similar symptoms and no motor disorders are also found to have evidence for depression, anxiety, and somatization [54]. In such patient groups, psychiatric disturbance is more closely associated with symptoms of chest pain than dysphagia [54]. Acute stress can modify esophageal contractions [55] and perception thresholds for heartburn [56]. Often unappreciated is the effect of stress on diaphragmatic crural function [57], contraction of which can impair esophageal emptying [58]. One has to be wary of this phenomenon in anxious patients, to avoid misdiagnosis of a disorder of smooth muscle LES relaxation. WHAT THERAPIES SHOULD BE USED IN PATIENTS WITH SENSORIMOTOR ESOPHAGEAL DISORDERS? When devising a treatment plan for esophageal sensorimotor disorders, several issues must be considered. The first issue is whether the severity of the disturbance and its effect on the patient’s overall health and quality of life are severe enough to warrant treatment. A patient with isolated episodes of brief chest discomfort or bolus hesitancy every few days or weeks from a focal and intermittent discoordination of contractions in the esophageal body may require no treatment other than an explanation and reassurance. Studies have suggested that following confirmation of an esophageal disorder by testing, patients have less hospital use and fewer absences from work and social functions [59]. Many patients who are found to have less severe motor disorders exhibit improvement in symptoms over time [60]. At the other extreme, the patient with substantial weight loss and dehydration from near daily regurgitation and vomiting or with recurrent aspiration pneumonia is going to require more definitive therapy. The second issue when considering treatment is that none of the therapies available at present correct the underlying disorder. These treatments are at best palliative for the dominant symptoms of the patient. All available treatments have the potential for side effects and complications, which need to be considered carefully in the context of the patient’s overall health, comorbid illnesses, and life expectancy. Treatments often lack a durable response or lose their benefit as the underlying disease progresses. The evidence for many treatments is anecdotal at best, with few controlled clinical trails to support efficacy. When competing treatments are available for a disorder, few have undergone comparisons in appropriately designed clinical trials of adequate length. If symptoms are severe enough to warrant active treatment, one then has to decide which pathophysiologic processes are responsible for the symptoms. Although the dichotomy is not perfect, motor disturbances are more likely to
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have symptoms of bolus transport (eg, dysphagia, regurgitation), whereas hypersensitivity is more likely to result in symptoms of pain. Treatment of Motor Disorders Motor disorders from a functional standpoint can be divided into two broad categories: disorders of outflow obstruction from an inadequately relaxing LES and disorders of peristaltic bolus transport in the esophageal body. Esophageal body disorders can be divided into disorders of inadequate peristaltic propulsive strength and disorders of abnormal contraction sequencing (spasm). Interactions between LES and esophageal body dysfunction determine the pattern of abnormal bolus transport and the therapeutic approach (Fig. 2). Findings on manometric and radiographic studies can help identify the disturbances of bolus transport.
Selection of Therapeutic Options for Motor Disorders Based on Pattern of Motor Disturbances
Motor Disturbance Weak/absent peristaltic contractions and no outflow obstruction
Motor Disturbance Disordered (spastic) esophageal contractions and no outflow obstruction
Motor Disturbance Outflow obstruction < driving force from peristaltic/spastic esophageal body contractions
Motor Disturbance Outflow obstruction < driving force from peristaltic/spastic esophageal body contractions
Dietary/Behavioral Eat upright Liberal use of liquids Carbonated drinks Thorough chewing Avoid gummy foods
Dietary/Behavioral Eat upright Hot beverages Avoid provocative foods Peppermint
Dietary/Behavioral Eat upright Hot beverages Avoid provocative foods
Dietary/Behavioral Eat upright Frequent smaller meals
Medical Therapy Contraction stimulants
Medical Therapy Contraction/tone inhibitors Botulinum toxin: body
Medical Therapy Contraction/tone inhibitors Botulinum toxin: LES Pneumatic dilation
Medical Therapy Botulinum toxin: LES Pneumatic dilation
Surgical Therapy Esophageal replacement
Surgical Therapy Long myotomy of esophageal body
Surgical Therapy Myotomy of LES Long myotomy of esophageal body
Surgical Therapy Myotomy of LES
Fig. 2. Algorithm for selecting therapies for esophageal motor disorders. LES, lower esophageal sphincter.
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Isolated disorders of inadequate propulsive strength leave bolus residue in the esophageal body. In the upright position the combined effects of gravity and the feeble propulsive force are usually sufficient to overcome resistance at the gastroesophageal junction and intragastric pressure, so that liquid boluses are almost completely cleared into the stomach. Nondeforming boluses that adhere to the esophageal wall may not clear at all until dissolved. The goal of therapy is to improve the strength of contractions, when possible. Isolated disorders of contraction sequencing are commonly accompanied by a failure of descending inhibition [61,62]. Contractions distal to the bolus impair its entry into the stomach and can move the bolus retrograde. In the absence of outflow obstruction and with the benefit of gravity, however, there is no progressive retention of bolus with repeated swallows. The goal of currently available therapy is to diminish or abolish these abnormal contractions. When outflow obstruction is present from abnormal LES relaxation, this needs to be reduced or eliminated to facilitate esophageal emptying. If peristaltic or spastic contractions can raise the pressure in the bolus sufficiently to propel it into the stomach, then significant esophageal retention is usually not observed. Symptoms may result from activation of pain receptors in regions where higher intrabolus pressures result in increased intramural tension. In this situation, reduction of both LES tone and esophageal body contractions may be beneficial. When esophageal body contractions are insufficiently vigorous to generate an adequate pressure gradient to force the bolus through the LES, however, then esophageal retention occurs and esophageal contractions cannot occlude the lumen (Fig. 3). On manometry isobaric pressure waves are observed [63]. In this situation, pharmacologic agents that relax all smooth muscle are not helpful, because the reduction in LES pressure is offset by the reduction in esophageal body contractility that serves to move the bolus into the stomach. In this situation, targeted reduction of the outflow resistance is required. Modifications of diet and lifestyle are the first line of treatment for motor disorders. Patients should eat and drink in an upright position and remain that way postprandially, so that gravity can facilitate esophageal clearance. Swallowing hot (60 C) water with meals may aid in bolus passage [64]. Peppermint may decrease spastic contractions [65]. Foods the patient identifies as provoking spasm should be avoided [66]. Patients with poor esophageal propulsive ability need to wash down food with liberal use of liquids. Carbonated beverages can also be helpful if significant outflow obstruction is absent. A limited number of pharmacologic agents are available to alter tonic and phasic contractions of the LES and esophageal body. For increasing contractions, the only pathway available at present is through agents that mimic acetylcholine or enhance the availability of acetylcholine. Bethanechol has been shown acutely to increase esophageal contractions and improve bolus clearance in patients with GERD and severe ineffective motility [67,68]. This has not been evaluated in chronic studies in patients with disorders of ineffective motility. More agents are available to inhibit contractions and tone. The major classes are nitrates, calcium channel blockers, anticholinergics, and phosphodiesterase
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Fig. 3. Progression from nonisobaric to isobaric waves in an achalasia patient. Manometric tracing shows a sequence of one dry swallow followed by five wet (5 mL water) swallows. The top seven channels show pressure data from recording sites in the esophageal body (E1–6) placed 3 cm apart and from the LES (recorded with a sleeve device). Channel E1-LES is the difference between these two channels, with a positive value being favorable for bolus passage from the esophagus through the LES. Pressure scales are 0 to 100 mm Hg, except for the bottom channel (50–þ50 mm Hg.) Note that the periods of favorable pressure differential for esophageal emptying are of short duration and low magnitude, insufficient to allow complete esophageal emptying. The first few swallows show pressure waveforms that are different throughout the esophagus (nonisobaric). As the esophagus fills with retained fluid, however, the basal pressure rises, and the contractions are no longer able to occlude the esophageal lumen. The pressure they generate is transmitted uniformly throughout the retained fluid, resulting in the same pressure waveform being recorded on all of the sensors in the esophageal body (isobaric waves) by the third wet swallow. DS, dry swallow; LES, lower esophageal sphincter; WS, wet swallow.
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inhibitors. Essentially, they serve to inhibit muscle tone directly or block the excitatory actions of acetylcholine. None work specifically on the LES or esophageal body. This may explain why nifedipine is reported to be beneficial in early achalasia [69], but does not improve esophageal emptying in most patients with established achalasia [70]. Symptomatic improvement in patients with spastic esophageal disorders has also been reported in patients with nitrates [71], and injection of botulinum toxin into the esophageal body [72,73]. With sildenafil, changes in motility were not accompanied by consistent improvement in symptoms [74]. All of these studies are unblinded and lack appropriate controls. Selective reduction in LES pressure can be achieved currently by injection of botulinum toxin into the LES, pneumatic dilation of the LES, or myotomy of the LES. The published trials of these therapies are largely confined to patients with the diagnosis of achalasia. Of the three, botulinum toxin has the least risk for complications. The treatments must be repeated, however, and some patients develop resistance, likely from the development of antibodies to the toxin. Comparative trials of botulinum toxin to pneumatic dilation have shown similar initial results but more durable results long term with pneumatic dilation [75]. Botulinum toxin should be reserved for patients who are too frail to undergo pneumatic dilation or myotomy, have a life expectancy of less than 6 months, or require a short-term intervention until more definitive therapy can be arranged. Pneumatic dilation is usually performed as an outpatient endoscopic procedure, with the patient able to return to usual activities the following day. The major immediate risk of the procedure is esophageal perforation, which occurs in about 2% and may require surgical repair. The risk for perforation increases with use of balloon pressures above 10 psi [76]. Patients often require one or two additional dilations to achieve a satisfactory clinical response in 80% to 90% of patients [77,78]. Younger patients, especially young men, are less likely to have a successful response [78,79]. Surgical myotomy has evolved to a laparoscopic abdominal procedure for most patients. The success with a single operation is in the range of 90% [78]. Although the need to add an antireflux to the myotomy is controversial [80], a recent randomized trial showed a benefit of a Dor antireflux procedure on esophageal acid exposure in the early postoperative period [81]. In patients with dysphagic symptoms from spastic esophageal contractions, extension of the myotomy up through the smooth muscle portion of the esophageal body can be considered, but the outcomes are not as uniformly beneficial as those for achalasia [82,83]. Rarely, patients with a dilated, completely dysfunctional esophagus require esophagectomy. Patients too frail to undergo esophagectomy may require feeding by placement of a percutaneous endoscopic gastrostomy. Treatment of Sensory Disorders Diet and lifestyle modifications for patients with a hypersensitive esophagus are mostly a matter of avoiding foods and drinks that reproducibly cause
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symptoms. Patients with a hyposensitive esophagus require counseling to avoid scalding liquids and pills that could injure the esophagus if their failed passage was not recognized. Such patients are also at risk for damage from unperceived acid reflux. Medical treatment for the hypersensitive esophagus has largely been with the use of low-doses of tricyclic antidepressants and trazodone [84,85]. Acute or short-term studies of the antidepressant citalopram [43], the 5-hydroxytryptamine4 receptor agonist tegaserod [86], and the phosphodiesterase inhibitor theophylline [87] have shown reduction in symptoms or elevation of experimental pain thresholds. Their potential for long-term benefit is unclear. Patients with an acid-sensitive esophagus may benefit from acid-suppression therapy. Anticonvulsive agents are being used for other pain disorders, but there are no reported trials of their use in patients with esophageal sensory disorders to date. Because patients can have both motor and sensory disorders of the esophagus, concurrent treatment for both may be indicated. The usual clinical practice is first to identify and treat motor disorders, with treatment for sensory disorders initiated on an empiric basis when symptoms persist and studies indicate that the motor disturbance has been reasonably palliated. Care must be taken, however, to avoid overly aggressive treatment of a motor disturbance when the symptoms are likely sensory in origin. For example, chest pain in patients with nutcracker esophagus responds poorly to myotomy [82]. WHAT ARE THE CAUSES OF PERSISTENT OR RECURRENT SYMPTOMS AFTER TREATMENT? A fairly long list of conditions needs to be considered when the patient has symptoms after treatment (Table 1). When symptoms persist early after
Table 1 Etiologies for symptoms after treatment of esophageal sensory and motor disorders Category
Specific Causes
Timeframe
Primary treatment failure Complication of treatment
Incomplete myotomy GERD, peptic ulcer, stricture Myotomy site scarring Postoperative hematoma Paraesophageal herniation Neuroma in operative field Refeeding edema Obesity Pill injury Cardiovascular disease Psychiatric disorder or stress Second sensory or motor disorder Dilated, sigmoid esophagus Aspiration pneumonia Esophageal cancer
Early Early–late Early–late Early Early–late Early–late Early Late Early–late Early–late Early–late Early–late Late Early–late Late
Iatrogenic injury Comorbid condition
Progression of disease Complication of disease
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treatment, the most likely problem is that the treatment simply failed to work. The reason for failure is often not evident, and the patient may need to be tried on a different therapy. A specific identifiable and remediable cause for treatment failure in achalasia is an incomplete myotomy, which could be treated with surgical completion of the myotomy or pneumatic dilation. The two most common reasons for patients with achalasia to develop symptoms after an initially successful course of therapy are the development of GERD and progression of the underlying disease. Although GERD can develop following pneumatic dilation, it is much more common after a myotomy [88] and becomes more prevalent with time even when an antireflux procedure has been performed [89]. Disease progression can result from redevelopment of esophageal outflow obstruction, further deterioration in the contractile ability of the esophageal body, or a combination of the two. With sufficient follow-up, nearly half of achalasia patients treated by pneumatic dilation or surgery develop recurrent or new symptoms that require additional treatment [88,90]. For this reason, patients with achalasia should remain in on-going follow-up after therapy to monitor for symptoms of disease progression or complications [91]. Diagnostic testing of persistent or recurring symptoms usually starts with endoscopy to look for the presence of esophagitis, stricture, neoplasm, and disrupted antireflux procedures. A timed barium esophagram can assess the functional impairment in esophageal emptying [92], and a solid bolus challenge may help detect a subtle stenosis. Manometry may be necessary to identify an incomplete myotomy, tight antireflux wrap, or inadequate reduction in LES pressure after pneumatic dilation. Esophageal pH-impedance monitoring can document symptomatic reflux. Rarely, CT scans of the chest are needed to identify seromas or hematomas that are causing outflow obstruction. There are two additional points worth making for motor disorders when the posttreatment symptom is primarily pain, rather than dysphagia or regurgitation. First, another disorder may be present: the patient who develops new chest pain years after stable symptom remission may have angina. Second, the patient may have visceral hypersensitivity compounded by the coexistence of a psychiatric disorder or psychosocial stressors. This constellation of problems is unlikely to be solved by ever more aggressive attempts at improving motor function. The depressed achalasia patient, whose dominant problem of chest pain persists after an esophagectomy for same, is the epitome an unacceptable clinical outcome. SUMMARY Despite advances in pharmacologic, endoscopic, and surgical treatment, esophageal motor and sensory disorders remain a challenging problem for management, especially when complicated by the additional problems of psychiatric disease and psychosocial stressors. Although symptoms from minor disorders may respond to reassurance, patients with more significant disorders require a lifetime of follow-up. Patients require counseling about the nature and prognosis of their disease and instruction on dietary and lifestyle modifications.
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[88] Vela MF, Richter JE, Khandwala F, et al. The long-term efficacy of pneumatic dilatation and Heller myotomy for the treatment of achalasia. Clin Gastroenterol Hepatol 2006;4(5): 580–7. [89] Csendes A, Braghetto I, Burdiles P, et al. Very late results of esophagomyotomy for patients with achalasia: clinical, endoscopic, histologic, manometric, and acid reflux studies in 67 patients for a mean follow-up of 190 months. Ann Surg 2006;243(2):196–203. [90] Lopushinsky SR, Urbach DR. Pneumatic dilatation and surgical myotomy for achalasia. JAMA 2006;296(18):2227–33. [91] Torbey CF, Achkar E, Rice TW, et al. Long-term outcome of achalasia treatment: the need for closer follow-up. J Clin Gastroenterol 1999;28(2):125–30. [92] Vaezi MF, Baker ME, Richter JE. Assessment of esophageal emptying post-pneumatic dilation: use of the timed barium esophagram. Am J Gastroenterol 1999;94(7):1802–7.
Gastroenterol Clin N Am 36 (2007) 577–599
GASTROENTEROLOGY CLINICS OF NORTH AMERICA
The Many Manifestations of Gastroesophageal Reflux Disease: Presentation, Evaluation, and Treatment Joel E. Richter, MD, FACP, MACG The Richard L. Evans Chair, Department of Medicine, Temple University School of Medicine, 3401 North Broad Street, 801 Parkinson Pavilion, Philadelphia, PA 19140, USA
G
astroesophageal reflux disease (GERD) is a common problem that is expensive to diagnose and treat in primary and specialty care settings. The annual direct and indirect cost for managing this disease is estimated to be more than $14 billion in the United States, of which 60% is spent on drugs [1]. There have been major advances in understanding and improving the diagnosis and treatment of GERD over the last 5 years, which are summarized in this article. DEFINITION Unfortunately there is no gold standard test for GERD. Because the reflux of acid, particularly after meals, is a physiologic process, the simple presence of gastroesophageal reflux (GER) or occasional symptoms of heartburn or acid regurgitation cannot be defined as a disease. Recently a group of 44 experts from 18 countries used a modified Delphi process to develop a globally acceptable definition and classification of GERD that can be applied in clinical practice and in research (Fig. 1) [2]. This international group defined GERD as ‘‘a condition which develops when the reflux of stomach contents causes troublesome symptoms and/or complications.’’ Troublesome symptoms are defined by the patient to affect their quality of life. Mild symptoms occurring 2 or more days per week or moderate to severe symptoms occurring more than 1 day per week are often considered troublesome by patients. Patients may be diagnosed based on typical symptoms alone or on tests demonstrating reflux of stomach contents (eg, pH testing, impedance monitoring) or the injurious effects of the refluxate (endoscopy, histology, electron microscopy), in the presence of typical or atypical symptoms or complications. This new definition also recognizes that the refluxate causing symptoms may be weakly acidic or gaseous. E-mail address:
[email protected] 0889-8553/07/$ – see front matter doi:10.1016/j.gtc.2007.07.014
ª 2007 Elsevier Inc. All rights reserved. gastro.theclinics.com
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Fig. 1. The overall Montreal definition of GERD and its constituent syndromes. (From Vakil N, Van Zanten SV, Kahrilas P, et al. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence based consensus. Am J Gastroenterol 2006;101:1900–20; with permission.)
The group further divided the manifestations of GERD into esophageal and extraesophageal syndromes, with extraesophageal syndromes divided into established and proposed associations. In primary care, most patients are initially uninvestigated and present with symptomatic syndromes, either typical reflux complaints of heartburn and regurgitation or reflux-related chest pain. After investigation, usually endoscopy with histology, patients can be further classified as having the ‘‘syndromes with mucosal injury’’ to include reflux esophagitis, stricture, Barrett esophagus, or esophageal adenocarcinoma. The proposed consensus definition thus allows symptoms to define the disease but permits further characterization if mucosal injury is found. This group also recognized laryngitis, cough, asthma, and dental erosions as possible extraesophageal syndromes of GERD. The statement was restrained in defining a causal relationship, however, because of the lack of high-level evidence, especially showing a beneficial effect of reflux treatments on the extraesophageal syndromes and the reality that these syndromes are usually multifactorial, with GERD as one of several potential aggravating cofactors. EPIDEMIOLOGY Prevalence and Incidence The prevalence and incidence of GERD was recently estimated in two systematic reviews that defined GERD as at least weekly heartburn and/or acid regurgitation and met criteria concerning sample size, response rate, and recall period [3,4]. The prevalence in the Western world generally ranges between
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15% and 25%, whereas in Asia the prevalence is reported to be less than 5% (Fig. 2). Time trends confirm a significant increase in the prevalence of reflux symptoms averaging 5% annually in North America, 27% annually in Europe, and only 1% in Asia [4]. The disease is a relapsing and remitting disorder, but in contrast to the data for period prevalence, there are few longitudinal studies that describe the incidence of heartburn in the population. Based on only two studies from the Western world, the incidence of GERD can be estimated at 5 per 1000 person-years or an adjusted yearly incidence of weekly heartburn of approximately 1.5% to 3%. Even less is known about the prevalence of reflux esophagitis. A recent population-based endoscopic study suggests that asymptomatic esophagitis is common. In a random sample of a Swedish adult population, reflux symptoms were reported by 40% and esophagitis was diagnosed in nearly 16%. One third of those who had esophagitis, however, had no symptoms of GERD [5]. Two other population-based studies found the prevalence of esophagitis to be nearly 12% in Italy but only 7% in Japan [4]. Risk Factors The effect of increasing age on the prevalence of GERD symptoms is unclear. European studies report a slight but significant association, but the relationship
Fig. 2. Prevalence of at least weekly heartburn or acid regurgitation in various regions of the world. Time trends suggest an increase in the prevalence of reflux symptoms in North America and Europe but not Asia. (From El-Serag HB. Time trends of gastroesophageal reflux disease: a systematic review. Clin Gastroenterol Hepatol 2007;5:17–26; with permission.)
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was not observed for heartburn with or without acid regurgitation in Olmstead County, Minnesota [6]. A recent study suggested an association between advancing age and milder reflux symptoms but more severe esophagitis [7]. All studies report a similar prevalence of heartburn in men and women [5]. On the other hand, endoscopy database studies find male sex a significant risk factor for reflux esophagitis [8]. Cross-sectional studies and systematic reviews consistently find that obesity is associated with a statistically significant increase in the risk for reflux symptoms, erosive esophagitis, Barrett esophagus, and esophageal adenocarcinoma [9–11]. In these studies, obesity (BMI >25) was associated with 2.5- to 3.0-fold increase in these presentations of GERD. The causative mechanism for this relationship is unknown. Helicobacter pylori infection is an environmental factor that has declined as GERD, Barrett esophagus, and esophageal adenocarcinoma have increased in developed countries [12]. A systematic review of observational studies has confirmed that there is a negative association between H pylori and GERD, although this finding is most apparent in Asian countries [13]. The causative mechanism for this protective effect is the H pylori-induced gastritis, involving the antrum and corpus, which decreases the parietal cell mass, reduces acid secretion, and elevates gastric pH [14]. Along with environmental factors, the epidemiology of GERD may be affected by genetics. There have been two studies [15,16] assessing the prevalence of reflux symptoms in monozygotic versus dizygotic twins. Data from the Swedish Twin Registry [15] suggested that 31% (95% CI, 23%–39%) of GERD is caused by additive genetic factors, whereas a United Kingdom Twin Registry study [16] reported that this value was 43% (32%–55%). Although one group defined a locus on chromosome 13 associated with severe pediatric GERD [17], this has not been confirmed in adults. The genetic mechanisms are unknown but may be related to a smooth muscle disorder associated with hiatal hernia, low LES pressure, and impaired esophageal motility. CLINICAL PRESENTATIONS Heartburn and acid regurgitation are the classic symptoms of GERD. Heartburn describes a burning feeling, rising from the stomach or lower chest and radiating toward the neck, throat, and occasionally, the back [18]. It occurs postprandially, particularly after large meals or after eating spicy foods, citrus products, fats, chocolates, or drinking alcohol. The supine position or bending over may exacerbate heartburn. Nighttime heartburn may cause sleeping difficulties and impair next-day function [19]. The frequency and severity of heartburn does not predict the degree of esophageal damage [7]. The effortless regurgitation of acidic fluid, especially after meals and worsened by stooping or the supine position, is suggestive of GERD. Among patients who have daily regurgitation, LES pressure is usually low, many have associated gastroparesis, and esophagitis is common, making this symptom more difficult to treat than
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classic heartburn. Symptoms such as dysphagia, odynophagia, globus sensation, burping, water brash, and cough are other possible presentations of GERD, but their diagnostic yield is uncertain. Odynophagia may be seen with severe reflux esophagitis, but usually suggests an infection or pill-related esophagitis. Water brash is the sudden appearance in the mouth of a salty fluid. It is not regurgitated fluid, but rather secretions from the salivary glands in response to acid reflux [20]. The clinical accuracy of heartburn or regurgitation in diagnosing GERD is difficult to define. A recent systematic review [21] identified seven studies that assessed the accuracy of these reflux symptoms in diagnosing GERD in more than 5000 patients. Endoscopy with the presence of esophagitis has excellent specificity; thus, it was used as the gold standard to assess the sensitivity of heartburn and regurgitation. Unfortunately the sensitivity of these classic reflux symptoms was poor, with a range of 30% to 76% and a pooled sensitivity of 55% (95% CI, 45%–68%). Many patients who have atypical upper gastrointestinal (GI) symptoms thus may have GERD. Some patients who have GERD are asymptomatic. This is particularly true in elderly patients, perhaps because of reduced gastric acidity from chronic H pylori infection or decreased pain perception. Many elderly patients present first with complications of GERD because of long-standing disease with minimal complaints. For example, up to one third of patients who have Barrett esophagus are insensitive to acid at the time of presentation [22]. DIAGNOSTIC TESTS A large number of tests are available for evaluating patients who have suspected GERD. Many times these tests are unnecessary, because the presence of frequent heartburn and acid regurgitation are sufficiently accurate to identify the disease and begin medical treatment. This is not always the case, however, and clinicians must decide which tests to choose so as to make the diagnosis in a reliable, timely, and cost-effective manner, depending on the information desired (Table 1) [23]. Upper Endoscopy The identification of esophagitis at the time of endoscopy is highly specific (90%–95%) for GERD [24], but has a sensitivity of only approximately 50%. Multiple classification systems for esophagitis have been proposed, some are confusing, and none have worldwide acceptance [25]. The most thoroughly evaluated esophagitis classification is the Los Angeles (LA) system, which is gaining acceptance in the United States and Europe (Fig. 3) [26]. In referral centers, approximately 50% of patients have esophagitis, but in primary care and the general population, the rate of esophagitis is more in the range of 10% to 30% [4]. Most patients who have esophagitis have mild LA grade A-B disease and only 10% have the more severe LA grade C-D esophagitis [27]. Endoscopy can also evaluate complications of GERD, such as peptic strictures and Barrett
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Table 1 Diagnostic tests for gastroesophageal reflux disease Tests for reflux Intraesophageal pH monitoring Ambulatory bilirubin monitoring (bile reflux) Ambulatory impedance and pH monitoring (non-acid reflux) Barium esophagram Tests to assess symptoms Empirical trial of PPIs Intraesophageal pH monitoring with symptom analysis
Tests to assess esophageal mucosal damage Endoscopy Esophageal mucosal biopsy Barium esophagram
Tests to assess esophageal function Esophageal manometry Esophageal impedance Barium esophagram with fluoroscopy
esophagus and is recommended if patients have alarm symptoms, such as progressive dysphagia, weight loss, or iron deficiency anemia [28]. In routine clinical practice, endoscopy is reserved for evaluating patients who have alarm symptoms, for suspected GERD complications, and for surveillance for Barrett esophagus in patients who have chronic reflux complaints [29]. Over the years esophageal biopsies have had a varying role in the evaluation of GERD. The presence of eosinophils (<15 per high powered field) and markers of increased epithelial turnover (basal cell hyperplasia and prolongation of rete peg) have reasonable sensitivity but poor specificity, whereas neutrophils in the esophageal mucosa are specific but not sensitive [30]. Electron microscopy of esophageal biopsies suggests that dilated intercellular spaces could be an early marker of mucosal injury, whereas the endoscopy still seems normal (Fig. 4) [31,32]. Several studies consistently find the intercellular spaces
Fig. 3. The Los Angeles classification for erosive esophagitis.
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at least two to three times greater in patients who have erosive and nonerosive GERD compared with healthy control subjects [32]. Aggressive acid suppression therapy seems to normalize the width of the intercellular spaces [32]. Unfortunately these spaces are more difficult to define by light microscopy. In clinical practice, biopsies are usually not taken in patients who have classic reflux esophagitis unless necessary to exclude neoplasm, infection, pill injury, bullous skin disease, or eosinophilic esophagitis (>20 eosinophils per HPF). The current primary indication for esophageal biopsies is to determine the presence of Barrett epithelium [29]. When this diagnosis is suspected, biopsies are mandatory and best done when esophagitis is healed. Esophageal pH Monitoring Ambulatory intraesophageal pH monitoring is the standard for establishing pathologic reflux [23]. Traditionally the pH probe is passed nasally, positioned 5 cm above the manometrically determined LES, and connected to a batterypowered data logger capable of collecting pH values every 4 to 6 seconds for 24 hours. Patients record meals, sleeping, and when symptoms are experienced. Acid reflux episodes are defined as a pH drop of less than 4. The total percent of time the pH is less than 4 is the most reproducible measure of GERD, with the reported upper limits of normal ranging from 4% to 5.5% [33]. The sensitivity of 24-hour pH monitoring in patients who have esophagitis approaches 90% with a specificity of 85% to 100%. In patients who have normal endoscopy in which pH testing may be most needed, the sensitivity is only 60% and the specificity from 85% to 90% [34]. Clinical indications for ambulatory pH monitoring include (1) before fundoplication to insure the presence of pathologic reflux in patients who have a normal endoscopy, (2) after antireflux surgery if heartburn symptoms persist, (3) patients who have reflux symptoms
Fig. 4. Intercellular spaces in esophageal mucosa from A) healthy subjects without reflux symptoms and B) GERD patients without esophagitis identified by transmission electron microscopy. (From Calabrese C, Fabbri A, Bortolotti M, et al. Dilated intercellular spaces as a marker of oesophageal damage: comparative results in gastro-oesophageal reflux disease with or without bile reflux. Aliment Pharmacol Ther 2003;18:525–32; with permission.)
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and a normal endoscopy not responding to PPI treatment, and (4) patients who have suspected extraesophageal symptoms of GERD [34]. Two new advances are improving the role of pH testing in evaluating GERD. The first is a wireless device (Bravo pH probe, Medtronics, Minneapolis, MN) the size of a vitamin pill attached, usually by endoscopy, 6 cm above the Z-line (Fig. 5) [35]. This decreases patient discomfort, allows for longer (48 hours or more) monitoring, and may increase test sensitivity by allowing patients to more comfortably carry out their usual activities [36]. The capsule detaches and passes spontaneously within 2 weeks. Rare patients may note severe pain after attachment, which resolves spontaneously with endoscopic removal. Two significant complications have occurred with this device—one report of esophageal bleeding requiring transfusion and one esophageal perforation [37]. The second technologic advancement combines multichannel intraluminal impedance monitoring with pH sensors to detect acid, weak acid, and non-acid reflux using a transnasal catheter over 24 hours [38]. The number of respective reflux episodes, rather than percentage of exposure time, is the critical measurement, with normal values established from United States and European studies [38]. The results of several studies suggest that impedance-pH monitoring is useful in the evaluation of patients who have PPI-resistant typical reflux symptoms, especially regurgitation complaints, and chronic unexplained cough [39–41]. Barium Esophagram The barium esophagram is inexpensive and less invasive than endoscopy. It is most useful in demonstrating strictures, rings, hiatus hernias, and major
Fig. 5. Wireless pH capsule attached to the esophagus 6 cm above the squamocolumnar junction.
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abnormalities in peristalsis. The barium esophagram’s ability to detect esophagitis varies, with sensitivities of 79% to 100% for moderate to severe esophagitis, whereas mild esophagitis is usually missed [23]. It is also not reliable for detecting Barrett esophagus. Esophageal Manometry Esophageal manometry allows assessment of LES pressure and relaxation and peristaltic activity, including contraction amplitude, duration, and velocity. It is generally not indicated in the evaluation of patients who have uncomplicated GERD, however, because most have normal resting LES pressure [42]. Esophageal manometry to document adequate esophageal peristalsis is traditionally recommended before antireflux surgery. If the study identifies ineffective peristalsis (low amplitude or frequent failed peristalsis), then a complete fundoplication may be contraindicated. This assumption has recently been challenged, however, by several studies finding that reflux control was better and dysphagia no more common in patients who had weak peristalsis after a complete as opposed to partial fundoplication [43]. An improvement of traditional manometry, combining it with impedance testing, is helping to clarify this controversy. Using this technology, a recent study found that less than 50% of patients who had ineffective peristalsis had a significant delay in esophageal bolus transit measured by impedance [44]. Proton Pump Inhibitor Test An empiric trial of acid suppression is the simplest method for diagnosing GERD and assessing its relationship to symptoms. With the advent of PPIs, this test has become the first diagnostic study used in patients who have classic or atypical reflux symptoms without alarming complaints. Symptoms usually respond to a PPI test in 1 to 2 weeks. If symptoms disappear with therapy and then return when medication is discontinued, GERD is established. A systematic review [45] identified 15 studies that assessed the accuracy of normal or high dose PPIs for 1 to 4 weeks in the diagnosis of GERD. The pooled sensitivity was good at 78% (95% CI, 66%–86%), but the specificity was poor at 54% (95% CI, 44%–65%) when 24-hour ambulatory pH was used as a gold standard. Nevertheless an empiric PPI trial for diagnosing GERD offers many advantages: the test is office-based, easily done, inexpensive (especially with over-the-counter PPIs), available to all physicians, and may avoid needless procedures. For example, one study showed a savings of greater than $570 per average patient because of a 59% reduction in the number of diagnostic tests (upper endoscopy, pH tests) [46]. Disadvantages are few, but include a placebo response and uncertain symptomatic endpoint if symptoms do not totally resolve with extended treatment. COMPLICATIONS There are few data on the long-term outcome of patients who have varying severities of GERD. Severity and duration of symptoms seem to have a poor correlation with the presence or severity of esophagitis [7]. Furthermore, there is
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some controversy whether GERD exists as a spectrum of disease severity or as a categoric disease in three distinct groups: nonerosive and erosive reflux disease and Barrett esophagus [24,47]. The recent European ProGERD study involving nearly 4000 patients sheds some light on the progression or regression of GERD over 2 years [47]. After endoscopy to assess the presence or absence of esophagitis, all patients were treated with 4 to 8 weeks of esomeprazole then returned to their primary care physician. Two years later all patients underwent a second endoscopy with biopsies. As shown in Fig. 6, after 2 years 25% of patients who had nonerosive GERD progressed to LA grade A-B esophagitis but severe LA grade C-D esophagitis was rare (<1%). Likewise, only 1.6% of LA grade A-B patients progressed to severe disease, whereas most (61%) regressed to nonerosive disease. Even the severe LA grade C-D patients had a good prognosis, with 42% regressing to milder esophagitis and 50% regressing to a nonerosive state. Patients who had LA grade C-D esophagitis were at a greater risk 2 years later for developing Barrett esophagus: 5.8% compared with 1.4% for LA grade A-B and 0.5% for nonerosive disease. These data suggest GERD more likely is a spectrum of disease that tends to regress in severity after it comes to medical attention, regardless of treatment. The progression of Barrett esophagus may be an artifact of better detection after esophagitis has healed [48]. Peptic Esophageal Strictures Esophageal strictures have a prevalence of approximately 0.1% and are associated with white race, male gender, and increasing age [49]. Patients usually
Fig. 6. Progression or regression of endoscopic findings (without relationship to symptoms) over 2 years in the large ProGERD study involving nearly 4000 patients. (Adapted from Labenz J, Nocon M, Lind T, et al. Prospective follow-up from the ProGERD study suggests that GERD is not a categorical disease. Am J Gastroenterol 2006;101:2457–62; with permission.)
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present with dysphagia for solids, but unlike malignant strictures, weight loss is uncommon because their appetite is good. As dysphagia progresses, heartburn often decreases, reflecting the stricture acting as a barrier to further reflux. Peptic strictures are smooth walled, tapered, circumferential narrowing in the lower esophagus that are usually less than 1 cm long. A mid to upper esophageal stricture should raise concern about Barrett esophagus or malignancy. Although once controversial, today a Schatzki ring is considered a forme fruste of an early peptic stricture [50]. All stricture patients should undergo endoscopy, at least initially, to confirm the benign nature of the disease and, if necessary, to take biopsies to exclude cancer and Barrett esophagus. Symptomatic patients can be dilated by various bougies [51]. Dysphagia relief generally occurs when the lumen is greater than 15 mm and associated esophagitis has healed [52]. Barrett Esophagus Barrett esophagus is the consequence of severe GERD in which the squamous epithelium of the distal esophagus is replaced by specialized columnar mucosa containing goblet cells (intestinal metaplasia). The disease is more common in white men, rare before age 50 years, and present in 1% to 2% of patients referred for endoscopy over this age threshold [8]. Bile reflux and obesity have been associated with an increased risk for Barrett esophagus [9,53]. The diagnosis can be suspected at endoscopy and its circumferential involvement and maximum proximal extension described using the new Prague classification [54]. Histology is required, however, to confirm the diagnosis and to define the potentially premalignant intestinal metaplasia. Detection of Barrett esophagus is highest after suspected patients have been on PPIs for 8 to 12 weeks [48]. In the era of PPIs, Barrett esophagus is easy to treat and only of major interest because of an increased risk for developing esophageal adenocarcinoma, estimated at between 0.5% and 1% each year [55]. Increased duration, frequency, and severity of reflux symptoms have been shown to be risk factors for this cancer [56]. Further details on Barrett esophagus can be found in several excellent reviews [57,58]. Extraesophageal Manifestations Gastroesophageal reflux may be the cause of a wide spectrum of conditions, including non-cardiac chest pain, asthma, posterior laryngitis, chronic cough, recurrent pneumonitis, and even dental erosion [59]. GERD-related chest pain may mimic angina pectoris, even to the point of being induced by exercise. Most of these patients also have heartburn symptoms [60]. The mechanism of the pain is poorly understood, likely because of the volume and duration of acid reflux, secondary esophageal spasm, or prolonged contractions of the longitudinal muscle [61]. The causal link between GERD and pulmonary and ear, nose, and throat complaints is much more circumspect [59]. Although the possible mechanisms from animal studies are plausible (ie, microaspiration and vagal reflex), most suspected patients are heartburn-free and do not have esophagitis, hiatus hernia, or low LES pressure. Unfortunately pH testing
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(distal or proximal), although frequently abnormal in these patients, does not predict their response to medical or surgical therapies. MEDICAL TREATMENT Lifestyle and Over-the-Counter Medications Numerous dietary and lifestyle modifications are advocated for the treatment of GERD. They are frequently first-line therapy for patients who have mild disease and often adjunct therapy even for patients on PPIs.What is the evidence, however? In a recent evidence-based review, studies of smoking, alcohol, chocolate, fatty foods, and citrus products showed physiologic evidence that their intake can adversely affect symptoms or esophageal pH. There was little evidence, however, that cessation of these products predictably improved GERD symptoms. Only elevation of the head of the bed, left lateral decubitus positioning, and weight loss was associated with GERD improvement in casecontrolled studies [62]. Over-the-counter (OTC) antacids, alginate/antacid combinations, and H2RAs are useful in treating mild and infrequent heartburn symptoms, especially when symptoms are brought on by lifestyle indiscretions. In one recent meta-analysis [63], the relative benefit increase compared with the overall placebo response was up to 41% with H2RAs, 60% with alginates, and 11% with antacids. Antacids rapidly relieve heartburn symptoms, the major reason these drugs are so popular for mild, intermittent symptoms. Although their onset of relief is not as rapid as antacids, OTC H2RAs have a longer duration of action, up to 6 to 10 hours. From a practical standpoint, they are most useful when taken before a potentially refluxogenic activity, such as a heavy meal, eating late at night, or exercise. Sales of these OTC medications in 2004 were considerable: more than $350 million for antacids and nearly $200 million for H2RAs [1]. Proton Pump Inhibitors PPIs revolutionized the treatment of GERD and currently are the mainstay of acute and maintenance treatment regimens. This class of drugs markedly diminishes gastric acid secretion over a 24-hour period by inhibiting the final common pathway of acid secretion, the HþKþ ATPase pump. Their superior efficacy compared with H2RAs is based on their ability to maintain an intragastric pH of less than 4 between 15 and 21 hours, compared with approximately 8 hours daily with H2RAs. In 2004, PPIs accounted for approximately 77% of the acid suppressant market, amounting to sales exceeding $9.5 billion [1]. In a recent Cochrane review [64], PPIs were more effective than placebo in healing esophagitis (RR ¼ 0.23; 95% CI, 0.01–0.05) with a number to treat (NNT) of 2 (95% CI, 1.4–2.5). The review also identified 26 trials involving 4064 patients that compared PPIs with H2RAs. PPIs were superior to H2RAs in healing esophagitis at 4 to 6 weeks (RR ¼ 0.47; 95% CI, 0.41– 0.53) with an NNT of 3 (95% CI, 2.8–3.6). Another Cochrane systematic review found that PPI therapy was superior to placebo and H2RAs in endoscopy-negative GERD and undiagnosed reflux symptoms in primary care,
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although the effect was not as marked as with esophagitis [65]. Cochrane reviews also have identified the superiority of PPIs over H2RAs in maintaining the remission of esophagitis over 6 to 12 months [66]. Among 10 randomized trials, the relapse rate for esophagitis was 22% on PPIs compared with 58% on H2RAs, with an NNT of 2.5 (95% CI, 2.0–3.4). Until recently the therapeutic efficacy between PPIs was similar. Recent large randomized controled trial (1000–2500 patients), however, have found the newest PPI, esomeprazole 40 mg, superior to omeprazole 20 mg and lansoprazole 30 mg in healing esophagitis [67]. The therapeutic advantage is minimal with mild LA grade A-B esophagitis (NNT 50 and 33, respectively) and greatest with severe LA grade C-D esophagitis (NNT 10 and 8, respectively). This superiority is related to higher systemic bioavailability and less inter-patient variability with esomeprazole. Treatment of Complicated Gastroesophageal Reflux Disease and its Extraesophageal Presentations The extensive use of PPIs has markedly affected treatment of peptic strictures and esophageal rings. Several studies in community and Veterans Affairs (VA) hospitals note an approximate 33% decline in the incidence of recurrent strictures. The timeline for this decrease parallels the marked increase in PPI use since 1995 (Fig. 7) [68]. Another study convincingly shows that in patients who have symptomatic Schatzki rings, maintenance PPI therapy after bougienage markedly decreases future relapses of the rings [69]. In a randomized study, 30 patients who had symptomatic rings without esophagitis were dilated and randomized to placebo or omeprazole 20 mg per day. In the treated group, one patient relapsed after 13 months, whereas seven patients relapsed on placebo after a mean of 20 months.
Fig. 7. Incidence of peptic esophageal stricture and use of PPIs between 1994 and 2000 in United Kingdom general practice. R, Spearman correlation test. (From Ruigomez A, Rodriguez LAG, Wallender MA, et al. Esophageal stricture: incidence, treatment patterns and recurrence rate. Am J Gastroenterol 2006;101:2685–92; with permission.)
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The efficacy of PPI treatment in the extraesophageal presentations of GERD is more variable. There are two systemic reviews [70,71], both suggesting that patients who have non-cardiac chest pain respond to PPIs better than to placebo. These reports identified eight RCTs that assessed 321 patients who had a pooled relative risk for continued chest pain after PPI therapy, compared with placebo of 0.54 (95% CI, 0.41–0.71), with an NNT of 3 (95% CI, 2–4). Systemic reviews, however, do not support the efficacy of aggressive acid suppression, particularly with PPIs in other extraesophageal disorders, such as chronic cough [72], asthma [73], or ear, nose, and throat disorders [74]. Sleep disturbances may occur in up to 75% of patients who have GERD, impairing quality of life. In a large multicenter study, patients who had GERD-associated sleep disturbances and nighttime heartburn were randomized to two doses of esomeprazole (40 mg and 20 mg) or placebo for 4 weeks [75]. GERD-related sleep disturbances resolved in significantly more patients on esomeprazole 40 mg (73.7%) or 20 mg (73.2%) than those who received placebo (41.2%). These changes were associated with improved sleep quality and daytime productivity. Refractory Gastroesophageal Reflux Disease Traditionally patients who have reflux symptoms no longer undergo initial endoscopy, but rather are given a 4- to 8-week trial of a PPI. Failure to improve occurs in 25% to 42% of patients, thus placing them in a more difficult to manage group. At this point the physician should insure patient compliance and review timing of the PPI dose (1/2 to 1 hour before meals). One recent study found that nearly 70% of primary physicians and 20% of gastroenterologists gave the PPI at bedtime or did not believe the relationship to meals was important [76]. Switching to a second generation PPI (ie, pantoprazole, esomeprazole) may be a reasonable alternative. This was recently confirmed in a multicenter study of patients who had persistent heartburn symptoms while receiving lansoprazole 30 mg once daily [77]. Switching to a single dose of esomeprazole (40 mg) was as effective as twice daily lansoprazole in relieving heartburn complaints over 8 weeks of therapy. Most physicians, however, increase the current PPI to twice daily dosing (before breakfast and dinner), with up to 25% of patients responding [78]. Those patients doing no better fall into the ‘‘refractory GERD’’ category [79]. As shown in Fig. 8, the critical diagnostic test is upper GI endoscopy, which identifies patients who have esophagitis or no esophagitis. The largest percentage of these patients have refractory symptoms with no esophagitis. These patients may require 24-hour pH testing on PPI therapy, impedance testing, and consideration of other diagnoses, such as achalasia, gastroparesis, and functional heartburn. Although much has been made recently of non-acid GER, there are no controlled data to help in treating this group of patients. Safety Concerns Initial concerns about PPIs causing gastric malignancies in rats have not been substantiated in other animal models or long-term patient studies. Fundic gland
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Fig. 8. Evaluation and potential causes of refractory gastroesophageal reflux disease.
polyps are the most common gastric polyp found at endoscopy. Their association with chronic PPI use has been a topic of debate since these drugs were first described. A recent study evaluated 599 patients of whom 322 used PPIs and 107 had fundic gland polyps [80]. Long-term PPI use was associated with up to a fourfold increase in the risk for fundic gland polyps. Low-grade dysplasia was found in one fundic gland polyp. Etiologically these polyps seem to arise because of parietal cell hyperplasia and parietal cell protrusions resulting from acid suppression. Recent studies confirm that chronic acid suppression may be associated with an increased risk for community-acquired pneumonias and enteric infections. In a large Scandinavian population-based study [81], the adjusted relative risk for pneumonia among current PPI users compared with those who stopped using PPIs was 1.89 (95% CI, 1.36–2.62). Current users of H2RAs had a 1.63-fold increased risk for pneumonia (95% CI, 1.07–2.48) compared with those who stopped. A significant positive dose–response relationship was observed in the PPI users. Likewise a recent systematic review found an increased risk for enteric infections with acid suppression [82]. The correlation was stronger with Salmonella, Campylobacter, and other enteric infections compared with Clostridium difficile, and greater with PPI compared with H2RA therapy. PPIs also may alter calcium metabolism through induction of hypochlorhydria interfering in insoluble calcium absorption or through reduced bone resorption through inhibition of osteoclastic vacuolar proton pumps. In a recent nested case-control study [83], the risk for hip fractures was significantly increased among patients prescribed more than 1 year of PPI therapy (OR, 1.44; CI, 1.30–1.59) and among those on long-term, high-dose PPIs (OR, 2.65; 95% CI, 1.80–3.90; P<.001). The strength of the association increased with increasing duration of PPI therapy. For elderly patients requiring long-term PPIs, it may be prudent to re-emphasize increased calcium intake,
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preferably from a dairy source, and co-ingestion of a meal when taking insoluble calcium supplements. New Drug Treatments New drug treatments have primarily targeted transient LES relaxation, the common motility abnormality in all forms of GERD. Several agents, including cholecystokinin A agonists, anticholinergic drugs, nitric oxide synthase inhibitors, morphine, cannaboid, and gamma-aminobutyric acid B (GABA) agonists have been shown to reduce transient LES relaxation and episodes of acid reflux [84]. The only agent available for oral therapy is baclofen, a GABA agonist. Several studies show that 10 to 20 mg of baclofen three to four times daily for up to 4 weeks reduces 24-hour esophageal acid and bilirubin reflux [85,86]. Baclofen needs to be titrated upward slowly, beginning at 5 mg daily and increased over 10 days to 40 to 60 mg per day. Side effects are common and include drowsiness, nausea, and the lowering of the threshold for seizures. New compounds with more specific and better targeted action need to be developed. Another approach has been to develop newer rapid-acting PPIs, such as potassium-competitive acid blockers (P-CAB). Unlike the traditional PPIs that bind irreversibly to the proton pump, this new class of compounds blocks acid secretion by way of potassium-competitive inhibition of the HþKþ ATPase. This results in rapid onset with almost complete acid blockade achieved within 30 minutes of administration [84]. Unfortunately recent phase III studies found the P-CABs no more effective than esomeprazole in the rapid relief of heartburn symptoms. ENDOSCOPIC TREATMENT Various endoscopic techniques for the treatment of GERD have been developed as alternatives to antisecretory therapy or antireflux surgery [87]. These techniques include the delivery of radiofrequency energy to the gastroesophageal junction (Stretta), injection of bulking agents (Eneryx), or implantation of a bioprosthesis (Gatekeeper) into the LES, and suture plication of the proximal gastric folds (Endocinch, Endoscopic Plication System). Studies to date have primarily enrolled PPI-dependent patients who do not have severe esophagitis or large hiatus hernia. As shown in Table 2, each of these techniques decreases reflux symptoms, improves quality of life, and decreases the need for antisecretory medications. Physiologic studies, however, are much less impressive, with LES pressure rarely increasing, pH normalizing in only 30% of patients, and even mild esophagitis infrequently healing. Sham studies with Stretta, Enteryx, and the Plication system likewise show a decrease in heartburn symptoms and improved quality of life after the active therapy compared with the sham group after 3 to 6 months [87]. Only the Plication study showed a significant decrease in pH values, by only 18%, whereas no change in pH or LES parameters was observed in studies using the other techniques [88]. Most studies of endoscopic therapy have only limited follow-up information on a small number of patients. The durability of these techniques beyond 1 to 2
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Table 2 Endoscopic treatments of gastroesophageal reflux disease: summary of symptoms, physiology, and safety data Stretta
Enteryx
EndoCinch
Plicator
Decreased Improved Decreased
Decreased Improved Decreased
Decreased Improved Decreased
Decreased Improved Decreased
Symptoms Heartburn Quality of life PPI use Esophageal parameters LES increase pH normalizes Esophagitis healing Safety Common complications
No 30% No
No 30% NS
No 20% No
No 30% No
Chest pain
Deaths
3
Chest pain Dysphagia ever 5–7
Pharyngitis Chest pain Abdominal pain 0
Pharyngitis Chest pain Dysphagia 0
Abbreviation: NS, not studied.
years remains unclear and seems to gradually decrease over time. The cost-effectiveness of these techniques is difficult to define. Most important, safety issues have haunted these procedures, especially when used in the broader community of gastroenterologists. Chest pain, bleeding, esophageal perforations, mediastinitis, and at least 8 deaths to date have been attributed to these endoscopic techniques. Serious adverse events, including deaths, led to the voluntary withdrawal of Enteryx by the manufacturer in September 2005 and suspension of the Gatekeeper clinical program in late 2005. A recent American Gastroenterological Association Institute medical position statement recommended that ‘‘current data suggest that there are no definite indications for endoscopic therapy for GERD at this time’’ [87]. SURGICAL MANAGEMENT Only surgical fundoplication can correct the physiologic factors contributing to GERD and prevent the need for long-term medication. Successful antireflux surgery involves (1) reducing the hiatal hernia back into the abdomen, (2) closing the opening in the diaphragmatic hiatus, (3) lengthening the intra-abdominal portion of the LES, and (4) strengthening the repair with a fundoplication. The most popular fundoplication is the 360 Nissen fundoplication. The partial posterior Toupet fundoplication is primarily used in patients who have aperistalsis or ineffective esophageal peristalsis. The latter is associated with less bloating and flatus, but not necessarily dysphagia when compared with a total fundoplication [89]. Most authorities in the United States believe the Nissen fundoplication is more durable. Antireflux surgery has undergone a resurgence since the advent of the laparoscopic operation. The number of adult antireflux procedures performed in
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the United States more than tripled from 11,000 per year in 1985 (open operation) to 40,000 in 2001, a population-based annual rate of 12.0 per 100,000 adults [90]. A systematic review identified six randomized controlled trials involving 449 patients that compared open and laparoscopic fundoplication [91]. There was no significant difference in recurrence rates between the procedures, and laparoscopic fundoplication was associated with lower operative morbidity (NNT to prevent complication ¼ 8; 95% CI, 3–16) and shorter hospital stay. What are the indications for surgical fundoplication in the era of inexpensive PPIs and proven long-term safety of these drugs? The most accepted indications [89] are: 1. Patients who have typical or atypical GER symptoms who respond to PPIs but who want surgery because of A desire for a permanent cure Patient preference An intolerance to PPIs 2. Failed medical therapy as a result of persistent volume regurgitation. Here heartburn symptoms are controlled, but regurgitation is a persistent problem. 3. Recurrent peptic strictures in younger patients 4. Respiratory complications related to regurgitation and recurrent aspiration
In patients who have Barrett esophagus, there is no convincing evidence that fundoplication reduces the long-term risk for esophageal adenocarcinoma [92]. Comparison studies of older medical treatments (antacids, H2RAs) consistently find surgical fundoplication better at healing esophagitis and relieving symptoms. There are few studies comparing fundoplication with long-term PPI therapy, but one study [93] suggested that both were equally effective in controlling symptoms over 5 years, provided patients in the medical treatment group were allowed to increase the dose of the drug to twice daily if necessary. Complications can occur after antireflux surgery, and many patients over time continue to require antireflux medications. A recent database analysis of the surgical experience in all VA medical centers nationwide may more closely reflect the surgical experience in community hospitals compared with highly specialized tertiary care centers [90]. In this report, more than 3000 patients undergoing antireflux surgery were identified between 1990 and 2001. Postoperative dysphagia was recorded in 19.4%, dilation was performed in 6.4%, and a repeat antireflux surgery was needed in 2.3% of patients. The surgical mortality rate was 0.8%. Approximately 50% of patients received multiple prescriptions for antireflux medications at a median of 5 years of follow-up evaluation after their surgery. Tertiary specialized centers are seeing an increased rate of fundoplication failures [94]. The most common reasons for failure are herniation of the intact fundoplication into the chest, slipped fundoplication with a recurrent hiatal hernia, probably caused by a short esophagus, paraesophageal hernia through an intact fundoplication, too tight a fundoplication, and malpositioned
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fundoplication, usually on the cardia of the stomach. Total breakdown of the fundoplication is now rare. Revisional antireflux surgery needs to be performed by experienced surgeons, can be done laparoscopically but many prefer an open approach, and has increased morbidity and mortality compared with the initial operation. SUMMARY Gastroesophageal reflux disease is a common problem that is expensive to diagnose and treat in primary and specialty care settings. This review has emphasized the major advances in understanding the diagnosis and treatment of GERD over the last 5 years. These are summarized below.
GERD is increasing in prevalence in the Western world, with important risk factors being obesity and healthy stomachs resulting from H. pylori eradication. The sensitivity of classic reflux symptoms is poor (55%) for the diagnosis of GERD. Response to the PPI test has good sensitivity (78%), but poor specificity (54%). Ambulatory esophageal pH testing is the most sensitive test for GERD, whereas endoscopy is the most specific. Medical treatment with PPIs and laparoscopic antireflux surgery have similar efficacy in the long-term treatment of GERD, but do have potential side-effects. Currently endoscopic treatment of GERD should not be a clinical alternative outside of research trials.
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Gastroenterol Clin N Am 36 (2007) 601–617
GASTROENTEROLOGY CLINICS OF NORTH AMERICA
New Observations on the Gastroesophageal Antireflux Barrier Larry Miller, MDa,*, Anil Vegesna, MDa, Amit Kalra, MDa, Ramashesai Besetty, MDa, Qing Dai, MDa, Annapurna Korimilli, MDa, James G. Brasseur, PhDb a
Department of Gastroenterology, Temple University Hospital, Gastroenterology Section, 8th Floor, Parkinson Pavilion, Philadelphia, PA 19043, USA b Department of Mechanical Engineering, The Pennsylvania State University, University Park, PA 16802, USA
THE GASTROESOPHAGEAL JUNCTION HIGH-PRESSURE ZONE In this article, the authors introduce the concept of a three-component, highpressure zone (HPZ) in the area of the gastroesophageal junction (GEJ). Some researchers have argued for a gastric HPZ component localized anatomically to the cardia of the stomach at the junction with the esophagus as the primary antireflux barrier (gastric sling fiber/clasp fiber complex [GSF/CF]). For these researchers, the lower esophageal sphincter (LES) is the GSF/CF complex. Other researchers argue that the intrinsic sphincter proximal to the GEJ, which is a physiologic rather than an anatomic sphincter, plays the major role in the antireflux barrier. For this group of researchers, the main intrinsic barrier to reflux is this physiologic LES that overlaps spatially with the extrinsic crural sphincter. Therefore, the term ‘‘LES’’ is used to identify two distinctly different parts of the gastroesophageal segment. The sphincteric components within the GEJ regulate the flow of food from the esophagus into the stomach; allow venting of gas and regurgitation from the stomach; and act as an antireflux barrier to gastric content. Several muscle groups are important in maintaining an antireflux barrier. The intrinsic smooth muscles of the abdominal esophagus and proximal stomach (GSF/CF complex) and the external skeletal muscles of the crural diaphragm each contribute to the HPZ in the resting state. The phrenoesophageal ligament anchors the distal esophagus to the costal diaphragm [1,2]. The magnitude and axial extent of the resting (baseline) intraluminal pressure at the esophagogastric segment are measures of the effectiveness of the antireflux barrier. Because the intrinsic and extrinsic sphincteric components This work was supported by grant RO1-DK-59500 from the National Institutes of Health.
*Corresponding author. E-mail address:
[email protected] (L. Miller). 0889-8553/07/$ – see front matter doi:10.1016/j.gtc.2007.07.008
ª 2007 Elsevier Inc. All rights reserved. gastro.theclinics.com
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are spatially superimposed in normal individuals, the squeeze pressure tending to close the GEJ is due to the combination of the corresponding muscle groups. Distinguishing the individual sphincteric components of the distal esophageal HPZ is important because it emphasizes the individual contributions of each to the antireflux barrier and makes clear which components are defective in various diseases. The thickness of the abdominal esophagus is greater than the esophageal body, and increases from the mediastinum to the gastric cardia [3,4]. Muscle thickness also changes when the lumen is stretched, and during contraction [5]. The physiologic sphincter within the distal esophagus (LES) has a rich nerve supply with a neuronal distribution that differs from that in the remainder of the tubular esophagus. In the physiologic sphincter (LES) within the distal esophagus, the myenteric plexus lies in several muscle planes, in contrast to the body of the esophagus, where the plexus lies between the longitudinal muscle and the circular muscle layers [6]. The diaphragm is composed of costal and crural components; the crural component integrates with the costal diaphragm above and is attached to the vertebral column below. The two diaphragmatic components have separate embryologic origins and different functions. The costal diaphragm is involved in respiratory activity. The crural diaphragm wraps sling-like around the abdominal esophagus, forming a canal through which the esophagus enters the abdomen. Contraction of the crural diaphragm exerts a pinchcock-like action at the GEJ HPZ, thereby forming an extrinsic sphincter mechanism [1,2]. The crural diaphragm alone can maintain a zone of high pressure at the abdominal-mediastinal junction in patients who have undergone surgical resection of the sphincter within the distal esophagus [7]. Liebermann-Meffert and colleagues [8] described the arrangement of the smooth muscles at the gastric side of the GEJ in detail from the anatomy of 32 cadavers. They demonstrated that this musculature consisted of ‘‘clasp’’ fibers on the lesser curvature side and ‘‘sling’’ fibers at the greater curvature side of the cardia. Stein and colleagues [9] hypothesized that the GSF/CF complex at the most proximal portion of the gastric cardia contributes to the antireflux barrier. These oblique muscle fibers of the stomach are arranged in a C-shaped configuration. This finding has recently been confirmed [10], as shall be discussed later. GASTROESOPHAGEAL REFLUX DISEASE In performing its function, the esophagus is exposed to various potentially noxious substances. Despite these physical and chemical challenges to its integrity and function, the organ remains healthy and functional in most humans because of various complex physiologic defenses. The major challenge to the integrity of esophageal function is gastroesophageal reflux. With chronic gastroesophageal reflux, aggressive factors may overcome the defensive factors, and the esophagus may be damaged [11,12].
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TRANSIENT LOWER ESOPHAGEAL SPHINCTER RELAXATION Because many patients who have gastroesophageal reflux disease (GERD) have a normal resting HPZ at the GEJ, it has become clear that factors other than the veracity of the HPZ must contribute to the pathogenesis of GERD, so that manometric measurement of resting GEJ pressure is not a complete assessment of the GEJ HPZ function. The GEJ HPZ pressure is known to drop transiently to baseline gastric pressure over extended periods not associated with swallowing, indicating transient loss of sphincteric tone. This phenomenon is referred to as ‘‘transient lower esophageal sphincter relaxation (TLESR)’’ [13] and is known to involve the relaxation of all sphincteric muscle components. TLESR has been the subject of intense research as a potential physiologic explanation for gastroesophageal reflux [12,14–16]. TLESR is normal, but TLESRs occur at a higher frequency and last longer in GERD patients [14,16,17]. By dividing the stomach into different compartments, Franzi and colleagues [18] showed that the cardiac region of the stomach has the lowest threshold for triggering stretch-induced transient relaxation of the sphincter muscles at the GEJ. Stretch of the cardia region is the major trigger for sphincteric relaxation, and may be the stimulus for TLESR. Vagal cooling abolishes the triggering of gastric cardia stretch-induced sphincteric relaxations, suggesting a vagallymediated reflex [19]. It has been appreciated increasingly that gastric cardia stretch-induced relaxations are integrated motor responses that also involve crural diaphragmatic inhibition [19–21]. HIATAL HERNIA In the presence of hiatal hernia, the crural diaphragm component of the sphincter complex is physically separated from the esophageal components [22]. Hiatal hernia causes a displacement of the crural diaphragm away from the intrinsic LES as part of the stomach herniates through the diaphragmatic hiatus and becomes trapped between the diaphragm and the intrinsic sphincter within the distal esophagus. Hiatal hernia has been implicated in the pathogenesis of GERD [23]. A possible mechanism for this functional decrement is entrapment of gastric juice above the hiatus, a phenomenon exacerbated by the loosening of the phrenoesophageal ligaments, which allows substantial movement of the intrinsic sphincter element relative to the hiatus. TLESRs are considered the physiologic mechanisms allowing venting of excess gas from the stomach, and TLESRs underlie virtually all episodes of gas reflux during belching [24,25]. By taking advantage of this fact, Vegesna and colleagues set out to develop a new method to induce and study TLESR. This technique consists of inflating the stomach with air at a constant flow, viewing the cardia through an endoscope in a retroflexed position, and measuring the intragastric pressure and volume at which the hiatus opens endoscopically. Normative data for intragastric pressure and volume were collected for these induced TLESRs and two endoscopic patterns of TLESR were described in normal subjects. It was found that the GEJ opened at a significantly
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lower pressure and volume in patients who had hiatal hernias, as compared with normal control subjects. Kahrilas and colleagues [26] found that infusion of air into the stomach of patients who had hiatal hernia increased the frequency of TLESR and that the resultant TLESR frequency was directly proportional to the separation between the squamocolumnar junction and the hiatus. These studies suggest that the perturbed anatomy associated with hiatal hernia predisposes to the elicitation of TLESR in patients who have GERD [27]. ULTRASOUND TECHNOLOGY Recently, high-frequency ultrasound combined with manometry (Fig. 1) has been used to evaluate the HPZ of the GEJ. Seven to nine different layers of the esophageal wall can be discerned on high-frequency ultrasound images with a 20-MHz transducer. The anatomy of these layers, especially the two layers of the muscularis propria (the circular smooth muscle and longitudinal smooth muscle), change in a dynamic fashion during esophageal contraction. Because cross-sectional images of the esophageal wall are recorded in real time, high-frequency endoluminal ultrasound provides a unique way to study the dynamics of motility and muscle function in the gastrointestinal tract.
Fig. 1. An ultrasound transducer with manometry assembly passed transnasally into the stomach and positioned at the GEJ HPZ.
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Because the diameter of the high-frequency ultrasound catheter is relatively small, the ultrasound transducer can be combined with a manometry catheter to study the relationship between anatomic structures and muscle physiologic and pathophysiologic events. Simultaneous ultrasound and manometry was originally developed by Miller and colleagues [28] to study the muscle physiology (by way of intraluminal pressure) and anatomy (muscle thickness and cross-sectional area) of peristaltic contractions simultaneously, in an effort to understand better the mechanics involved in swallowing (Fig. 2). This technology has subsequently been used to evaluate the GEJ HPZ [29]. Lui and colleagues [4] were the first to study the anatomy of the GEJ HPZ using high-resolution ultrasound. They showed that the circular and longitudinal smooth muscles of the sphincter within the distal esophagus were thicker than the respective muscles layers of the body of the esophagus. THE NORMAL OVERLAPPING GASTROESOPHAGEAL SPHINCTERS Several recent studies [10,29–33] used simultaneous ultrasound and manometry to study the anatomy and physiology of the GEJ HPZ. High-frequency ultrasound was colocalized with manometric pressure during breath holding under full inspiration and full expiration with a machine pull-through of a simultaneous ultrasound/manometry catheter assembly from the stomach into the thoracic esophagus. For each pull-through, axial locations of the margins of
Fig. 2. Ultrasound image with concurrent manometric pressure (46 mm Hg) and respiratory cycle (nasal airflow cannula). Note that the ultrasound image on the left is simultaneous with the manometry tracing on the right (indicated by the vertical line), allowing for synchronization of the ultrasound image with the pressure generated by the muscles in that image.
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the right crus muscle were localized and quantified. Pressures were referenced to intragastric pressure. Spatial references used in this study were the inferior margin of the right crus of the diaphragm and the initiation of the pull-through (pull-through start position). The in vivo results showed that the mean muscle thickness in the region of the GEJ HPZ increases continuously through the abdominal esophagus to the esophago-cardiac junction. Muscle thickness was highly nonuniform around the lumen perimeter; at each axial location, the maximum/minimum thickness ratio was at least 150%. It was concluded that the variation in muscle thickness is largest where the diaphragmatic crus contacts the outer wall of the esophagus [10]. McCray and colleagues [30], using simultaneous ultrasound and manometry, noted that the crural diaphragm was anatomically superimposed on the intrinsic LES proximal to the GEJ, causing compression so that the anatomy of the sphincter within the distal esophagus appears asymmetric, thus accounting for the asymmetry in the pressure profile. McCray and colleagues [30] were also the first to use simultaneous ultrasound and manometry to evaluate the HPZ of the distal esophagus and differentiate the pressure profile generated by the intrinsic LES proximal to the GEJ from the pressure profile generated by the crural diaphragm. In these initial studies, normal volunteers were evaluated using a simultaneous ultrasound/manometry catheter. The catheter was positioned in the proximal stomach and then pulled through the HPZ at a constant velocity during maximal end inspiration. Manometric pressures and ultrasound images were recorded. The cross-sectional surface area on sonographic images of the sphincter within the distal esophagus and crural diaphragm, and the manometric pressures of the HPZ, were plotted against distance. The HPZ in the distal esophagus was correlated with sonographic imaging. The crural diaphragm was imaged most distally, an overlap of the crural diaphragm and the LES more proximally and the LES alone in the most proximal portion of the GEJ HPZ (Fig. 3). In all volunteers, peak pressure corresponded to an overlap of the crural diaphragm and the LES. Brasseur and colleagues [29] used simultaneous ultrasound and manometry to study the gastroesophageal HPZ with pharmacologic manipulation, evaluating the anatomic and physiologic relationships between the various components of the GEJ HPZ. High-frequency ultrasound was colocalized with manometric pressure during breath hold during inspiration and expiration in 15 normal volunteers. Machine pull-throughs of the simultaneous ultrasound and manometry catheter assembly from the stomach into the thoracic esophagus at constant velocity were performed. Pull-throughs were repeated before and after intravenous administration of atropine to attenuate the pressure from the cholinergic intrinsic sphincter components. The inferior margin of the right crural diaphragm and the initiation of the pull-through (pull-through start position) were used as axial spatial references. The cholinergic contribution to the intrinsic sphincter was reconstructed by subtracting the postatropine pressure profiles from the preatropine pressure profiles. In a separate protocol, it was shown that the cholinergic component of the intrinsic sphincter closely
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Fig. 3. Cross-section of the esophagus at the area of the LES. The crural diaphragm is outlined. (From McCray WH Jr, Chung C, Parkman HO, et al. Use of simultaneous high-resolution endoluminal sonography (HRES) and manometry to characterize high pressure zone of distal esophagus. Dig Dis Sci 2000;45(8):1660–6; with permission.)
approximated the entire intrinsic sphincter. This intrinsic component displayed two distinct peaks in both inspiration and expiration that separated by roughly 1 cm during the displacement of the costal diaphragm from its inferior to its superior-most positions. They concluded that the distal peak reflected the GSF/CF muscles, whereas the proximal peak reflected the intrinsic physiologic sphincter within the abdominal esophagus (Fig. 4). By superimposing the three pressure curves (preatropine total pressures, post-tropine atropine-resistant pressures, and the subtracted cholinergic pressure contribution), it was possible to separate and study each of the sphincteric components of the normal GEJ HPZ individually and as an overlapping group for the first time in vivo. Using this technique, it was possible to evaluate how each component of the GEJ HPZ moved with respect to each of the other components during respiration. It was found that the crus muscle moved approximately 1.9 cm between inspiration and expiration. The inferior margin of the right crus muscle was found to be at the inferior margin of the postatropine HPZ in both full inspiration and full expiration. The anatomic crus was 2 cm in length, independent of positioning of the costal diaphragm, indicating that the axial length of the crural diaphragm remains constant during respiration. The upper intrinsic sphincter moved rigidly with the crural diaphragm, indicating a tight attachment with the phrenoesophageal ligament. The upper intrinsic sphincter and crural sphincter separated by about 1 cm from the lower intrinsic sphincter (GSF/CF complex) during inferior-to-superior excursion of the costal diaphragm. To determine the extent to which the cholinergic component of the intrinsic sphincter (subtracted curves) approximated the complete intrinsic sphincter,
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Fig. 4. Combined HPZ and its extrinsic and intrinsic components for the full inspiration (FI on left) and full expiration (FE on right) respiratory states in 15 normal control subjects. The vertical line indicates the lower margin of the crural diaphragm. The red curves are preatropine pressures, reflecting the combined external and internal sphincters. The green curves are the postatropine pressures, approximating the extrinsic crural sphincter. The blue curves are the subtracted (preatropine minus postatropine) pressures, reflecting the cholinergic intrinsic sphincter components, shown to approximate closely the full intrinsic sphincter [10]. Note that the intrinsic sphincter pressure curves display two peaks in both full inspiration and full expiration. Brasseur and colleagues [10] propose that the distal peak reflects the GSF/CF complex, whereas the proximal peak reflects a physiologic sphincter (upper LES) within the abdominal esophagus that overlaps the crural sphincter (LES).
a second protocol was performed in which the crural diaphragm was pharmacologically paralyzed (the external sphincter, rather than the internal sphincters as in the previous study) to isolate directly the intrinsic sphincteric contribution to the GEJ HPZ [29,31]. Normal control subjects undergoing general anesthesia for nonesophageal surgery were evaluated by placing a simultaneous ultrasound/manometry probe into the stomach. Cisatracurium was given to paralyze the crural diaphragm. The probe was withdrawn at a constant velocity, and ultrasound images and pressure tracings were recorded simultaneously during inspiratory pause on a ventilator. Ensemble averaging of pressure was performed and referenced to the inferior margin of the crural diaphragm, as in the atropine study. Comparisons were made between the full intrinsic sphincter pressure profile from the cisatracurium study, and the cholinergic intrinsic sphincter pressure profile from the atropine study. The same two pressure peaks in the same relative geographic locations with respect to the crural diaphragm were seen in both pressure profiles (compare Fig. 5 A and B), indicating that the cholinergic contribution to pressure with the double-peaked structure was a good approximation of the intrinsic component of the gastroesophageal sphincter. The study [29,31] concluded that the intrinsic sphincter is composed of two components, an upper physiologic sphincter that overlaps and moves with the crural sphincter, and a lower anatomic component at the junction between the gastric cardia and esophagus, formed by the GSF/CF complex.
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Fig. 5. (A) Ensemble averaged pressures, referenced to the crural sphincter, of the normal control group evaluated pre- and postatropine in full inspiration (the same curve as in Fig. 4). The two peaks of the cholinergic pressure contribution are identified. (B) Ensemble averaged pressures from seven patients undergoing crural diaphragm paralysis, showing two peaks during full inspiration in the intrinsic sphincter complex. Comparing Fig. 5A with Fig. 5B, the same double peak is evident in the same relative positions. It was concluded that the subtracted curves from the atropine experiment approximate very well the intrinsic esophageal sphincter in normal healthy subjects. (From Brasseur JG, Ulerich RU, Dai Q, et al. Pharmacologic separation of the gastroesophageal segment into three sphincteric components. Am J Physiol 2007;580:961–75; with permission.)
GASTROESOPHAGEAL REFLUX DISEASE Miller and colleagues [32], using simultaneous ultrasound and manometry, discovered that an abnormality of the GSF/CF complex exists in patients who have GERD. The distal pressure profile caused by the GSF/CF complex, seen in normal control subjects, was lacking in patients who had GERD (Fig. 6). The relative contributions of each of the components of the GEJ HPZ were evaluated and compared in GERD patients and normal control subjects, to determine which abnormalities predispose patients to reflux. High-frequency endoluminal ultrasound and simultaneous manometry were used to evaluate patients who had GERD during inspiration and expiration, as in the previous studies in normal volunteers. Earlier, the normal intrinsic sphincter HPZ was described as containing two peaks that separate between inspiration and expiration. However, in all GERD patients, the intrinsic sphincter pressure profiles displayed a complete absence of the distal peak in both inspiration and expiration, indicating an absence of tone in the GSF/CF complex. The proximal
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Fig. 6. The top plot is an ensemble-averaged graph from seven patients with GERD. The red curve is the preatropine pressure, whereas the green curve is the postatropine pressure from the crural diaphragm. The blue curve is the cholinergic contribution of the intrinsic sphincter, approximating the full intrinsic sphincter. Note that the intrinsic sphincter (blue curve) contains only the proximal pressure peak, implying the presence of only the upper intrinsic sphincter. The distal pressure peak that arises from the GSF/CF complex is completely absent. By comparison, the bottom plot shows normal subjects with a distal peak formed from a tonic GSF/CF complex. (From Brasseur JG, Ulerich RU, Dai Q, et al. Pharmacological separation of the gastroesophageal segment into three sphincteric components. Am J Physiol 2007;580:961–75; with permission.)
pressure peak, reflecting the physiologic upper LES in the abdominal esophagus, was present in the same axial location relative to the crural diaphragm as in the normal volunteers. It was concluded that GERD patients lack the pressure profile consistent with the GSF/CF complex. ENDOSCOPIC TREATMENTS FOR GASTROESOPHAGEAL REFLUX DISEASE Surgical and endoscopic treatments for GERD focus on altering the structure of the gastroesophageal segment by directly modifying its mechanical properties. These methods rely on the augmentation of the natural barriers to reflux. To evaluate the effects of endoscopic plication in patients who have GERD, Miller and colleagues [34] performed a study to evaluate the mechanisms of action of endoscopic plications. High-frequency ultrasound and simultaneous manometry were used to evaluate GERD patients in a fashion similar to the previous studies. Eight of 10 patients (80%) had a significant clinical benefit
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after endoscopic-plication, with elimination or a marked decrease in symptoms. Pre-plication, all of the patients demonstrated an absent GSF/CF pressure profile described earlier. Post-plication, the distal pressure profile was re-established in the GERD patients who responded to therapy at the same location as the distal pressure peak in normal volunteers (Fig. 7). Dai and colleagues [35] were able to localize endoscopic plications with respect to the crural diaphragm and the upper LES to determine the physiologic effects of the plications. Simultaneous ultrasound and manometry were performed in patients who had GERD, before and after endoscopic plication. Ultrasound images were analyzed for the configuration of the plications, depth of sutures, location of the plications with respect to the crural diaphragm, and changes in the pressure profile. Three-dimensional reconstruction of the ultrasound images was performed. It was found that the plications appeared as hypoechoic round structures on two-dimensional ultrasound and hypoechoic spherical structures on three-dimensional ultrasound (Fig. 8). The sutures within the plications appeared as hyperechoic lines. Most of the sutures were localized to the submucosa, and most of the plications were located at, or just below, the right crus of the diaphragm. The distal portion of the pressure profile in the GEJ HPZ was lengthened in the area of the plications. SURGICAL TREATMENTS FOR GASTROESOPHAGEAL REFLUX DISEASE The sonographic and manometric characteristics of Nissen fundoplication were evaluated to determine the effects of gastric smooth muscle tone versus physical
Fig. 7. Pressure profiles through the GEJ HPZ before versus after EndoCinch in a patient with GERD referenced to the right crural diaphragm. The blue curve is the pre-EndoCinch pressure profile and the yellow curve is the post-EndoCinch pressure profile. The horizontal lines indicate the locations of the endoscopic plications (red, pink, and green lines), and the axial location of the crural diaphragm, located by ultrasound imaging, is indicated by the light blue and light green lines. (Data from Miller LS, Dai Q, Dimitriou J, et al. Endoscopic plication (Endocinch) repairs a physiologic defect in patients with gastroesophageal reflux disease (GERD): absent pressure profile due to the gastric sling fibers [abstract]. Gastroenterology 2004;126:A-330.)
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Fig. 8. A three-dimensional reconstructed ultrasound image of the area of the GEJ. The dark circular areas represent the muscularis propria. The hypoechoic region within the submucosa (marked plication) represents the area where the endoscopic plication was performed. White lines within the plication represent suture.
mechanical compression on the antireflux barrier after Nissen fundoplication. Dai and colleagues [36] used simultaneous high-frequency ultrasound and manometry to evaluate this area before and after the administration of intravenous atropine. An investigator blinded to the pressure profile marked the beginning of the Nissen fundoplication and the beginning of the crural diaphragm on ultrasound. The beginning of the Nissen fundoplication was defined as the first area at which multiple layers of the gastric wall were seen on ultrasound images (Fig. 9). The margins of the crural diaphragm were defined from ultrasound imaging of the crus muscles outside the wall of the stomach and esophagus. The area under the pressure curve was evaluated between the beginning of the Nissen fundoplication and the beginning of the crural diaphragm; the peak pressure within the Nissen fundoplication was also assessed. The area under the pressure curve decreased by 44% (P<.0001) and the peak pressure decreased by 32% (P<.0001) within the Nissen fundoplication after the administration of atropine. It was concluded that the antireflux barrier caused by a Nissen fundoplication is in large part due to the tonic contraction of the gastric smooth muscle in the wrap of the Nissen fundoplication, and is not simply due to the mechanical effect of the wrap compressing the esophagus. Based on these data, it was hypothesized that the Nissen fundoplication, like endoscopic plication, in part prevents reflux by artificially bolstering the area of the defective GSF/CF complex, and that tonic contraction of the muscle in the gastric wrap is an important factor in generating this antireflux barrier. THE BIOMECHANICS OF THE GASTROESOPHAGEAL JUNCTION HIGH-PRESSURE ZONE Stresses at the GEJ HPZ can be calculated from data generated using simultaneous ultrasound and manometry during bolus distension (strain) of the esophagus (Fig. 10). To evaluate further the pathophysiologic mechanisms of the diseased sphincter in GERD patients, Schiffner and colleagues [33] evaluated the geometry, stiffness, and wall tension of the gastroesophageal segment in
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Fig. 9. Cross-sectional sonograms through the gastric fundus. (A) The mucosal folds of the stomach (F) and the echo-free water (W) are shown in the lumen. (B) A cross-sectional sonogram through the Nissen fundoplication. Multiple layers (arrowheads) of the stomach wall are shown as alternately hypo- and hyperechoic structures around the ultrasound transducer (T). (C) A crosssectional sonogram through Nissen fundoplication showing the gastric folds (arrowheads). (D) A cross-sectional sonogram of the gastric esophageal junction showing the crural diaphragm (arrows) as a belt-like hypoechoic structure. T, Transducer. (Graph) Preatropine (blue) and postatropine (red) pressure curves. The area under the curve between lines N and D is significantly less for the postatropine pressure (red) than for the preatropine pressure curve (blue). N, beginning of the Nissen; D, the beginning of the diaphragm. (Data from Dai Q, Chung C, Nowrouzzadeh F, et al. Simultaneous ultrasound (US) and manometry in the evaluation of Nissen fundoplication [abstract]. Gastroenterology 2003;124:A-418.)
the resting state and during luminal opening, and made comparisons with normal subjects and the same GERD patients after endoscopic plication (Fig. 11). Deglutitive inhibition during swallowing was used to measure the mechanical properties of the normal, abnormal, and endoscopically plicated
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Fig. 10. Pressure difference, radius, total muscle layer thickness, total muscle layer area, and circular muscle wall stress against time for a normal control subject during swallowing. The ‘‘log ratio’’ is a parameter used in the calculation of wall stress.
gastroesophageal segment at the location of the peak resting state pressure. The peak HPZ pressure was typically about 1 cm above the plications. Esophageal lumen radii, areas, and muscle thicknesses were measured during opening. A force balance was applied to calculate wall tension.
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Fig. 11. Average stress-to-stretch ratio plots for normal control subjects (black), patients with GERD pre-EndoCinch (red) and the same GERD patients post-EndoCinch (green). The stress-tostretch ratio is shifted to the right in the GERD patients compared with the normal controls, but shifts back to the left after the endoscopic plications. The stiffness of the muscle wall surrounding the GEJ was approximately six times lower in the GERD patients than in the normal control subjects; however, after placement of endoscopic plications, the average stiffness was found to approximate normal values after opening had occurred and the muscle was sufficiently stretched.
Schiffner and colleagues [33] found that the stiffness of the muscle wall surrounding the GEJ was approximately six times lower in the GERD patients than in the normal control subjects. After placement of the endoscopic plications, the average stiffness was found to approximate normal values, but only after the segment had already opened. It was concluded that the plications increased the stiffness of the esophagogastric segment, but only after opening. SUMMARY The use of high-frequency ultrasound transducers combined with manometry in the gastrointestinal tract has yielded important findings concerning the anatomy, physiology, and pathophysiology of the HPZ of the GEJ, and the sphincteric muscles within. These transducers have made previously invisible portions of the gastrointestinal tract accessible to investigation. The components of the HPZ of the distal esophagus have been isolated and the movements of these components have been studied individually and as a group. Three distinct HPZs have been identified and correlated with anatomic structures. These components are the extrinsic sphincter (crural diaphragm) and the two components of the intrinsic sphincter (an upper LES [the physiologic extrinsic sphincter] and an a lower LES [the GSF/CF complex]). The possible underlying pathophysiology of GERD (eg, the absence of tone and flaccidity in the gastric sling and clasp fiber muscle complex) has been explored. The biomechanics of the GEJ HPZ have been investigated. The mechanism of action of standard surgical and newer endoscopic therapies for GERD has also been defined.
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[25] Wyman JB, Dent J, Heddle R, et al. Control of belching by the lower esophageal sphincter. Gut 1990;31:639–46. [26] Kahrilas PJ, Shi G, Manka M, et al. Increased frequency of transient lower esophageal sphincter relaxation induced by gastric distension in reflux patients with hiatal hernia. Gastroenterology 2000;118(4):688–95. [27] Kalra A, Vegesna AK, Besetty R, et al. Induced transient lower esophageal sphincter relaxation (TLESR) in normal control subjects and in patients with hiatal hernia. Gastroenterology 2007; in press. [28] Miller LS, Liu JB, Colizzo FP, et al. Correlation of high-frequency esophageal ultrasonography and manometry in the study of esophageal motility [erratum appears in Gastroenterology 1996 Feb; 110(2)]. Gastroenterology 1995;109(3):832–7. [29] Brasseur JG, Ulerich RU, Dai Q, et al. Pharmacological separation of the gastro-esophageal segment into three sphincteric components. Am J Physiol 2007;580(3):961–75. [30] McCray WH Jr, Chung C, Parkman HP, et al. Use of simultaneous high-resolution endoluminal sonography (HRES) and manometry to characterize high pressure zone of distal esophagus. Dig Dis Sci 2000;45(8):1660–6. [31] Dai QS, Soliman AS, Patel D, et al. Simultaneous ultrasound and manometry during pharmacologic paralysis of the crural diaphragm allows spatial localization of the two components of the intrinsic gastroesophageal junction high pressure zone (GEJHPZ) [abstract]. Gastroenterology 2004;126:A-636. [32] Miller LS, Ulerich R, Thomas BJ, et al. A new theory to explain the pathophysiology of GERD. Pharmacological separation of the gastro-esophageal junction high pressure zone (GEJHPZ) demonstrates an absent gastric sling fiber pressure profile in patients with GERD. Gastroenterology 2004;A-126(4 suppl 2). [33] Schiffner BJ, Miller LS, Dai Q, et al. Opening stiffness and geometry of the esophageal gastric segment in health, with GERD, and after endoscopic surgery. Gastroenterology 2005;128:A-396. [34] Miller LS, Dai Q, Dimitriou J, et al. Endoscopic plication (Endocinch) repairs a physiologic defect in patients with gastroesophageal reflux disease (GERD): absent pressure profile due to the gastric sling fibers [abstract]. Gastroenterology 2004;126:A-330. [35] Dai Q, Thomas BJ, Dimitriou J, et al. 2-D and 3-D endoluminal ultrasound localization of endoscopic plications with simultaneous manometry (location of plications and depth of sutures). Gastroenterology 2004;59:A244. [36] Dai Q, Chung C, Nowrouzzadeh F, et al. Simultaneous ultrasound (US) and manometry in the evaluation of Nissen fundoplication [abstract]. Gastroenterology 2003;124:A-418.
Gastroenterol Clin N Am 36 (2007) 619–647
GASTROENTEROLOGY CLINICS OF NORTH AMERICA
Gastroparesis: Symptoms, Evaluation, and Treatment William L. Hasler, MD Division of Gastroenterology, University of Michigan Health System, University of Michigan Hospital, 3912 Taubman Center, Box 0362, Ann Arbor, MI 48109, USA
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astroparesis is a disorder that presents with symptoms of gastric retention with objective evidence of delayed gastric emptying in the absence of mechanical obstruction. Diabetic, idiopathic, and postsurgical gastroparesis are the most common forms; however, many other conditions are associated with symptomatic delayed gastric emptying (Table 1). Its main symptoms include nausea, vomiting, early satiety, postprandial fullness, and abdominal pain; however, gastroparesis also has nongastrointestinal manifestations. Gastroparesis is estimated to affect up to 4% of the population and may produce mild, intermittent symptoms with little impairment of daily function or relentless vomiting with total disability and frequent hospitalizations. Therapies include dietary measures, drugs that have motor stimulatory or antiemetic effects, endoscopic treatments, and surgery. CLINICAL MANIFESTATIONS Gastroparesis presents with a variety of symptoms. In one study, nausea was reported by 93% of patients, whereas early satiety and vomiting were noted by 86% and 68%, respectively [1]. In a second series, nausea, vomiting, bloating, and early satiety were reported by 92%, 84%, 75%, and 60% [2]. These symptoms are the main targets of therapy with antiemetic agents and drugs that stimulate gastric propulsion. Many patients in both case series (89% and 46%) also reported abdominal pain (Table 2). No treatments have been characterized to treat pain associated with gastroparesis. Some individuals report heartburn from acid reflux into the esophagus as their only symptom of gastroparesis. In these cases, reflux is facilitated by fundic distention that increases the rate of transient lower esophageal sphincter relaxations. Although some gastroparetics with frequent vomiting lose weight and develop malnutrition, most
Dr. Hasler is on the Speaker’s Bureau and has received grant funding from Novartis Pharmaceuticals. He also has received grant funding from and is a past consultant for SmartPill Corporation. This work was supported by grant 1 U01 DK073985-01 from the National Institutes of Health.
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Table 1 Etiologies of gastroparesis Disorder
N
%
Idiopathic Postviral Diabetes Postsurgical Parkinson’s disease Collagen vascular disease Intestinal pseudo-obstruction Miscellaneous
52 12 42 19 11 7 6 9
35.6 8.2 28.8 13 7.5 4.8 4.1 6.2
Data from Soykan I, Sivri B, Saroseik I, et al. Demography, clinical characteristics, psychological and abuse profiles, treatment, and long-term follow-up of patients with gastroparesis. Dig Dis Sci 1998;43:400.
patients were overweight or obese in one series indicating that the disorder does not necessarily restrict food intake [3]. Phytobezoars may complicate gastroparesis and typically present with worsening epigastric pain, nausea, early satiety, bloating, or a palpable epigastric mass. Gastric ulcer, small intestinal obstruction, and gastric perforation also occur as consequences of bezoars. Elimination of bezoars is accomplished by endoscopic destruction and lavage; enzymatic digestion (papain, cellulose, or N-acetylcysteine); and dietary exclusion of foods high in indigestible residue. Variably delayed gastric emptying in diabetics with gastroparesis may lead to unpredictable food delivery to the small intestine, which can cause highly erratic glycemic control with both severe hypoglycemia and hyperglycemia [4]. ETIOLOGY Gastroparesis is a consequence of many systemic illnesses, it may complicate selected surgical procedures, or it may be idiopathic. In a case series of 146 gastroparesis patients seen at a large United States tertiary medical center, 29% of cases had underlying diabetes, 13% developed symptoms after gastric surgery,
Table 2 Characteristics of pain in 28 gastroparesis patients Characteristic
%
Localized Upper abdominal location Constant Burning, vague, or crampy Nocturnal Exacerbated by meals Relief by meals
76 36 28 64 80 60 15
Data from Hoogerwerf WA, Pasricha PJ, Kalloo AN, et al. Pain: the overlooked symptom in gastroparesis. Am J Gastroenterol 1999;94:1029–33.
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and 36% were idiopathic [2]. Gastroparesis most often presents in young individuals with a mean age of onset of 34 years. Eighty-two percent of cases occur in women. Diabetic Gastroparesis Epidemiology The systemic disease most often complicated by development of gastroparesis is diabetes mellitus. Nausea, vomiting, and early satiety are common in those who have had diabetes for many years. In a population-based survey, 18% of diabetics reported upper gastrointestinal symptoms [5]. Delayed gastric emptying usually only develops with diabetes (usually type I) of more than 10 years duration. The prevalence of delayed emptying among individuals with longstanding type 1 diabetes ranges from 27% to 58% [6]. Likewise, gastroparesis is present in up to 30% of patients with type 2 diabetes [7]. Diabetes more profoundly affects gastric motor function than small bowel transit, indicating an increased sensitivity of the stomach to diabetic damage. In diabetics on hemodialysis, development of gastroparesis correlates with the presence of orthostatic hypotension, prior myocardial infarction or cerebrovascular accident, and gangrene of the extremities [8]. Patients with diabetes secondary to chronic pancreatitis also may develop gastroparesis. Pathogenesis Delayed emptying of solid foods in diabetic gastroparesis generally is believed to result from impaired phasic antral contractions, but other factors contribute to impaired gastric evacuation. Increased postprandial antral diameter is demonstrable on ultrasound, suggestive also of tonic motor defects. Increased liquid retention in the fundus and prolonged solid food retention in both the proximal and distal stomach occur in diabetics with gastroparesis, demonstrating altered intragastric distribution. Emptying also may be delayed from increased outflow resistance in the pylorus or small intestine. Improperly timed pyloric contractions of abnormal intensity (>10 mm Hg) and duration (>3 minutes) leading to pylorospasm are observed in some diabetics [9]. Others exhibit abnormal postprandial bursts of jejunal contractions, which act as brakes to gastric outflow [10]. The pathogenesis of delayed emptying in patients with long-standing diabetes is poorly understood, but evidence suggests an important causative role for autonomic nerve damage. Gastric acid output in response to sham feeding is reduced by two thirds in diabetics, indicative of vagal neuropathy [11]. Vagal denervation of the proximal or whole stomach accelerates rather than slows postprandial liquid emptying in nondiabetics, however, and generalized loss of vagal function cannot be the sole cause of gastric dysfunction in diabetes [12]. Histologic study of vagus nerves from affected diabetics reveals variable degrees of myelin degeneration [13]. Many diabetics with gastroparesis exhibit evidence of autonomic dysfunction, such as postural hypotension or loss of vagotonic reflexes, which slow the heart. In studies of type I diabetics, delayed emptying has been associated with autonomic but not peripheral neuropathy
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[14]. As further evidence of autonomic damage, jejunal burst contractions in human diabetics are morphologically similar to those seen after sympathectomy in dogs [10]. Recent investigations suggest that factors other than vagal or autonomic neuropathy play pathogenic roles in diabetic gastroparesis. In 20 type 1 and type 2 diabetics, the prevalence of autonomic neuropathy increased from 35% to 80% over 12 years [15]. Rates of solid and liquid gastric emptying did not worsen over this same time period, however, indicating that progressive neuropathy did not promote development of gastroparesis. Studies in diabetic animal models report impaired contractility at the smooth muscle cell level. In four diabetics with gastroparesis who underwent gastric resection, histologic examination revealed gastric smooth muscle degeneration and fibrosis and the presence of unique eosiniphilic inclusion bodies within the muscle tissue [16]. In concert with enteric nerves and smooth muscle, the interstitial cells of Cajal (ICCs) play a crucial role in regulating gastric motor function. One subset of ICCs in the circular muscle relays and amplifies information from enteric neurons to smooth muscle cells, whereas another population in the myenteric plexus generates rhythmic electrical depolarizations (slow waves) that control the frequency and direction of gastric contractions. In a histologic study from diabetics with gastroparesis undergoing gastric surgery, disruption of gastric ICC networks correlated with loss of normal slow wave cycling on preoperative testing [17]. Tissues from patients with type 2 diabetes reportedly show ICC losses, which are more prominent in circular muscle than in the myenteric plexus [18]. One unpublished small case series suggests that the histopathology of diabetic gastroparesis is highly variable even for similar degrees of gastric stasis. In this study, gastric tissue from one individual with an abrupt symptom onset and well-controlled diabetes showed no morphologic abnormalities, whereas tissue from another with long-standing, poorly controlled diabetes exhibited smooth muscle fibrosis, loss of myenteric neurons, and reduced staining for many neurotransmitter and ICC markers [19]. The observation that the mitochondrial DNA mutation 3243 predisposes to gastroparesis in type 2 diabetics suggests that genetic factors may contribute to disease development [20]. Metabolic factors participate in the control of gastric emptying. Hyperglycemia in the absence of neuropathy or myopathy disrupts normal antral motor complexes at plasma glucose levels as low as 140 mg/dL in healthy humans [21]. In type 1 and type 2 diabetics, gastric emptying of liquids is delayed when blood glucose levels exceed 270 mg/dL [7]. Likewise in type 1 diabetics, delays in solid emptying are observed during periods of hyperglycemia, which improve during euglycemia. Conversely, hypoglycemia accelerates gastric emptying in healthy volunteers and type 1 diabetics [22]. Finally, there is compelling evidence suggesting that selected gastric symptoms in diabetics may relate to factors other than delayed emptying. Some patients with diabetes report severe nausea and vomiting, yet exhibit no gastric retention on scintigraphy, whereas many asymptomatic diabetics exhibit markedly delayed emptying. Even when symptoms are quantified concurrently
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during performance of scintigraphy, symptom correlations with emptying rates are poor [23]. Studies examining the relation of specific symptoms to rates of gastric emptying report correlations only between postprandial fullness and gastric stasis [24]. Other potential causes of symptoms include altered relaxant properties of the gastric fundus and heightened perceptual sensitivity to noxious stimulation of the gastric wall. Impairment of postprandial fundic accommodation has been observed in diabetic patients [25]. In another study of type 1 diabetics with dyspepsia and autonomic dysfunction, gastric distention evoked exaggerated nausea, bloating, and abdominal pain, suggesting defects in visceral afferent function [26]. The correlation of accommodation and visceral sensory defects with the degree of symptoms in diabetic patients has not been well studied. Idiopathic Gastroparesis Epidemiology Idiopathic gastroparesis is at least as common as diabetic gastroparesis in most case series [2]. Patients typically are young or middle aged and up to 90% are women. Although many individuals report an insidious clinical course with no obvious trigger of disease, one quarter of patients present with an acute onset of symptoms, often in association with acute gastroenteritis or with viral prodromal symptoms, such as diarrhea, fever, myalgias, and headache [27]. Postinfectious idiopathic gastroparesis seems to have a relatively good prognosis with symptom resolution over several years compared with disease not occurring after a viral prodrome. In most cases, the offending organism is not characterized. Transient slowing of gastric emptying develops after acute infection with parvovirus-like agents (Norwalk agent) and with Lyme disease. Eight of 11 children with acute onset gastroparesis in one study tested positive for rotavirus infection [28]. In immunosuppressed individuals, cytomegalovirus, EpsteinBarr virus, varicella zoster virus, and herpes simplex virus may be implicated in development of gastroparesis. In one case, postinfectious gastroparesis occurred as part of a larger dysautonomic syndrome also involving cardiac conduction and bladder function [29]. Gastroparesis also has been observed after vaccination for tetanus, anthrax, and hepatitis [30]. It is difficult to distinguish idiopathic gastroparesis from functional dyspepsia in some cases, leading some to speculate they are variants of the same disorder. As with idiopathic gastroparesis, some functional dyspeptics present after an acute infection. Furthermore, approximately one third of patients with functional dyspepsia exhibit delayed emptying. The postprandial distress subtype of functional dyspepsia in the current Rome III criteria is characterized by gastroparesis-like symptoms including postprandial fullness and early satiety [31]. Other Rome III diagnoses with symptom overlap with idiopathic gastroparesis include chronic idiopathic nausea and functional vomiting [31]. The prevalence of delayed emptying in these syndromes has not been characterized. From a diagnostic standpoint, a presentation of predominant pain and less nausea is considered to be more typical of functional dyspepsia, whereas dominant nausea with minimal pain is more consistent with idiopathic gastroparesis [32].
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Pathogenesis The pathogenic basis of idiopathic gastroparesis is less well studied than for diabetic gastroparesis. Most patients do not exhibit underlying neuropathy. A study of intragastric acidity measured by a radiotelemetry capsule observed lower preprandial and postprandial pH in patients with idiopathic gastroparesis versus diabetics with gastroparesis, suggesting a lesser degree of vagal neuropathy in individuals with idiopathic disease [33]. Similarly, plasma pancreatic polypeptide responses to sham feeding are normal in patients with idiopathic gastroparesis but are markedly blunted in diabetics with gastric stasis, indicative of greater vagal damage secondary to diabetes [34]. As in diabetic gastroparesis, histologic examination of tissue from patients with idiopathic gastroparesis undergoing gastric resection may reveal loss of ICCs and myenteric neurons [17,35]. Isolated gastric myopathy also has been described as a cause of idiopathic gastroparesis [36]. Inflammatory mechanisms may play a role in some cases. Prominent eosinophilic infiltrates were noted in the smooth muscle layers and around nerve fibers in the gastric wall in tissues from two gastroparetics undergoing gastrectomy [37]. Another patient with idiopathic gastroparesis exhibited increases in CD4þ and CD8þ T lymphocytes in the gastric myenteric plexus and reductions in myenteric neuronal staining for tachykinins [38]. As in diabetic disease, symptoms with idiopathic gastroparesis may result from factors other than delayed emptying. In a study of 58 patients with idiopathic gastroparesis, impaired fundic accommodation correlated with the degree of early satiety and weight loss, whereas hypersensitivity to balloon inflation correlated with epigastric pain, early satiety, and weight loss [39]. Postsurgical Gastroparesis Epidemiology Gastroparesis may complicate several operations performed on the stomach. Approximately 5% of patients who undergo vagotomy and drainage for ulcer disease or malignancy experience nausea, vomiting, and early satiety secondary to postoperative gastric stasis. Gastroparesis may even be a consequence of highly selective vagotomy. Roux-en-Y gastrojejunostomies may be complicated by the Roux stasis syndrome, which is characterized by intractable nausea, vomiting, abdominal pain, and delayed gastric emptying occurring as a consequence of either spastic or retroperistaltic Roux limb contractions [40]. Esophagectomy with gastric pull-through into the thoracic cavity or with colonic interposition may cure esophageal neoplasm; however, this operation predisposes to gastroparesis. Half of patients undergoing pylorus-preserving Whipple procedures for pancreatic cancer or chronic pancreatitis may develop delayed emptying. Gastroparesis commonly occurs after lung and heart-lung transplantation and may cause microaspiration into the transplanted lung. Gastric bypass and gastroplasty performed for morbid obesity delay gastric emptying of solids and promote fundic distention leading to early satiety, anorexia, and weight loss. Some individuals exhibit rapid emptying of caloric liquids, however, which may limit the degree of weight loss [41].
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In recent years, many cases of postsurgical gastroparesis have occurred after open or laparoscopic fundoplication for gastroesophageal reflux disease. In many instances, it is uncertain if gastric motor impairments were present before surgery or if they occurred as a consequence of the operation. It has been estimated that 4% to 40% of patients undergoing laparoscopic fundoplication develop intraoperative vagal damage to some degree [42]. Some centers have advocated preoperative gastric emptying scintigraphy in those being considered for fundoplication to detect individuals at risk for this complication. Pathogenesis Abnormalities of antral peristalsis and fundic tone are demonstrable in patients with postsurgical gastroparesis. In one study, eight of nine patients with gastroparesis had no fasting motor cycles, whereas asymptomatic postoperative controls exhibited normal migrating motor complex activity [43]. Increases in intragastric volumes, impaired proximal gastric responses to meals and to balloon inflation, and heightened perception of gastric distention also have been observed after vagotomy, documenting both motor and afferent defects in this condition [44]. Mechanisms underlying development of the Roux stasis syndrome are uncertain. One investigation suggested that vagotomy predisposes to gastric stasis but not Roux limb dysfunction in these patients [45]. In dogs, the syndrome can be avoided by preserving neuromuscular continuity between the proximal jejunum and Roux limb [46]. Gastroparesis occurring after fundoplication likely results from operative compression or severing of the vagus nerves. As evidence of this, one study reported reductions in antral postprandial phasic contractions after fundoplication [47]. Other Causes of Gastroparesis Approximately 25% to 30% of cases of gastroparesis are not idiopathic and are not secondary to diabetes or postoperative gastric motor dysfunction. The etiologies of disease in these instances include disorders with isolated gastric dysmotility, conditions with diffuse motor dysfunction involving most or all of the gastrointestinal tract, and nongastrointestinal diseases with associated delays in gastric emptying. Other disorders with isolated gastric motor dysfunction Many disorders may present with isolated impaired gastric motor function. The prevalence and pathogenic importance of gastroparesis in patients with gastroesophageal reflux are not well defined. Some studies have reported delayed emptying of liquids, solids, or mixed meals in up to 57% of patients, whereas other investigations have observed no abnormalities [48]. Delays in gastric emptying in patients with gastroesophageal reflux disease correlate poorly with symptoms, lower esophageal sphincter pressure, and cumulative esophageal acid exposure. Delayed gastric emptying is observed in up to 60% of individuals with nonobstructing pancreatic carcinoma and in smaller numbers of patients with other malignancies [49]. Antineuronal antibodies may be detectable in some of these cases, suggesting an immunologic basis
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for the gastric motor defect [50]. Severe nausea, vomiting, and impaired gastric evacuation of liquid and solid meals are common after abdominal irradiation. Delayed emptying of solids is observed in atrophic gastritis patients with or without pernicious anemia [51]. In this condition, decreases in gastric secretion increase the time needed to fragment solid foods to tiny particles. The median arcuate ligament syndrome, an entity caused by compression of the celiac axis by a fibrous band, presents with postprandial pain, nausea, vomiting, weight loss, and delayed gastric emptying, which are relieved by surgical decompression [52]. Ischemic gastroparesis results from celiac arterial occlusion [53]. Disorders of diffuse gastrointestinal dysfunction with associated gastroparesis Gastroparesis is frequently found in patients with diffuse disorders of gut motility, such as chronic intestinal pseudo-obstruction. These individuals commonly present with a broader range of clinical manifestations, however, including small intestinal bacterial overgrowth, nutritional deficiencies, bowel habit abnormalities, and pneumatosis intestinalis. Heartburn, dysphagia, bloating, nausea, and vomiting are consequences of smooth muscle and enteric neuronal damage of the esophagus and stomach in patients with scleroderma. The prevalence of delayed emptying in scleroderma is estimated to be 40% to 67%, whereas the rates in polymyositis-dermatomyositis and systemic lupus erythematosus are lower [54]. Gastric stasis is described in smooth muscle disorders, such as myotonic dystrophy and progressive muscular dystrophy. Primary or secondary amyloidosis can cause neuropathic or myopathic intestinal pseudoobstruction. Gastric stasis is found in 19% to 64% of patients with chronic constipation or constipation-predominant irritable bowel syndrome and has been associated with idiopathic megarectum [55]. Other cases of intestinal pseudoobstruction are familial, occur after a viral prodrome, or present as a paraneoplastic phenomenon most often in association with small cell lung carcinoma [56]. The classic infectious cause of disrupted gastrointestinal motor activity is Chagas’ disease, in which the myenteric plexus is damaged by Trypanosoma cruzi infection. In addition to producing an achalasia-like picture, Chagas’ disease may cause gastroparesis, megaduodenum, and chronic intestinal pseudoobstruction and several extraintestinal manifestations. Other infections that produce generalized gut dysmotility include varicella zoster, Epstein-Barr virus, Clostridium botulinum, and HIV. Nongastrointestinal disorders with associated delays in gastric emptying Neurologic diseases without intrinsic gut neuromuscular dysfunction may present with delays in gastric emptying. More than 7% of a large case series of patients with gastroparesis had underlying Parkinson’s disease [2]. Predictors of delayed emptying in Parkinson’s patients include the severity of somatic motor impairment, such as action tremor [57]. Medications used to treat Parkinson’s may exacerbate gastric stasis in this condition. Disturbed gastric motility also is observed with cerebrovascular accident; migraine headaches; high cervical spine injury; and with peripheral nerve disorders, such as stiff-man syndrome and Charcot-Marie-Tooth syndrome. Some patients with familial
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dysautonomia, Shy-Drager syndrome, Guillain-Barre´ syndrome, and multiple sclerosis may exhibit gastric stasis or intestinal pseudo-obstruction. Gastroparesis rarely is found in patients with eating disorders. Retarded gastric emptying of semisolid or solid foods and reduced amplitudes of fasting and postprandial antral contractions are observed in some patients with anorexia nervosa [58]. It is unclear whether these gastric motor disturbances cause symptoms or are consequences of the disorder, because malnutrition itself impairs gastric evacuation and improved nutrition promotes accelerated solid phase emptying [59]. In rare instances, bulimia nervosa patients exhibit delayed gastric emptying. Rumination syndrome usually is not associated with gastric stasis and may be suggested by detection of characteristic simultaneous contractions on antroduodenal manometry reflective of increases in abdominal wall tone. One study, however, reported small reductions in postprandial antral contractions in patients with rumination [60]. Cyclic vomiting syndrome is characterized by intermittent attacks of relentless nausea and vomiting with prolonged intervening asymptomatic periods [31]. Most recent investigations observe acceleration rather than delay of early gastric emptying in adults with cyclic vomiting syndrome [61]. One investigation, however, reported delayed solid gastric emptying in two of eight patients and reduced antral motor activity after eating in five patients [62]. Other systemic conditions affect gastric emptying and produce symptoms of gastroparesis. Studies of gastric emptying during nausea of first-trimester pregnancy using nonradioactive methods have reported variable results with some studies showing delays and others observing normal emptying [63]. Gastroparesis or intestinal pseudo-obstruction may complicate severe hypothyroidism and hyperparathyroidism and hypoparathyroidism. Other diseases associated with gastroparesis include chronic pancreatitis, cystic fibrosis, cirrhosis, and chronic renal insufficiency. Genetic disorders, such as Turner’s syndrome, may predispose to delays in gastric emptying. Many prescription medications delay emptying as can tobacco, excess ethanol, or cannabis use. Total parenteral nutrition impairs gastric evacuation. This effect correlates with increases in serum glucose and is minimized by replacement of half of the amino acid content with branched-chain amino acids [64]. Agents that delay gastric emptying include the following: Ethanol (high concentration) Aluminum hydroxide antacids Muscarinic cholinergic receptor antagonists b-adrenoceptor agonists Calcitonin Calcium channel antagonists Glucagon Interleukin-1 L-dopa Lithium Omeprazole
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Opiates Phenothiazines Progesterone Sucralfate Tetrahydrocannabinol Tobacco Tricyclic antidepressants
APPROACH TO DIAGNOSIS Initial Evaluation A careful history is critical for the initial evaluation of the patient with presumed gastroparesis to assess symptom severity and to screen for other diseases with similar presentations. Mild cases present with intermittent symptoms that subside when the stomach is empty and return when it is full. Because gastroparesis preferentially affects emptying of solids, patients may report greater symptoms after large solid meals compared with a liquid diet. In severe disease, patients may report progressive nausea, distention, and pain, which build up over several days only to be relieved by vomiting of old food residue. The most extreme cases present with relentless nausea and retching even under fasting conditions and symptoms of dehydration including lightheadedness, dry mouth, and decreased urine output. Hematemesis indicates mucosal injury, such as a Mallory-Weiss tear. The interview can elicit histories of diseases, such as diabetes or scleroderma, prior gastric surgery or abdominal irradiation, or a recent viral prodrome. Quantification of the severity and character of gastroparesis symptoms has been facilitated by the introduction of validated surveys. The most widely used questionnaire for this purpose is the Gastroparesis Cardinal Symptom Index, which is a symptom score validated in seven university-based clinical practices in the United States that correlates well with patient and physician ratings of gastric symptom severity [65]. The Gastroparesis Cardinal Symptom Index is comprised of three subscales (postprandial fullness and early satiety, nausea and vomiting, and bloating) and represents a subset of the more comprehensive Patient Assessment of Gastrointestinal Symptoms [66]. Using these questionnaires, investigators are beginning to classify patients with gastroparesis into different subgroups based on predominant symptom profiles. Although these surveys currently are most useful for enrollment in research trials, it has been proposed that they may serve a clinical role very similar to the Rome criteria in the future in helping health care providers to select symptom-based management approaches. The physical examination serves two roles in evaluating the patient with presumed gastroparesis: to assess the gravity of the presenting complaint and to facilitate diagnosis. Poor skin or eyeball turgor, dry mucous membranes, and resting or orthostatic tachycardia or hypotension mandate prompt fluid resuscitation. Many individuals exhibit abdominal distention and tympany with or without epigastric tenderness. With gastric retention of liquids, a succussion
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splash occasionally is heard by gently rocking the patient from side to side. Sclerodactyly raises concern for scleroderma, whereas a malar rash suggests possible systemic lupus erythrematosus. Peripheral or autonomic neuropathies are associated with many etiologies of gastroparesis. Cachexia, palpable masses, lymphadenopathy, or hepatomegaly suggest occult neoplasm causing either gastric outlet obstruction or paraneoplastic gastroparesis. Selected laboratory and structural tests may direct further management of the patient with presumed gastroparesis. Serum electrolytes evaluate for hypokalemia and contraction alkalosis in patients with vomiting. A complete blood count excludes anemia and serum protein and albumin screen for nutritional deficits in individuals with long-standing symptoms. Blood tests for diabetes, uremia, thyroid or parathyroid disease, and pernicious anemia and serologic studies for connective tissue diseases are indicated in some cases. Serologic markers in patients with paraneoplastic gastroparesis include type 1 antineuronal nuclear antibody, anti-Purkinje cell cytoplasmic antibody, and ganglionic nicotinic acetylcholine receptor antibody [67]. Such antineuronal antibodies also may be detected in some patients with idiopathic gastroparesis of an autoimmune basis [68]. For suspected small bowel obstruction, flat and upright abdominal radiographs are obtained, which can be followed by barium radiography if indicated. If the history suggests possible gastric outlet obstruction, upper endoscopy or upper gastrointestinal barium radiography is obtained. Furthermore, upper endoscopy performed in individuals with flares of gastroparesis symptoms commonly reveals mucosal lesions, such as reflux or Candida esophagitis, that may respond to treatments other than those given specifically for gastroparesis [69]. In the absence of mechanical obstruction, gastroparesis may be inferred by the finding of retained food or a bezoar on endoscopy. Demonstration of Gastric Functional Impairment Gastric scintigraphy is the most widely accepted test for diagnosis of gastroparesis and uses a 99mTc-sulfur colloid label bound to a solid food. Liquid-phase scans are believed to be less sensitive for detecting the disorder. Solid-phase emptying exhibits a biphasic curve with an initial lag phase, during which the food is mixed in the stomach, followed by a linear emptying phase, which persists until the stomach is emptied. The pattern of solid emptying in gastroparesis may be variable, with some individuals exhibiting prolongation of the lag phase, whereas others show slowed linear emptying after a normal lag phase. A major drawback of gastric scintigraphy has been a lack of standardization of criteria used to diagnose gastroparesis across all medical centers. In a survey of gastric emptying tests performed in academic and community hospitals in Canada, 28% of nuclear medicine departments defined the cutoff for gastroparesis as the degree of gastric retention more than 2 standard deviations above the mean, whereas 26% used 1 standard deviation, 6.5% used 1.5 standard deviations, and 40% did not have objective criteria [70]. Among medical centers surveyed, only 18% validated their results in a population of healthy
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volunteers. Recently, researchers have advocated acceptance of uniform standards of gastric scintigraphy performance and interpretation. A standardized method using a meal of toast, jam, and EggBeaters labeled with 99mTc-sulfur colloid was recently validated [71]. With this technique, gastric retention greater than 60% at 2 hours and greater than 10% at 4 hours are consistent with gastroparesis (Fig. 1). Even using such a standardized protocol, however, the diagnosis of gastroparesis may not be clear-cut. In one investigation, 37% of patients with normal emptying at 2 hours exhibited delayed emptying at 4 hours, whereas 19% with delayed emptying at 2 hours showed normalization at 4 hours [72]. Although gastric scintigraphy is routinely performed for diagnosis of gastroparesis, its use has not been rigorously subjected to outcomes analysis. Indeed, one investigation reported that findings of gastric emptying scanning did not influence clinical management of patients undergoing the test [73]. Other techniques for measuring gastric emptying have been promoted. Performance of breath testing after ingestion of nonradioactive 13C-labelled nutrient substrates, such as octanoate and acetate, can assess gastric emptying of both solids and liquids. These methods measure liberation of 13CO2 in expired breath samples after duodenal assimilation of the ingested compound and are reliable only in persons with normal digestive and absorptive function. Emptying results from the 13C-octanoate and 13C-acetate breath tests show fair to good correlations with scintigraphy [74]. A second recently approved method involves ingestion of a radiotelemetry capsule that continuously transmits
Fig. 1. Box and whiskers plots are shown for percent gastric retention at 1, 2, and 4 hours after consuming a low-fat test meal in healthy volunteers from 63 men and 60 women. The box represents the median and the first and third quartile, whereas the whiskers show the tenth and ninetieth percentile values. At 1 and 2 hours, women had greater degrees of gastric retention. At 4 hours, the percent retention was similar in men and women. (From Tougas G, Eaker EY, Abell TL, et al. Assessment of gastric emptying using a low fat meal: establishment of international control values. Am J Gastroenterol 2000;95:1460; with permission.)
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information on luminal pH and pressure profiles to a receiver worn by the patient. With this test, gastric emptying is determined by measuring the time from ingestion of the capsule to the time a pH reading of near neutrality is recorded reflecting passage into the proximal duodenum. Correlation coefficients between the capsule technique and gastric scintiscans for detection of gastroparesis exceed 0.8 [75]. This method has potential additional abilities to quantify motility indices in the distal stomach and transit, pH, and motor patterns in the small intestine and colon. Ultrasonography also can be used to quantify gastric emptying. After ingestion of a liquid, antral scanning is performed in transverse sections and gastric volumes are calculated as a function of time. Solid meals cannot be used because of their echogenic nature. These techniques may be preferred over scintigraphy in selected patients, such as pregnant women in whom radioactive tracers are contraindicated. MRI also has been proposed to assess gastric emptying and correlates well with findings of scintigraphy in healthy volunteers. Single-photon emission CT uses intravenously administered 99mTc-pertechnetate that accumulates within the gastric wall rather than the lumen, and provides a three dimensional outline of the stomach [76]. This technique offers the advantage of measuring regional gastric volumes in real-time to assess fundic accommodation and intragastric distribution. A potential drawback of single-photon emission CT is the need for large radiation doses. Other tests of gastric function performed in academic centers that specialize in the care of patients with disordered gut motor activity can complement the findings of gastric emptying testing. A variant of gastric scintigraphy, dynamic antral scintigraphy, has been used in research to image nonocclusive antral contractions in real time but this method has not been used clinically [77]. Gastrointestinal manometry involves peroral placement of a catheter to monitor antroduodenojejunal pressures over 6 to 8 hours. The initial 4 to 5 hours records fasting motility, during which one or more fasting motor complexes are usually observed. Motor activity then is measured for 2 hours after a solid meal, which should induce a fed pattern. In some centers, manometry is used to test effects of motor-stimulating drugs or to record motor activity for 24 hours in ambulatory fashion. Manometry is considered for patients with unexplained symptoms, who have not responded to treatment, or who are being considered for surgery or enteral versus parenteral nutrition. Gastroparesis is characterized by loss of normal fasting migrating motor complexes and reduced fed antral contractions and, in some cases, pylorospasm [9]. Manometry is most useful in excluding associated small intestinal dysmotilities, including those with myopathic (contractile amplitude <30 mm Hg with normal morphology) and neuropathic (intense, uncoordinated burst contractions) patterns. Small intestinal motor dysfunction is detected in 17% to 85% of patients with gastroparesis [10]. Clinical management is influenced in approximately 20% to 25% of patients undergoing gastrointestinal manometry [78]. Electrogastrography (EGG) measures gastric slow wave activity by electrodes affixed to the skin overlying the stomach. Under healthy conditions, EGG recordings exhibit
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a uniform three cycle per minute waveform that increases in amplitude with ingestion of water or a nutrient meal. EGG abnormalities include rhythm disruption for more than 30% of the recording time including tachygastria (frequency >4 cycles per minute) and bradygastria (<2 cycles per minute) and lack of a signal amplitude increase with eating. EGG abnormalities are prevalent in patients with gastroparesis and some patients with nausea and vomiting and normal emptying. Impairment of the amplitude response to meals correlates with delayed emptying in patients with gastroparesis [79]. The importance of EGG dysrhythmias in symptom generation is supported by observations that selected antiemetics normalize slow wave frequencies [80]. Other electrical techniques, such as epigastric impedance and applied potential tomography, use cutaneous electrodes to measure changes in resistance afforded by liquid meals, which correlate with the rate of emptying. Because gastric myoelectric disturbances have unproved roles in symptom pathogenesis and because no therapies have been characterized specifically to target these abnormalities, EGG, epigastric impedance, and applied potential tomography have not achieved widespread acceptance as useful diagnostic tests. Satiety testing involves the ingestion of water or a liquid nutrient until the patient reports maximal fullness. Volumes consumed in functional dyspeptics with early satiety are reduced versus healthy volunteers, reflective either of impaired accommodation or visceral hypersensitivity [81]. THERAPY OF GASTROPARESIS A range of options are available for therapy of gastroparesis including nutrition modifications, medications to stimulate gastric emptying, drugs that reduce vomiting, endoscopic and surgical approaches, and psychological interventions. To facilitate treatment selection, a classification of gastroparesis severity has been proposed [32]. Grade 1 or mild gastroparesis is characterized by intermittent, easily controlled symptoms with maintenance of weight and nutritional status. In general, patients with grade 1 gastroparesis are treated with dietary modification and avoidance of medications that can exacerbate the condition. Grade 2 or compensated gastroparesis is characterized by symptoms of moderate severity that are partially controlled with prescription drugs. In general, patients with grade 2 gastroparesis still maintain nutrition and are hospitalized infrequently. These individuals are often given prokinetic and antiemetic agents in combination for symptom control. Grade 3 or gastroparesis with gastric failure is characterized by medication-refractory symptoms, inability to maintain oral nutrition, and frequent emergency room visits or hospitalizations. Individuals with grade 3 gastroparesis often require intermittent intravenous fluids and medications, consideration of enteral or parenteral nutrition, and endoscopic or surgical therapy. Dietary and Nonmedicinal Measures Several dietary and nonmedicinal measures designed to compensate for motor impairment of the stomach have been advocated for gastroparesis. Ingesting
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multiple small meals each day, rather than two or three large ones, enhances the efficiency of trituration. Because liquids empty more rapidly than solids, reduction of solid food intake is desired. Carbonated liquids are avoided to limit gastric distention. To minimize any inhibition of gastric emptying by lipids, a diet with restricted fat content should be consumed. Inclusion of indigestible fiber in a meal delays its emptying from the stomach and may promote phytobezoar formation [82]. Conversely, reducing the amount of indigestible dietary fiber may decrease symptoms of gastroparesis. Medications that inhibit gastrointestinal motility should be discontinued if possible. In diabetic gastroparesis, maintenance of euglycemia may avoid the inhibitory effects of hyperglycemia on gastric motor function. Prokinetic Medication Therapy Medications that stimulate gastric emptying are the mainstay of treatment of gastroparesis of moderate severity or greater (Table 3). Prokinetic drugs currently available worldwide with reported symptom benefits in gastroparesis include metoclopramide, erythromycin, and domperidone. Bethanechol has little role in the present management of gastroparesis. Other prokinetic therapies showing promise in gastroparesis have been removed from the market as a consequence of cardiovascular risks. There have been few direct comparison trials of these agents in gastroparesis. A meta-analysis reported that erythromycin was most potent at stimulating gastric emptying, whereas erythromycin and domperidone both were superior to metoclopramide in control of symptoms [83]. This conclusion should be interpreted with caution because of possible publication bias favoring only positive reported trials. Metoclopramide Metoclopramide is a substituted benzamide with several prokinetic actions including serotonin 5-hydroxytryptamine (HT)4 receptor facilitation of myenteric cholinergic transmission, dopamine D2 receptor antagonism in the gastric myenteric plexus, and direct stimulation of gut smooth muscle contraction by
Table 3 Medications with gastric prokinetic properties Medication
Mechanisms of action
Dosing
Metoclopramide
Dopamine D2 receptor antagonist 5-HT4 receptor facilitation of acetylcholine release from enteric nerves 5-HT3 receptor antagonist Motilin receptor agonist Peripheral dopamine D2 receptor antagonist Muscarinic receptor agonist Acetylcholinesterase inhibitor
5–20 mg qid
Erythromycin Domperidone Bethanechol Pyridostigmine
50–250 mg qid 10–30 mg qid 25 mg qid 30–60 mg tid
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muscarinic receptor sensitization. The drug also has antiemetic effects by brainstem dopamine D2 receptor antagonism and vagal and brainstem 5-HT3 receptor antagonism. The prokinetic properties of metoclopramide are restricted to the proximal gut, increasing esophageal, antral, and small bowel contractions and accelerating gastric emptying. Gastroduodenal coordination is further facilitated by the drug’s actions to relax the pylorus and duodenal bulb. Metoclopramide is administered orally in pill or liquid suspension form to outpatients with gastroparesis. Intravenous forms commonly are used for inpatients who cannot retain oral medications. For individuals with vomiting that precludes oral intake, metoclopramide administered subcutaneously may provide symptom control [84]. There have been at least five controlled trials of metoclopramide in gastroparesis and at least four open label case series [85]. In these nine trials, symptom benefits were observed in seven studies, whereas stimulatory effects on gastric emptying were noted in five. Patients may develop tolerance to the prokinetic action of metoclopramide over time; however, its antiemetic effects are sustained [43]. Side effects limit use of metoclopramide in up to 30% of patients. Drowsiness, fatigue, agitation, and sleep disturbances are common adverse reactions. Dystonias also are several fold more common in patients less than 30 years old than in older adults. Dopamine receptor antagonism may induce hyperprolactinemia, causing impotence, galactorrhea, or amenorrhea. These effects are reversible on drug discontinuation. Irreversible tardive dyskinesia is a catastrophic consequence of metoclopramide therapy, which occurs with a prevalence of 1% to 10% when the drug is taken for more than 3 months [86]. Because this condition is disabling and can develop without warning, it should be discussed in detail with the patient before prescription of metoclopramide. This risk should be carefully documented in the patient record. Erythromycin Erythromycin evokes gastrokinetic effects by action on neural and smooth muscle receptors for the hormone motilin, the physiologic regulator of fasting gastroduodenal motor complexes. Erythromycin is the most potent stimulant of solid and liquid gastric emptying, inducing powerful, distally propagating, lumen-obliterating antral contractions. Unfortunately, this effect can counteract small intestinal feedback control of gastroduodenal motility and impair gastric sieving of solids leading to duodenal delivery of incompletely triturated food particles [87]. The drug can be used intravenously in hospitalized patients and in liquid or pill form orally to outpatients at low doses. When given acutely, erythromycin can facilitate passage of nasoenteric tubes for supplemental nutrition [88]. At least three controlled trials and six open labeled trials have been published on use of erythromycin in gastroparesis; other studies have examined the benefits of the drug in functional dyspepsia with delayed gastric emptying [85]. Symptom benefits were observed in six of nine gastroparesis studies. Motor stimulatory effects of erythromycin have been correlated with improved
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glycemic control in a study of diabetics with gastroparesis. The usefulness of long-term erythromycin for treating gastroparesis has not been convincingly demonstrated. Tolerance to its prokinetic action with chronic oral use has been reported in gastroparesis patients [89]. In vitro experiments verify motilin receptor down-regulation with chronic erythromycin exposure [90]. Because erythromycin has no independent antiemetic effect, the symptom benefits of chronic therapy may be of short duration in many patients. Side effects of erythromycin include abdominal pain, nausea, and vomiting at higher doses that are believed to relate to induction of intense, prolonged, spastic motor activity in the stomach and upper intestine. Erythromycin also has been associated with an increased risk of sudden cardiac death [91]. In a large Medicaid cohort, the sudden death rate of current erythromycin users was 2.01 times as high as prior erythromycin users or current amoxicillin users. The risk of death was further increased in those who also were on CYP3A inhibitors including selected antipsychotics, cardiac antiarrhythmics, antifungals, calcium antagonists, antidepressants, and antiemetics. Before prescribing erythromycin, the patient’s record should be reviewed to prevent potentially dangerous drugdrug interactions. Domperidone Domperidone, a benzimidazole derivative, is a peripheral dopamine D2 receptor antagonist with benefits similar to those of metoclopramide. Domperidone does not cross the blood-brain barrier, however, and central nervous system side effects are minimal. Because brainstem structures regulating vomiting are outside the blood-brain barrier, domperidone has a potent central antiemetic action. The prokinetic effects of domperidone are limited to the proximal gut, increasing lower esophageal pressure, accelerating gastric emptying, and enhancing gastroduodenal coordination. The drug is approved in most countries except for the United States for oral prescription. An intravenous form was withdrawn after case reports of death from cardiac arrhythmias. Domperidone has shown symptom efficacy in controlled trials in patients with gastroparesis and diabetic gastropathy [92]. The benefits of domperidone are sustained while its prokinetic effects wane with time, emphasizing the importance of the drug’s central antiemetic actions. Because of its action only on peripheral dopamine receptors, domperidone is an especially useful drug for Parkinson’s disease patients who have gastrointestinal dysmotility [93]. The side effect profile of domperidone is superior to that of metoclopramide. Hyperprolactinemia may develop with domperidone, however, because of the porous blood-brain barrier in the anterior pituitary. Gynecomastia, galactorrhea, amenorrhea, or impotence may develop with chronic domperidone use. The Food and Drug Administration (FDA) has not approved domperidone for prescription in the United States. Traditionally, domperidone has been obtainable from foreign pharmacies, over the Internet, and from compounding pharmacies in the United States. The FDA has discouraged these practices, but has made the drug available in the past under the auspices of a program
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to academic clinicians who submit an Investigational New Drug application to the FDA and who obtain Institutional Review Board approval from the prescribing institution. Other prokinetic drugs Other drugs exhibit gastric motor stimulatory properties and have been used in gastroparesis; however, clinical trials to document their clinical benefits have not been published. A study of the 5-HT4 partial receptor agonist tegaserod in healthy subjects noted accelerated gastric emptying that was more prominent in men [94]. An unpublished trial comparing motor responses to 8 weeks of different doses of tegaserod with placebo reported stimulatory effects of active drug on gastric emptying at doses of 18 and 24 mg per day, although symptom responses were not quantified [95]. This drug was recently withdrawn, however, because of an observed statistically significant increase in risk of cardiovascular complications. Cisapride is a 5-HT4 receptor agonist with weak 5-HT3 antagonist properties that once was widely used to treat gastroparesis. This drug was withdrawn from the market in the United States in 2000 because of numerous reports of sudden death from cardiac arrhythmias. Although the drug still is obtainable from overseas Web sites, a recent consensus document did not recommend its use in gastroparesis [32]. Bethanechol contracts gut smooth muscle by action on muscarinic receptors, but its prokinetic effects in the esophagus and stomach are less impressive. The drug increases lower esophageal sphincter pressure, reduces gastroesophageal reflux, and increases fundoantral contractions, but does not induce propulsive contractions or accelerate gastric emptying [96]. Prominent adverse effects include abdominal cramps, skin flushing, diaphoresis, lacrimation, salivation, nausea, vomiting, bronchoconstriction, urinary urgency, and miosis. Dangerous cardiovascular effects include abrupt decreases in blood pressure in hypertensive patients and atrial fibrillation in individuals with hyperthyroidism. Likewise, cholinesterase inhibitors, such as physostigmine, increase gastric contractions but have limited action to accelerate gastric emptying. Physostigmine has recently been noted to reduce symptoms in a patient with gastroparesis secondary to underlying autoimmune disease [68]. Other macrolide compounds including clarithromycin and azithromycin show similar prokinetic effects as erythromycin by action as motilin receptor agonists; however, their use in gastroparesis has not been rigorously investigated. Antiemetic Medication Therapy Antiemetic agents without motor stimulatory activity are often used alone or in concert with prokinetic drugs to treat gastroparesis; however, there have been no controlled clinical trials on their use in this condition. Emetic stimuli act on different receptor sites within the peripheral and central nervous system, which then provide input to nuclei in the brainstem to activate the stereotypic vomiting response. Antiemetic medications act on distinct receptor subtypes in the different emetic receptor sites (Table 4). The most common antiemetic drugs are the phenothiazines (eg, prochlorperazine and thiethylperazine), which are
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Table 4 Antiemetic drug classes Drug class
Examples
Dopamine antagonists
Prochlorperazine, thiethylperazine Scopolamine Dimenhydrinate, meclizine Ondansetron, granisetron Aprepitant Dronabinol Amitriptyline, nortriptyline Mirtazepine Lorazepam
Muscarinic antagonists Histamine H1 antagonists Serotonin 5-HT3 antagonists Neurokinin NK1 antagonists Cannabinoids Tricyclic antidepressants Other antidepressants Benzodiazepines
Effects on gastric emptying Variable Delay Delay Variable Delay Delay Delay ? ?
dopamine and cholinergic receptor antagonists acting on the area postrema in the brainstem. One case report noted benefits of thiethylperazine in gastroparesis [97]. Furthermore, the benefits of metoclopramide and domperidone may relate more to their antiemetic effects instead of their prokinetic actions because their clinical efficacy correlates poorly with stimulation of gastric evacuation. Serotonin 5-HT3 receptor antagonists (eg, ondansetron and granisetron) are effective for chemotherapy-induced emesis, postoperative vomiting, and vomiting of pregnancy, but their use in gastroparesis has not been studied. Most 5-HT3 receptor antagonists have no effects on gastric emptying. Low-dose tricyclic antidepressants were reported to reduce symptoms for a mean of 5 months in patients with functional vomiting [98]. In an unpublished report, 88% of diabetics with nausea and vomiting reported symptom benefits from tricyclic agents that in many cases were superior to those with prokinetic drugs [99]. Nearly one third of patients had delayed gastric emptying, suggesting these agents may have use in gastroparesis. The antidepressant mirtazapine also reduced gastroparesis symptoms in one individual [100]. Muscarinic M1 receptor antagonists (eg, scopolamine) and histamine H1 receptor antagonists (eg, dimenhydrinate and meclizine) most often are used for conditions that affect vestibular pathways, such as motion sickness. Both drug classes inhibit gastric emptying. Cannabinoids (eg, dronabinol) are useful for chemotherapy-induced emesis, but their benefit in gastroparesis has not been evaluated. Cannabinoids also delay gastric emptying. Benzodiazepines are used for anticipatory nausea and vomiting before chemotherapy, but their efficacy in gastroparesis is unknown. These drugs may be useful for their sedating effects or in those with associated anxiety. The neurokinin NK1 receptor antagonist aprepitant treats both acute and delayed chemotherapy-induced nausea and vomiting, but its actions on gastric motor activity and symptoms in gastroparesis are uninvestigated. Complementary and alternative therapies are increasingly used to treat nausea and vomiting of diverse etiologies. Ginger, a traditional Chinese remedy
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with weak 5-HT3 antagonist characteristics, has antiemetic actions in some clinical settings but its benefits in gastroparesis are unexplored. Acupressure and acustimulation on the P6 acupuncture point on the wrist reduces nausea postoperatively, after chemotherapy, and during first-trimester pregnancy. One group observed benefits with acupuncture in diabetic gastroparesis [101]. Medications for Control of Symptoms Other than Nausea and Vomiting Symptoms other than nausea and vomiting may predominate in gastroparesis. Early satiety has been related to defects in fundic accommodation in patients with functional dyspepsia, and responses did not correlate with delays in gastric emptying [102]. Nitrates, buspirone, sumatriptan, and selective serotonin reuptake inhibitors have been proposed as therapies to promote fundic relaxation. The use of fundic relaxants in managing early satiety in gastroparesis is uninvestigated. Epigastric pain is disabling in some individuals with gastroparesis. In functional dyspepsia, epigastric pain correlates with hypersensitivity to gastric balloon inflation [103]. Pain in gastroparesis has been postulated to stem from sensory rather than motor dysfunction, and therapies to reduce afferent dysfunction may be more effective than prokinetic agents for this symptom. This hypothesis has not been tested. Finally, the ability of prokinetic agents to stabilize glycemic control has been studied in poorly controlled diabetics with gastroparesis. Some studies report reductions in blood glucose levels with erythromycin or cisapride therapy, whereas others observe no effect on either short-term or long-term glycemic control; no consensus opinion has formed on this issue [104]. Endoscopic Treatment The therapeutic endoscopist may participate in the care of selected cases of gastroparesis. Injection of botulinum toxin into the pylorus has been proposed as treatment transiently to reverse the pylorospasm of gastroparesis, which is postulated to result from loss of tonic inhibitory neural activity. Botulinum toxin may promote pyloric relaxation by prevention of unopposed cholinergic contractile activity within the pylorus [32]. In patients with gastroparesis, pyloric botulinum toxin reduces phasic contractions and pyloric tone under fasting and fed conditions [105]. Several case series have reported reduced symptoms and acceleration of delayed gastric emptying after botulinum toxin treatment [106,107]. In the largest series, 43% of 63 patients noted reduced symptoms for a mean of 5 months [108]. An unpublished study of 78 patients observed similar response rates in diabetic (55%), idiopathic (51%), and postsurgical (44%) gastroparesis [109]. In this study, higher doses of botulinum toxin (150–200 units) had greater symptom benefits than lower doses (75–100 units). To date, no adequately powered placebo-controlled trials have been published to confirm the efficacy of pyloric botulinum toxin in gastroparesis. Other endoscopic procedures provide symptom relief in some cases of gastroparesis. Placing a venting gastrostomy affords the ability intermittently to release retained gas and liquid, thereby relieving fullness, discomfort, and
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distention-related nausea and vomiting [110]. Pneumatic dilation of the pylorus has reported anecdotal benefits; however, the efficacy of this practice has not been proved. Surgical Management Surgical intervention is increasingly used to treat medically refractory forms of gastroparesis. The most common operation, implantation of a gastric electrical stimulator, has been performed in more than 1500 patients worldwide over the past decade. Other procedures, such as gastric resection and pancreatic transplantation for diabetics, are performed less often and their benefits are not well documented. Gastric electrical stimulation Several studies suggest that treating gastroparesis with exogenous electrical stimulation is feasible and effective. In a case series of electrical pacing of the human gut, 7-second impulses delivered every 60 minutes to the stomach through enterally passed electrodes reduced the duration of paralytic ileus by 50% compared with nasogastric suction alone [111]. An early trial of gastric pacing reported slow wave entrainment in 10 of 16 patients with postsurgical gastroparesis, although accelerated gastric emptying was not observed [112]. The most successful trial of gastric pacing involved delivery of high energy, electrical stimuli at a rate slightly above the normal slow wave frequency through surgically implanted electrodes to nine patients with medication-resistant gastroparesis (five diabetic, three idiopathic, one postsurgical) [113]. In this study, pacing entrained the slow wave in all individuals and underlying dysrhythmias were reversed in two patients. After 1 month, symptoms of gastroparesis markedly improved, eight patients no longer required jejunal feedings, and gastric emptying was significantly accelerated. This method is impractical for long-term use, however, because the energy needed to pace the stomach mandates external current sources, which are unwieldy and are too large for implantation. Because of the drawbacks of pacing, investigators have searched for other electrical stimulation parameters that might benefit patients with gastroparesis. Initial unpublished case series using an implantable gastric neurostimulator that delivers brief, low-energy impulses at a frequency of 12 cycles per minute reported impressive reductions in nausea and vomiting in patients with medication-refractory gastroparesis. Because of this apparent benefit, the FDA approved the gastric stimulator as a humanitarian use device. A humanitarian use device is a medical device that treats a disorder affecting less than 4000 patients per year in the United States and may have efficacy when no treatment alternatives exist. In 2000, the device received humanitarian device exemption approval to be used for refractory diabetic and idiopathic gastroparesis. For humanitarian device exemption approval, the FDA judges the probable benefit of a device with the expectation that controlled clinical trials ultimately will demonstrate usefulness. Implantation of the gastric neurostimulator is restricted to centers in which Institutional Review Board approval has been granted. Since
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evaluation by the FDA, the gastric stimulator has shown efficacy in several studies. In an uncontrolled multicenter trial, 35 of 38 patients experienced greater than 80% reductions in nausea and vomiting, which persisted for 2.9 to 15.6 months with associated 5.5% increases in weight [114]. Many individuals discontinued supplemental enteral or parenteral nutrition; however, one quarter required subtotal gastrectomy for symptom control or device removal for complications. Other uncontrolled studies of diabetic, idiopathic, and postsurgical gastroparesis report similar long-term decreases in nausea and vomiting with associated improvements in body mass index, serum albumin, and glycemic control. Larger case series of greater than 120 patients observe prolonged 60% reductions, which persist for at least 10 years. In the only published controlled trial of gastric stimulation, 33 patients with idiopathic or diabetic gastroparesis completed an initial 2-month double-blind, crossover, sham stimulation-controlled phase followed by a 12-month uncontrolled observation period with the device activated [115]. During the blinded phase, vomiting episodes were 14% less when the device was on versus off. During the open trial phase, symptom reductions were more impressive. Because only modest benefits were observed during the blinded phase, larger, more prolonged controlled investigations are mandated to confirm that the method truly is beneficial. Complications including infection, lead dislodgement, and bowel obstruction necessitate device removal in more than 10% of cases. The mechanism of action of gastric stimulation does not relate to acceleration of gastric emptying or reversal of slow wave dysrhythmias [114,115]. In rats, neurostimulation increases vagal activity, whereas pacing has no effect on vagal firing [116]. In dogs, gastric stimulation reduces fundic tone suggesting its benefits stem from relaxant effects on the proximal stomach [117]. In humans with gastroparesis, electrical stimulation enhances tolerance of noxious fundic distention indicating possible effects on visceral sensory pathways [118]. Finally, the reported ability of transcutaneous electrical nerve stimulation to relieve symptoms in a case of gastroparesis suggests that direct gastric wall stimulation may not be needed [119]. Other operative interventions Other operations are rarely considered for patients with gastroparesis unresponsive to drug therapy. The benefits of operations involving gastric drainage or partial resection to facilitate emptying of an atonic stomach are unproved for gastroparesis. Uncontrolled case series do not provide encouraging results from such operations and no controlled studies have been performed. Surgical pyloroplasty has shown benefit in an unpublished series of patients with diabetic gastroparesis [120]. Reconstruction of a gastroenteric anastomosis (ie, conversion of a Billroth I to a Billroth II or vice versa) is rarely effective in gastroparetics. Performance of completion gastrectomy with preservation of only a small cuff of gastric tissue is an established treatment of postsurgical gastroparesis, however, providing long-term symptom benefits to 43% to 67% of patients [121,122]. The use of subtotal gastrectomy for diabetic gastroparesis
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was promoted in a small series of seven patients [123]. Overwhelming extraintestinal complications developed in three patients, however, two of whom died; the benefits of surgery were difficult to evaluate. Pancreas transplants have been advocated for poorly controlled diabetes to prevent further progression of pre-existing severe disease complications, such as neuropathy or retinopathy. Studies of pancreatic transplantation, however, report no convincing evidence to suggest that this surgery improves gastric function in patients with diabetic gastroparesis. Enteral and Parenteral Nutrition Some patients with medication-refractory gastroparesis benefit from alternate routes of nutrition either on an intermittent basis when symptom flares develop or for permanent caloric and fluid support. In diabetic gastroparesis, surgical jejunostomy placement for enteral feeding improves overall health status with trends to reduced gastrointestinal symptoms and hospitalization rates and enhanced nutrition [124]. Recently, jejunostomy placement by interventional radiology or endoscopy has become feasible. Indications for enteral nutrition include evidence of significant malnutrition (eg, >10% weight loss over 6 months) unresponsive to dietary modification; development of essential mineral deficiencies or electrolyte disturbances; and frequent hospitalizations producing profound disability [32]. Total parenteral nutrition is less desirable over a prolonged period because of the risks of infectious and hepatobiliary complications and the extreme costs of therapy. Short-term total parenteral nutrition may be offered to reverse rapid weight decline and to ensure adequate fluid delivery. Permanent total parenteral nutrition usually is needed only for gastroparesis patients with superimposed severe intestinal dysmotility who cannot tolerate enteral feeding. Psychologic Measures Patients with gastroparesis commonly experience many psychologic consequences of their gastrointestinal disease including anxiety, depression, somatization, and markedly reduced quality of life [2]. The degree of psychologic impairment correlates strongly with symptom severity in patients with diabetic gastroparesis [125]. Despite these observations, the role of the mental health specialist in managing gastroparesis has not been defined. Small studies have reported benefits with biofeedback or hypnosis [126]. CONTROVERSIES AND FUTURE DIRECTIONS Investigation of the natural history, pathogenesis, evaluation, and treatment of gastroparesis will be active in the coming years. Validation of quantitative symptom surveys will facilitate careful stratification of gastroparesis into different subtypes based on symptom severity and predominant symptoms. Current therapies largely focus on use of prokinetic drugs, regardless of the clinical presentation. Furthermore, recent studies of potential future treatments demonstrate potent stimulatory effects for a variety of new drugs including ghrelin, an endogenous neurohumoral mediator involved in food intake; novel motilin
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receptor agonists, such as mitemcinal; and new serotonin receptor agents, such as mosapride and renzapride [127]. Recent observations suggest that factors other than delayed emptying participate in symptom generation in gastroparesis. Future investigations will focus on therapies that relieve dominant symptom profiles, which may result from different pathophysiologic defects. It can be speculated that prokinetic agents may be most beneficial for symptoms directly referable to delays in gastric emptying, such as fullness, bloating, or gastroesophageal reflux. Conversely, early satiety may be better managed with agents that promote fundic relaxation, whereas pain would be controlled with drugs to modulate visceral sensation [128]. Weight loss could be reversed by therapies acting on peripheral and central satiety mechanisms. Further investigation into the inflammatory basis of gastroparesis may define subpopulations that may benefit from anti-inflammatory therapies, as has been observed in a case responsive to corticosteroids [38]. Ongoing progress depends on continuing support from patient advocacy groups, the pharmaceutical industry, independent research foundations, academic centers, and the federal government. References [1] Hoogerwerf WA, Pasricha PJ, Kalloo AN, et al. Pain: the overlooked symptom in gastroparesis. Am J Gastroenterol 1999;94:1029–33. [2] Soykan I, Sivri B, Saroseik I, et al. Demography, clinical characteristics, psychological and abuse profiles, treatment, and long-term follow-up of patients with gastroparesis. Dig Dis Sci 1998;43:2398–404. [3] Bizer E, Harrell S, Koopman J, et al. Obesity is common in gastroparesis despite nausea, vomiting, and early satiety [abstract]. Gastroenterology 2005;128:M1895. [4] Kong MF, Horowitz M, Jones KL, et al. Natural history of diabetic gastroparesis. Diabetes Care 1998;22:503–7. [5] Bytzer P, Talley NJ, Leemon M, et al. Prevalence of gastrointestinal symptoms associated with diabetes mellitus. Arch Intern Med 2001;161:1989–96. [6] Horowitz M, Maddox AF, Wishart JM, et al. Relationships between oesophageal transit and solid and liquid gastric emptying in diabetes mellitus. Eur J Nucl Med 1991;18: 229–34. [7] Horowitz M, Harding PE, Maddox AF, et al. Gastric and oesophageal emptying in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 1989;32:151–9. [8] Eisenberg B, Murata GH, Tzamaloukas AH, et al. Gastroparesis in diabetics on chronic dialysis: clinical and laboratory associations and predictive features. Nephron 1995;70: 296–300. [9] Mearin F, Camilleri M, Malagelada J-R. Pyloric dysfunction in diabetics with recurrent nausea and vomiting. Gastroenterology 1986;90:1919–25. [10] Camilleri M, Malagelada J-R. Abnormal intestinal motility in diabetics with the gastroparesis syndrome. Eur J Clin Invest 1984;14:420–7. [11] Feldman M, Corbett DB, Ramsey EJ, et al. Abnormal gastric function in longstanding insulin-dependent diabetic patients. Gastroenterology 1979;77:12–7. [12] Clarke RJ, Alexander-Williams J. The effect of preserving antral innervation and of a pyloroplasty on gastric emptying after vagotomy in man. Gut 1973;14:300–7. [13] Kristensson K, Nordborg C, Olsson Y, et al. Changes in the vagus nerve in diabetes mellitus. Acta Pathol Microbiol Scand 1971;79:684–5. [14] Merio R, Festa A, Bergmann H, et al. Slow gastric emptying in type I diabetes: relation to autonomic and peripheral neuropathy, blood glucose, and glycemic control. Diabetes Care 1997;20:419–23.
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Gastroenterol Clin N Am 36 (2007) 649–664
GASTROENTEROLOGY CLINICS OF NORTH AMERICA
Functional Dyspepsia: Mechanisms of Symptom Generation and Appropriate Management of Patients Michael Camilleri, MD Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER) Group, Mayo Clinic College of Medicine, Charlton 8-110, 200 First Street, SW, Rochester, MN 55905, USA
W
ith the exception of predominant heartburn, which can be easily distinguished from dyspepsia using simple questionnaires [1], the management of upper abdominal symptoms not caused by an organic disorder remains a challenge. Systematic reviews of large trials show that suppressing acid secretion and eradicating Helicobacter pylori, prokinetics, and antidepressants have inconsistent effects on the treatment of functional dyspepsia [2,3]. This inconsistent therapeutic efficacy has been attributed to the heterogeneity of patients, and the contribution of multiple mechanisms to development of symptoms. To achieve greater therapeutic efficacy, it may be necessary to target the therapeutic approach to a specific pathophysiology (eg, impaired gastric emptying). To provide more homogeneous patients for inclusion in clinical trials, the Rome II consensus criteria recommended distinguishing between patients with epigastric pain and those with discomfort as a means of identifying pathophysiologically distinct subgroups [4]. This recommendation was partly evidence based, if one accepted the notion that the term ‘‘discomfort’’ was a catch-all for a variety of symptoms other than pain. Those ‘‘discomfort’’ symptoms included nausea, early satiety, and postprandial fullness. The Rome III consensus criteria [5] proposed differentiating two subcategories of functional dyspepsia: postprandial distress syndrome (early satiation or postprandial fullness) and epigastric pain syndrome (pain or burning in the epigastrium). Moreover, these disorders were distinguished from:
Belching disorders, comprising aerophagia (troublesome repetitive belching with observed excessive air swallowing) and unspecified belching (no evidence of excessive air swallowing) Nausea and vomiting disorders, comprising chronic idiopathic nausea (frequent bothersome nausea without vomiting); functional vomiting (recurrent
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vomiting in the absence of self-induced vomiting, or underlying eating disorders, metabolic disorders, drug intake, or psychiatric or central nervous system disorders); and cyclic vomiting syndrome (stereotypical episodes of vomiting with vomiting-free intervals) Rumination syndrome, characterized by effortless regurgitation of recently ingested food into the mouth followed by rechewing and reswallowing, or expulsion of food
The new classification of functional dyspepsia requires further validation with physiologic measurements. Symptom or symptom combinations, however, have already been shown to be significantly associated with specific disturbances of gastric function in relatively large studies in the literature. Almost 80% of patients with dyspepsia have two or more upper gastrointestinal symptoms [6]. Clinicians should comprehensively characterize dyspeptic symptoms rather than focusing on the predominant symptom. The term ‘‘dyspepsia’’ is derived from the term for ‘‘bad digestion’’ in Greek. The relationship between meals and dyspeptic symptoms is also critical, as evidenced by a large epidemiologic study in the United States [7] and a population-based study in Olmsted County, Minnesota [8]. The latter identified that meals evoked symptoms in 60% of those with dyspepsia. The timing of symptoms in relation to meals may also be useful: symptoms occurring relatively promptly (eg, during or within 30 minutes after food ingestion) are less likely to be caused by delayed gastric emptying, but they may result from rapid initial gastric emptying that delivers a high osmotic load to the small intestine. As discussed later, the small intestine may be the source of dyspeptic symptoms (eg, because of mechanical distention). MECHANISMS IN FUNCTIONAL DYSPEPSIA Fig. 1 summarizes the mechanisms considered to be important in the etiology of functional dyspepsia [6]. Although some studies suggest association of H pylori infection with epigastric pain in dyspeptics [9,10], systematic review of the epidemiologic studies of H pylori infection and functional dyspepsia found no evidence for a significant association [11]. Moreover, there are no consistent differences in the prevalence and severity of individual dyspeptic symptoms, gastric emptying rate, gastric relaxation after a meal, and sensitivity to gastric distention based on H pylori positive or negative status [12–14]. Delayed gastric emptying in functional dyspepsia reflects the overlap between the functional syndrome and idiopathic gastroparesis. Delayed gastric emptying may result from antral hypomotility and, possibly, duodenojejunal dysmotility, which have been documented in functional dyspepsia [15]. In the largest of the studies reported in the literature, gastric emptying of solids was delayed in about 30% of the patients with functional dyspepsia [16–18]. Patients with delayed gastric emptying of solids are more likely to report postprandial fullness, nausea, and vomiting [16,19], although a large multicenter study using a stable isotope breath test to measure gastric emptying failed to find any association between symptoms and gastric emptying status [20]. Delayed gastric emptying for liquids has been reported to be associated with postprandial fullness [16]. In a study from France,
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Fig. 1. Normal fasting and postprandial gastric function and pathophysiologic mechanisms putatively involved in functional dyspepsia. ANS/CNS, autonomic nervous system/central nervous system. (From Tack J, Bisschops R, Sarnelli G. Pathophysiology and treatment of functional dyspepsia. Gastroenterology 2004;127:1239–55; with permission.)
only 5% of 190 patients with nonulcer dyspepsia had delayed gastric emptying of liquids measured by scintigraphy [21], and delayed gastric emptying of solids is more frequently encountered. Efferent vagal dysfunction has been observed in several studies [22,23] and has been proposed to be a possible mechanism underlying both impaired accommodation to a meal [24] and antral hypomotility [22]. Accommodation of the stomach provides a reservoir for the meal, enabling an increase in gastric volume without an increase in pressure, and facilitating intragastric digestion. Preferential accumulation of food in the distal stomach was interpreted as indicative of reduced accommodation of the proximal stomach [25–28], and subsequent studies have shown reduced proximal gastric relaxation in response to a meal in patients with functional dyspepsia [29,30]. Impaired gastric accommodation (tone measured by barostat or volume measured by 99mTc single-photon emission CT [SPECT]) was present in about 40% of the patients with functional dyspepsia [29,31–34]. Together, impaired gastric emptying and reduced gastric volume response to feeding were observed in 60% of a tertiary care group of patients with functional dyspepsia (Fig. 2) [34]. Excessive proximal gastric contraction in the postprandial period is also evident by phasic contractility. The latter is usually suppressed with the receptive relaxation and accommodation response to feeding. A Mayo Clinic study first documented increased phasic volume events in the postprandial period in
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Fig. 2. Comparison of gastric volume post-300 mL Ensure meal in healthy controls and in patients with functional dyspepsia. Impaired gastric emptying or accommodation was observed in 60% of patients with functional dyspepsia in a tertiary care study. (Modified from Bredenoord AJ, Chial HJ, Camilleri M, et al. Gastric accommodation and emptying in evaluation of patients with upper gastrointestinal symptoms. Clin Gastroenterol Hepatol 2003;1:264– 72; with permission.)
patients with functional dyspepsia [12]. In a study from Leuven, a small subset (15%) of dyspeptic patients displayed this unsuppressed phasic contractility of the proximal stomach [35] and was associated with bloating and, paradoxically, with absence of nausea. Phasic fundic contractions induce transient increases in gastric wall tension, and careful and detailed observations suggest that such contractions can be perceived and cause postprandial symptoms in functional dyspepsia [36]. Patients with functional dyspepsia have enhanced sensitivity to gastric distention [32,37–41]. The distal stomach is less compliant than the proximal stomach and may be the site of origin of symptoms caused by distension [42]. In general, gastric hypersensitivity was associated with symptoms of postprandial pain, belching, and weight loss [37], although other studies have failed to confirm association between hypersensitivity and symptom pattern [32,43]. Whereas dyspeptic symptoms are triggered or aggravated by meal ingestion in approximately 60% of patients [8], it is relevant to note that postprandial (rather than fasting) sensitivity to gastric distention was significantly associated with the severity of meal-related symptoms in functional dyspepsia [44]. In functional dyspepsia, symptoms (eg, nausea) may be induced by meals rich in fat [45]. Increased sensitivity to lipid emulsion or hydrochloric acid infusion into the duodenum was documented in functional dyspepsia [46,47], but
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it is unclear whether either of these studies apply to the delivery of fat in meals or of acidic content to the duodenum [48–50]. Spontaneous duodenal exposure to endogenous acid was increased in patients with functional dyspepsia who displayed delayed clearance of exogenous duodenal acid [51]. Such patients had higher severity scores of several dyspeptic symptoms. There is evidence of an association between psychopathology and functional dyspepsia [52] and between psychologic factors, gastric function, and symptoms in functional dyspepsia [53,54]. A community-based study demonstrated high somatic symptom scores were the most closely related disturbance in patients with functional dyspepsia. In contrast, gastric motor physiology and satiation testing were not abnormal in patients recruited from the community [8]. THE ASSOCIATION BETWEEN SYMPTOMS AND PATHOPHYSIOLOGY IN DYSPEPSIA Previous studies have typically appraised the association between severity of individual symptoms and pathophysiology (Table 1). A review of these studies summarized that 40% to 50% of patients with dyspepsia have impaired gastric accommodation after meal ingestion, 34% to 66% have gastric hypersensitivity, and 23% to 59% have delayed gastric emptying [6]. Moreover, delayed gastric emptying was associated with early satiety; nausea; vomiting and fullness; impaired gastric accommodation with early satiety and fullness and weight loss in two of four studies; and visceral hypersensitivity with pain, belching, and weight loss in one of four studies [6].
Table 1 Summary of reported associations between pathophysiologic mechanisms and symptom pattern in functional dyspepsia Mechanism
Associated symptoms
References
H pylori infection
Epigastric pain
Delayed gastric emptying
Postprandial fullness, nausea, vomiting
Impaired accommodation
Early satiety, weight loss
Unsuppressed phasic contractility Duodenal lipid hypersensitivity Duodenal acid hypersensitivity
Bloating, absence of nausea Nausea
Stanghellini, et al [9]; Tucci, et al [10]; Perri, et al [19] Tack, et al [6]; Sarnelli, et al [16]; Stanghellini, et al [18] Tack, et al [29]; Kim, et al [31]; Boeckxstaens, et al [32] Simren, et al [35]
Nausea
Barbera, et al [46,47] Samsom, et al [50]
Data from Tack J, Bisschops R, Sarnelli G. Pathophysiology and treatment of functional dyspepsia. Gastroenterology 2004;127:1239–55; with permission.
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CAMILLERI
The ability to address the mechanisms causing symptoms is hindered by the limited repertoire of symptoms and by the relatively large number and spectrum of underlying physiologic disturbances in dyspepsia. The available evidence suggests that the symptom profile is not specific for a particular physiologic disturbance. For example, early fullness, nausea, bloating, and upper abdominal discomfort may be associated with delayed gastric emptying [16,18,55], accelerated gastric emptying [55], or gastric dysaccommodation [29]. The latter may be associated with accelerated emptying of liquids or delayed emptying of solids and may reflect impaired vagal function in dyspepsia [15,22,23]. To assess further the relationship between dyspepsia symptoms and potential risk factors, the Leuven group undertook a factor analysis of their rich clinical experience [56]. This analysis revealed four main factors in patients with dyspepsia: Factor 1: nausea, vomiting, early satiety, and weight loss; and associated with younger age, female gender, and sickness behavior Factor 2: postprandial fullness and bloating Factor 3: pain symptoms and several psychosocial dimensions Factor 4: belching unrelated to psychosocial dimensions
Factors 1 and 2 were associated with delayed gastric emptying, and factors 3 and 4 were associated with gastric hypersensitivity to mechanical distention of the stomach. Karamanolis and colleagues [57] mined the same large database: 720 patients were screened for H pylori infection; 592 prospectively underwent noninvasive gastric emptying test for solids and liquids, and 332 had gastric accommodation and sensation test with an invasive barostat method. They assessed whether the predominant upper gastrointestinal symptom was a good predictor of pathophysiology in dyspepsia. Although the association of early satiety after meals and impaired gastric accommodation is impressive and confirms prior studies [29], the ‘‘predominant’’ symptom does not allow greater prediction of the pathophysiology demonstrable in functional dyspepsia. The barostat-based method used in the study to assess gastric accommodation and sensitivity does not reliably assess gastric physiology during fasting, however, because of the perturbation associated with the intrabag pressure necessary to maintain the bag in apposition with the gastric wall to measure tone. Moreover, it measures proximal but not distal gastric function, and the intragastric bag displaces the meal to the antrum, causing antral distention [58] and, potentially, increased reflex fundic relaxation. Recent studies suggest that both fasting gastric volume and antral function may be important determinants of symptoms in dyspepsia. Fasting gastric volume (measured noninvasively by SPECT) is a significant contributor to development of symptoms following a challenge meal in dyspepsia [55]. Antrofundic reflexes are impaired in dyspepsia [59], and the sensation of fullness has been associated with antral rather than fundic dimensions in other studies in health or dyspepsia [32,60].
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Using noninvasive, validated techniques, the author showed that 72% of patients with functional dyspepsia had increased postprandial upper gastrointestinal sensitivity to a challenge liquid nutrient meal and 52% had reduced postmeal gastric volume [55]. Gastric emptying of solids measured by scintigraphy was accelerated in 41% of patients at 1 hour, whereas 41% had delayed emptying at 4 hours [55]. Half of the variability in dyspepsia symptom scores (Fig. 3) was attributable to the combination of rapid gastric emptying (at 1 hour); delayed gastric emptying at 4 hours and gastric volumes (particularly fasting gastric volume); in addition to the demographic factors, age, and body weight [55]. TREATMENT OF FUNCTIONAL DYSPEPSIA Given the new insights [5] on the classification of functional upper gastrointestinal syndromes, it is relevant carefully to evaluate the patient’s symptoms before applying an empirical approach to treatment. There is ample evidence from meta-analyses that eradication of H pylori and anti–acid secretory therapy (Fig. 4) are ineffective in functional dyspepsia that is not dominated by heartburn. Fig. 5 provides a proposed algorithm for management of patients with dyspepsia that reflects the recent classification of upper functional upper gastrointestinal syndromes [5], data from the literature, and clinical experience. General Measures By definition, most patients presenting with functional dyspepsia have undergone upper gastrointestinal endoscopy, and biopsies and these are normal or unremarkable. Reassurance and education are the first steps in management. Dietary recommendations have not been systematically studied. Eating more frequent, smaller meals and avoiding food that aggravates symptoms are logical. Eradication of H pylori infection has no place in the treatment of functional dyspepsia.
Fig. 3. Independent and additive contributory effects of fasting gastric volume (z-axis) and gastric emptying (x-axis) on maximum tolerated volume and postmeal scores. GE, gastric emptying. (From Delgado-Aros S, Camilleri M, Cremonini F, et al. Contributions of gastric volumes and gastric emptying to meal size and postmeal symptoms in functional dyspepsia. Gastroenterology 2004;127:1685–94; with permission.)
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CAMILLERI
Fig. 4. Meta-analysis of proton pump inhibitors in treatment of functional dyspepsia. PPI, proton pump inhibitors. (From Wang WH, Huang JQ, Zheng GF, et al. Effects of proton pump inhibitors on functional dyspepsia: a meta-analysis of randomized placebo-controlled trials. Clin Gastroenterol Hepatol 2007;5:178–85; with permission.)
Acid-Suppressive Drugs In patients with concomitant or dominant symptoms of gastroesophageal reflux, specifically heartburn and regurgitation, a trial of antisecretory therapy is indicated. Large studies in functional dyspepsia have shown that treatment with proton pump inhibitors was approximately 10% to 15% better than placebo in patients with functional dyspepsia [61]; this positive effect seems to be related to relief of reflux-like symptoms. Prokinetic Agents Metoclopramide, domperidone, cisapride, and tegaserod are widely used in functional dyspepsia, but evidence of efficacy is most convincing for those with delayed gastric emptying. Because some patients with dyspepsia have accelerated gastric emptying, a gastric emptying test should be performed to select patients for prokinetic therapy. Metoclopramide and domperidone are dopamine receptor agonists (that confers some of their antinausea properties) with a stimulatory effect on upper gastrointestinal motility. Unlike metoclopramide, domperidone does not cross the blood-brain barrier. Cisapride facilitates the release of acetylcholine in the myenteric plexus by stimulation of 5-HT4 receptors and accelerates gastric emptying. Cisapride availability is restricted because of cardiac safety issues, and coadministration with drugs that inhibit cytochrome P-450 3A4 should be avoided or cautiously monitored. Tegaserod, a 5-HT4 agonist,
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Fig. 5. Algorithm for management of functional dyspepsia reflecting current classification of upper functional gastrointestinal disorders. EGD, esophagogastroduodenoscopy; PPI, proton pump inhibitors.
also accelerates gastric emptying [62], but its efficacy in dyspepsia remains unclear. Prokinetics are the only pharmacotherapies with any substantive evidence to support use to correct gastric emptying and relieve symptoms in patients with dyspeptic symptoms and delayed gastric emptying (Table 2) [63–79]. Even the most robust papers in the literature, however, used trial methods that are suboptimal by current standards. Itopride is an anticholinesterase that showed significant promise in a phase IIB trial [80]; however, subsequent studies (as yet unreported) have not confirmed the initial promise. Antidepressants and Behavioral Approaches There is some evidence that tricyclic antidepressants affect gastric sensitivity [81], but large controlled trials have not been conducted. Pharmacodynamic studies [82] do not suggest that antidepressants alter the maximum tolerated volume of a nutrient meal. Controlled trials of antidepressants and behavioral therapy have shown benefit in dyspepsia but the generalizability of the data, the specific subgroup that benefits, and the cost-effectiveness require further study [83,84]. Hypnotherapy is effective in specialized centers [85], and this may be achieved in part by acceleration of gastric emptying [86]. This author restricts the use of antidepressants to patients with functional abdominal pain syndromes, including epigastric pain syndrome.
658
Table 2 Review of oral pharmacotherapy for gastroparesis (including idiopathic form) in studies involving at least 15 patients Reference
Medication and study design
No.
Dose
Study length
Outcome results
10 mg QID
3 wk
Improved symptoms by 29%
10 mg QID
3 wk
Improved symptom score by 25%; improved GE by 25% Symptoms improved by 39% Reduction on symptoms score by 25%; increased weight Improved GE solid without significantly reducing symptoms 10 patients improved GE; 7 patients >20% improved overall symptom score Symptoms improved; GE decreased by 72% Symptoms improved by 55%; GE improved by 24%
Perkel, et al [63]
Metoclopramide DB, PC, PG, RCT
28
McCallum, et al [64]
Metoclopramide, PC, RCT
18
Diabetic (5), postsurgical (4), idiopathic (19) Diabetic
Patterson, et al [65]
Metoclopramide RCT, DB, multicenter Cisapride, open label
45
Diabetic
10 mg QID
4 wk
21
Diabetic (9) Idiopathic (12)
10 mg TID
1y
Diabetic (7); scleroderma (2); idiopathic (29) Diabetic (6); idiopathic (24)
20 mg TID
6 wk
20 mg TID
2y
Abell, et al [66]
Richards, et al [67]
Cisapride, DB, PC, RCT
38
Kendall, et al [68]
Cisapride, open label
30
Dutta, et al [69]
Cisapride, RCT, DB, PC Cisapride, RCT, DB, PC
51
Diabetic
10 mg TID
2 wk
19
Diabetic
10 mg QID
1y
Braden, et al [70]
CAMILLERI
Cause
19
Diabetic
20 mg QID
4 wk
Soykan, et al [72]
Domperidone DB, PC, PG RCT Domperidone open label
17
20 mg QID
2y
Silvers, et al [73]
Domperidone single-blind
287
Diabetic (3), postsurgical (2), idiopathic (12) Diabetic
20 mg QID
4 wk
Patterson, et al [65]
Domperidone DB, RCT
48
Diabetic
20 mg QID
4 wk
Franzese, et al [74]
Domperidone versus cisapride RCT
28
Diabetic children
D: 0.9 mg/kg C: 0.8 mg/kg
8 wk
Improved symptoms; improved GE by 37% Symptom score improved by 68% Symptoms improved in 208 of 269 patients by 63% Symptom score improved by 41% Domperidone superior for symptom relief and improved GE
FUNCTIONAL DYSPEPSIA
Champion, et al [71]
This provides an appraisal of the outcomes that might be expected in functional dyspepsia with delayed gastric emptying. Abbreviations: CT, randomized controlled trial; DB, double blind; GE, gastric emptying; PC, placebo controlled; PG, parallel group; XO, crossover.
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CAMILLERI
Experimental approaches using medications that relax the gastric fundus include sildenafil (phosphodiesterase-5 inhibitor), clonidine (a2- adrenoreceptor agonist), sumatriptan (5-HT1 receptor agonist), buspirone (nonselective 5-HT1 receptor agonist) may have promise in functional dyspepsia based on pharmacodynamic studies. However, formal trials are awaited. The 5-HT3 receptor antagonist, alosetron, showed benefit in a phase IIB study in functional dyspepsia [87], but the mechanism of the efficacy is unclear and it has not been pursued. Although dysaccommodation and gastric hypersensitivity are relevant mechanisms for dyspepsia, there is as yet no treatment proved to benefit patients’ symptoms. A LOOK TO THE FUTURE The availability of valid, noninvasive point-of-service methods (eg, stable isotope gastric emptying tests) to determine whether gastric emptying is rapid or delayed, and of imaging methods, such as MRI, SPECT or three-dimensional ultrasound, to measure fasting and postprandial gastric volumes may help triage patients to receive therapy that is more likely to be effective than the current empirical approaches with acid suppressants, prokinetics, or antidepressants, which are based on individual physician preference. Functional dyspepsia remains a challenge and presents unmet clinical need. References [1] Tack J, Caenepeel P, Arts J, et al. Prevalence of acid reflux in functional dyspepsia and its association with symptom profile. Gut 2005;54:1370–6. [2] Moayyedi P, Soo S, Deeks J, et al. Eradication of Helicobacter pylori for non-ulcer dyspepsia. Cochrane Database Syst Rev 2005;(1):CD002096. [3] Moayyedi P, Soo S, Deeks J, et al. Pharmacological interventions for non-ulcer dyspepsia. Cochrane Database Syst Rev 2004;(4):CD001960. [4] Talley NJ, Stanghellini V, Heading RC, et al. Functional gastroduodenal disorders. Gut 1999;45:II37–42. [5] Tack J, Talley NJ, Camilleri M, et al. Functional gastroduodenal disorders. Gastroenterology 2006;130:1466–79. [6] Tack J, Bisschops R, Sarnelli G. Pathophysiology and treatment of functional dyspepsia. Gastroenterology 2004;127:1239–55. [7] Camiilleri M, Dubois D, Coulie B, et al. Prevalence and socioeconomic impact of upper gastrointestinal disorders in the United States (results of the US Upper Gastrointestinal Study). Clin Gastroenterol Hepatol 2005;3:543–52. [8] Castillo EJ, Camilleri M, Locke GR, et al. A community-based, controlled study of the epidemiology and pathophysiology of dyspepsia. Clin Gastroenterol Hepatol 2004;2:985–96. [9] Stanghellini V, Tosetti C, Paternico A, et al. Predominant symptoms identify different subgroups in functional dyspepsia. Am J Gastroenterol 1999;94:2080–5. [10] Tucci A, Corinaldesi R, Stanghellini V, et al. Helicobacter pylori infection and gastric function in patients with chronic idiopathic dyspepsia. Gastroenterology 1992;103:768–74. [11] Danesh J, Lawrence M, Murphy M, et al. Systematic review of the epidemiological evidence on Helicobacter pylori infection and nonulcer or uninvestigated dyspepsia. Arch Intern Med 2000;160:1192–8. [12] Thumshirn M, Camilleri M, Saslow SB, et al. Gastric accommodation in non-ulcer dyspepsia and the roles of Helicobacter pylori infection and vagal function. Gut 1999;44:55–64.
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[13] Rhee PL, Kim YH, Son HJ, et al. Lack of association of Helicobacter pylori infection with gastric hypersensitivity or delayed gastric emptying in functional dyspepsia. Am J Gastroenterol 1999;94:3165–9. [14] Sarnelli G, Janssens J, Tack J. Helicobacter pylori is not associated with symptoms and pathophysiological mechanisms of functional dyspepsia. Dig Dis Sci 2003;48:2229–36. [15] Greydanus MP, Vassallo M, Camilleri M, et al. Neurohormonal factors in functional dyspepsia (insights on pathophysiological mechanisms). Gastroenterology 1991;100: 1311–8. [16] Sarnelli G, Caenepeel P, Geypens B, et al. Symptoms associated with impaired gastric emptying of solids and liquids in functional dyspepsia. Am J Gastroenterol 2003;98:783–8. [17] Maes BD, Ghoos YF, Hiele MI, et al. Gastric emptying rate of solids in patients with nonulcer dyspepsia. Dig Dis Sci 1997;42:1158–62. [18] Stanghellini V, Tosetti C, Paternico A, et al. Risk indicators of delayed gastric emptying of solids in patients with functional dyspepsia. Gastroenterology 1996;110:1036–42. [19] Perri F, Clemente R, Festa V, et al. Patterns of symptoms in functional dyspepsia: role of Helicobacter pylori infection and delayed gastric emptying. Am J Gastroenterol 1998;93: 2082–8. [20] Talley NJ, Verlinden M, Jones M. Can symptoms discriminate among those with delayed or normal gastric emptying in dysmotility-like dyspepsia? Am J Gastroenterol 2001;96: 1422–8. [21] Couturier O, Bodet-Milin C, Querellou S, et al. Gastric scintigraphy with a liquid-solid radiolabeled meal: performances of solid and liquid parameters. Nucl Med Commun 2004;25: 1143–50. [22] Hjelland IE, Hausken T, Svebak S, et al. Vagal tone and meal-induced abdominal symptoms in healthy subjects. Digestion 2002;65:172–6. [23] Holtmann G, Goebell H, Jockenhoevel F, et al. Altered vagal and intestinal mechanosensory function in chronic unexplained dyspepsia. Gut 1998;42:501–56. [24] Troncon LE, Thompson DG, Ahluwalia NK, et al. Relations between upper abdominal symptoms and gastric distension abnormalities in dysmotility like functional dyspepsia and after vagotomy. Gut 1995;37:17–22. [25] Ricci R, Bontempo I, La Bella A, et al. Dyspeptic symptoms and gastric antrum distribution: an ultrasonographic study. Ital J Gastroenterol 1987;19:215–7. [26] Hausken T, Berstad A. Wide gastric antrum in patients with non-ulcer dyspepsia: effect of cisapride. Scand J Gastroenterol 1992;27:427–32. [27] Troncon LEA, Bennett RJM, Ahluwalia NK, et al. Abnormal distribution of food during gastric emptying in functional dyspepsia patients. Gut 1994;35:327–32. [28] Gilja OH, Hausken T, Wilhelmsen I, et al. Impaired accommodation of proximal stomach to a meal in functional dyspepsia. Dig Dis Sci 1996;41:689–96. [29] Tack J, Piessevaux H, Coulie B, et al. Role of impaired gastric accommodation to a meal in functional dyspepsia. Gastroenterology 1998;115:1346–52. [30] Salet GAM, Samsom M, Roelofs JMM, et al. Responses to gastric distention in functional dyspepsia. Gut 1998;42:823–9. [31] Kim DY, Delgado-Aros S, Camilleri M, et al. Noninvasive measurement of gastric accommodation in patients with idiopathic nonulcer dyspepsia. Am J Gastroenterol 2001;96: 3099–105. [32] Boeckxstaens GE, Hirsch DP, Kuiken SD, et al. The proximal stomach and postprandial symptoms in functional dyspeptics. Am J Gastroenterol 2002;97:40–8. [33] Piessevaux H, Tack J, Walrand S, et al. Intragastric distribution of a standardized meal in health and functional dyspepsia: correlation with specific symptoms. Neurogastroenterol Motil 2003;15:447–55. [34] Bredenoord AJ, Chial HJ, Camilleri M, et al. Gastric accommodation and emptying in evaluation of patients with upper gastrointestinal symptoms. Clin Gastroenterol Hepatol 2003;1:264–72.
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Gastroenterol Clin N Am 36 (2007) 665–685
GASTROENTEROLOGY CLINICS OF NORTH AMERICA
Irritable Bowel Syndrome: Current Approach to Symptoms, Evaluation, and Treatment Elizabeth J. Videlock, BS, Lin Chang, MD* Center for Neurovisceral Sciences and Women’s Health, Division of Digestive Diseases, David Geffen School of Medicine at UCLA and VA Greater Los Angeles Healthcare System, CURE Building 115, Room 223, 11301 Wilshire Boulevard, Los Angeles, CA 90073, USA
I
rritable bowel syndrome (IBS) is a common functional gastrointestinal (GI) disorder. It has a very high prevalence, estimated to be 10% to 20% in the general population [1]. IBS accounts for significant health care costs with annual direct and indirect costs estimated at $1.35 billion and at least $200 million, respectively [2]. IBS patients use more health care services than the general population, even for non–GI-related concerns [3,4]. This article provides clinicians with a current, concise, and evidence-based review of the symptoms, diagnostic evaluation, and treatment of IBS. A clear understanding of recommended diagnostic and therapeutic approaches leads to greater patient satisfaction and reduced health care costs. CLINICAL FEATURES OF IRRITABLE BOWEL SYNDROME Gastrointestinal Symptoms The main symptom of IBS is chronic or recurrent abdominal pain or discomfort associated with altered bowel habits. The new Rome III criteria for the diagnosis of IBS were published in 2006 and are listed in Box 1 [1]. The following are not part of the diagnostic criteria but are considered supportive symptoms: abnormal stool frequency (<3 bowel movements per week or >3 bowel movements per day); abnormal stool form (lumpy-hard stool or loose-watery stool); defecation; straining; urgency; a feeling of incomplete evacuation; and passing mucus and bloating. The previous Rome II classification of IBS subtype was based on a combination of symptoms including stool frequency and form, and defecation-related symptoms. This classification was suboptimal because it was not evidencebased and because there was inconsistency with regard to the correct subclassification of patients with frequent hard stools or infrequent watery stools. Furthermore, cluster analysis and symptom studies have shown that stool *Corresponding author. E-mail address:
[email protected] (L. Chang). 0889-8553/07/$ – see front matter doi:10.1016/j.gtc.2007.07.002
Published by Elsevier Inc. gastro.theclinics.com
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Box 1: The symptom-based Rome III criteria for the diagnosis of IBS These criteria should be filled for the last 3 months with symptom onset at least 6 months before diagnosis. Recurrent abdominal pain or discomforta at least 3 days per month in the last 3 months that is associated with two or more of the following: Improvement with defecation Onset associated with a change in frequency of stool Onset associated with a change in form (appearance) of stool a
Discomfort means an uncomfortable sensation not described as pain.
frequency is within normal range for most IBS patients [1]. Based on more recently published studies characterizing the bowel habits of the IBS subgroups [5–7], stool form was found to be the best predictor of predominant bowel habit in IBS. Furthermore, stool form is a better reflection of intestinal transit time. For these reasons, stool form rather than frequency determines classification according to Rome III. The subtype classification is illustrated in Fig. 1. The category of alternating IBS (IBS-A) should be reserved for patients with bowel habits that have changed over time (eg, weeks to months). Patients with both diarrhea and constipation that may alternate within hours or days were classified as IBS-A according to Rome II, but should now be referred to as IBS-M. The prevalence of IBS-D, IBS-C, and IBS-M are similar, but IBS-M is the subtype most frequently encountered in primary care. Patients change
Fig. 1. The Rome III classification for subtyping IBS by bowel habit predominance. Patients are classified as IBS with constipation (IBS-C) if 25% of stools are hard or lumpy and <25% are loose (mushy) or watery. IBS with diarrhea (IBS-D) describes patients with 25% of stools loose or watery and <25% hard or lumpy. Mixed IBS (IBS-M) describes patients with 25% of stools hard and lumpy and 25% of stools loose or watery. IBS patients are unsubtyped (IBS-U) if not enough stools are abnormal to meet criteria for any other subtype.
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subtypes frequently, with 29% moving from IBS-C to IBS-D within 1 year [8]. Because of this symptom instability, the terms ‘‘IBS with diarrhea’’ and ‘‘IBS with constipation’’ are preferred over the previously used terms of ‘‘diarrheaand constipation-predominant IBS’’ [8]. IBS-C and IBS-D patients have different symptom profiles, with IBS-C patients reporting more overall symptoms (both lower and upper abdominal pain) and particularly bloating [9]. Symptoms of IBS and functional dyspepsia overlap significantly and respond similarly to treatment. It has been argued that they are different manifestations of one condition [10]. Extraintestinal Symptoms and Comorbid Disorders IBS patients make more health care visits and incur more health care costs than non-IBS patients. More than half of additional visits and additional costs are for non-GI concerns [11]. Non-GI symptoms that are more common in IBS than controls include the following (prevalence): headache (23%–45%); back pain (27%–81%); fatigue (36%–63%); myalgia (29%–36%); dyspareunia (9%–42%); urinary frequency (21%–61%) and other urinary symptoms; and dizziness (11%–27%) [11]. IBS patients with comorbid somatic disorders (eg, fibromyalgia) report more severe IBS symptoms and lower health-related quality of life (HRQOL) [11]. Common comorbid GI and other somatic disorders are listed in Table 1. Although it seems that these comorbid disorders and IBS may have distinct contributing factors to their pathophysiology, there are common themes that are mostly related to psychologic symptoms and stress reactivity [11]. Stress is defined as acute threats to the homeostasis of an organism, be they real (physical) or perceived (psychologic). Sustained, threatening life events (psychosocial stressors) predict symptom exacerbation in established IBS patients [12–14], and the development of IBS symptoms in asymptomatic individuals following a gastroenteric infection (postinfectious IBS) [13,15]. Stress-induced changes in pain modulation (hyperalgesia) and cognitive processes (hypervigilance toward viscerosomatic stimuli) may play a key role in the pain and discomfort characteristic of these disorders. Although these mechanisms may be shared, they may be more specifically related to one particular stimulus depending on the condition. For example, IBS patients may have developed persistent symptom-specific anxiety from previously threatening visceral stimuli (eg, food or GI infection), whereas fibromyalgia patients have symptomspecific anxiety to somatic stimuli (eg, muscle injury). These threatening events, which are attached to their symptoms, may be involved in the development of anticipatory or anxiety-related responses [16] related to symptom recurrence. Symptom-specific anxiety can amplify the perception of visceral and somatic afferent input to the brain, thereby contributing to pain-related symptoms. A recently developed reliable, validated scale called the Visceral Sensitivity Index measures GI-specific anxiety (ie, fear of visceral sensations) and may be useful for clinical assessment, treatment outcome studies, and mechanistic studies of the role of anxiety in IBS presentation [17]. In addition,
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Table 1 Comorbidity with irritable bowel syndrome
Disorder Gastrointestinal Gastroesophageal reflux disease Functional dyspepsia Other somatic Fibromyalgia Chronic fatigue syndrome Chronic pelvic pain Temporomandibular joint disorder Interstitial cystitis a
% Prevalence of IBS in patients with the disorder
% Prevalence of the disorder in patients with IBS
47
46.5
28–47
28–57
32–77 35–92 29–79 64a
28–65 14a 35a 16a
30.2a
—
Based on results of only one study [11].
a path analysis demonstrated that GI-specific anxiety mediates the relationship between general psychologic distress measures and GI symptom severity. The Visceral Sensitivity Index was related to GI, but not non-GI, symptom severity [18]. There is a higher prevalence of psychiatric disorders in the IBS population than in controls. This is true in the community (prevalence of 18%) [19]; in clinics (prevalence of 40%–60%) [20]; and in referral centers (prevalence with lifetime history of 94%) [19]. Although comorbidity is highest in the health care–seeking population, the prevalence in IBS nonpatients (ie, individuals who have not sought health care for their IBS symptoms) is greater than that seen in the general population, which suggests that psychiatric disorders influence health care seeking, but are not the primary cause. Somatization disorder deserves special mention. The diagnostic criteria for somatization disorder, a psychiatric disorder that is characterized by multiple medically unexplained symptoms, include a history of multiple pain symptoms; GI symptoms; sexual dysfunction or pain; and pseudoneurologic symptoms, such as weakness or urinary retention [21]. There is a high degree of overlap between IBS and somatization disorder, and patients with IBS who meet criteria for somatization disorder have more psychiatric comorbidity, more severe symptoms, and are less responsive to treatment [22]. Although IBS patients with somatization disorder do not have increased numbers of health care visits compared with IBS, they do incur more expenditures, which suggests both that somatization disorder is an important factor in health care use by IBS patients and that increased health care use may be mediated by physicians [23]. Symptom Severity There are no consensus criteria that have been established to determine severity of IBS. This is caused in part by the large number of factors that influence
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severity and the wide gap between patient and physician perceptions of severity. Current research suggests that a multidimensional view of illness severity is more useful than one that is based on GI symptom intensity. Factors that are important to consider when assessing severity are HRQOL, psychosocial factors, health care use behaviors, disability, and the overall degree to which the illness affects the patient’s life [24,25]. A preliminary report identified several predictors for patient-assessed ‘‘overall severity of GI symptoms’’ [26]. The predictors included multiple symptoms, such as ratings of abdominal pain and discomfort (pain, bloating); defecation-related symptoms (straining, urgency); and illness-related anxiety (‘‘something serious is wrong with my body’’). More recent epidemiologic data suggest a prevalence of severe or very severe IBS ranging from 3% to 69%, which is higher than previously thought [24]. Gender Differences Gender differences in IBS are difficult to measure because most research participants are female; however, differences have been shown both in prominent symptoms and in the response to treatment. Although in the community the ratio of women to men with IBS is estimated to be 2:1, this difference is even greater in the health care–seeking population, with women leading men by an estimated ratio of 2 to 4:1 [27]. A recently published study, however, found equal prevalence of men and women with IBS in newly developing Asian countries [28]. Compared with men with IBS, women with IBS report greater overall IBS symptom severity, intensity of abdominal pain and bloating, impact of symptoms on daily life, and lower HRQOL [29,30]. It is not known, however, if this is caused by differences in the sensation of pain, cognitive response to pain, or reporting bias [27]. Women also report more extraintestinal symptoms, such as nausea, urinary urgency, and dyspareunia, and are more likely to report symptoms of constipation and bloating [31–35]. Symptoms in women vary according to the menstrual cycle, with increased reporting of GI symptoms in the late luteal and menses phases when compared with the midfollicular phase [36]. In particular, women report looser stools and more GI symptoms just before and during menses and rectal sensitivity has been shown to be greater in women with IBS in menses compared with women with IBS in other phases of the menstrual cycle [37]. With regard to gender differences in IBS treatment, serotonergic agents, such as the 5-hydroxytryptamine (HT)3 antagonist alosetron, seem to have a more robust effect in women with IBS-D than in men [38,39]. This difference could be related to small sample sizes, differences in drug metabolism, or the interaction between serotonin and estrogen [27] but is likely related to a combination of gender-based differences in peripheral and central mechanisms. DIAGNOSTIC EVALUATION OF IRRITABLE BOWEL SYNDROME The diagnosis of IBS is symptom-based because there are not yet diagnostic biomarkers for IBS. The symptom-based Rome III criteria had a sensitivity of 0.707 and a specificity of 0.878 in the validation sample of 328 patients
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who had received a clinical diagnosis of IBS [40]. Although the presence of ‘‘red flag’’ or alarm signs and symptoms may indicate a need for further diagnostic work-up, it is not recommended that patients with red flag symptoms be excluded from the diagnosis of IBS. On average, IBS patients report the presence of at least 1.65 red flag symptoms [41]. Nocturnal symptoms (40%) and onset over the age of 50 (32%) were most common alarm signs. Alarm signs and symptoms include the following: Age 50 Unintentional weight loss Family history of GI malignancy Severe unrelenting large-volume diarrhea Fevers, chills, recent travel to endemic region Nocturnal symptoms Hematochezia Relevant findings on physical examination (arthritis, skin lesions, lymphadenopathy, abdominal mass)
Historically, IBS has been a diagnosis of exclusion, but current best evidence suggests that a battery of diagnostic tests is not necessary because the prevalence of organic disease is not increased in the population with symptoms of IBS without alarm features, and the positive predictive value of such tests remains small [42,43]. Diagnostic tests are likely unnecessary, including blood tests, stool tests, lactulose breath tests, abdominal imaging, and colonic imaging; however, further research on the use of diagnostic testing is warranted. Diagnostic tests may reveal incidental findings or findings that are not related to the symptoms of IBS. Additionally, a negative finding on colonoscopy is not associated with an increased sense of reassurance in patients with IBS [44]. There are several scenarios in which diagnostic testing is recommended: (1) stool ova and parasite testing for patients who have recently traveled to endemic regions or for immunocompromised individuals, (2) colonoscopy in patients over 50 years of age for colon cancer screening, and (3) testing in patients who have not improved despite symptom-based treatment. There is good evidence that serologic testing for celiac disease followed by endoscopic biopsy confirmation of positive results is a cost-effective strategy in North American IBS-D patients [45]. Small bowel bacterial overgrowth has been theorized to play a role in the symptoms of IBS. Although some studies have shown an increased prevalence of small bowel bacterial overgrowth in IBS as diagnosed by a lactulose breath test [46,47], the use of this diagnostic tool is limited by the lack of evidence that treatment of small bowel bacterial overgrowth with antibiotics leads to longterm abatement of IBS symptoms. Testing for lactase deficiency is not generally recommended because true lactose malabsorption is not well-correlated with reported lactose intolerance [48] and because lactose restriction has not been shown to improve IBS symptoms [49,50]. This is likely because lactose intolerance coexists with IBS but is not the predominant cause of symptoms.
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TREATMENT Patient-Centered Care A good health care provider–patient relationship is the cornerstone of effective care of IBS. The quality of this relationship has been shown to improve patient outcomes [51]. Elements of a good provider-patient relationship include a nonjudgmental patient-centered interview, a careful and cost-effective evaluation, inquiry into the patient’s understanding of the illness, patient education, and involvement of the patient in treatment decisions [6]. Because IBS is a chronic disease, it is important to assess specific reasons for the current visit, which may differ among patients (eg, concern about cancer, worsening pain, lack of response to treatment, and so forth) [52]. An intrinsic part of the clinical assessment is the psychosocial interview, which is usually quite relevant in IBS patients. Because IBS patients may have stress-related symptoms or comorbid psychologic symptoms, the psychosocial interview may uncover previously unexpressed associated symptoms and concerns that could be contributing to the patient’s illness severity, daily functioning, and health-related outcome. Addressing psychosocial factors may improve health status and treatment response [53]. Diet Many patients report an inconsistent symptom response to certain foods, and a 1- to 2-week food and symptom diary can aid in careful analysis of potential food triggers. Although most patients cannot completely control symptoms through diet alterations alone, diet-related exacerbations may be minimized. Common food triggers include high-fat foods, raw fruits and vegetables, and caffeinated beverages. There is some evidence that the symptoms of IBS are related to a visceral hypersensitivity to low-grade immune reactivity that does not cause symptoms in the general population. A group in the United Kingdom conducted a randomized controlled trial of food elimination based on IgG levels. IBS patients were given either a list of foods to which they had increased levels of IgG or a sham diet of similar foods to eliminate. Twenty-eight percent of patients adhering to the true diet had global improvement of symptoms versus 16.7% on sham diets. This difference was statistically significant and corresponds to a numberneeded-to-treat of 9. A larger percentage of patients who fully adhered to the diet had improved symptoms (54% versus 15% of strict adherers to the sham diet), corresponding to a number-needed-to-treat of 2.5. Additionally, resumption of the regular diet caused a worsening of symptoms in a greater percentage of those following the true diet than the control diet. There was not a significant effect on HRQOL. It has been suggested, however, that the effect seen in this study was a result of diet alone regardless of IgG levels. IgG levels have not been shown to be predictive of food intolerance and a large percentage of patients in the true diet treatment group eliminated milk and wheat, which are known to affect symptoms in IBS [54,55]. Modification of diet may affect symptoms regardless of whether or not there is true food intolerance.
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Pharmacologic Agents In 2002, the American College of Gastroenterology (ACG) Functional Gastrointestinal Disorders Task Force published a comprehensive systematic review on the treatment of IBS [56]. In a subsequent publication in 2005, Schoenfeld [57] updated and expanded on the ACG’s review. The section of this article focusing on pharmacologic treatment summarizes these findings, taking into account high-quality trials that have since been published (Table 2). Bulking Agents Bulking agents include psyllium, methylcellulose, corn fiber, calcium polycarbophil, and ispaghula husk. Fiber supplementation has often been used as initial management of IBS; however, the ACG Functional Gastrointestinal Disorders Task Force evaluated randomized, placebo-controlled treatment trials for IBS and found that none of the trials of bulking agents were of high quality [56]. A meta-analysis showed a small, but significant improvement with soluble fiber (psyllium, ispahula, calcium polycarbophil), but not with insoluble fiber (corn, wheat bran) [58]. This meta-analysis is limited by the inclusion of results from divergent studies and the extrapolation of end points [57]. Fiber may increase stool frequency in IBS-C, but it is not clear whether this is well-correlated with relief of pain or other symptoms. Additionally, bulking agents in quantities that are therapeutic can cause adverse effects including bloating and abdominal pain and discomfort, and it may be helpful to recommend a gradual initiation of the dose to minimize side effects, particularly in those who have relatively little fiber in their diets or those with predominant bloating [57]. Antidiarrheal Agents The use of antidiarrheal agents has shown no benefit for global IBS symptoms or abdominal pain [56,57]. Loperamide seems to be effective at prolonging intestinal transit time and improving stool consistency in IBS-D. These agents may be very useful in some IBS-D patients to manage stool urgency, frequency, and fecal incontinence. They can be used on a more regular basis in patients with more frequent symptoms or on an as-needed basis. It is often useful for patients to use antidiarrheals prophylactically before leaving the house, a long car trip, a meal, or a stressful event. This can decrease both the diarrhea and the anticipatory stress often felt by patients before a known symptom trigger. Laxatives Osmotic laxatives are available over the counter and are widely used in the treatment of IBS-C and chronic constipation. Although no randomized, controlled studies have shown efficacy of laxatives in IBS, they may be useful in treating the constipation symptoms in those with IBS-C. Osmotic laxatives, such as polyethylene glycol or magnesium-containing products, are generally safe and well tolerated. Polyethylene glycol can be easily titrated by the patient, allowing adjustment in stool frequency and consistency as symptoms vary.
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Table 2 Agents available to treat irritable bowel syndrome by predominant symptom Constipation Drug class
Generic name
Dose
Bulking agents
Psyllium
1–3 Tbsp qd
Methylcellulose Polycarbophil
1–3 Tbsp qd 2–4 tablets qd
Milk of magnesia Magnesium citrate Sodium phosphate Lactulose Polyethylene glycol Sorbitol Cascara sagrada Senna
1–2 Tbsp qd to bid 6–12 oz 1 tspn in 8 oz fluid 1–2 Tbsp qd–bid 17 g in 8 oz fluid 1–2 Tbsp qd–bid 325 mg or 1 tspn qhs 187-mg tablets; 1–2 tablets qhs 1–2 Tbsp qd 10 mg 1–2 tablets qhs or 1 suppository qhs 100 mg; 1–3 tablets qhs 1 tsp–1 Tbsp qhs 6 mg bid Available only through restricted-use program
Laxatives Osmotic
Stimulants
Riconleic acid Diphenylmethane derivatives Emollients
Docusates
5-HT4 agonist
Mineral oil Tegaserod
First-line treatment for mild-moderate constipation. Start with 4 g/d, gradually increase over 2–3 weeks to 20–25 g/d
Diarrhea Drug class
Generic name
Antidiarrheals
Loperamide
1 tablet qid
Binding agents 5-HT3 antagonist
Diphenoxylate Cholestyramine Alosetron
1–2 tablets tid 1 g bid to qid 0.5 mg–1 mg qd–bid
Tricyclic Amitriptyline antidepressants Doxepin
10–150 mg qhs 10–150 mg qhs
Use prophylactically (start at 1 per day but can use up to 8 per day)
For women with severe IBS-D who have failed conventional therapy. Available only through restricted-use program. Very sedating Very sedating (continued on next page)
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Table 2 (continued) Imipramine Clomipramine Trimipramine Desipramine
10–150 25–100 10–150 10–150
mg mg mg mg
qhs qhs qhs qhs
Nortriptyline
10–150 mg qhs
Antispasmodics
Hyoscamine sulfate
TCAs SSRIs
Dicyclomine Propantheline hydrochloride Clidinium þ chlordiazepoxide Hyoscamine þ scopolamine þ atropine þ phenobarbital See above Fluoxetine
0.125 mg sl/po qid prn, 0.375 mg po bid 10 mg po bid 15 mg tid a.c. and 30 mg qhs 5–10 mg tid–qid
Most empiric evidence for efficacy. Less sedation and constipation Least sedating
Pain/Bloating
SNRIs
5-HT4 agonist Antibiotics Probiotics
1–2 tablets tid–qid
See above 10–40 mg qd
Citalopram
20 mg qd
Paroxetine
20–50 mg qd
Sertraline Escitalopram
25–100 mg qd 10 mg qd
Venlafaxine Duloxetine
37.5–75 mg bid–tid 40–60 mg qd
Tegaserod Rifaximin Bifidobacterium infantis VSL # 3
See above 400 mg tid 1 tablet qd 1 packet bid
Long half-life; less withdrawal effects Less side effects and drug interactions Short half-life; more likely withdrawal effects. Greater anticholinergic effect; use in IBS-D Requires dose ranging Less side effects and drug interactions FDA approved for depression and diabetic neuropathy. Unlabeled uses include chronic pain syndromes, fibromyalgia, stress incontinence. Ongoing open labeled trial for IBS.
Abbreviations: a.c., before meals; bid, twice daily; g, grams; mg, milligrams; oz, ounces; qd, daily; qhs, at night; qid, four times daily; Tbsp, tablespoon; tid, three times daily; tspn, teaspoon.
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Lactulose and sorbitol may also increase stool frequency, but are often associated with the side effects of bloating or cramping in IBS patients. Stimulant laxatives, such as senna, cascara, or bisacodyl, are useful on an intermittent basis for refractory constipation, although frequently cause cramping, loose stools, and urgency. Antispasmodics Antispasmodics work either by a direct effect on intestinal smooth muscle (eg, mebeverine, pinaverine) or by their anticholinergic or antimuscarinic properties (eg, dicyclomine, hyoscyamine). A meta-analysis evaluated 23 randomized clinical trials (RCTs) and reported a significantly higher global improvement with drug versus placebo (56% versus 38%) and a greater pain improvement (53% versus 41%) [59]. The ACG systematic review, however, evaluated 18 English-language RCTs assessing the efficacy of antispasmodic agents [56]. This review concluded that there is little evidence for the efficacy of antispasmodics for global relief of IBS symptoms [57]. Most of these studies have short duration, small sample sizes, and suboptimal quality. Of three higher-quality RCTs [60–62], only one showed a significant difference between placebo and treatment (dicyclomine), but this was using a dose high enough to cause 15% of the treatment group to withdraw from the study because of adverse effects compared with no withdrawals in the placebo group [62]. Side effects of these agents include dry mouth, constipation, urinary retention, and visual disturbances. Serotonergic Agonist or Antagonists Tegaserod Tegaserod is a selective 5-HT4 partial agonist that stimulates gut transit and may also have an effect on visceral sensation [63,64]. Tegaserod was approved by the Food and Drug Administration (FDA) for the treatment of IBS-C in women and more recently has been approved for the treatment of chronic constipation in men and women under the age of 65. On March 30, 2007, however, Novartis Pharmaceuticals suspended marketing of Zelnorm (tegaserod) because of important safety information. This suspension occurred at the request of the FDA because of the incidence of cardiovascular ischemic events being significantly higher with Zelnorm treatment than with placebo treatment (13 per 11,614 [0.11%] with Zelnorm and 1 per 7031 [0.01%] with placebo [P ¼ .024]). Several large and well-designed trials have shown tegaserod to be more effective than placebo in improving symptoms of IBS-C [65–68]. More recent studies have shown that tegaserod remains as effective with repeated use (after a treatment-free interval) as it is in initial therapy, and there is no rebound effect (worsening of symptoms after treatment withdrawal) [69,70]. In addition to improving IBS-C symptoms, tegaserod has been proved to improve outcomes related to productivity and work impairment [71]. Alosetron Alosetron is a 5-HT3 receptor antagonist that is currently available under a restricted use program and is approved only for women with severe IBS-D who
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have failed conventional therapy. This restriction is because of the occurrence of GI-related adverse events including ischemic colitis and serious complications of severe constipation. These events occurred at a rate of 1.1 per 1000 patient years for ischemic colitis and 0.66 per 1000 patient years for serious complications of constipation [72]. A recent systematic review concluded that there is a significantly increased rate of ischemic colitis among alosetron-using patients compared with placebo-using patients (0.15% versus 0.0%), but no significant difference in the rate of serious complications of constipation. All of the alosetron-using patients with ischemic colitis had a reversible colopathy without long-term sequelae and most cases occurred within the first month of treatment [73]. The restriction notwithstanding, alosetron has been proved efficacious in seven placebo-controlled trials with over 3000 patients with nonconstipation IBS. Five of the seven studies showed relief of abdominal pain or discomfort and two showed relief of urgency [72]. There is a recently published placebo-controlled long-term study that demonstrated significant efficacy of alosetron compared with placebo over a treatment period of 48 weeks [74]. Alosetron is not FDA-approved for the treatment of IBS-D in men, but one trial did show an increased rate of relief from symptoms during 8 weeks of treatment with 1 mg alosetron twice a day (53%) compared with placebo (40%) [39]. Alosetron significantly reduced stool consistency scores indicating more formed stools; however, no significant effects of alosetron were seen with regard to the other secondary symptom end points. Antidepressants Tricyclic antidepressants The rationale of using antidepressants in IBS is that these agents may alter pain perception by a central modulation of visceral afferents, treat comorbid psychologic symptoms, and alter GI transit. Different classes of antidepressants likely act by different combinations of mechanisms. Tricyclic antidepressants are the best studied, and are often used at low doses, because their major impact in IBS may be more associated with an analgesic effect rather than treatment of psychologic symptoms. A systematic review found that none of the seven randomized placebo-controlled trials evaluating the effect of tricyclic antidepressants in the treatment of IBS were of high quality because of relatively small sample sizes and poorly defined primary and secondary end points [56]. A large randomized 12-week placebo-controlled trial, which evaluated the efficacy of desipramine in treating moderate to severe functional bowel disorders, conducted by Drossman and colleagues [75], however, was published subsequent to the systematic review. Desipramine was shown to have statistically significant benefit over placebo in the per protocol analysis, which included only those patients who completed treatment (responder rate 73% versus 49%), but not in the intention-to-treat analysis. The lack of benefit in the intention-to-treat analysis may have been related to a significant drop out rate primarily because of symptom side effects. This study also found that the patients most likely to improve with desipramine were patients with
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IBS-D, no depression, and mild to moderate symptoms. The most common side effects associated with tricyclic antidepressants include dry mouth, constipation, and drowsiness. Often initiating the drug at the lowest available dose and increasing it gradually can minimize adverse events while trying to achieve a therapeutic effect (eg, starting dose of 10 mg at bedtime and increasing up to 75 mg if needed). In patients who have coexistent sleep disturbances, amitriptyline may be a good choice because it has a greater sedative effect caused by its more potent antihistaminic effects. Desipramine and nortriptyline are less sedating. If a tricyclic antidepressant is used in IBS-C, desipramine should be considered because it has less anticholinergic effects and is less constipating than the other tricyclic antidepressants. Selective serotonin reuptake inhibitors Selective serotonin reuptake inhibitors are commonly used to treat IBS even though there have been relatively few placebo-controlled trials. Preliminary evidence suggests that selective serotonin reuptake inhibitors have an effect on overall HRQOL, symptom frequency, and abdominal pain, and these effects seem to be independent of effects on mood. A RCT of paroxetine in IBS patients who failed therapy with a high-fiber diet showed a greater increase in overall well-being with paroxetine than placebo [76]. This was true for depressed and nondepressed participants [76]. Fluoxetine was evaluated in 44 patients with IBS-C and was more effective than placebo in decreasing the frequency of symptoms including abdominal discomfort and bloating and increasing frequency of bowel movements and improving consistency of stool [77]. A controlled crossover study of citalopram in 23 nondepressed IBS patients showed an improvement in abdominal pain, bloating, and overall well-being [78]. There is more evidence for the efficacy of tricyclic antidepressants as analgesics, but tricyclic antidepressants are not as well tolerated as selective serotonin reuptake inhibitors. Large, high-quality trials are needed to evaluate the effectiveness of selective serotonin reuptake inhibitors in IBS; however, in patients with severe IBS, treatment with selective serotonin reuptake inhibitors may be helpful and has been shown to be cost-effective when compared with routine care [79]. Combined serotonin-norepinephrine reuptake inhibitors, such as venlaxifine and duloxetine, may have possible beneficial effects in IBS but further studies are needed. Antibiotics Small bowel bacterial overgrowth has been theorized to play a role in IBS and is supported by an abnormal lactulose breath test in most IBS patients [46,47]. Rifaximin is an antibiotic that has very low systemic absorption and broad-spectrum activity against gram-positive and gram-negative aerobes and anaerobes. In a randomized, double-blind placebo-controlled trial, 400 mg of rifaximin given three times per day for 10 days was superior to placebo in improving global symptoms (mean improvement of 36.4% versus 21%) and bloating (but not abdominal pain, diarrhea, or constipation). The effects were present throughout the 10-week follow-up of the study. Although difficult to evaluate in a small
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sample (N ¼ 87), adverse effects were uncommon and included nausea and abdominal pain [80]. Future studies including an ongoing multicenter RCT will likely provide more information on the efficacy of this antibiotic treatment in IBS. Probiotics Probiotics are hypothesized to work by several mechanisms. These include a shift from a proinflammatory to an anti-inflammatory cytokine profile, the reduction of bile acid delivery to the colon, and alteration of motility [81]. A trial of probiotics comparing either Bifidobacterium infantis (B infantis) or Lactobacillus salivarius with placebo in 75 patients with IBS over a 12-week treatment period showed a significant reduction in abdominal pain and discomfort, bloating, and difficulty with bowel movements with B infantis but not with L salivarius [82]. IBS patients were found to have a decreased blood interleukin-10/interleukin-12 ratio indicative of a proinflammatory, Th-1 state. Normalization of this ratio occurred in patients who received B infantis but not in those taking L salivarius or placebo. A larger study (N ¼ 362) from the same group further evaluated B infantis in a capsule formulation in women with IBS seen in a primary care setting. A dose of 1 108 colony-forming units given once a day over 4 weeks significantly reduced specific symptoms of IBS and global assessment compared with placebo or lower doses of B infantis. A higher dose of B infantis was not observed to be beneficial, but this may have been caused by problems with dissolution of the capsule [83]. Data from placebo-controlled trials also exists for VSL# 3, a probiotic that is a combination of three species of Bifidobacteria, four species of Lactobacilli, and Streptococcus salivarius ssp. thermophilus. VSL#3 decreased flatulence but did not show clinical efficacy for overall relief of IBS symptoms [84,85]. Another probiotic mixture (Lactobacillus rhamnosus GG, L rhamnosis LC705, Bifidobacterium breve Bb99, and Propionibacterium freudenreichii ssp. shermanii JS) was effective in reducing IBS symptoms overall, but when the effect on individuals symptoms was analyzed, there was only a statistically significant reduction of borborygmi, and HRQOL was not significantly improved [86]. Novel Drugs in Development for Irritable Bowel Syndrome There are a number of drugs in various phases of drug development that are being studied for the treatment of IBS. Many of these agents have novel mechanisms of action. Drugs undergoing phase III clinical trials for IBS include the chloride channel activator lubiprostone and the 5-HT4 agonist–5-HT3 antagonist renzapride. Lubiprostone is a FDA-approved treatment of chronic constipation in men and women that was demonstrated to be efficacious at a dose of 24 lg twice daily in improving stool frequency, stool form, and straining [87,88]. Renzapride improved stool consistency and frequency in IBS-C patients but provided no overall relief of abdominal pain and discomfort [89]. Camilleri and colleagues [90] reported that renzapride was associated with an improvement in bowel function scores and a significant linear dose response for colon transit in 48 IBS-C patients, but there was no significant effect on
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gastric emptying and small intestinal transit. Acceleration of colon transit positively correlated with improvements in ease of passage and stool form but not with stool frequency. Tack and colleagues [91] recently showed that a dose of 2 mg twice daily reduced overall colonic transit time and in the cecum– ascending colon and descending colon. Other drugs in various stages of development for IBS include a CRF1 antagonist; neurokinin antagonists; guanylate cyclase-C agonist (linaclotide); 2,3-benzodiazepine (dextofisopam); kappa opioid antagonist (asimadoline); serotonin noradrenergic reuptake inhibitor (duloxetine); novel serotonergic agents; and opioid receptor agents. Nonpharmacologic Agents There are several psychologic treatments for which there is convincing evidence of efficacy. Cognitive-behavioral therapy is a short-term, goal-oriented form of psychotherapy that focuses on the role that thoughts play in determining behaviors and emotional responses. In IBS, the overall negative effect of symptoms may be increased by such thoughts as ‘‘there is something wrong with my body’’ or ‘‘what will people think if I go to the bathroom again?’’ [92] Cognitive-behavioral therapy helps patients to identify these thoughts as they occur and to find alternative, more constructive ways to view the situation. It also helps people become aware of and be more in control of their own autonomic physiology. Cognitive-behavioral therapy was more effective than patient education in terms of global well-being and satisfaction with treatment and no different than desipramine in one randomized controlled trial [75]. In another high-quality study, cognitive-behavioral therapy was shown to improve symptoms but was no different than standard care or relaxation therapy [93]. Gut-directed hypnotherapy is another area in which there has been substantial research. Gut-directed hypnotherapy is hypnosis that is directed toward relaxation and control of intestinal motility by repeated suggestion of control over symptoms followed by ego-strengthening [94]. It is difficult to compare studies, because they have used different controls and end points and because hypnosis is highly operator-sensitive. Yet, many have reported positive results, and a recent systematic review [95] concluded that the evidence suggests that hypnotherapy is effective, but warned that the studies were conducted in referral centers and the subjects for the most part had refractory IBS of a long duration, and so the results may not apply to all clinic settings [95]. Complementary and Alternative Medicine Because even the most effective treatments for IBS do not help all patients, many turn to complementary and alternative medicine in search of other treatment options. Furthermore, many patients prefer complementary and alternative medicine treatments because they view them as natural and time-tested. In addition, complementary and alternative medicine treatments often provide a more holistic approach and meaningful clinician-patient relationship than western medicine. It is important for clinicians to have an understanding of these treatments and whether there is any evidence for their efficacy.
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Acupuncture has been a popular therapy for IBS patients. Despite the fact that theory predicts effectiveness of a treatment modulating ascending pain stimuli, it has not been well-studied and conclusions across studies are difficult to make because of nonstandardized experimental and placebo treatment modalities. The authors of a recent Cochrane review concluded that acupuncture was likely no better than sham acupuncture, but may have been better than other controls; however, more research is required to make any recommendations because of the heterogeneity of the studies [96]. Herbal medicine is another area of complementary and alternative medicine in which patients express interest. Theoretically, this is more amenable to rigorous randomized and controlled study designs, but few high-quality studies have been published. The best evidence is for Chinese herbal medicine. Bensoussan and colleagues [97] showed an improvement in symptoms and global scores over placebo for patients treated either with standard or individualized Chinese herbal medicine. Only those who received individualized Chinese herbal medicine treatment maintained a more sustained relief of their IBS symptoms. Peppermint oil has smooth muscle relaxant effects and there is some evidence that it may improve symptoms [98]. Other alternative or herbal medicines that have been studied are extract of artichoke [99], carmint [100], the herbal mixture STW 5 [101], and melatonin [102,103]. SUMMARY IBS is a prevalent and heterogeneous disorder and patient care should be focused on reducing costs and improving patient satisfaction and HRQOL. The cultivation of a trusting and cooperative clinician-patient relationship reduces the ordering of unnecessary diagnostic tests and facilitates a collaborative effort of patient and clinician to find the treatment that provides the most relief of symptoms, and the greatest management of their illness and improvement of HRQOL. References [1] Longstreth GF, Thompson WG, Chey WD, et al. Functional bowel disorders. Gastroenterology 2006;130(5):1480–91. [2] Inadomi JM, Fennerty MB, Bjorkman D. The economic impact of irritable bowel syndrome. Aliment Pharmacol Ther 2003;18(7):671–82. [3] Levy RL, Von Korff M, Whitehead WE, et al. Costs of care for irritable bowel syndrome patients in a health maintenance organization. Am J Gastroenterol 2001;96(11):3122–9. [4] Longstreth GF, Wilson A, Knight K, et al. Irritable bowel syndrome, health care use, and costs: a U.S. managed care perspective. Am J Gastroenterol 2003;98(3):600–7. [5] Tillisch K, Labus JS, Naliboff BD, et al. Characterization of the alternating bowel habit subtype in patients with irritable bowel syndrome. Am J Gastroenterol 2005;100(4): 896–904. [6] Drossman DA. The functional gastrointestinal disorders and the Rome III process. Gastroenterology 2006;130(5):1377–90. [7] Mearin F, Balboa A, Badia X, et al. Irritable bowel syndrome subtypes according to bowel habit: revisiting the alternating subtype. Eur J Gastroenterol Hepatol 2003;15(2):165–72. [8] Longstreth GF, Thompson WG, Chey WD, et al. Functional bowel disorders. Gastroenterology 2006;130:1480–91.
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Gastroenterol Clin N Am 36 (2007) 687–711
GASTROENTEROLOGY CLINICS OF NORTH AMERICA
Constipation: Evaluation and Treatment of Colonic and Anorectal Motility Disorders Satish S.C. Rao, MD, PhD, FRCP (Lon)a,b,* a
Division of Gastroenterology & Hepatology, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA b Division of Gastroenterology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, 4612 JCP, Iowa City, IA-52242, USA
C
onstipation is a polysymptomatic disorder and not a single disease. Because it represents many symptoms that affect colonic and anorectal function, the estimates of its prevalence have been imprecise. Likewise, the number of patients with this condition who seek medical care and the costs of diagnostic tests or treatment are not accurately known. This article focuses on the colonic and anorectal motility disturbances that are associated with chronic constipation and their management. EPIDEMIOLOGY Recent estimates based on householder surveys in North America suggest a prevalence rate of 15% to 20% for chronic constipation [1–3]. However, other figures have been quoted and the discrepancies in the literature are largely due to how the problem has been defined or reported. The prevalence of constipation increases with age, especially in those over the age of 65 years [4–6]. It also affects work-related productivity and leads to more absences from school [7]. Constipation is associated with significantly lower quality of life and higher psychological distress [8]. Furthermore, these effects tend to be more common in patients with constipation-predominant irritable bowel syndrome (IBS-C) and dyssynergia than in patients with slow transit constipation [9,10]. A recent community survey estimated an average cost of $200 per patient within a large health maintenance organization group for the management of constipation [11].
This work was supported in part by grant DK57100-0441 from the National Institutes of Health and in part by the Department of Internal Medicine, University of Iowa Carver College of Medicine.
*Division of Gastroenterology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, 4612 JCP, Iowa City, IA-52242. E-mail address:
[email protected] 0889-8553/07/$ – see front matter doi:10.1016/j.gtc.2007.07.013
ª 2007 Elsevier Inc. All rights reserved. gastro.theclinics.com
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FUNCTIONAL SUBTYPES There is emerging consensus amongst experts that in the absence of alarm symptoms, such as weight loss, bleeding, recent change in bowel habit, and significant abdominal pain; or secondary causes, such as drugs, metabolic disorders, colorectal cancer, or local painful lesions, such as anal fissure [12], most patients with a complaint of constipation have a functional disorder affecting the colon or anorectum. At least three subtypes have been recognized, although overlap exists. Slow transit constipation is characterized by prolonged delay in the transit of stool through the colon. This delay may be due to a primary dysfunction of the colonic smooth muscle (myopathy) or its nerve innervation (neuropathy), or it could be secondary to an evacuation disorder, such as dyssynergic defecation. Dyssynergic defecation, also known as obstructive defecation [13], anismus [14], pelvic floor dyssynergia [15], or outlet obstruction [16,17], is characterized by either difficulty or inability with expelling stool from the anorectum [13]. Many patients with dyssynergic defecation also have prolonged colonic transit [9]. A third subtype is comprised of patients with IBS-C in whom abdominal pain, with or without bloating, is a prominent symptom together with altered bowel habit [18]. These subjects may or may not have slow transit or dyssynergia. DEFINITION Recent reviews and guidelines have addressed issues related to the definition of this common complaint [15,19–23]. Although infrequent defecation has generally been used to define constipation, such symptoms as excessive straining, passage of hard stools, or feeling of incomplete evacuation have only recently been recognized as equally important and perhaps more common [1]. Thus, a definition that does not address the heterogeneity of symptoms that affect a patient with constipation is not only inaccurate, but also may lead to inadequate management. To improve the diagnosis of constipation and to develop more uniform standards for performing clinical research, consensus criteria have been proposed by an international panel of experts [13,21,23,24]. Rome III criteria define functional constipation primarily on the basis of symptoms alone [23,24], whereas dyssynergic defecation is defined both on the basis of symptoms and objective physiological criteria [13,25]. The Rome III criteria for functional constipation [24] is shown in Box 1 [26]. A modification of the Rome III criteria [23] for dyssynergia is shown in Box 2. A discussion of IBS-C is omitted from this article, as this topic is discussed in the article by Videlock and Chang, elsewhere in this issue. PATHOPHYSIOLOGY The right colon performs several complex functions that include mixing, fermentation and salvage of the ileal effluent, secretion, and desiccation of the intraluminal contents to form stool. The left colon serves as a conduit for desiccation and more rapid transport of stool and the rectosigmoid region serves as a sensorimotor organ that facilitates the awareness, retention, and
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Box 1: Diagnostic criteria for functional constipation with criteria fulfilled for the last 3 months and symptom onset at least 6 months before diagnosis 1. Must include two or more of the following: a. Straining during at least 25% of defecations b. Lumpy or hard stools in at least 25% of defecations c. Sensation of incomplete evacuation following at least 25% of defecations d. Sensation of anorectal obstruction or blockage during at least 25% of defecations e. Manual maneuvers to facilitate for at least 25% of defecations (eg, digital evacuation, support of the pelvic floor) f. Fewer than three defecations per week 2. Loose stools rarely present without the use of laxatives 3. Insufficient criteria for IBS From Longstreth GF, Thompson WG, Chey WD, et al. Functional bowel disorders. Gastroenterology 2006;130:1480–91; with permission.
evacuation of stool when socially conducive. These functions are regulated by neurotransmitters, such as serotonin, acetylcholine, calcitonin gene-related peptide and substance P; intrinsic colonic reflexes; and a plethora of learned and reflex mechanisms that govern stool transport and evacuation, most of which are incompletely understood. Constipation may result from structural, mechanical, metabolic, or functional disorders that affect the colon or anorectum either directly or indirectly. As demonstrated in a study of healthy subjects showing that defecation could Box 2: Criteria for dyssynergic defecation A. Patients must fulfill the symptomatic criteria for functional constipation as defined in Box 1. B. Constipated patients must fulfill two or more of the following physiologic criteria: 1. Dyssynergic pattern of defecation (types 1–3 (see Fig. 3)) 2. Inability to expel a balloon or stool-like device, such as a fecom, within 1 minute. 3. A prolonged colonic transit time (ie, >6 markers on a plain abdominal radiograph taken 120 hours after ingestion of one Sitzmarks capsule containing 24 radio-opaque markers) 4. Inability to expel barium or >50% retention during defecography From Rao SSC. Dyssynergic defecation. Gastroenterol Clin North Am 2001;30:97–114; with permission.
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be postponed for several days [27], there is a significant interaction between the brain and the gut. This means that neurological dysfunction and abnormalities of afferent and efferent brain–gut connections may have profound effects on colonic and anorectal function. Pathophysiology of Slow Transit Constipation Because colonic motor activity is intermittent, variable, and influenced by sleep, waking, meals [28–30], physical [31] and emotional stressors [32–34], and differences in regional colonic motor function [35], the pathophysiology of constipation continues to evolve. However, recent studies have shed more light. It has been shown that patients with slow transit constipation exhibit significant impairment of phasic colonic motor activity both in stationary [28] and in prolonged 24-hour ambulatory colonic motility recordings [36,37]. Furthermore, it has been shown that the gastrocolonic responses following a meal (Fig. 1) and the morning waking responses after sleep are also significantly diminished, but the diurnal variation of colonic motor activity is preserved [37]. In contrast, periodic rectal motor activity, a three-cycles-per-minute activity that predominately occurs in the rectum and rectosigmoid region and is invariably seen at nighttime [38], significantly increases in patients with slow transit constipation [39]. This excessive uninhibited distal colonic activity may serve as a nocturnal break and retard colonic propulsion of stool [39]. Previous studies have shown that the high amplitude, prolonged duration, propagated contractions (HAPCs) are significantly decreased in constipated patients [40,41]. Furthermore, in constipated patients, the velocity of propagation is slower, waves have a greater tendency to abort prematurely, and their amplitude is also decreased [40,42]. Studies that have combined manometry with barostat recordings have shown decreased colonic tone and phasic responses to a meal, although the barostat measurements per se could not distinguish patients with normal transit, slow transit, or pelvic floor dysfunction [19,43,44]. Slow transit constipation may also be associated with autonomic dysfunction [45,46]. Several recent studies have demonstrated a paucity of interstitial cells of Cajal, suggesting the possibility of an underlying neuropathy in these individuals [47]. Because these observations were made on colectomy specimens obtained from patients with chronic constipation, it is unclear whether they represent a primary entity or whether they are secondary to the use of drugs, the use of cathartics, or behavioral changes over many years. Rarely, slow transit constipation may be associated with a more generalized dysmotility and forms part of a pseudo-obstruction syndrome [48,49]. Because constipation is associated with hard stools, one possible hypothesis is that excessive absorption of water from stool may desiccate colonic contents. However, the colonic absorptive function seems to be relatively well preserved in patients with constipation [50]. In one study, abnormally impaired hormonal responses to ingested water load were reported, but its significance is unclear [51]. Finally, in younger adults, more women than men seek medical help
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Fig. 1. The effects of a meal on a six-channel colonic manometry recording in a normal subject (A) and in a patient with slow transit constipation (B). Constipated patients show impaired postprandial or gastrocolonic motor response.
for constipation, suggesting a possible role for endocrine or hormonal imbalance [51]. A decreased level of ovarian and adrenal steroid hormones has been reported [52], but has not been confirmed. In fact, routine estrogen and progesterone levels are not impaired in most women with constipation. Also, the relationship between menstrual cycle and gut transit remains controversial [52]. Both slower transit during the luteal phase [53] and normal transit have been reported [54]. Studies of neurotransmitters in the colonic wall have also provided conflicting data [55]. A decrease in vasoactive intestinal polypeptide
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levels [56] and an increase in serotonin levels in the circular muscle [57] have been reported. In an intriguing study of G-protein–mediated smooth muscle contractility, colectomy specimens from women with slow transit constipation showed down-regulation of progesterone-dependent contractile G proteins and up-regulation of inhibitory G proteins when compared with those from nonconstipated controls [58]. These changes were probably due to an over-expression of progesterone receptors [59]. This study offers some mechanistic insights as to why women are more prone to constipation. Most recently, it has been observed that there is a higher prevalence of methanogenic flora in constipated patients [60–62] and that infusion of methane gas impairs muscle contractions [63]. Further study is needed to determine whether methanogenic flora predisposes an individual to develop constipation or is a consequence of altered colonic physiology. Pathophysiology of Dyssynergic Defecation In two thirds of patients, dyssynergic defecation appears to be an acquired behavioral disorder of defecation. In the remaining one third, the process of defecation may not have been learnt in childhood [9]. Earlier studies suggested that paradoxical anal contraction or involuntary anal spasm (anismus) during defecation might cause dyssynergic defecation [14,17,64]. Of healthy subjects, 20% to 30% may also exhibit paradoxical anal contraction [35,65,66]. Based on the notion that dyssynergic defecation is a spasmodic dysfunction of the anal sphincter, myectomy of the anal sphincter has been performed [17,67]. Although preliminary studies were encouraging, a more critical assessment has shown that myectomy helps only 10% to 30% of patients [67]. Similarly, most patients who received botulinum toxin injections as a method of paralyzing the anal sphincter muscle and reversing the anal spasm did not improve [68,69]. In a prospective study, most patients with dyssynergic defecation showed abnormal coordination of the abdominal, rectoanal, and pelvic floor muscles during attempted defecation [25]. This failure of rectoanal coordination may consist of several mechanisms that include impaired rectal contraction, paradoxical anal contraction, or inadequate anal relaxation [25]. Thus, incoordination or dyssynergia of the muscles involved in defecation is most likely responsible for this problem [13]. Additionally, nearly half of dyssynergic patients exhibited impaired rectal sensation [25]. CLINICAL FEATURES Constipated patients present with a constellation of symptoms that include a feeling of incomplete evacuation; excessive straining; passage of hard, pellet-like stool; digital disimpaction or vaginal splinting; a lump-like sensation; or blockage in the anal region [9,13]. Additionally, they may report infrequent defecation, often less than three bowel movements per week; abdominal or anorectal discomfort; pain; or bloating [9]. Patients may misrepresent their symptoms or may feel embarrassed to admit the use of digital maneuvers to
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disimpact stool or to splint their vagina to facilitate defecation. However, by establishing a trustworthy relationship or through the use of symptom questionnaires or stool diaries [9], it is possible to define the nature of bowel dysfunction in these patients. A detailed inquiry that includes the nature of the problem, precipitating events, the duration and severity of the problem, and its onset, whether from childhood or following surgery, may all prove beneficial. A long history of recurring problems refractory to dietary measures or laxatives often suggest a functional colorectal disorder, whereas a history of recent onset should alert the physician to seek and exclude an organic illness, including neoplastic disease. The history should also include an assessment of stool frequency, stool consistency, stool size, and degree of straining during defecation, and a history of ignoring a call to stool. The Bristol Stool Scale is an invaluable tool in the assessment of constipation. This not only correlates with transit time but is also the best descriptor of stool form and consistency [70,71]. A dietary history should include an assessment of the amount of fiber and fluid intake, the number of meals, and when they are consumed. Many patients tend to skip breakfast as a result of the ‘‘early morning rush.’’ This may prove to be a handicap because there is a two- to threefold increase in colonic motility after waking [30] and after a meal [28,29]. Thus, skipping breakfast and not devoting time toward bowel function in the morning may deprive the colon of an important physiological stimulus. The history should also include the number and type of laxatives and frequency of their use. A family history of using laxatives and a family history of bowel dysfunction may also be important. In one survey, a family history was noted in 30% of patients [9]. Obstetrical, surgical, and drug history is also useful. A history of back trauma or neurological problems may provide additional clues regarding the etiology of constipation. In the elderly, fecal incontinence may be a presenting symptom of stool impaction. However, symptoms alone do not appear to differentiate constipated patients into the three common pathophysiologic subgroups [72]. In a prospective survey of 120 patients with dyssynergic defecation, excessive straining was reported by 85% of patients, a feeling of incomplete evacuation by 75%, the passage of hard stools by 65%, and a stool frequency of fewer than three bowel movements per week by 62% [9]. Amongst this group, 66% used digital maneuvers to facilitate defecation [9]. In another study of 134 patients, two or fewer stools per week, laxative dependency, and constipation since childhood were associated with slow transit constipation, whereas backache, heartburn, anorectal surgery, and a lower prevalence of normal stool frequency were reported by patients with pelvic floor dysfunction [73]. It was concluded from this study that symptoms were good predictors of transit time, but poor predictors of pelvic floor dysfunction. In another study of 190 patients, stool frequency alone was of little value in the evaluation of constipation but a sense of obstruction or digital-assisted evacuation was specific but not sensitive for difficult defecation [72]. Thus, symptom assessment should be combined with objective testing to better assess the nature of a patient’s complaint.
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PHYSICAL EXAMINATION A thorough physical examination that includes a detailed neurological examination should be performed to exclude systemic illnesses that may cause constipation. The abdomen must be carefully examined for the presence of stool, particularly in the left or right lower quadrant. A normal physical examination is not uncommon but it is important to exclude a gastrointestinal mass. Anorectal inspection may reveal skin excoriation, skin tags, anal fissure, or hemorrhoids. Perineal sensation and the anocutaneous reflex can be assessed by gently stroking the perineal skin in all four quadrants with the help of a cotton bud (Q-Tip) or with a blunt needle. Normally, stroking the perianal skin invokes a reflex contraction of the external anal sphincter. If absent, one should clinically suspect neuropathy. A careful digital rectal examination should be performed to identify the presence of a rectal stricture, stool, or blood in the stool. During digital examination, it is important to ask the patient to bear down as if to defecate. During this maneuver, the examiner should perceive relaxation of the external anal sphincter together with perineal descent. If these features are absent, one should suspect functional obstructive or dyssynergic defecation [13]. DIAGNOSTIC PROCEDURES The first step in making a diagnosis of constipation is to exclude an underlying metabolic or pathologic disorder because constipation may be the first symptom of many organic conditions, such as colon cancer. A complete blood count, biochemical profile, serum calcium, glucose levels, and thyroid function tests are usually sufficient for screening purposes. If there is a high index of suspicion, serum protein electrophoresis, urine porphyrins, serum parathyroid hormone, and serum cortisol levels may be requested. Most patients, once organic disorders have been excluded, are found to have a functional neuromuscular disorder. An evaluation of the distal colonic mucosa through flexible sigmoidoscopy may provide evidence for chronic laxative use or may reveal melanosis coli or other mucosal lesions, such as solitary ulcer syndrome, inflammation, or malignancy. Slow transit constipation may coexist with dyssynergic defecation [25,74] and hence assessment of colonic transit together with anorectal function is useful. RADIOGRAPHIC STUDIES A plain radiograph of the abdomen may provide evidence for an excessive amount of stool in the colon. If colonoscopy has not been performed, a barium enema may be useful for excluding colonic pathology. Patients with constipation may have a redundant sigmoid colon, a megacolon, or megarectum. The presence of Hirschsprung’s disease can also be detected by barium enema, although manometry and histology are required to confirm the diagnosis. Colonic Transit Study Because a patient’s recall of stool habit is often inaccurate, an assessment of colonic transit time enables the physician to better understand the rate of stool
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movement through the colon [75]. Several techniques have been described for performing this test [29]. These include the single capsule technique [4] and the multiple capsule technique [76]. The validity of multiple capsule techniques has been questioned [77]. However, for routine clinical purposes, a single capsule technique is sufficient. This test is performed by having the patient swallow a single Sitzmarks capsule (Konsyl Pharmaceuticals, Fort Worth, Texas) containing 24 radio-opaque markers on day 1 and by obtaining a plain radiograph of the abdomen on day 6 (ie, 120 hours later). This study may reveal one of three patterns: Normal transit: less than five markers remaining in the colon [19] Slow transit: six or more markers scattered throughout the colon Functional obstructive or dyssynergic defecation pattern: six or more markers in the rectosigmoid region with a near normal transit of markers through the rest of the colon
Two thirds of patients with dyssynergic defecation may exhibit a mixed pattern consisting of both slow transit and obstructive delay [25]. In some patients with constipation, the colon transit time may be normal. In these subjects it is important to exclude pelvic floor dysfunction. Assessment of colonic transit using a novel, wireless capsule technique— SmartPill (SmartPill Corporation, Buffalo, New York)—provides a noninvasive technique of assessing not only colonic transit time but also simultaneously gastric emptying and small bowel transit time (Fig. 2). It also provides information regarding colonic contractile activity and pH. Preliminary studies in healthy controls have shown that the colonic transit time as assessed by the SmartPill correlates very well with that of the Sitzmarks technique [78]. Anorectal Manometry Anorectal manometry provides a comprehensive assessment of the pressure activity in the rectum and anal sphincter region together with an assessment of rectal sensation, rectoanal reflexes, and rectal compliance [34,35]. The technique of anorectal manometry and its utility has been discussed previously [35]. It helps to exclude the possibility of Hirschsprung’s disease. Normally, when a balloon is distended in the rectum, there is reflex relaxation of the internal anal sphincter that is mediated by the myenteric plexus. This reflex response is absent in patients with Hirschsprung’s disease, but this condition is rare in adults. Manometry helps to detect abnormalities during attempted defecation. When a subject attempts to defecate normally, rectal pressure rises. This rise is synchronized with a fall in anal sphincter pressure, in large part due to relaxation of the external anal sphincter (Fig. 3). This maneuver is under voluntary control and is primarily a learned response. The inability to perform this coordinated movement represents the chief pathophysiologic abnormality in patients with dyssynergic defecation [13,25]. This inability may be due to impaired rectal contraction, paradoxical anal contraction, impaired anal
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Fig. 2. Whole gut transit time in a patient with slow transit constipation showing prolonged colonic residence time as assessed by wireless capsule technology (SmartPill). The gastric and small bowel residence times appear to be within normal limits. GRT, gastric residence time; SBRT, small bowel residence time.
relaxation, or a combination of these mechanisms. Based on these features, at least three types of dysfunction have been recognized [79]: Type 1: The patient can generate an adequate pushing force (rise in intra-abdominal and intrarectal pressure) along with a paradoxical increase in the anal sphincter pressure. Type 2: The patient is unable to generate an adequate pushing force (no increase in intrarectal pressure), but can exhibit a paradoxical anal contraction. Type 3: The patient can generate an adequate pushing force (increase in intrarectal pressure), but has absent or incomplete (<20%) sphincter relaxation (ie, no decrease in anal sphincter pressure).
In addition to the motor abnormalities just described, sensory dysfunction may also be present. The threshold for first sensation and the threshold for a desire to defecate may be higher in about 60% of patients with dyssynergic defecation [25]. This may also be associated with increased rectal compliance. During attempted defecation, some subjects may not produce a normal relaxation largely because of the laboratory conditions [35,65]. Hence, the occurrence of this pattern alone should not be considered as diagnostic of dyssynergic defecation (see diagnostic criteria). By observing the manometric recordings during attempted defecation, it is possible to identify the sequence
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Fig. 3. A normal and abnormal (dyssynergic) pattern of defecation. A normal pattern consists of a rise in the intrarectal pressure coordinated with relaxation of anal sphincter pressure. In contrast, a dyssynergic pattern is associated with a paradoxical increase in anal sphincter pressure. Typical patterns for a normal and dyssynergic pattern of defecation as measured during anorectal manometry with a pressure sensor in the rectum and a pressure sensor in the anal canal.
that most closely resembles a normal pattern of defecation (see Fig. 3). This recording can be used to measure the intrarectal pressure, the anal residual pressure, and the percentage of anal relaxation [35,65]. From these measurements, it is possible to estimate an index of the forces required to perform defecation—the defecation index [35]. The defecation index may serve as a simple and quantifiable measure of the recto-anal coordination during defecation [13,35]. Balloon Expulsion Test This test provides an assessment of the patient’s ability to defecate in the laboratory. Either a silicone-filled stool-like device such as the fecom [80] or a 4-cm long balloon filled with 50 mL of warm water is placed in the rectum [35]. A stopwatch is started and the attendant leaves the room to provide privacy for the patient during balloon expulsion. The patient is asked to expel the device and then immediately stop the clock. Most normal subjects can expel a stool-like device within 1 minute [35]. If the patient is unable to expel the device within 3 minutes, the clinician should suspect dyssynergic defecation. Defecography Defecography provides useful information about anatomical and functional changes of the anorectum. It is performed by placing approximately 150 mL of barium into the patient’s rectum and having the subject squeeze, cough, and bear down. In patients with dyssynergic defecation, the test may reveal poor activation of levator muscles, prolonged retention of contrast material, inability to expel the barium, or the absence of a stripping wave in the rectum. Patients may find this test embarrassing. Also, the type and consistency of
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barium paste varies considerably among different centers [80]. Because of these inherent deficiencies, defecography should be regarded as an adjunct to clinical and manometric assessment of anorectal function and should not be relied upon as a sole test for assessing defecatory dysfunction [23]. Colonic Manometry The advent of solid-state manometry probes and portable recorders now enables investigators to perform ambulatory colonic manometry over prolonged periods [29,30,34]. Studies have revealed that the colonic motor patterns are complex [34,79] and that the activity is intermittent, variable, and influenced by many factors, such as sleep, waking, meals [29,30,34], and stressors [30,33,81]. The hallmarks of colonic pressure activity are HAPCs, as well as the meal-related and postwaking increase in colonic motor activity [34,37]. Colonic manometry has been shown to be useful in the management of refractory constipation in children [82], but a recent study showed that the test is also useful in adults and can facilitate the selection of patients for surgery [37]. In a case-controlled study, most patients with manometric features of colonic neuropathy (absence of any two of three normal colonic motor responses and presence of HAPCs, gastrocolonic response, and morning waking response) failed to respond to aggressive medical treatment and had a better clinical outcome after colectomy, whereas those with a myopathy and those with a normal colonic motor activity responded adequately to medical treatment [37]. Thus, colonic manometry can serve as an adjunct to current methods of assessing colonic function, particularly in patients with severe constipation [37]. An evidence-based summary of the utility of physiologic and imaging tests in the evaluation of chronic constipation [83] is shown in Table 1 [84]. MANAGEMENT OF CONSTIPATION The first step in managing constipation is to exclude a secondary cause for constipation. This can be accomplished by performing the appropriate tests outlined above. Constipation may be caused by anatomical lesions of the colon or rectum, endocrine or metabolic disorders, neurologic diseases, or a variety of drugs [12]. Constipation is a common and often overlooked adverse effect of many drugs. Some drugs have anticholinergic effects, others desiccate stool, and several others, including analgesics, can cause constipation by altering colonic motility, by interfering with intrinsic colonic reflexes, or by reducing the awareness for stooling. A few other factors merit further discussion. An evidence-based summary of treatment options for chronic constipation [85,86] is shown in Table 2. Fluid Intake and Exercise General measures that include adequate hydration, regular nonstrenuous exercise, and dedicated time for passing bowel movements may all be useful, but there is little evidence to support this. In a small study (six tests and nine controls) of healthy volunteers, consumption of extra fluid produced no
Clinical utility Test
Strength
Weakness
Evidence
Recommendation (grade)a
Colonic transit study with radio-opaque markers Colonic transit study with scintigraphy
Evaluates presence of slow, normal, or rapid colonic transit; inexpensive and widely available Evaluates presence of slow, normal, or rapid colonic transit; provides a whole evaluation of the gut transit Identifies dyssynergic defecation, rectal hyposensitivity, rectal hypersensitivity, impaired compliance, Hirschsprung’s disease Simple, inexpensive, bedside assessment of the ability to expel a simulated stool; identifies dyssynergic defecation Identifies colonic myopathy, neuropathy, or normal function facilitating selection of patients for surgery
Inconsistent methodology; validity has been questioned
Good
B2
Useful to classify patients according to pathopysiological subtypes
Expensive, time-consuming, limited availability, lack of standardization
Good
B2
Useful to classify patients according to pathopysiological subtypes
Lack of standardization
Good
B2
Lack of standardization
Good
B2
Invasive, not widely available, lack of standardization
Fair
B3
Useful to establish the diagnoses of Hirschsprung’s disease, dyssynergic defecation, and rectal hypo- and hypersensitivity Normal balloon expulsion test does not exclude dyssynergia; should be interpreted alongside results of other anorectal tests Adjunct to colorectal function tests; useful before considering colectomy
Anorectal manometry
Balloon expulsion test
Colonic manometry
Comment
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Grade A1: excellent evidence in favor of the test based on high specificity, sensitivity, accuracy, and positive predicative values. Grade B2: good evidence in favor of the test with some evidence on specificity, sensitivity, accuracy, and predictive values. Grade B3: fair evidence in favor of the test with some evidence on specificity, sensitivity, accuracy, and predictive values. Grade C: poor evidence in favor of the test with some evidence on specificity, sensitivity, accuracy, and predictive values. a Grades for levels of evidence modified from Sackett DL. Rules of evidence and clinical recommendations on the use of antithrombotic agents. Chest 1986;89:2S–3S. Modified from Remes-Troche JM, Rao SS. Diagnostic testing in patients with chronic constipation. Curr Gastroenterol Rep 2006;8:422.
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Table 1 Evidence-based summary of the utility of physiologic tests for chronic constipation
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Table 2 Evidence-based summary for the treatment of constipation Treatment modalities commonly used for constipation Bulking agents Psyllium Calcium polycarbophil Bran Methycellulose Osmotic laxatives Lactulose Polyethylene glycol Wetting agents Dioctyl sulfosuccinate Stimulant laxatives Senna Bisacodyl Others Tegaserod Lubiprostone Biofeedback therapy for dyssynergic defecation Surgery in the treatment of severe colonic inertia
Recommendation level and grade of evidence Level Level Level Level
II; grade B III; grade C III; grade C III; grade C
Level II; grade B Level I; grade A Level III; grade C Level III; grade C Level III; grade C Level I; grade A Level I; grade B Level I; grade A Level II; grade B
Level I: good evidence—consistent results from well-designed, well-conducted studies. Level II: fair evidence—results show benefit, but strength is limited by the number, quality, or consistency of the individual studies. Level III: poor evidence—insufficient because of limited number or power of studies, and flaws in their design or conduct. Grade A: good evidence in support of the use of a modality in the treatment of constipation. Grade B: moderate evidence in support of the use of a modality in the treatment of constipation. Grade C: poor evidence to support a recommendation for or against the use of the modality. Grade D: moderate evidence against the use of the modality. Grade E: good evidence to support a recommendation against the use of a modality. Data from Remes-Troche JM, Rao SSC. Defecation disorders: neuromuscular aspects and treatment. Curr Gastroenterol Rep 2006;8(4):291–9.
difference in stool output [87]. The role of exercise in improving colonic function is also controversial. Epidemiologic studies suggest that sedentary folks are three times more likely to report constipation [88]. However, the effects of exercise and gut transit time are inconsistent. A recent study showed that exercise decreases the number of phasic contractions in the colon and that this effect depends on the intensity of exercise [31]. Also, there was a proportionate increase in the number of propagated contractions, particularly in the postexercise period, which may accelerate colonic transit [31]. Most patients who have a normal bowel pattern usually empty stools at approximately the same time every day [89]. This fact suggests that the initiation of defecation is in part a conditioned reflex. Therefore, ritualizing bowel habit may be useful and it is advisable to encourage patients to establish a regular pattern of bowel movement. Colonic motor activity is more active after
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waking and after a meal [29,30]. Hence, the optimal time for bowel movement is usually within the first 2 hours after waking and after breakfast. Other general measures include timed toilet training that consists of educating patients to attempt a bowel movement at least twice a day, usually 30 minutes after meals, and to strain for no more than 5 minutes. During attempted defecation, patients must be instructed to push at a level of 5 to 7, assuming a maximum effort of straining of 10. They should also be encouraged to capitalize on the physiological events that stimulate colonic motility, such as the waking and the postprandial gastrocolonic responses [13]. Diet and Fiber A high fiber diet increases stool weight and accelerates colonic transit time [90]. In contrast, diet that is deficient of fiber may lead to constipation [90,91]. Constipated patients who had either slow transit or pelvic floor dysfunction responded poorly to dietary supplementation with 30 g of fiber per day, whereas those patients without an underlying motility disorder either improved or became symptom-free [92]. Thus, fiber intake may not be a panacea for all patients. A systematic review found 18 double-blind studies related to this issue [93]. Six trials that evaluated bulk laxatives or dietary fiber showed an average weighted increase of 1.4 (95% CI, 0.6–2.2) bowel movements per week, whereas the seven trials that evaluated laxative agents other than bulk, showed an increase of 1.5 (95% CI, 1.1–1.8) bowel movements per week. Other direct comparisons between laxatives and fiber were inconclusive because of the limited number of studies, small sample size, and problems with methodology. With regards to symptom improvement, fiber consistently decreased abdominal pain and improved stool consistency, but the difference was not statistically significant when compared with other laxatives [93]. In general, a fiber intake of 20 to 30 g of fiber per day is optimal. Laxatives Laxatives still remain the mainstay of treatment for constipation. About $821 million was spent on over-the-counter laxatives in the United States [94]. Several recent reviews have discussed the common classification of laxatives, their mode of action, the recommended dosage, and potential side effects [19,20]. In addition, a meta-analysis has examined the use of bulk and nonbulk laxatives in patients with constipation [93]. Although there are a variety of preparations, including several over-the-counter compounds, the laxatives that are frequently recommended include milk of magnesia, lactulose, senna compounds, bisacodyl, and polyethylene glycol preparations. In a trial of constipated elderly patients, sorbitol administered as 70% syrup was as efficacious as lactulose in improving symptoms but was cheaper and better tolerated during a 4-week trial [95]. In another trial of 77 elderly nursing home residents, a senna fiber combination was felt to be better than lactulose in improving stool frequency, stool consistency, and ease of passage. In terms of costs, the senna fiber combination was 40% cheaper [96].
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Polyethylene glycol is a large polymer that is not degraded by bacteria and serves as an osmotic laxative. Recent double-blind studies conducted over a 2-week [97] and an 8-week period [98] showed that polyethylene glycol 3350 solutions increased stool frequency and improved bowel symptoms. In a longterm multicenter study of polyethylene glycol 4000, 14.6 g twice a day improved stool frequency, reduced straining effort, softened stools, and decreased the need for oral laxatives and enemas compared with placebo [99]. Among those who completed the study, the stool frequency at baseline was 1.5 versus 1.8; after 2 weeks of treatment with polyethylene glycol 4000 was 8.3 versus 7.4; and after 6 months of polyethylene glycol or placebo was 7.7 versus 5.4, respectively. Thus, polyethylene glycol may be effective in the long term. However, there was a 30% dropout in the polyethylene glycol group and a 60% dropout in the placebo group, raising concerns about efficacy and tolerance. Hence, confirmatory trials are awaited. Slow Transit Constipation Before labeling a patient as suffering with either slow transit constipation or colonic inertia, it is important to exclude pelvic floor dysfunction. Ideally, slow transit constipation should be treated with an agent that restores normal colonic function. Table 2 [86] shows a list of agents that are currently available or in phase III/IV clinical trials for the treatment of constipation. These include secretagogues and prokinetics. Drugs in the former category include lubiprostone, colchicine, and misoprostol [100]. Lubiprostone is an oral bicyclic fatty acid that belongs to a new class of drugs called prostones. It activates the type 2 chloride channels that are located on the intestinal epithelial cell leading to an active secretion of chloride in the intestinal lumen [101]. In healthy humans, a whole-gut scintigraphic study reported that lubiprostone slowed gastric emptying, but accelerated small bowel transit time and colonic transit time at 24 hours [102]. In randomized controlled studies with an intention to treat analysis, lubiprostone significantly increased the number of spontaneous bowel movements per week, improved straining effort, raised overall satisfaction with bowel habit, and produced softer stools when compared with placebo [103]. Likewise, recent studies of tegaserod, which is a serotonin compound and a 5-hydroxytryptamine 4 (5HT4) partial agonist, revealed that the drug accelerates gastric emptying and colonic transit time [104]. Furthermore large randomized controlled trails in United States and Europe have revealed that tegaserod increases the number of complete spontaneous bowel movements per week, relieves other bothersome constipation-related symptoms, and improves overall bowel satisfaction [103,105]. Recent open-labeled studies reveal that the effects of the drug are sustained over 12 months. Just recently, sales of tegaserod have been suspended because of a 0.01% incidence of coronary and cerebrovascular events. Hence, the drug is not currently available. Table 3 provides information regarding the drug profiles for lubiprostone and tegaserod.
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Table 3 Pharmacologic profiles of lubiprostone and tegaserod
Drug class Mechanism of action
Lubiprostone
Tegaserod
Chloride channel activator Increases intestinal fluid secretion
5HT4 agonist Stimulates the peristaltic reflex
Indications
Chronic idiopathic constipation in male and female patients
Dose and administration Adverse events
24 lg twice daily orally with food Nausea (31.1%) Diarrhea (13.2%) Headache (13.2%) Abdominal pain (6.7%)
Stimulates intestinal secretion Inhibits visceral sensitivity Chronic idiopathic constipation in male and female patients aged <65 years, IBS-C in female patients 6 mg twice daily orally before meals Headache (15%) Diarrhea (7%) Abdominal pain (5%) Nausea (5%)
Emerging Therapies A number of treatments are currently being investigated in clinical trials. Renzapride and mosapride are both 5-hydroxytryptamine 3 (5-HT3) agonists– 5-HT4 antagonists that have very similar mechanisms of action. In preliminary studies, both agents demonstrated clinically significant dose-related acceleration of colonic transit. Currently, renzapride is being evaluated in IBS-C patients and there is also potential to research the effects of the agents in patients with chronic constipation [106]. Another drug, alvimopan, is a peripherally acting l–opioid receptor antagonist. This agent does not cross the blood–brain barrier and, therefore, does not inhibit the analgesic effect of opioids. In a physiologic study, alvimopan reversed opioid-induced delayed colonic transit in healthy subjects [107]. Another 21-day randomized trial assessed alvimopan in 168 patients with opioid-induced bowel dysfunction. Within 8 hours of treatment, at least one bowel movement was achieved in 54% of subjects who received 1 mg alvimopan and in 43% of those who received 0.5 mg compared with 29% of those who received placebo [108]. Alvimopan is effective in the treatment of acute postoperative ileus [109]. Linaclotide, a guanylate cyclase C agonist accelerates gut transit and is being tested in patients with constipation [110,111]. Dyssynergic Defecation The treatment of a patient with dyssynergic defecation consists of standard treatment for constipation, including diet, laxatives, timed toilet training, and other measures outlined above, together with specific treatment consisting of neuromuscular conditioning using biofeedback techniques [13]. Other avenues that have been tried include botulinum toxin injection [68,69], anal myectomy, and surgical approaches [17,67]. Details regarding the specifics of performing
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biofeedback therapy have been discussed previously [13]. The purpose of biofeedback therapy is to restore a normal pattern of defecation by using an instrument-based education program. The primary goals are to correct the underlying dyssynergia that affects the abdominal, rectal, and anal sphincter muscles, and to improve the rectal sensory perception. Patients are initially taught diaphragmatic breathing techniques to improve their abdominal pushing effort and to synchronize this with anal relaxation. Thereafter, visual or auditory feedback techniques are used to provide input to the patient regarding his or her performance during attempted defecation maneuvers. The patient’s posture and breathing techniques are also corrected using verbal reinforcement techniques. The number of training sessions should be customized to the patient’s need. Three recent randomized controlled studies have bolstered the evidence supporting the use of biofeedback therapy in dyssynergic defecation. Chiarioni and colleagues [112] compared polyethylene glycol (n ¼ 55) with five weekly biofeedback sessions (n ¼ 54) in patients who were nonresponders to conservative therapy. At 6 months, major improvements were reported by patients enrolled in the biofeedback arm (43 of 54 or 80%) compared with the polyethylene glycol and counseling group (12 of 55 or 22%). The benefit of biofeedback was sustained at 12 and 24 months. A second study by Chiarioni [113] in 2005 compared the benefits of biofeedback in patients with slow transit constipation to those with dyssynergia. At 6 months, greater improvement was seen in the dyssynergia group compared with the slow transit only group (71% versus 8% reported improved satisfaction). This study suggests that biofeedback helps patients with dyssynergia but not patients with slow transit. Finally, a recent study by Rao and colleagues [114] compared biofeedback with sham biofeedback or standard therapy of diet, exercise, and laxatives in 77 patients. Dyssynergia was corrected in 79% of patients in the biofeedback group compared with 4% in the sham group. The number of complete spontaneous bowel movements was higher in the biofeedback group compared with sham group (Fig. 4), and overall bowel satisfaction also improved in the biofeedback group. Balloon expulsion time and the colonic transit time decreased significantly in the biofeedback group. Thus, biofeedback therapy appears to be the preferred method of treatment for patients with dyssynergic defecation. Stool Impaction and Refractory Constipation Including Surgery Patients with stool impaction or those with hard stools that are difficult to expel require digital disimpaction. This can be painful and may require sedation or anesthesia. Once the colon has been cleaned, these patients require a rigorous bowel-conditioning regime of laxatives and suppositories to prevent stool impaction. Glycerin or bisacodyl suppository together with enemas are usually successful, but have not been prospectively assessed. Additional measures include saline or osmotic laxatives or polyethylene glycol solutions. After establishing a bowel regime, it is important to assess these patients for an underlying colonic or generalized motility disorder.
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Fig. 4. Effects of biofeedback, sham feedback, and standard therapy on the number of complete spontaneous bowel movements per week in patients with dyssynergic defecation. (From Rao SS, Seaton K, et al. Randomized controlled trial of biofeedback, sham feedback, and standard therapy for dyssynergic defecation. Clin Gastroenterol Hepatol 2007;5:335; with permission.)
In patients with constipation that is refractory to medical therapy, surgery can be an option. However, before considering surgery, it is important to establish that the problem is confined to the colon and does not represent a generalized neuromuscular dysfunction of the gut. It has been suggested that segmental colonic resection may be beneficial in some situations, particularly in children [115]. Controlled data are lacking however. Children with refractory constipation may also have neuromuscular dysfunction confined to welldefined colonic segments [115]. Surgical options for refractory constipation include colectomy and ileostomy or ileorectal anastomosis [116]. The use of laparoscopic colectomy may further help to improve this procedure [117]. In a large series of carefully selected patients, results of surgery were quite favorable [116]. However, surgery should be considered as a last resort for patients with constipation. It is important to emphasize that colectomy with ileorectal anastomosis does not improve symptoms in patients with dyssynergic defecation unless their dyssynergia has been corrected. Similarly, colectomy may not offer symptom relief for constipated patients with abdominal pain or psychosocial problems [118]. EVIDENCE-BASED SUMMARY FOR THE TREATMENT OF CONSTIPATION A systematic review of the literature using an evidence-based approach for various treatment options is summarized in Table 2. For each specific content area, the supporting evidence was graded using a three-point graded scale [86]. Level 1 evidence was derived from one or more randomized clinical trials. Level 2 evidence was supported by one or more well-designed cohort or case-control studies. Level 3 evidence was derived from expert opinion, based on clinical experience. Evidence was further subdivided into five
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categories: A—good evidence in favor of the intervention; B—moderate evidence in favor of the intervention; C—poor evidence to support a recommendation for or against the use of the intervention; D—moderate evidence against the intervention; E—good evidence against the intervention. SUMMARY Constipation is a common polysymptomatic clinical disorder that affects up to 20% of the world’s population. It leads to significant economic burden, loss of work-related productivity, and diminished quality of life. Studies over the past decade have led to an improved understanding of the underlying mechanisms, especially as they relate to colonic and anorectal function. Although many conditions, such as metabolic problems, fiber deficiency, anorectal problems, and drugs, can cause constipation, when these conditions are excluded, functional chronic constipation consists of three overlapping subtypes: slow transit constipation, dyssynergic defecation, and irritable bowel syndrome with constipation. The Rome criteria may serve as a useful guide for making a clinical diagnosis of functional constipation. Today, an evidence-based approach can be used to treat patients with chronic constipation. The availability of specific drugs for the treatment of chronic constipation, such as tegaserod and lubiprostone, has enhanced the therapeutic armamentarium for the management of these patients. Randomized controlled trials have also established the efficacy of biofeedback therapy in the treatment of dyssynergic defecation. References [1] Pare P, Ferrazzi S, Thompson WG, et al. An epidemiological survey of constipation in canada: definitions, rates, demographics, and predictors of health care seeking. Am J Gastroenterol 2001;96:3130–7. [2] Stewart WF, Liberman JN, Sandler RS, et al. Epidemiology of constipation (EPOC) study in the United States: relation of clinical subtypes to sociodemographic features. Am J Gastroenterol 1999;94:3530–40. [3] Pare P, Ferrazzi S, Thompson WG. A Longitudinal Survey of Self-reported Bowel Habits in the United States. Dig Dis Sci 1989;34:1153–62. [4] Talley NJ, Fleming KC, Evans JM, et al. Constipation in an elderly community: a study of prevalence and potential risk factors. Am J Gastroenterol 1996;91:19–25. [5] Sonnenberg A, Koch TR. Physician visits in the United States for constipation: 1958 to 1986. Dig Dis Sci 1989;34:606–11. [6] Higgins PD, Johanson JF. Epidemiology of constipation in North America: a systematic review. Am J Gastroenterol 2004;99:750–9. [7] Martin BC, Barghout V, Cerulli A. Direct medical costs of constipation in the United States. Manag Care Interface 2006;19:43–9. [8] Chang L, Toner BB, Fukudo S, et al. Gender, age, society, culture, and the patient’s perspective in the functional gastrointestinal disorders. Gastroenterology 2006;130:1435–46. [9] Rao SS, Tuteja AK, Vellema T, et al. Dyssynergic defecation: demographics, symptoms, stool patterns, and quality of life. J Clin Gastroenterol 2004;38:680–5. [10] Pare P, Gray J, Lam S, et al. Health-related quality of life, work productivity, and health care resource utilization of subjects with irritable bowel syndrome: baseline results from LOGIC (Longitudinal Outcomes Study of Gastrointestinal Symptoms in Canada), a naturalistic study. Clin Ther 2006;28:1726–35, discussion 1710–1.
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[105] Kamm MA, Muller-Lissner S, Talley NJ, et al. Tegaserod for the treatment of chronic constipation: a randomized, double-blind, placebo-controlled multinational study. Am J Gastroenterol 2005;100:362–72. [106] Camilleri M, McKinzie S, Fox J, et al. Effect of renzapride on transit in constipation-predominant irritable bowel syndrome. Clin Gastroenterol Hepatol 2004;2:895–904. [107] Gonenne J, Camilleri M, Ferber I, Burton D, Baxter K, Keyashian K, Foss J, Wallin B, Du W, Zinsmeister AR. Effect of alvimopan and codeine on gastrointestinal transit: a randomized controlled study. Clin Gastroenterol Hepatol 2005;3:784–91. [108] Paulson DM, Kennedy DT, Donovick RA, et al. Alvimopan: an oral, peripherally acting, mu-opioid receptor antagonist for the treatment of opioid-induced bowel dysfunction– a 21-day treatment-randomized clinical trial. J Pain 2005;6:184–92. [109] Camilleri M. Alvimopan, a selective peripherally acting mu-opioid antagonist. Neurogastroenterol Motil 2005;17:157–65. [110] Currie M. Effects of a single dose administration of MD-1100 on safety,tolerability,exposure, and stool consistency in heathy subjects. Am J Gastroenterol 2005;100:S328. [111] Kurtz C. Effects of multi-dose administration of MD-1100 on safety,tolerability,exposure, and pharmacodynamics in healthy subjects. Gastroenterology 2006;130:A26. [112] Chiarioni G, Whitehead WE, Pezza V, et al. Biofeedback is superior to laxatives for normal transit constipation due to pelvic floor dyssynergia. Gastroenterology 2006;130: 657–64. [113] Chiarioni G, Salandini L, Whitehead WE. Biofeedback benefits only patients with outlet dysfunction, not patients with isolated slow transit constipation. Gastroenterology 2005;129:86–97. [114] Rao SS, Seaton K, Miller M, et al. Randomized controlled trial of biofeedback, sham feedback, and standard therapy for dyssynergic defecation. Clin Gastroenterol Hepatol 2007;5:331–8. [115] Lorenzo DIC, Flores AF, Reddy SN, et al. Use of Colonic Manometry to Differentiate Causes of Contractable Constipation in Children. J Pediatr 1992;120:690–5. [116] Pemberton JH, Rath DM, Ilstrup DM. Evaluation and surgical treatment of severe chronic constipation. Ann Surg 1991;214:403–11, discussion 411–3. [117] Ho YH, Tan M, Eu KW, et al. Laparoscopic-assisted compared with open total colectomy in treating slow transit constipation. Aust N Z J Surg 1997;67:562–5. [118] Nyam DC, Pemberton JH, Ilstrup DM, et al. Long-term results of surgery for chronic constipation. Dis Colon Rectum 1997;40:273–9.
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GASTROENTEROLOGY CLINICS OF NORTH AMERICA
Gastrointestinal Electrical Stimulation for Treatment of Gastrointestinal Disorders: Gastroparesis, Obesity, Fecal Incontinence, and Constipation Zhiyue Lin, MS, Irene Sarosiek, MD, Richard W. McCallum, MD, FACP, FRACP(AUST), FACG* Center for GI Nerve and Muscle Function, Department of Internal Medicine, University of Kansas Medical Center, Mail Stop 1058, 3910 Rainbow Boulevard, Kansas City, KS 66160, USA
G
astrointestinal electrical stimulation (GES) was advocated as a possible treatment for gastric motor dysfunction as early as in 1963. Bilgutay and colleagues [1] reported the use of transluminal electrical stimulation by the tip of a nasogastric tube to induce peristalsis and shorten recovery from ileus after laparotomy. They stimulated the stomachs of both dogs and humans with pulse bursts and observed augmented gastric contractions fluoroscopically and increased gastric emptying but did not record either electrical or mechanical activity. Subsequent randomized controlled studies, however, failed to confirm any significant effect of this type of gastrointestinal stimulation on the duration of postoperative ileus [2–4]. In the late 1960s and early 1970s, experiments, primarily in the canine model, began to elucidate the nature of gastrointestinal myoelectrical activity, how to record it, and its relation to contractions [5–13]. Since that time there have been numerous reports on the applications of electrical stimulation to affect gastrointestinal motility both acutely and chronically [14–72]. Different methods of electrical stimulation have been derived from the variation of stimulation parameters, including long-pulse stimulation, short-pulse stimulation, and stimulation with a train of pulses. Electroacupuncture may also be considered as a methodologic variation of electrical stimulation because electrical stimuli are delivered by needles inserted into acupuncture points associated with the gastrointestinal tract [73]. Long-pulse electrical stimulation is able to entrain gastrointestinal slow waves and improve gastric emptying and intestinal transit [17,25– 27,31,32,54,55,74,75]. Its effects are probably not mediated by the cholinergic or vagal pathway [56,75]. Short-pulse electrical stimulation has no acute effects *Corresponding author. E-mail address:
[email protected] (R.W. McCallum).
0889-8553/07/$ – see front matter doi:10.1016/j.gtc.2007.07.007
ª 2007 Elsevier Inc. All rights reserved. gastro.theclinics.com
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on gastrointestinal slow waves, but seems to improve gastroparetic symptoms of nausea and vomiting [51–53,76–78]. Its effect may be vagally mediated [56,76]. Stimulation with trains of short pulses and multiple electrodes seem effective in acceleration of gastric emptying [79,80]. The minimally invasive method of electroacupuncture seems to improve gastric slow wave, migrating motor complex and gastric emptying, and vagal activity [73,81]. Physiologically, a number of studies in both humans and dogs [17–55,74–77,79,80] have investigated the effect of GES on normalization of gastrointestinal myoelectrical dysrhythmias; entrainment of gastric or intestinal slow waves [32,54,57]; and effects on gastrointestinal contractile activity or motility [25,53,73], gastric emptying [17,24,25,55,77], and gastrointestinal symptoms [51,52,55,77]. Although some of the results are still equivocal, most of these studies seem to indicate that electrical stimulation depending on the parameters and the pacing site being used is able to alter certain gastrointestinal functions. METHODS OF GASTROINTESTINAL ELECTRICAL STIMULATION Technically, GES can be achieved by different positioning of stimulation electrodes summarized as follows: 1. Intramuscular electrodes. Most commonly, stimulation electrodes are secured in the muscularis propria of the gastrointestinal tract. The advantage of this method is the guaranteed contact and direct effect on the targeted organ. The disadvantage is its invasiveness. Surgical procedure is required using either laparotomy or laparoscopy. 2. Intraluminal or mucosal electrodes. Alternatively, electrodes may be placed on the mucosal surface of the gastrointestinal tract. The major disadvantage of this method is that the contact between the stimulation electrode and mucosa is not guaranteed when suction electrodes or intraluminal electrodes are used, especially for electrical stimulation of the stomach. Intestinal electrical stimulation using intraluminal ring electrodes, however, is feasible [58]. 3. Serosal electrodes for temporary or external stimulation. These can be easily removed at the end of the studies. There have been no infection concerns with this technique. 4. Electroacupuncture. Electroacupuncture may be considered as electrical stimulation by electrodes (needles) placed at the acupuncture points. Electroacupuncture is frequently used in Asian countries for the treatment of various diseases. Electrical stimulation is applied to the acupuncture needles inserted into the acupuncture points associated with a specific organ, such as ST36 or Zusanli for the stomach [73]. The electrical stimulus is a pulse train with a frequency of 10 to 40 trains per minute. The train duration is in the order of seconds. The frequency of the pulses in a train is about 10 to 100 Hz and its width is usually in the order of microseconds.
Gastric Electrical Stimulation In most previous studies, electrical stimulation was applied in the area of the physiologic gastric pacemaker in the mid-body of the stomach or to the
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proximal part of the antrum using one pair of electrodes (ie, forward singlechannel electrical stimulation). In contrast to forward (or antegrade) electrical stimulation the electrodes can be positioned in the distal part of the antrum near the pylorus and this reverses the normal aborad direction of gastrointestinal contractions. This is called ‘‘backward’’ (or retrograde) pacing [7,25,33,39]. Forward pacing Single-channel stimulation. Electrical stimulus consists of a series of pulses, usually in a rectangular shape with a constant current. Several stimulation parameters are involved in electrical stimulation, including stimulation frequency, pulse width, and amplitude. Various methods of electrical stimulation are derived from the variations of electrical stimulus. These include long-pulse stimulation, short-pulse stimulation, and stimulation with trains of pulses instead of single pulse. Other parametric variations include the stimulation frequency and the pulse amplitude (or strength), which is in the order of a few milliampere. Long-pulse stimulation has been used most often and is called ‘‘electrical pacing’’ or ‘‘gastric pacing’’ because it is able to ‘‘pace’’ or entrain natural slow waves. In this method, the pulse width is in the order of milliseconds (10– 600 milliseconds) and the stimulation frequency is in the vicinity of the physiologic frequency of the gastric slow wave (Fig. 1A) [17,25–27,32,33,54, 55,74,75]. Complete entrainment of gastric slow waves has been achieved in both humans and dogs using electrical stimulation with long pulses [24,33,35,45,46,54,75], although some early studies reported difficulty in entraining gastric slow waves [31–39]. Entrainment of gastric slow waves using electrical stimulation with long pulses makes it possible for the normalization of gastric dysrhythmias as observed in a few clinical studies in postsurgical patients and patients with gastroparesis [32,39,54,55]. In a recent study performed in patients with gastroparesis [54], the pulse width reported for the entrainment of gastric slow waves was about 300 milliseconds. The entrainment was 100% when the pacing frequency was 10% higher than the intrinsic frequency compared with about 70% when the pacing frequency was 30% higher than the intrinsic frequency. In addition, there was a maximal driven frequency identified, which was about 4.3 cpm in patients with gastroparesis [54]. The pulse width in short-pulse stimulation is substantially shorter and is in the order of a few hundred microseconds. The stimulation frequency is usually threefold to fourfold higher than the physiologic frequency of the gastric slow wave (Fig. 1B) [51–53,76,77]. Recent reports in dogs have suggested that electrical stimulation given at frequencies, much higher than the intrinsic gastric slow wave frequency (IGF), may strengthen gastric contractions and accelerate gastric emptying. Johnson and coworkers [76] and Familoni and colleagues [53] examined the effectiveness of electrical stimulation with a frequency ranging from 3 to 30 cpm (pulse amplitude, 2 mA; width, 300 ls) by serosal electrodes positioned in the corpus
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Fig. 1. Three forms of stimuli used for GES. (A) Long pulses. (B) Short pulses. (C) Train of short pulses.
of the stomach in six dogs and found that the greatest increase in amplitude of gastric myoelectrical activity and contractile response occurred at a stimulation frequency of 30 cpm. No future studies have confirmed these findings. The effect of short-pulse stimulation on gastric slow waves and gastric slow wave responses to a meal was studied in 15 patients with gastroparesis refractory to standard medical therapy [82]. In this study, one pair of stimulating electrodes was surgically placed into the muscularis propria of the stomach at about 10 cm proximal to the pylorus using a commercial pulse generator (Medtronic, Minneapolis, Minnesota) permanently implanted in the abdomen. The stimulation was composed of a frequency of 12 cpm, pulse width of 330 ls, and pulse amplitude of 5 mA, as previously described [77]. In addition, two pairs of temporary cardiac pacing wires were sutured on the serosal surface of the stomach at 2 and 6 cm above the pylorus for the recording of gastric myoelectrical activity before and during GES. Electrical stimulation with these high-frequency parameters significantly enhanced the slow wave amplitude and propagation velocity, and resulted in significant improvement in nausea and vomiting but did not entrain the gastric slow wave or improve gastric emptying after 3 months of GES (Table 1).
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Table 1 Results of gastric myoelectric activity at baseline and during GES Before GES Pre DF (cpm) Post DF (cpm) dP (dB) Propagation velocity (cm/s)
3.4 3.2 0.1 0.5
0.3 0.4 0.9 0.2
At Initiation of GES
At 3 Months of GES
P Value
3.2 3.2 3.5 0.7
3.1 3.1 5.5 0.8
NS NS <.05 <.05
0.7 0.6 5.3* 0.4*
0.4 0.4 4.7* 0.4*
Abbreviations: dP, postprandial power change of gastric myoelectrical activity; GES, gastric electrical stimulation; NS, not significant; Post DF, postprandial dominant frequency of the slow wave; Pre DF, preprandial dominant frequency of the slow wave. *P <.05 versus before GES.
In stimulation with trains of short pulses, the stimulus is composed of a repetitive train of short pulses (Fig. 1C) and is derived from the combination of two signals: continuous short pulses (pulse width <100 ls) with a high frequency (in the order of 5–100 Hz); and a control signal to turn the pulses on and off, such as x seconds ‘‘on’’ and y seconds ‘‘off.’’ The addition of x and y then determines the frequency of the pulse train. This kind of stimulation has been frequently used in electroacupuncture [73] and some recent studies called sequential (neural) electrical stimulation [79,80]. Multichannel stimulation. There have been two publications reporting the efficiency and efficacy of multichannel GES in healthy dogs [83,84]. In the first, eight pairs of bipolar electrodes were implanted on the serosa of the stomach along the greater curvature at intervals of 2 cm with the most distal pair 2 cm above the pylorus. GES was applied by the first (most proximal in the stomach), third, fifth, and seventh (most distal) pairs using a four-channel electrical stimulator with adjustable frequency, amplitude, pulse width, and time delay among different channels. The other pairs (two, four, six, and eight) were used for recording GMA. The major findings were as follows: the gastric slow waves in the entire stomach could be entrained in every dog with a pacing frequency 1.1 times the intrinsic frequency, pulse width of 40 milliseconds, and pulse amplitude of 1 mA for the most proximal pair, 0.8 mA for third, 0.6 mA for fifth, and 0.4 mA for seventh pair of electrodes; and the stimulation energy required to entrain the slow waves was about one thirtieth of that required for the single-channel stimulation. In a second experiment, an intestinal fistula was made in each dog at 20 cm beyond the pylorus for the assessment of gastric emptying of liquids (237 mL of osmolite). Compared with the control session (no pacing), four-channel stimulation but not single channel significantly accelerated gastric emptying of liquids (Fig. 2). These data suggested that multichannel stimulation is more efficient and more effective than single stimulation for the entrainment of slow waves and acceleration of gastric emptying of liquids in this dog model. In the second study, the seven dogs equipped with four pairs of serosal electrodes and a duodenal cannula were studied in four randomized sessions (saline, vasopressin, single-channel long-pulse GES using the first [proximal]
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* P<0.05 GE of Different Stimulation
Percentage of GE (%)
50
*
45
*
*
40
*
35
*
30 25 20 15 10 5 15 min
30 min
45 min
60 min
75 min
90 min
Time Baseline
Single Stimulation
Multiple Stimulation
Fig. 2. Gastric emptying (emptied phenol red) with control, one-channel GES, and four-channel GES. Delayed gastric emptying in the control session was induced by intestinal balloon distention. *P <.05 versus corresponding value in the control session by paired t test.
pair of electrodes, and two-channel long-pulse GES using the first and third pairs of electrodes). Both stimulation techniques normalized gastric dysrhythmias induced by vasopressin but showed no effects on vasopressin-induced emetic response, whereas the two-channel but not single-channel GES significantly increased gastric empting. A longer-term multichannel GES study is needed to verify the results. In contrast to previous investigations, which relied on stimulus parameters that entrained the slow wave and thereby used the intrinsic conduction mechanisms of the stomach, Mintchev and coworkers [79,80] used successive rings of electrodes affixed to the gastric serosa in sequential fashion from the proximal to the distal stomach for delivery of current pulses 1000 times the frequency of the intrinsic slow wave. Two canine studies have been reported thus. All these dogs underwent implantation of four to six sets of stimulation electrodes, each set consisting of two to six electrodes placed circumferentially on the serosa. Microprocessor-controlled phase-locked bipolar trains of 50-Hz rectangular voltage (14 V in the first and 8–12 V in the second study) were used to produce artificial contractions. The half-time of gastric emptying of water was reduced from 25.3 to 6.7 minutes [79] and the ingested pellets were expelled out of the stomach more rapidly with electrical stimulation [80]. These observations seemed to suggest that this mode of gastric depolarization may hold promise for the generation of propulsive motor patterns in the case of patients with gastric atony, who are nonresponsive to conventional therapies [85], but more long-term data are needed. Backward (or reverse) pacing In backward pacing, stimulation electrodes are positioned in the distal part of the antrum near the pylorus to reverse the normal aborad direction of gastric
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contractions [7,25,33,39,86]. The effect of backward pacing on gastric myoelectrical activity was first reported in 1974 by Kelly [33] in four dogs using two pairs of bipolar electrodes implanted on the anterior wall of the gastric corpus and antrum, about 14 cm and 1 cm proximal to the gastroduodenal junction, respectively. The stimuli used were rectangular pulses of current at strength of 2 mA, duration of 100 milliseconds, and a period of 11 seconds. They observed that the pacemaker potentials generated by electric stimuli in the corpus were propagated aborad to the gastroduodenal junction, and those generated in the antrum were propagated orad to the corpus. The first study on gastric emptying with backward pacing in a dog model was performed by Sarna and colleagues [7]. Electrical stimulation was at a frequency of 5.8 to 6 pulses per minute, 50- to 80-millisecond pulse width, and pulse amplitude of 20 to 14 V by two bipolar stimulating electrodes implanted into the gastric muscle of 10 healthy dogs. The stimulating electrodes were 1 to 2 cm from the pylorus, one on the anterior wall and one on the posterior wall. This study showed that backward pacing was able to reverse the normal aborad direction of gastric contractions and to delay gastric emptying of both liquid and solid meal. Miedema and colleagues [39] reported a more systematic study on backward pacing in humans in 1992. In this study, 10 patients undergoing cholecystectomy had four pairs of temporary serosal electrodes positioned along the greater curvature of the stomach at intervals of 3 cm. The most distal pair of electrodes was 2 cm above the pylorus. A square-wave pacing stimulus with maximal amplitude of 4 V and duration of 60 milliseconds was applied to the most proximal pair of electrodes for forward pacing and to the most distal pair of electrodes for backward pacing. The stimulus frequency was at least 0.5 cpm faster than IGF. They found that regular gastric slow waves had a frequency of 3.2 cpm and no obvious gastric dysrhythmias on postoperative day 1. Backward pacing at a frequency of 3.9 cpm from the most distal pair of electrodes successfully entrained the slow waves at the proximal sites in 6 of 10 patients on postoperative day 1 (Fig. 3B). Intestinal Electrical Stimulation Intestinal pacing is a term used for electrical stimulation that results in a complete entrainment of intrinsic electrical activity of the intestine. It holds promise as a method of controlling gut motility and luminal transit of chyme [15]. Pacing a segment of the intestine is accomplished by applying suitable electrical stimuli to the muscularis propria usually at a frequency equal to or slightly faster than the natural slow-wave frequency recorded at the site of the stimulating electrodes. Forward intestinal pacing An early report on forward intestinal pacing was from Sawchuck and colleagues [71], who paced the small bowel of rats after vagotomy, antractomy, and Roux-en-Y enterostomy. In a canine model of Roux stasis syndrome, forward stimulation of Roux limb was shown to override ectopic pacemakers in
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Fig. 3. (A) Placement of serosal electrodes. Distance between two adjacent pairs of electrodes is 4 cm and the most distal pair of electrodes is 2 cm above the pylorus. (B) Gastric slow waves recorded from serosal electrodes in one patient during backward electrical pacing (frequency, 3.2 cpm; pulse width, 300 ms; amplitude, 4 mA) at S4. Gastric slow waves entrained by electrical stimuli propagated in orad direction (first two lines with arrows) into corpus (S1). When pacing stopped, natural pacemaker is restored after compensatory pause.
the Roux limb [40], accelerated gastric emptying of liquids [72] and solids [37], and reduced jejunogastric reflux [66]. Intestinal electrical stimulation using either serosal electrodes [57] or intraluminal ring electrodes [58] with long pulses has been shown capable of entraining intestinal slow waves. Similar to gastric pacing, the complete entrainment was achieved with a pacing frequency 10% higher than the intrinsic frequency of the intestinal slow wave. Beyond this frequency, only partial entrainment was possible. The maximal driven frequency was about 38% higher than the intrinsic frequency. Similar results were obtained using intraluminal ring electrodes [58]. Stimulation energy required for the entrainment of intestinal slow waves was found to be lower than that for the entrainment of gastric slow waves [57,58]. Backward intestinal pacing Several studies have demonstrated that backward intestinal pacing slows intestinal transit, induces retrograde propagated intestinal contractions, and
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improves intestinal absorption [44,47]. Kelly and Code [44] showed that backward stimulation of the canine duodenum led to an orad propagation of duodenal contractions, resulting in slowing of duodenal transit and gastric emptying. Likewise, backward electrical stimulation of the canine jejunum slowed the transit of the chyme in the paced segment, resulting in an enhanced absorption of water, nutrients, and electrolytes [47]. A number of other studies have shown similar effects of backward intestinal stimulation in canine models of short bowel and dumping syndromes [36,38,40,51]. Electrical Stimulation of the Colon The first report regarding electrical stimulation of the colon to modulate colonic motility was published in 1995 by Hughes and colleagues [87]. Since then, researchers have investigated the possibilities to activate or inhibit the colonic transit electrically, or to elicit colon peristalsis. Similar to GES, electrical stimulation of the colon can be achieved intramuscularly, serosally, or intraluminally through bipolar electrodes in single-site or in multisite stimulation systems as detailed in a recent review article [88]. CLINICAL APPLICATIONS OF GASTROINTESTINAL ELECTRICAL STIMULATION Treatment of Gastroparesis Gastroparesis is characterized by delayed gastric emptying of solids without evidence of mechanical obstruction and presents with nausea and early satiety in mild cases, and chronic vomiting, dehydration, and weight loss in severe cases [89,90]. Abnormalities in gastric myoelectrical activity may lead to impaired gastric motility, and in turn to delayed gastric emptying [91–99]. The most common treatment for gastroparesis is to use prokinetic agents, such as metoclopramide, erythromycin and domperidone. Recently, GES has been investigated as a therapeutic option in the management of medication refractory gastroparesis [16,51,52,54–74,77,98]. Based on the stimulation parameters, two different methods have been used for the long-term treatment of patients with gastroparesis: GES with long pulses and low stimulation frequency [54,55,74]; and GES with short pulses and high stimulation frequency [51,52,77,98]. Long-pulse and low-frequency stimulation Early data on GES for the treatment of patients with diabetic gastroparesis were reported in 1987 [27]. The stimulating pulses had a frequency of 3 cpm and amplitude of 2 mA (pulse width of 300 milliseconds), and were delivered to a pair of gastric electrodes serosally attached in the mid-corpus and gastric emptying of a solid meal measured scintigraphically was accelerated. This led to a canine model of gastroparesis and confirmed that GES at the intrinsic frequency of the slow wave can recoordinate slow waves uncoupled by the acute administration of glucagon and vagotomy, improving the rate of gastric emptying [17]. To derive effective pacing parameters for the entrainment of gastric slow waves in humans, a more systematic study on the effect of the
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long-pulse and low-frequency GES in a group of patients with severe gastroparesis was performed [54,74]. In this study, four pairs of temporary cardiac pacing wires were implanted on the serosa of the stomach along the greater curvature at intervals of 2 to 3 cm during surgery for the placement of a jejunal feeding tube. The most distal electrode was 2 cm above the pylorus (Fig. 3A). The most proximal pair of electrodes in the mid-corpus delivered electrical stimulation, whereas the other electrode sites recorded gastric electrical activity. Gastric pacing at a frequency up to 10% higher that the IGF and with an amplitude of 4 mA and a pulse width of 300 milliseconds was able completely to entrain the gastric slow wave and normalize gastric dysrhythmias. The clinical efficacy using these stimulating parameters chronically was next assessed in nine gastroparetic patients [55]. After 1 month of GES with a portable gastric stimulator, gastroparetic symptoms markedly improved, eight patients no longer required supplemental jejunal feedings, and gastric emptying of a solid meal improved significantly (Fig. 4). More recently, the same group investigated the effectiveness and safety of a multichannel electrical pacing device for the treatment of patients with diabetic gastroparesis. Preliminary results suggest that multipoint (using two channels) and synchronized gastric electrical pacing can normalize and enhance gastric slow wave activity, accelerate gastric emptying, and improve upper gastrointestinal symptoms. This new approach could lead to advances in electrical stimulation therapy for gastroparesis beyond the outcomes being achieved by the Enterra (Medtronic, Minneapolis, Minnesota) device, which is the currently commercially available implantable device (see later). Short-pulse and high-frequency stimulation Based on results in a canine model that GES with short pulses delivered at a frequency four times higher than IGF elicited an increased motility index,
Fig. 4. Effect of gastric pacing on gastric emptying of radionuclide solid meal. In comparison with baseline test without pacing (dashes line), gastric retention at 90 minutes and 2 hours was significantly reduced at conclusion of outpatient treatment with gastric pacing (solid line).
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Familoni and colleagues [52] used GES at 12 cpm with a pulse width of 330 microseconds and pulse amplitude of 2 mA for the treatment of a diabetic patient with refractory gastroparesis. GES was delivered first by temporary mucosal electrodes inserted through a percutaneous gastrostomy and subsequently by implanted intramuscular electrodes. Gastric emptying improved from less than 2% at baseline to 28% after 1 week of GES from the mucosal electrodes. GES by implanted intramuscular electrodes was able to improve symptoms and gastric emptying (28% at 4 weeks, 97% at 15 weeks, and 56% at 52 weeks postsurgery) [52]. In the late 1990s, implantable pulsegenerators, which were programmable to deliver stimuli similar to these preliminary studies, were manufactured by Medtronic. The device can be implanted surgically by laparotomy or laparoscopy (Fig. 5). The efficacy of chronic GES with this implantable device in the treatment of symptomatic patients with gastroparesis was investigated in a multicenter Worldwide Anti-Vomiting Electrical Stimulation Study trial [51]. Thirty-three patients with long-term gastroparesis were studied for up to 12 months using the implantable device. During the abdominal surgery, one pair of unipolar electrodes, 10 mm apart, was implanted into the muscularis propria of the stomach at 9.5 and 10.5 cm proximal to the pylorus for electrical stimulation and connected to the pulse generator, which was positioned in a subcutaneous pocket above the abdominal wall fascia (Fig. 6) [98]. The initial design of the Worldwide Anti-Vomiting Electrical Stimulation Study was a double-blinded crossover (1 month of either on or off) followed by 12-month open label. In the double-blinded section of the study, there was a clear patient preference (three to one) for having the device turned on and there was a statistically significant difference in the improvement of gastroparetic symptoms in the diabetic subgroup during their month turned on compared with off, but not for the idiopathic subgroup. Subsequently, vomiting and quality of life were significantly improved at 6 and 12
Fig. 5. View of implantable pulse generator during laparotomy with electrodes attached to the proximal antrum.
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Fig. 6. Abdominal radiograph showing gastric stimulator implanted in upper quadrant.
months of GES for both idiopathic and diabetic groups. In most of these patients there was some acceleration of gastric emptying of solids, but this had not returned to the normal by 1 year. The long-term outcomes in gastroparetic patients receiving GES therapy beyond 3 years were most recently reported by presenting per protocol analysis and intention-to-treat analysis [100]. Both analyses demonstrated that total symptom scores, hospitalization days, nutrition status, and the use of medications were all significantly reduced at 1 year and sustained beyond 3 years. Average total symptom scores decreased by 62.5% for the 37 patients completing 3 years of GES (Fig. 7). Mean hemoglobin A1c level in diabetics was significantly reduced from 9.5% to 7.9% at 3 years. It is concluded that a significant improvement in symptoms and all measures of clinical outcome can be maintained for greater than 3 years with GES in patients with refractory gastroparesis, whereas their gastric emptying still remains slow (approximately 20% have been shown to normalize their gastric emptying). Treatment of Obesity The prevalence of obesity is rising to epidemic proportions around the world at an alarming rate. Obesity is one of the most prevalent public health problems in the United States. Morbid obesity or clinically severe obesity (body mass index [BMI] 40 or >100 lbs over normal weight) affects more than 15 million Americans and causes an estimated 300,000 deaths per year. The treatment of obesity and its primary comorbidities costs the United States health care system more than $99 billion each year [101–104]. Moreover, obesity is associated with an increased prevalence of socioeconomic hardship because of a higher rate of disability, early retirement, and widespread discrimination [105–108]. The conventional treatments of obesity can be classified into three categories: (1) basic treatment, (2) pharmacotherapy, and (3) surgical treatment. Although surgical treatment induces satisfactory long-term weight loss, its
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TSS in Severity by PP and ITT/LOCF Baseline
3 years
1 year
TSS in severity (0-28)
25 *p<0.05 Compared to baseline 20 15 10
* *
*
*
5 0 PP (N=55:42:37)
ITT (N=55)
Fig. 7. Comparison of total symptom scores (TSS, mean SE) in severity at baseline, 1 year, and 3 years of GES therapy using per protocol (PP) analysis and intention-to-treat (ITT) analysis imputed by last observation carried forward (LOCF).
application is limited because of substantial risks and complications associated with the surgical procedure [109,110]. The development of novel and less invasive therapies for obesity is desirable. Recently, there has been considerable interest in application of retrograde (backward) GES for the treatment of obesity to induce electrical waves propagating retrograde from the antrum to the proximal stomach, interrupting the normal and physiologic electrical waves, which propagate from the proximal to the distal stomach. Consequently, gastric dysrhythmia is induced and the regular propagation of gastric electrical waves is impaired with slowing of gastric emptying and feeling of fullness and satiety (Fig. 8). The severity of impairment is determined by the strength of electrical stimulation. Based on studies of GES to modify eating behavior in swine [59,60], a pilot study for treatment of morbid obesity in humans with GES was initiated in four subjects with BMI less than 40 in 1995 [61]. At laparoscopy, platinum electrodes were implanted intramuscularly on the anterior gastric wall at the lesser curvature. Stimulating parameters were as follows: 180 to 400 microseconds pulse width, frequency 40 to 100 Hz, 2 seconds on and 3 seconds off, and burst amplitude 3 to 8.5 mA. In 1998, a second study was performed on an additional 10 patients (BMI 40–62) in the same way as the pilot study except that the lead position was near the fundus in three patients. At a maximum follow-up of 6 to 12 months (mean, 8.5), the mean excess BMI loss was 26.7 10 for stimulating the antrum (N ¼ 7) and 13.7 7 for stimulating the fundus (N ¼ 3). Positioning the electrodes at the antrum resulted in better weight loss than at the fundus. At 21 months after implant the 10-patient group lost 20.2 12.2 (mean standard deviation) percent excess BMI loss, food intake was reduced because of an early and increased satiety, and there were no deaths or other major complications [68]. The shortcomings of these two studies are that they were not conducted in a controlled fashion and the patient population was too small to draw conclusions.
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Delayed gastric emptying Normal pacemaker
Normal slow waves Artificial pacemaker
Retrogradely propagated electrical wave
Fig. 8. Sacral nerve stimulation for fecal incontinence and constipation.
Recently, a multicenter, randomized, double-blinded clinical trial of 6-month on and off was performed to evaluate the safety and efficacy of a transcend implantable gastric stimulation system (Transneuronix, Mt. Arlington, New Jersey) [72]. One hundred patients (86 women, 14 men; mean age, 40 years [23–54]; mean BMI, 46 [38–56]; mean weight, 284 lbs [186–403]) were enrolled. The stimulating lead was laparoscopically placed in the anterior medial wall of the stomach along the lesser curvature near the location of the vagus nerve and connected to a subcutaneous implantable gastric stimulator. Electrical stimulation was off in half of subjects (control group) and on in half of subjects (treatment group) for 6 months (pulse amplitude, 6–10 mA; width, 208 microseconds; and frequency, 40 Hz [2 seconds on and 3 seconds off]). At 7 months after implantation the nonfunctioning (turned off) devices were also activated. Patients were seen in clinic monthly for 24 months. The results were negative, although the investigation confirmed the safety of the procedure and a small subset of patients did lose weight. Identifying the most effective lead insertion location and the optimal stimulation parameters may be best investigated in an animal model before future human investigation. Also, patient selection should be more rigorous and include psychologic testing. Treatment of Fecal Incontinence Fecal incontinence is the inability to control bowel movements, causing stool (feces) to leak unexpectedly from the rectum. Fecal incontinence can range from an occasional leakage of stool while passing gas to a complete loss of bowel control. Common causes of fecal incontinence involve muscle or nerve damage caused by a weakened anal sphincter function associated with aging, and as a result of childbirth injury. Two percent of the general population is affected, and the prevalence rises with age [111], affecting up to 11% of men and 26% of women over 50 limiting social and professional function [112].
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A possible treatment for fecal incontinence is sacral nerve stimulation (Fig. 9). The sacral nerves run from the spinal cord to muscles in pelvis. These nerves regulate the sensation and strength of the rectal and anal sphincter muscles. Direct electrical stimulation of these nerves is a promising treatment option for fecal incontinence caused by nerve damage. Medtronic InterStim Therapy (Medtronic), which uses mild electrical pulses to stimulate sacral nerves associated with pelvic floor control, has been used since 1993 to treat common forms of bladder control and urinary incontinence. Previous reports from single-center studies led to a multicenter trial in 34 patients at eight European and United States medical centers [113]. Patients were carefully screened and tested for 2 weeks with an external device and if at least a 50% improvement in symptoms occurred, they were then eligible for permanent implantation. Frequency of incontinence episodes decreased from a mean of 16.4 per week before implant to 3.1 at 1 year after implant, and 2 after 2 years. This decrease in the number of incontinence episodes was sustained with 71% of patients having at least a 50% improvement in number of incontinent days per week at 36 months and the ability to postpone defecation and empty the bowel completely were improved. Furthermore, patients who had a previous sphincter repair showed comparable improvement in fecal incontinence and quality of life measures. During the trial, adverse events included infections, which were treated with antibiotics, and pain, which was resolved with reprogramming, medication, or repositioning the neurostimulator.
Fig. 9. Diagram showing the principle of the retrograde GES. Electrical stimulation from an ectopic gastric pacemaker located in the distal stomach may delay gastric emptying.
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In Europe, InterStim Therapy was approved in 1994 to treat fecal incontinence. A clinical trial of 100 patients at 15 clinical sites has been completed in the United States. These data are being prepared for presentation to the Food and Drug Administration, and approval is expected in 2008. Treatment of Constipation Constipation is a condition of the digestive system, where there is stooling (<3 per week) or passage of hard feces that are difficult to eliminate and may be extremely painful. In severe cases (fecal impaction) it leads to symptoms of bowel obstruction. Causes of constipation may be dietary, hormonal, a side effect of medications, or a disorder of colon motility, and anatomic reasons. Constipation is a very common complaint in Western society, with a prevalence ranging from 2% to 28% [114]. Classically, functional constipation has been divided into three subgroups, depending on the probable cause of the disorder: (1) slow-transit constipation, (2) pelvic floor dysfunction, and (3) constipation-predominant irritable bowel syndrome. Patients with slow-transit constipation accounted for up to 11% of the constipation population [115]. Currently available treatments are laxatives, prokinetic agents, biofeedback, and relaxation therapy. A small number of patients with drug-refractory constipation undergo surgery, which is a subtotal colectomy and ileorectal anastomosis, associated with some morbidity [116,117]. Alternative treatment modalities for this disorder could be of substantial value to patients. Electrical stimulation of the colon could activate colonic motility in slow-transit patients, or enhance the pelvic floor condition [88]. Although electrical stimulation of the colon has been successful in improving animal models of constipation, there have been a few evaluations of its use for constipation in humans. Two earlier studies have reported the effects of temporary stimulation. The first involved temporary stimulation for 3 weeks by a percutaneous electrode, and demonstrated a symptomatic improvement in two of eight patients with slow-transit constipation [118]. In a second report 10 patients complaining of difficulty with rectal evacuation underwent temporary stimulation for 7 days [119]. Difficulty with rectal evacuation, time for evacuation, and number of unsuccessful attempts at defecation all decreased. The first report of permanent sacral nerve stimulation for treatment of idiopathic constipation in 2002 described four patients with severe constipation who failed conservative therapy and were being considered for a colostomy [120]. With both temporary and permanent stimulation for median follow-up of 8 months (range, 1–11), patients experienced an increased bowel frequency, improved ease of evacuation, and improved associated symptoms of abdominal pain and bloating and quality of life. A multicenter study is currently nearing completion. FUTURE DIRECTIONS AND DEVELOPMENTS Gastric or intestinal electrical stimulation with long pulses is able to pace the stomach or intestine, and has a great therapeutic potential for gastrointestinal dysrhythmias and improving gastric emptying in gastroparesis. The role of intestinal pacing needs to be explored for the treatment of chronic intestinal
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pseudo-obstruction [121]. Recent studies suggested a loss of interstitial cells of Cajal in patients with intestinal pseudo-obstruction, constipation [122], and gastroparesis [123], and it remains to be determined whether gastric or intestinal pacing is able to entrain or normalize slow waves in those patients with a loss of interstitial cells of Cajal. Gastric stimulation with short pulses (about 300 microseconds, Enterra device) seems to have an antiemetic effect in patients with severe nausea and vomiting, although more double-blinded studies need to address remaining questions about clinical efficacy. Retrograde stimulation to retard rapid or dumping-type emptying or slow normal gastric emptying has an exciting potential in treating obesity. SUMMARY GES as a modality in clinical settings is still in its infancy. Currently, at least three issues need to be addressed: (1) more controlled trials, (2) define the mechanisms of action, and (3) new device development. Current implantable stimulators used for GES were designed for cardiac or nerve stimulation. Cardiac muscle and nerve have a rapid response to electrical stimulation, whereas smooth muscles of the gastrointestinal tract are slow to respond and long pulses may be needed to alter their functions. Accordingly, further development is required for new devices. Electrical stimulation of the gut, including electroacupuncture, has great potential therapy for gut disorders. This article summarizes the current state of the art. References [1] Bilgutay AM, Wingrove R, Grifen WO, et al. Gastro-intestinal pacing: a new concept in the treatment of ileus. Ann Surg 1963;158(3):338–48. [2] Quast DC, Beall AC, DeBakey ME. Clinical evaluation of the gastrointestinal pacer. Surgery, Gynecology & Obstetrics 1965;120:35–7. [3] Berger T, Kewenter J, Kock NG. Response to gastrointestinal pacing: antral, duodenal and jejunal motility in control and postoperative patients. Ann Surg 1966;164(1):139–44. [4] Moran JM, Nabseth DC. Electrical stimulation of the bowel. Arch Surg 1965;91:449–51. [5] Sarna SK, Daniel EE. Gastrointestinal electrical activity: terminology. Gastroenterology 1975;68:1631–5. [6] Hinder RA, Kelly KA. Human gastric pacemaker potential: site of origin, spread, and response to gastric transsaction and proximal gastric vagotomy. Am J Surg 1977;133: 29–33. [7] Sarna SK, Bowes KL, Daniel EE. Gastric pacemakers. Gastroenterology 1976;70: 226–31. [8] Hermon-Taylor J, Code CF. Localization of the duodenal pacemaker and its role in the organization of duodenal myoelectric activity. Gut 1971;12:40–7. [9] Szurszewski JH, Elveback LR, Code CF. Configuration and frequency gradient of electric slow wave over canine small bowel. Am J Physiol 1970;218:1468–73. [10] Bunker CE, Johnson LP, Nelsen S. Chronic in situ studies of the electrical activity of the small intestine. Arch Surg 1967;95:259–68. [11] Christensen J, Schedl HP, Clifton JA. The small intestine basic electrical rhythm (slow wave) frequency gradient in normal men and in patients with a variety of diseases. Gastroenterology 1966;50:309–15.
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[12] Diamant NE, Rose PK, Davison EJ. Computer simulation of intestinal slow-wave frequency gradient. Am J Physiol 1970;219(6):1684–90. [13] Eagon JC, Soper NJ. Gastrointestinal pacing. Surg Clin North Am 1993;73:1161–72. [14] Akwari OE, Kelly KA, Steinbach JH, et al. Electric pacing of intact and transected canine small intestine and its computer model. Am J Physiol 1975;229:1188–97. [15] Richter HM III, Kelly KA. Effect of transection and pacing on human jejunal pacemaker potentials. Gastroenterology 1986;91:1380–5. [16] Karistrom L, Kelly KA. Ectopic jejunal pacemakers and gastric emptying after Roux gastractomy: effect of intestinal pacing. Surgery 1989;106:867–71. [17] Bellahse`ne B-E, Lind CD, Schirmer BD, et al. Acceleration of gastric emptying with electrical stimulation in a canine model of gastroparesis. Am J Physiol 1992;262:G826–34. [18] Bjorck S, Kelly KA, Phillips SF. Mechanisms of enhanced canine enteric absorption with intestinal pacing. Am J Physiol 1987;252:G548–53. [19] Collin J, Kelly KA, Phillips SF. Absorption from the jejunum is increased by forward and backward pacing. Br J Surg 1979;66:489–92. [20] Collin J, Kelly KA, Phillips SF. Enhancement of absorption from the intact and transected canine small intestine by electrical pacing. Gastroenterology 1968;76:1422–8. [21] Courtney TL, Schirmer BD, Bellahse`ne B-E, et al. Gastric electrical stimulation as a possible new therapy for patients with severe gastric stasis [abstract]. Gastroenterology 1991;100(5):A22. [22] Cranley B, Kelly KA, Go VLW, et al. Enhancing the anti-dumping effect of Roux gastrojejunostomy with intestinal pacing. Ann Surg 1983;198(4):516–24. [23] Cullen JJ, Kelly KA. The future of intestinal pacing. Gastroenterol Clin N Am 1994;23(2): 391–402. [24] Eagon JC, Kelly KA. Effect of electrical stimulation on gastric electrical activity, motility and emptying. Neurogastroenterol Motil 1995;7:39–45. [25] Eagon JC, Kelly KA. Effects of gastric pacing on canine gastric motility and emptying. Am J Physiol 1993;265:G767–74. [26] Eagon JC, Kelly KA. Gastric pacing reverses canine peristalsis, slows emptying, and strengthens contractions. Am J Surg 1993;163:628. [27] Bellahse`ne B-E, Schirmer BD, Updike OL, et al. Effect of electrical stimulation on gastric emptying. Dig Dis Sci 1987;32:902. [28] Eagon JC, Ritman EL, Kelly KA. Antral volume changes during gastric pacing. Gastroenterology 1992;103:1397. [29] Gladen HE, Kelly KA. Enhancing absorption in the canine short bowel syndrome by intestinal pacing. Surgery 1980;88(2):281–6. [30] Grundfest-Broniatowski S, Moritz A, Ilyes L, et al. Voluntary control of an ileal pouch by coordinated electrical stimulation: a pilot study in the dog. Dis Colon Rectum 1988;31: 261–7. [31] Hocking MP. Postoperative gastroparesis and tachygastria: response to electrical stimulation and erythromycin. Surgery 1993;114:538–42. [32] Hocking MP, Vogel SB, Sninsky CA. Human gastric myoelectrical activity and gastric emptying following gastric surgery and with pacing. Gastroenterology 1992;103: 1811–6. [33] Kelly KA. Differential responses of the canine gastric corpus and antrum to electrical stimulation. Am J Physiol 1974;226(1):230–4. [34] Kelly KA. Pacing the gut. Gastroenterology 1992;103(6):1967–9. [35] Kelly KA, La Force RC. Pacing the canine stomach with electrical stimulation. Am J Physiol 1972;222(3):588–94. [36] Layzell T, Collin J. Retrograde electrical pacing of the small intestine: a new treatment for the short bowel syndrome? Br J Surg 1981;68:711–3. [37] Miedema BW, Kelly KA. The Roux stasis syndrome: treatment by pacing and prevention by use of an uncut roux limb. Arch Surg 1992;127:295–300.
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[38] Miedema BW, Sarr MG, Hanson RB, et al. Electric and motor patterns associated with canine jejunal transit of liquids and solids. Am J Physiol 1992;262:G962–70. [39] Miedema BW, Sarr MG, Kelly KA. Pacing the human stomach. Surgery 1992;111: 143–50. [40] Morrison P, Miedema BW, Kohler L, et al. Electrical dysrhythmias in the Roux jejunal limb: cause and treatment. Am J Surg 1990;160:252–6. [41] O’Connell PR, Kelly KA. Enteric transit and absorption after canine ileostomy: effect of pacing. Arch Surg 1987;122:1011–7. [42] Reiser SB, Schusdziarra V, Bollschweiller E, et al. Effect of enteric pacing on intestinal motility and hormone secretion in dogs with short bowel. Gastroenterology 1991;101: 100–6. [43] Reiser SB, Weiser HF, Schusdziarra V, et al. Effect of pacing on small intestinal motor activity and hormonal response in dogs. Dig Dis Sci 1989;34(4):579–84. [44] Kelly KA, Code CF. Duodenal-gastric reflux and slowed gastric emptying by electrical pacing of the canine duodenal pacemaker potential. Gastroenterology 1977;72:429–33. [45] Sarna SK, Daniel EE. Electrical stimulation of gastric electrical control activity. Am J Physiol 1973;225(1):125–31. [46] Sarna SK, Daniel EE. Electrical stimulation of small intestinal electrical control activity. Gastroenterology 1975;69(3):660–7. [47] Sarr MG, Kelly KA, Gladen HE. Electrical control of canine jejunal propulsion. Am J Physiol 1981;240:G355–60. [48] Sawchuk A, Nogami W, Goto S, et al. Reverse electrical pacing improves intestinal absorption and transit time. Surgery 1986;100(2):454–9. [49] Soper MJ, Geisler KL, Sarr MG, et al. Regulation of canine jejunal transit. Am J Physiol 1990;259:G928–33. [50] Waterfall WE, Miller D, Ghista DN. Electrical stimulation of the human stomach [abstract]. Dig Dis Sci 1985;30(8):799. [51] Abell T, McCallum RW, Hocking M, et al. WAVESS study group, gastric electrical stimulation for medically refractory gastroparesis. Gastroenterology 2003;125:421–8. [52] Familoni BO, Abell TL, Nemoto D, et al. Electrical stimulation at a frequency higher than basal rate in human stomach. Dig Dis Sci 1997;42:885–91. [53] Familoni BO, Abell T, Nemoto D, et al. Efficacy of electrical stimulation at frequencies higher than basal rate in canine stomach. Dig Dis Sci 1997;42:892–7. [54] Lin ZY, McCallum RW, Schirmer BD, et al. Effects of pacing parameters in the entrainment of gastric slow waves in patients with gastroparesis. Am J Physiol [Gastrointest Liver Physiol 37] 1998;274:G186–91. [55] McCallum RW, Chen JDZ, Lin ZY, et al. Gastric pacing improves gastric emptying and symptoms in patients with gastroparesis. Gastroenterology 1998;114:456–61. [56] Wang Z, Qian L, Ueno T, et al. Mechanisms of various gastric electrical stimulations [abstract]. Gatroenterology 2000;118(4):A669. [57] Lin XM, Peters L, Zhang M, et al. Entrainment of small intestinal slow waves with electrical stimulation in dogs. Dig Dis Sci 2000;45:652–6. [58] Lin XM, Hayes J, Peters LJ, et al. Entrainment of intestinal slow waves with electrical stimulation using intraluminal electrodes. Ann Biomed Eng 2000;28:582–7. [59] Cigaina V. Gastric peristalsis control by mono situ electrical stimulation: a preliminary study. Obes Surg 1996;6:247–9. [60] Cigaina V. Long-term effects of gastric pacing to reduce feed intake in swine. Obes Surg 1996;6:250–3. [61] Cigaina V, Rigo V, Greenstein RJ. Gastric myo-electrical pacing as therapy for morbid obesity: preliminary results. Obes Surg 1999;9:333–4. [62] Ouyang H, Adler S, Yin J, et al. Therapeutic potential of chronic gastric electrical stimulation for obesity and its possible mechanisms: a preliminary canine study. Dig Dis Sci 2003;48:698–705.
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[63] Eagon JC, Miedema BW, Kelly KA. Postgastrectomy syndrome. Surg Clin North Am 1992;72:445–65. [64] Kelly KA, Becker JM, van Heerden JA. Reconstructive gastric surgery. Br J Surg 1981;68: 687–91. [65] Gustavsson S, Ilstrup DM, Morrison P, et al. Roux-Y stasis syndrome after gastrectomy. Am J Surg 1988;155:490–4. [66] Karlstrom L, Soper NJ, Kelly KA, et al. Ectopic jejunal pacemakers and enterogastricreflux after Roux gastractomy: effect of intestinal pacing. Surgery 1989;106:486–95. [67] Abo M, Liang J, Qian LW, et al. Distention-induced myoelectrical dysrhythmia and effect of intestinal pacing in dogs. Dig Dis Sci 2000;45:129–35. [68] Cigaina V, Saggioro A. Pacing the stomach: five years experience with an obese patient population. Gastroenterology 2001;102(5):A43. [69] Becker JM, Sava P, Kelly KA, et al. Intestinal pacing for canine postgastrectomy dumping. Gastroenterology 1983;84:383–7. [70] Morrison PD, Kelly KA. Increasing antidumping effect of intestinal pacing with motor-active agents. Dig Dis Sci 1986;31:422–7. [71] Sawchuk A, Canal D, Grosfeld JL, et al. Electrical pacing of the Roux limb resolves delayed gastric emptying. J Surg Res 1987;42:635–41. [72] Shikora SA, Bessier M, Fisher BL, et al. Laparoscopic insertion of the implantable gastric stimulator (IGS): initial surgical experience. Obes Surg 2000;10:[appendix 3-A]. [73] Qian LW, Peters LJ, Chen JDZ. Effects of electroacupuncture on gastric migrating myoelectrical complex in dogs. Dig Dis Sci 1999;44:56–62. [74] Chen JDZ, Lin ZY, Schirmer BD, et al. Long-term gastric pacing with a portable gastric pacemaker to aid gastric emptying in humans. In: Proceedings of IEEE 17th Annual Conference of Engineering in Medicine and Biology Society. Montreal, Canada; 1995. p. 1691–2. [75] Qian L, Lin X, Chen JDZ. Normalization of atropine-induced postprandial dysrhythmias with gastric pacing. Am J Physiol 1999;276:G387–92. [76] Johnson B, Familoni BO, Abell T, et al. Development of a canine model for gastric pacing. Gastroenterology 1990;98:A362. [77] Forster J, Sarosiek I, Delcore R, et al. Gastric pacing: a novel surgical treatment for gastroparesis. Am J Surg 2001;182(6):676–81. [78] Tack J, Coulie B, Van Cutsem E, et al. The influence of gastric electrical stimulation on proximal gastric motor and sensory function in severe idiopathic gastroparesis. Gastroenterology 1999;116:A1090. [79] Mintchev MP, Sanminguel CP, Bowes KL. Microprocessor controlled movement of liquid gastric content using sequential neural electrical stimulation. Gut 1998;43: 607–11. [80] Mintchev MP, Sanminguel CP, Amaris M, et al. Microprocessor-controlled movement of solid gastric content using sequential neural electrical stimulation. Gastroenterology 2000;118:258–63. [81] Ouyang H, Zhu HB, Ueno T, et al. Electro-acupuncture accelerates gastric emptying and increases vagal activity. Gastroenterology 2000;118:A850. [82] Lin ZY, Forster J, Sarosiek I, et al. Gastric slow wave responses during high-frequency gastric electrical stimulation for the treatment of gastroparesis. Neurogastroenterol Motil 2004;16(2):205–12. [83] Chen JDZ, Xu X, Zhang M, et al. Efficient and efficacy of multi-channel gastric electrical stimulation. Neurogastroenterol Motil 2005;17(6):878–82. [84] Song G, Hou X, Yang B, et al. Two-channel gastric electrical stimulation accelerates delayed gastric emptying induced by vasopressin. Dig Dis Sci 2005;50(4):662–8. [85] Hasler WL. The brute force approach to electrical stimulation of gastric emptying: a future treatment for refractory gastroparesis. Gastroenterology 2000;118:433–42. [86] McCallum RW, Lin ZY, Chen JDZ, et al. Acute effect of backward pacing on gastric slow waves in humans. Dig Dis Sci 1998;43(7):1593.
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[87] Hughes SF, Scott SM, Pilot MA, et al. Electrically stimulated colonic reservoir for total anorectal reconstruction. Br J Surg 1995;82:1321–6. [88] Sevcencu C. Electrical stimulation: an evolving concept in the treatment of colonic motor dysfunction. Neurogastroenterol Motil 2006;18(11):960–70. [89] Hornbuckle K, Barnett JL. The diagnosis and work-up of the patient with gastroparesis. J Clin Gastroenterol 2000;30:117–24. [90] Soykan I, Sivri B, Sarosiek I, et al. Demography, clinical characteristics, psychological and abuse profiles, treatment, and long-term follow-up of patients with gastroparesis. Dig Dis Sci 1998;43:2398–404. [91] You CH, Lee KY, Chey WY, et al. Electrogastrographic study of patients with unexplained nausea, bloating and vomiting. Gastroenterology 1980;79:311–4. [92] Telander RL, Morgan KG, Kreulen DL, et al. Human gastric atony with tachygastria and gastric retention. Gastroenterology 1978;75:495–501. [93] Bortolotti M, Sarti P, Barara L, et al. Gastric myoelectric activity in patients with chronic idiopathic gastroparesis. Journal of Gastrointestinal Motility 1990;2:104–8. [94] Geldof H, van der Schee EJ, Van Blankenstein M, et al. Electrogastrographic study of gastric myoelectrical activity in patients with unexplained nausea and vomiting. Gut 1986;26: 799–808. [95] Chen J, McCallum RW. Gastric slow wave abnormalities in patients with gastroparesis. Am J Gastroenterol 1992;87:477–82. [96] Abell TL, Camilleri M, Hench VS, et al. Gastric electromechanical function and gastric emptying in diabetic gastroparesis. Eur J Gastroenterol Hepatol 1991;3:163–7. [97] Kendall BJ, McCallum RW. Gastroparesis and current use of orikinetic drugs. Gastroenterologist 1993;1:107–14. [98] McCallum RW, Lin ZY, Wetzel P, et al. Clinical response to gastric electrical stimulation in patients with postsurgical gastroparesis. Clin Gastroenterol Hepatol 2005;3:49–54. [99] McCallum RW, Lin Z, Sarosiek I, et al. Preliminary results of multipoint gastric electrical pacing for the treatment of patients with diabetic gastroparesis. Gastroenterology 2007;132: A-112. [100] Lin Z, Sarosiek I, Forster J, et al. Symptom responses, long-term outcomes and adverse events beyond 3 years of high-frequency gastric electrical stimulation for gastroparesis. Neurogastroenterol Motil 2006;18:18–27. [101] Klein S. Obesity. Clinical Perspectives in Gastroenterology 2000;3:232–6. [102] Martin LF, Hunter SM, Lauve RM, et al. Severe obesity: expensive to society, frustrating to treat, but important to confront. South Med J 1995;88:895–902. [103] Colditz GA. Economic costs of obesity. Am J Clin Nutr 1992;55(Suppl 2):503S–7S. [104] Wolf AM, Colditz GA. Current estimates of the economic cost of obesity in the United States. Obes Res 1998;6:97–106. [105] Enzi G. Socioeconomic consequences of obesity: the effect of obesity on the individual. Pharmacoeconomics 1994;5(Suppl 1):54–7. [106] AACE/ACE position statement on the prevention, diagnosis, and treatment of obesity. Endocr Pract 1998;4:297–330. [107] Bray GA, Greenway FL. Current and potential drugs for treatment of obesity. Endocr Rev 1999;20(6):805–75. [108] Hvizdos KM, Markham A. Orlistat: a review of its use in the management of obesity. Drugs 1999;58(4):743–60. [109] Sagar PM. Surgical treatment of morbid obesity. Br J Surg 1995;82:732–9. [110] Consensus development conference panel. Gastrointestinal surgery for severe obesity. Ann Intern Med 1991;15:956–61. [111] Campbell AJ, Reinken J, McCosh L. Incontinence in the elderly: prevalence and prognosis. Age Aging 1985;14:65–70. [112] Roberts RO, Jacobsen SJ, Reilly WT, et al. Prevalence of combined fecal and urinary incontinence: a community based study. J Am Geriatr Soc 1999;47:837–41.
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[113] Matzel KE, Kamm MA, Stosser M, et al. Sacral spinal nerve stimulation for faecal incontinence: multicenter study. Lancet 2004;363:1270–6. [114] Loke GR III, Pemberton JH, Phillips SF. AGA technical review on delayed colonic transit. Gastroenterology 2000;119:1161–78. [115] Nyam DC, Pemberton JH, Ilstrup DM, et al. Long-term results of surgery for chronic delayed colonic transit. Dis Colon Rectum 1997;40:273–9. [116] Picarsky AJ, Singh JJ, Weiss EG, et al. Long-term follow-up of patients undergoing colectomy for colon inertia. Dis Colon Rectum 2001;44:179–83. [117] FirtzHarris GP, Garcia-Aguilar J, Parker SC, et al. Quality of life after subtotal colectomy for slow transit delayed colonic transit: both quality and quantity count. Dis Colon Rectum 2003;46:433–40. [118] Malouf AJ, Wiesel PH, Nicholis T, et al. Sacral nerve stimulation for idiopathic slow transit constipation. Gastroenterol Clin North Am 2001;118:4444–8. [119] Ganio E, Masin A, Ratto C, et al. Short-term sacral nerve stimulation for functional anorectal and urinary disturbances: results in 40 patients. Dis Colon Rectum 2001;44:1261–7. [120] Kenefick NJ, Nichlls RJ, Cohen RG, et al. Permanent sacral nerve stimulation for treatment of idiopathic constipation. Br J Surg 2002;89:882–8. [121] Chen JDZ, Lin HC. Intestinal pacing accelerates delayed transit induced by ileal brake. Dig Dis Sci 2003;48:251–6. [122] Isozaki K, Hirita S, Miyagawa J, et al. Deficiency of c-kitþcells in patients with a myopathic form of chronic idiopathic intestinal pseudo-obstruction. Am J Gastroenterol 1997;92: 332–4. [123] Forster J, Damjanov I, Lin Z, et al. Absence of interstitial cells of Cajal in patients with gastroparesis and correlation with clinical findings. J Gastrointest Surg 2005;9(1):102–8.
Gastroenterol Clin N Am 36 (2007) 735–748
GASTROENTEROLOGY CLINICS OF NORTH AMERICA
Bacteria: A New Player in Gastrointestinal Motility Disorders—Infections, Bacterial Overgrowth, and Probiotics Eamonn M.M. Quigley, MD, FRCP, FACP, FACG, FRCPI Department of Medicine, Alimentary Pharmabiotic Centre, University College Cork, Clinical Sciences Building, Cork University Hospital, Cork, Ireland
T
his article addresses the novel and somewhat unexpected topic of the contribution of bacteria to dysmotility. It begins with a short discussion of a well-worn subject: the contribution of bacterial overgrowth to the clinical features of ‘‘classical,’’ or well-established, motility disorders, as well as to the less well recognized motility complications of common systemic disorders. However, the main focus of this article is on an emerging topic: the possible role of the enteric flora in the basic pathogenesis of one of the most common putative motor disorders, irritable bowel syndrome (IBS).
BACTERIAL OVERGROWTH IN ESTABLISHED MOTILITY DISORDERS Small intestinal bacterial overgrowth (SIBO) has long been recognized as an important consequence of severe dysmotility and is a common feature of established chronic pseudo-obstruction syndromes, be they primary or secondary. Common, well-recognized, and clinically important examples of secondary chronic pseudo-obstruction syndromes include diabetes mellitus and scleroderma. SIBO may be a critical contributor to the development of diarrhea, maldigestion, malabsorption, and malnutrition in affected patients through competition with the host for luminal nutrients, through luminal deconjugation of bile salts, and through direct (and indirect) effects on mucosal morphology and permeability. As in other instances where the primary cause is not amenable to curative therapy, the management of SIBO in such individuals is based on antibiotic therapy. This issue has been reviewed in detail elsewhere [1,2] and will not be discussed further in this article. Suffice it to say that for those in whom intestinal stasis is present and especially where intestinal dysmotility is a prominent factor, as in chronic intestinal pseudo-obstruction, prokinetic E-mail address:
[email protected] 0889-8553/07/$ – see front matter doi:10.1016/j.gtc.2007.07.012
ª 2007 Elsevier Inc. All rights reserved. gastro.theclinics.com
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agents appear to offer considerable additional therapeutic potential. While some evidence suggests that prokinetics, such as cisapride and erythromycin, are effective, especially in cases of chronic intestinal pseudo-obstruction [3], the ability of these agents to reduce bacterial contamination in SIBO has been scarcely studied. In one small study, the somatostatin analog octreotide, which induces migrating-motor-complex–like activity in the small intestine, was shown to reduce symptoms and breath-hydrogen excretion in patients with scleroderma [4]. However, a subsequent study in an experimental animal model failed to replicate this effect [5]. Subsequently, it has been shown that the net effect of this agent in humans is also to delay, and not to accelerate transit [6]; rendering a real prokinetic effect unlikely. DYSMOTILITY AND BACTERIAL OVERGROWTH IN COMMON SYSTEMIC DISORDERS Less heralded, but no less important, is the potential contribution of SIBO to both symptomatology and clinical features in a variety of disorders where dysmotility is a factor. For example, Husebye and colleagues [7] clearly related the occurrence of SIBO to enteric dysmotility among patients with symptomatic radiation enteritis. Small intestinal bacterial contamination has also been linked to abnormal small bowel motility, and especially disruption of the migrating motor complex, in pancreatitis [8], liver disease [9,10], and short bowel syndrome [11]. These observations support the critical role of interdigestive motility in the prevention of small intestinal bacterial overgrowth and resultant translocation in normal humans [12]. Dysmotility and SIBO are especially prevalent in chronic liver disease and especially among those with cirrhosis complicated by portal hypertension [10]. In this context, SIBO is thought to predispose to translocation [13] and, ultimately, to play a major role in the development of both spontaneous bacterial peritonitis [14,15] and gram-negative sepsis [16]. Furthermore, human studies have demonstrated the ability of cisapride to reduce bacterial overgrowth in chronic liver disease [17]. Cisapride is, however, no longer available. More recently, interest has increased in the potential contributions of the enteric flora and their interactions with the host in the pathogenesis of one of the new pandemics of the West: the related disorders of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steato-hepatitis [18]. Wigg and colleagues [19], for example, documented bacterial overgrowth in 50% of their patients with chronic liver disease due to NAFLD and related its occurrence to elevated systemic levels of tumor necrosis factor alpha (TNFa). The answers to whether and in what manner enteric dysmotility contributes to overgrowth in this context are unclear. Over a quarter of a century ago, bacterial overgrowth was proposed as a potential cause of unexplained diarrhea and malabsorption in the elderly [20] and continues to be recognized as an important factor in the precipitation of these disorders in this patient population [21]. Given the prevalence of comorbid disorders and especially of neurological diseases associated with enteric
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dysmotility per se in this age group, the delineation of the basic etiology of overgrowth in a given patient is difficult. While there is paltry convincing evidence for a clinically significant age-related deterioration in small intestinal motor function, it must be conceded that this has not been an extensively studied subject [22]. Some have indeed suggested that the development of overgrowth is not a phenomenon of the aging process but rather the consequence of disabilities that commonly afflict the aged [23,24]. BACTERIAL OVERGROWTH IN INTESTINAL DISEASE: CONTRIBUTIONS OF DYSMOTILITY Bacterial overgrowth has also been documented in a variety of intestinal disorders, such as jejunal diverticulosis [1], Crohn’s disease, and celiac sprue. In the case of jejunal diverticulosis, the development of the diverticula has been linked to a primary disorder of enteric muscle and nerve [25]. While the development of bacterial overgrowth in Crohn’s disease can usually be explained on the basis of the presence of a stricture, a coloenteric fistula, or both, it has been suggested that intestinal stasis based on motor dysfunction may also play a role [26]. Bacterial overgrowth is a recognized complication of celiac sprue and its occurrence has, in this context, also been linked with abnormal motor patterns in the small intestine [27,28]. Suffice it to say that any disorder that promotes small intestinal stasis—that is, metabolic disorders, such as thyroid dysfunction, or iatrogenic disorders, such as narcotic ingestion—predisposes to bacterial overgrowth. While the contributions of bacteria to diverticulitis and its complications, such as peridiverticular abscess, are obvious, less well known are the potential contributions of the colonic flora (microbiota) to the basic pathogenesis of diverticulosis. Long assumed to reflect a disorder of colonic and especially sigmoid colon muscle function, the extent to which the flora contribute to the development of the underlying motor abnormality, diverticula, symptoms, diverticulitis, or diverticular colitis has been scarcely explored, despite the ever-increasing prevalence of these disorders. THE ROLE OF BACTERIA IN IRRITABLE BOWEL SYNDROME The relationship of bacteria, antibiotics, and IBS is complex and contains several distinct and even contradictory strands [29]:
Epidemiological evidence that antibiotic use may predispose to IBS or to exacerbations thereof Epidemiological, clinical, and experimental evidence for the existence of postinfectious IBS Evidence, both experimental and clinical, for a role for low-grade inflammation (perhaps triggered by luminal bacteria) in IBS The suggestion that IBS may be associated with SIBO or other changes in the gut flora Accumulating evidence to indicate that manipulation of the gut flora by antibiotics or probiotics may ameliorate symptoms in IBS
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In a survey of 421 subjects in a primary care practice in the United Kingdom, antibiotic use was strongly associated with an increased risk of IBS (odds ratio 3.7) [30]. Privileged childhood living conditions were also an important risk factor, which, according to the investigators, was consistent with an allergic or infectious etiology for IBS. Other epidemiological studies have come to similar conclusions [31]. This association may reflect the impact of broad-spectrum antibiotics on the colonic flora, or be a mere epiphenomenon relating either (1) to the use of antibiotics for illnesses or infections that triggered IBS or (2) to the overprescribing of antibiotics in this patient population. Some support for the proposal that antibiotic use may actually predispose to IBS comes from an animal model where disruption of the flora by antibiotic administration was associated with an intensification of both visceral hypersensitivity and mucosal inflammation [32]. First reported by McKendrick and Read [33], the occurrence of IBS following episodes of bacteriologically confirmed gastroenteritis has now been documented in several studies [34–37]. Most recently, postinfectious IBS has been described following an outbreak of viral gastroenteritis [38]. The risk of developing IBS following an episode of gastroenteritis is in the order of 4% to 23% with females, those with a more severe initial illness, and those with premorbid psychopathology being most at risk [34,36,37,39–42]. Several have documented a link between the development of IBS following prior exposure to an infectious agent and persisting low-grade inflammation or evidence of immune activation [40,41,43,44]. In one study, an increase in the number of chronic inflammatory cells in the rectal mucosa was seen only among those exposed patients who had developed IBS [40]. Others have demonstrated a persisting increase in rectal mucosal enteroendocrine cells, T lymphocytes, and gut permeability in patients with postdysenteric IBS [41,43]. Postinfectious IBS may explain only a minority (perhaps 5%–10%) of cases of IBS, but does provide a clear link between exposure to an environmental agent, be it bacterial or viral; persistent, albeit subtle, mucosal inflammation; and the development of IBS in predisposed individuals [42]. Though by no means proven, it may well be possible to extend to IBS in general the concept of luminal triggering by bacteria and other microorganisms of mucosal inflammation. While it is possible that asymptomatic, or forgotten, episodes of enteric infection could contribute on a larger scale to the pathogenesis of IBS, one could also invoke either (1) qualitative or quantitative changes in the colonic or small intestinal flora, or (2), as has been proposed in inflammatory bowel disease, a dysfunctional interaction between elements of the flora and the host. What Is The Evidence for Immune Activation and Inflammation in Irritable Bowel Syndrome? Support for an inflammatory basis for IBS in humans comes from both the mucosal and systemic compartments of the immune system. Direct evidence of a role for mucosal inflammation was first provided by Chadwick and
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colleagues [45]. They evaluated 77 IBS patients, of whom 55% would be considered as diarrhea-predominant; none had a confirmed infectious origin for their IBS. On conventional histology, 31 demonstrated microscopic inflammation and 8 fulfilled criteria for lymphocytic colitis. However, among the group with ‘‘normal’’ histology, immunohistology revealed increased intraepithelial lymphocytes as well as an increase in CD3þ and CD25þ cells in the lamina propria; all, therefore, showed evidence of immune activation. In an accompanying editorial, Collins [46] suggested that the increased presence of CD25þ cells may have indicated ‘‘auto- or exogenous antigen challenge in these patients, and that the CD25þ cells are preventing the progression to a more florid inflammatory response.’’ The bacteria–inflammation axis was firmly on the map. There may even be a genetic contribution to the development of this apparently aberrant response to a luminal antigen, be it bacterial or otherwise, in IBS. While direct linkages between a particular genotype or several genotypes and mucosal inflammation have not been established, TNFa and interleukin-10 gene polymorphisms have been described among IBS patients [47,48]. Is this subtle inflammatory state really of any relevance to the basic pathognensis of IBS? A direct linkage between immune activation and symptom development has been provided by a number of disparate sources. Firstly, Barbara and colleagues [49] demonstrated not only an increased prevalence of mast cell degranulation in the colon in IBS, but also a direct correlation between the proximity of mast cells to neuronal elements and pain severity. This concept was taken a step further by Cenac and colleagues [50], who demonstrated (1) that protease activity in colonic biopsies is increased in IBS patients, (2) that these proteases signal to sensory nerves and generate visceral hypersensitivity through protease-activated receptor 2, and (3) that trypsin and tryptase, products of mast cells, are the most likely contributors to this increased proteolytic activity. Interestingly, they were not able to document any increase in mast cell numbers, nor did they find clear differences in proteolytic activity between the various IBS subtypes. The concept that inflammation and immune activation can promote visceral hypersensitivity, a phenomenon regarded by many as pervasive among IBS subjects, is supported by considerable data from experimental animal models [32,51–53]. Others have focused attention on the systemic compartment. Among a group of 78 unselected IBS patients, O’Mahony and colleagues (including the author) [54] demonstrated, in peripheral blood mononuclear cells, an alteration in the ratio between the cytokines interleukin-10 and interleukin-12, which became skewed toward a Th1, pro-inflammatory profile. Very recently, Liebregts and colleagues [55] extended these findings. At baseline, the production of the cytokines TNFa, interleukin-1b, and interleukin-6 was increased in their IBS patients; stimulation with the bacterial lipo-polysaccheride, derived from Escherichia Coli, resulted in an increased production of interleukin-6, in comparison to controls [55]. The latter is consistent with the demonstration by Dinan and colleagues (including the author) [56] of increased cytokine levels,
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including interleukin-6, in serum from IBS patients. Dinan and colleagues also identified a relationship between elevated levels of pro-inflammatory cytokines in the peripheral blood and disturbed hypothalamic–pituitary–adrenal axis function, suggesting that mucosal inflammation, perhaps triggered by luminal bacteria, could even disrupt the gut–brain axis in IBS [56]. While these disparate findings support the inflammatory hypothesis in IBS, several gaps remain. Firstly, correlations between the mucosal, enteric, and systemic immune compartments have not been examined. Secondly, while it is attractive to impugn the enteric flora as the initiator of these mucosal and systemic immune changes [57], this role has not been established and a role for a central ‘‘driver’’ of immune activation or even bidirectional effects along the brain–gut axis cannot be discounted. Finally, it is also possible that these changes are secondary to bowel dysfunction. Thus, Khalif and colleagues [58] demonstrated a variety of immune abnormalities in subjects with constipation who were normalized following alleviation of constipation by a laxative. Are There Qualitative or Quantitative Changes in The Enteric Flora in Irritable Bowel Syndrome? For some time, various studies have suggested the presence of qualitative changes in the colonic flora in IBS patients, with a relative decrease in the population of bifidobacteria as the most consistent finding [59–62]. However, these findings have not always been reproduced and the methods employed have been subject to question. Specifically, many of these studies rely on culturing of fecal samples, an approach that not only provides a poor reflection of the distribution of bacteria within the colon as well as across its diameter, but also certainly fails to detect many metabolically active species that remain unculturable by current methods. The application of genomic and metabolomic technologies to this issue should provide a more comprehensive picture of the status of the colonic flora in IBS. It is, indeed, reasonable to imagine that qualitative changes in the colonic flora, be they primary or secondary, could lead to the proliferation of species that produce more gas [63,64] and short chain fatty acids and are more avid in the deconjugation of bile acids. Each of these consequences could, in turn, lead to clinically significant changes in water and electrolyte transport in the colon and affect colonic motility and/or sensitivity. Disturbances in the colonic flora could be a consequence, rather than the cause of, altered bowel habit, as suggested by the reversible changes documented by Khalif and colleagues [58] in their subjects with constipation. More recently, the role of the gut flora in IBS has been taken a stage further with the suggestion that some IBS patients may harbor quantitative changes in the indigenous flora in the small intestine: SIBO [65–69]. The occurrence of SIBO has been associated with abnormalities in small intestinal motor function [70] and its eradication with symptomatic relief [65,66,68]. These striking results have been the target of much criticism on several grounds [71–74]. Firstly, IBS symptoms are nonspecific and may be mimicked by SIBO,
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regardless of etiology; patient selection is, therefore, an issue. Secondly, the hydrogen breath test, which has been most widely used in the diagnosis of SIBO in this context, is subject to considerable error, especially in relation to altered small bowel transit [75]. Thirdly, studies of the impact of eradication have, for the most part, been short-lived. Finally, others have failed to confirm these findings [76–78]. Most important of these studies of bacterial overgrowth in IBS is the large study by Posserud and colleagues [78] in which they performed jejunal cultures and small intestinal manometry in 162 IBS subjects and documented the same rate of bacterial overgrowth (4%, using the most widely accepted definition) in IBS and control subjects; IBS subjects with overgrowth were more likely to demonstrate abnormal motility. While arguments will continue regarding the accuracy, relevance, and appropriateness of various diagnostic tests in the detection of overgrowth in the context of IBS, it appears that diagnostic shortcomings, patient selection, and symptomatic overlap have contributed greatly to the overgrowth iceberg in IBS whereas in reality it is, for the most part, no more than a mirage. Will Altering The Flora with Antibiotics or Probiotics Have An Impact in Irritable Bowel Syndrome? The principal evidence for a role for antibiotics in IBS comes from studies among the aforementioned IBS patients with associated SIBO [65,66,68]. However, the eradication of SIBO, as proposed by these investigators, may not be the sole explanation for these responses, which could also be explained on the basis of an effect on the colonic flora [64,79]. This suggestion is also supported by the recent report from Sharara and colleagues [80] that described an amelioration of gas-related symptoms with antibiotic therapy among a group of patients with bloating and flatulence, who did not have evidence of SIBO. The fact that not all of these patients fulfilled Rome II criteria for IBS does not detract from the relevance of their finding to IBS because this rather restrictive instrument does not accord due prominence to bloating and distension and, in any event, because Rome II patients fared, if anything, better when treated with the poorly absorbed antibiotic rifaximin. One can reasonably hypothesize, based on the findings of Sharara and colleagues, that quantitative or qualitative changes in the intestinal microflora led to subtle and local increases in gas production that, though sufficient to be sensed as bloating or distension in a suitably attuned individual, did not lead to a detectable elevation in breath hydrogen excretion [79]. This contention is supported by the presence of a good correlation between improvements in symptom scores and reductions in breath hydrogen excretion among treatment responders; antibiotic therapy suppressed the abnormal flora, bacterial fermentation, and related symptoms. The response was far from overwhelming and the duration of the study was exceedingly short in a condition that is notoriously chronic and remittent. The results of a large controlled trial of rifaximin in IBS have just been reported. Eighty-seven patients who satisfied Rome I criteria for IBS were randomized to receive either rifaximin 400 mg three times a day or placebo
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for 10 days and then assessed 10 weeks later. Global improvement was greater in the rifaximin-treated group, which experienced a 36.4% improvement compared with 21% in the placebo-treated group. This was a surprisingly low placebo response rate and a therapeutic gain of questionable significance [81]. Results of breath hydrogen testing were not presented. As pointed out by Drossman [82] in an accompanying editorial, several limitations to this study weaken its impact. Firstly, recruitment was very unequal between the two study centers; secondly, the primary endpoint was not defined a priori; and, thirdly, the method of analysis was somewhat unusual. These results are far less impressive than one was led to expect from the initial studies from these same investigators and also cast further doubt on the importance of bacterial overgrowth in IBS. Finally, one must remain reluctant, pending long-term studies, to recommend a prolonged course of antibiotic therapy to any population, regardless of the safety profile of a given antibiotic. Given their safety profile, probiotics, if effective, would at first sight appear to be more attractive as potential manipulators of the gut flora in IBS. Are probiotics effective in IBS? Several factors complicate the interpretation of clinical trials of probiotic preparations in IBS. Many studies have been underpowered and some earlier studies were even uncontrolled and not blinded. Furthermore, results between studies are difficult to compare because of differences in study design, use of nonvalidated and differing endpoints, and variations in probiotic dose and strain. Nevertheless, there has been some, but by no means consistent, evidence of symptom improvement [83]. In reviewing earlier trials, Hamilton-Miller [84], while drawing attention to their many shortcomings in terms of study design, concluded that there was, overall, sufficient evidence of efficacy of probiotics to warrant further evaluation. Furthermore, some more recent studies have employed probiotic ‘‘cocktails’’ rather than single isolates, rendering it difficult to deduce what the active moieties were [85–90]. In light of the aforementioned issues and challenges, research at Cork Alimentary Pharmabiotic Center, the author’s institution, has focused on the evaluation of well-characterized (in terms of antibacterial, antiviral, and immune-modulating effects) probiotic strains in prospective trials using products and formulations subjected to rigorous quality control measures. In the first of Cork Alimentary Pharmabiotic Center’s recent studies, the author and colleagues compared, for the first time, the effects of two probiotic strains on symptoms in 75 patients with IBS. The author and colleagues demonstrated superiority for Bifidobacterium infantis 35624 over both a Lactobacillus and placebo for each of the cardinal symptoms of IBS (abdominal pain or discomfort, distension or bloating, and difficult defecation), as well as for a composite score [54]. More recently, the author and colleagues replicated these results in a much larger, dose-ranging, primary-care–based study involving 360 IBS subjects, where B infantis, in an encapsulated formulation and in a dose of 108, was associated with significant improvements in the cardinal symptoms of IBS and in the subjects’ global assessment of all symptoms; at study end,
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over 60% of subjects randomized to the Bifidobacterium felt better than before therapy, a therapeutic gain of over 20% over placebo [91]. In both studies, a positive impact on IBS symptomatology occurred independent of any effect on stool frequency; indicating that observed effects were not attributable to either a laxative or an antidiarrheal effect. These studies, with this particular B infantis strain, provide, therefore, evidence for a benefit in IBS for a clearly defined single-organism probiotic preparation and, thereby, suggests that some strains may be more effective than others for this indication. How do probiotics work in IBS? Are these symptomatic improvements merely a reflection of the displacement of more gas-producing, bile-salt–deconjugating species, or is there a more fundamental effect? That the immunemodulating properties of strains, such as B infantis, may be relevant to IBS in humans is suggested by the author and colleagues’ demonstration of the normalization of a baseline pro-inflammatory state [54]. Animal models provide further insights demonstrating the ability of a variety of probiotic strains to reduce visceral hypersensitivity and spinal afferent traffic [32,51–53,92]; one species, Lactobacillus acidophilus, has been shown to induce the expression of l-opioid and cannabinoid receptors in human intestinal epithelial cells [92]. IS THERE A DIAGNOSTIC CATEGORY THAT LIES BETWEEN IRRITABLE BOWEL SYNDROME AND CHRONIC INTESTINAL PSEUDO-OBSTRUCTION? Clinicians often see patients with severe IBS-type symptoms who also exhibit some of the clinical, radiological, and manometric features of chronic intestinal pseudo-obstruction but who do not meet any of the widely accepted diagnostic criteria for chronic intestinal pseudo-obstruction. Wingate and colleagues [93] used the term enteric dysmotility to refer to this group and suggested that they represented a true motility disorder. Several lines of evidence can be mustered to support this concept, including the demonstration, over the years, of a variety of transit and manometric abnormalities in some IBS patients [94]. Perhaps the IBS patients with overgrowth fall into this category rather than IBS per se? This possibility is supported by the aforementioned study by Posserud and colleagues [78], which correlated overgrowth with dysmotility and also documented a higher than normal prevalence of overgrowth, defined according to a more lenient manner than is conventional, in a minority of their IBS patients. Tornblom and colleagues addressed this issue in 10 patients with severe IBS by full-thickness jejunal biopsies obtained at laparoscopy [95]. In 9, they found low-grade infiltration of lymphocytes in the myenteric plexus; 4 of these had an associated increase in intraepithelial lymphocytes and 6 demonstrated evidence of neuronal degeneration. Interestingly, 3 of their patients reported an acute onset of their ‘‘IBS.’’ For 2 of those 3 patients, acute onset of ‘‘IBS’’ was possibly precipitated by gastroenteritis. It is hoped that new biomarkers will enable clinicians to define whether this intermediate group (enteric dysmotility) actually exists or merely represents more noise at the fuzzy end of the IBS spectrum.
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SUMMARY Many recent findings add to a growing body of evidence to suggest that IBS, like inflammatory bowel disease, may result, in part at least, from a dysfunctional interaction between the indigenous flora and the intestinal mucosa, which in turn leads to immune activation in the colonic mucosa. This does not place IBS within the spectrum of inflammatory bowel disease, where the intensity and distribution of the inflammatory process are vastly different [96]. Some propose that bacterial overgrowth is a common causative factor in the pathogenesis of symptoms in IBS; others point to evidence suggesting that the cause stems from more subtle qualitative changes in the colonic flora. Neither hypothesis has been confirmed, but the likelihood now seems remote that bacterial overgrowth will prove to be a major factor in what will eventually be defined as IBS. Nevertheless, short-term therapy with either antibiotics or probiotics does seem to reduce symptoms among IBS patients. It seems most likely that the benefits of antibiotic therapy are mediated through subtle and perhaps localized quantitative and/or qualitative changes in the colonic flora. How probiotics exert their effects remains to be defined but an anti-inflammatory effect seems likely. While this approach to the management of IBS is in its infancy, it is evident that manipulation of the flora, whether through the administration of antibiotics or probiotics, deserves further attention in IBS. Given the chronic and relapsing nature of IBS and the risks attendant on long-term antibiotic use, the use of probiotics provides a far more appealing option. References [1] Quigley EM. Small bowel bacterial overgrowth. In: Weinstein WM, Hawkey CJ, Bosch J, editors. Clinical gastroenterology and hepatology. Philadelphia: Elsevier Mosby/Saunders; 2006. [2] Quigley EM, Quera R. Small intestinal bacterial overgrowth: roles of antibiotics, prebiotics and probiotics. Gastroenterology 2006;130(2 Suppl 1):S78–90. [3] Quigley EM. Chronic intestinal pseudo-obstruction. Curr Treat Options Gastroenterol 1999;2:239–50. [4] Soudah HC, Hasler WL, Owyang C. Effect of octreotide on intestinal motility and bacterial overgrowth in scleroderma. N Engl J Med 1991;325:1461–7. [5] Nieuwenhuijs VB, van Duijvenbode-Beumer H, Verheem A, et al. The effects of ABT-29 and octreotide on interdigestive small bowel motility, bacterial overgrowth and bacterial translocation in rats. Eur J Clin Invest 1999;29:33–40. [6] Von der Ohe MR, Camilleri M, Thomforde GM, et al. Differential regional effects of octreotide on human gastrointestinal motor function. Gut 1995;36:734–8. [7] Husebye E, Skar V, Hoverstad T, et al. Abnormal intestinal motor patterns explain enteric colonization with gram-negative bacilli in late radiation enteropathy. Gastroenterology 1995;109:1078–89. [8] Van Felius ID, Akkermans LM, Bosscha K, et al. Interdigestive small bowel motility and duodenal bacterial overgrowth in experimental acute pancreatitis. Neurogastroenterol Motil 2003;15:267–76. [9] Chesta J, Defilippi C, Defilippi C. Abnormalities in proximal small bowel motility in patients with cirrhosis. Hepatology 1993;17:828–32.
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[10] Gunnarsdottir SA, Sadik R, Shev S, et al. Small intestinal motility disturbances and bacterial overgrowth in patients with liver cirrhosis and portal hypertension. Am J Gastroenterol 2003;98:1362–70. [11] Quigley EMM, Thompson JS. The intestinal motor response to resection. Gastroenterology 1993;105:791–8. [12] Vantrappen G, Janssens J, Hellemans J, et al. The interdigestive motor complex of normal subjects and patients with bacterial overgrowth of the small intestine. J Clin Invest 1977;59:1158–66. [13] Sorell WT, Quigley EM, Jin G, et al. Bacterial translocation in the portal hypertensive rat: studies in basal conditions and on exposure to hemorrhagic shock. Gastroenterology 1993;104:1722–6. [14] Chang CS, Chen GH, Lien HC, et al. Small intestine dysmotility and bacterial overgrowth in cirrhotic patients with spontaneous bacterial peritonitis. Hepatology 1998;28:1187–90. [15] Bauer TM, Steinbruckner B, Brinkmann FE, et al. Small intestinal bacterial overgrowth in patients with cirrhosis: prevalence and relation with spontaneous bacterial peritonitis. Am J Gastroenterol 2001;96:2962–7. [16] Bauer TM, Schwacha H, Steinbruckner B, et al. Small intestinal bacterial overgrowth in human cirrhosis is associated with systemic endotoxemia. Am J Gastroenterol 2002;97: 2364–70. [17] Madrid AM, Hurtado C, Venegas M, et al. Long-term treatment with cisapride and antibiotics in liver cirrhosis: effect on small intestinal motility, bacterial overgrowth, and liver function. Am J Gastroenterol 2001;96:1251–5. [18] Solga SF, Diehl AM. Non-alcoholic fatty liver disease: lumen–liver interactions and possible role for probiotics. J Hepatol 2003;38:681–7. [19] Wigg AJ, Roberts-Thomson IC, Dymock RB, et al. The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor a in the pathogenesis of non-alcoholic steatohepatitis. Gut 2001;48:206–11. [20] Roberts SH, James O, Jarvis EH. Bacterial overgrowth syndrome without ‘‘blind loop’’: a cause for malnutrition in the elderly. Lancet 1977;2:1193–5. [21] Hoffmann JC, Zeitz M. Small bowel disease in the elderly: diarrhoea and malabsorption. Best Pract Res Clin Gastroenterol 2002;16:17–36. [22] O’Mahony D, O’Leary P, Quigley EM. Aging and intestinal motility: a review of factors that affect intestinal motility in the aged. Drugs Aging 2002;19:515–27. [23] Mitsui T, Kagami H, Kinomoto H, et al. Small bowel bacterial overgrowth and rice malabsorption in healthy and physically disabled older adults. J Hum Nutr Diet 2003;16:119–22. [24] Mitsui T, Shimaoka K, Goto Y, et al. Small bowel bacterial overgrowth is not seen in healthy adults but is in disabled older adults. Hepatogastroenterology 2006;53:82–5. [25] Krishnamurthy S, Kelly MM, Rohrmann CA, et al. Jejunal diverticulosis. A heterogenous disorder caused by a variety of abnormalities of smooth muscle or myenteric plexus. Gastroenterology 1983;85:538–47. [26] Castiglione F, Del Vecchio Blanco G, Rispo A, et al. Orocecal transit time and bacterial overgrowth in patients with Crohn’s disease. J Clin Gastroenterol 2000;31:63–6. [27] Tursi A, Brandimarte G, Giorgetti G. High prevalence of small intestinal bacterial overgrowth in celiac patients with persistence of gastrointestinal symptoms after gluten withdrawal. Am J Gastroenterol 2003;98:720–2. [28] O’Leary C, Quigley EM. Small bowel bacterial overgrowth, celiac disease, and IBS: what are the real associations? Am J Gastroenterol 2003;98:720–2. [29] Quigley EM. Bacterial flora in irritable bowel syndrome: role in pathophysiology, implications for management. J Dig Dis 2007;8:2–7. [30] Mendall MA, Kumar D. Antibiotic use, childhood affluence and irritable bowel syndrome (IBS). Eur J Gastroenterol Hepatol 1998;10:59–62. [31] Maxwell PR, Rink E, Kumar D, et al. Antibiotics increase functional abdominal symptoms. Am J Gastroenterol 2002;97:104–8.
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[32] Verdu EF, Bercik P, Verma-Gandhu M, et al. Specific probiotic therapy attenuates antibiotic induced visceral hypersensitivity in mice. Gut 2006;55:182–90. [33] McKendrick MW, Read MW. Irritable bowel syndrome–post-salmonella infection. J Infect 1994;29:1–3. [34] Neal KR, Hebdon J, Spiller R. Prevalence of gastrointestinal symptoms six months after bacterial gastroenteritis and risk factors for development of the irritable bowel syndrome. Br Med J 1997;314:779–82. [35] Garcia Rodriguez LA, Ruigomez A. Increased risk of irritable bowel syndrome after bacterial gastroenteritis: cohort study. BMJ 1999;318:565–6. [36] Mearin F, Perez-Oliveras M, Perello A, et al. Dyspepsia and irritable bowel syndrome after a Salmonella gastroenteritis outbreak: one-year follow-up cohort study. Gastroenterology 2005;129:98–104. [37] Marshall JK, Thabane M, Garg AX, et al. the Walkerton Health Study Investigators. Incidence and epidemiology of irritable bowel syndrome after a large waterborne outbreak of bacterial dysentery. Gastroenterology 2006;131:445–50. [38] Marshall JK, Thabane M, Borgaonkar MR, et al. Postinfectious irritable bowel syndrome after a food-borne outbreak of acute gastroenteritis attributed to a viral pathogen. Clin Gastroenterol Hepatol 2007;5:457–60. [39] Gwee KA, Graham JC, McKendrick MW, et al. Psychometric scores and persistence of irritable bowel after infectious diarrhoea. Lancet 1996;347:150–3. [40] Gwee K-A, Leong Y-L, Graham C, et al. The role of psychological and biological factors in post-infective gut dysfunction. Gut 1999;44:400–6. [41] Dunlop SP, Jenkins D, Neal KR, et al. Relative importance of enterochromaffin cell hyperplasia, anxiety, and depression in postinfectious IBS. Gastroenterology 2003;125:1651–9. [42] Spiller RC. Postinfectious irritable bowel syndrome. Gastroenterology 2003;124: 1662–71. [43] Spiller RC, Jenkins D, Thornley JP, et al. Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut 2000;47:804–11. [44] Gwee K-A, Collins SM, Read NW, et al. Increased rectal mucosal expression of interleukin 1 beta in recently acquired post-infectious irritable bowel syndrome. Gut 2003;52:523–6. [45] Chadwick V, Chen W, Shu D, et al. Activation of the mucosal immune system in irritable bowel syndrome. Gastroenterology 2002;122:1778–83. [46] Collins SM. A case for an immunological basis for irritable bowel syndrome. Gastroenterology 2002;122:2078–80. [47] Gonsalkorale WM, Perrey C, Pravica V, et al. Interleukin 10 genotypes in irritable bowel syndrome: evidence for an inflammatory component? Gut 2003;52:91–3. [48] van der Veek PP, van den berg M, de Kroon YE, et al. Role of tumor necrosis factor-alpha and interleukin-10 gene polymorphisms in irritable bowel syndrome. Am J Gastroenterol 2005;100:2510–6. [49] Barbara G, Stanghellini V, De Giorgio R, et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 2004;126:693–702. [50] Cenac N, Andrews CN, Holzhausen M, et al. Role for protease activity in visceral pain in irritable bowel syndrome. J Clin Invest 2007;117:636–47. [51] Ait-Belgnaoui A, Han W, Lamine F, et al. Lactobacillus farciminis treatment suppresses stressinduced visceral hypersensitivity: a possible action through interaction with epithelial cells cytoskeleton contraction. Gut 2006;55:1090–4. [52] Kamiya T, Wang L, Forsythe P, et al. Inhibitory effects of Lactobacillus reuteri on visceral pain induced by colorectal distension in Sprague-Dawley rats. Gut 2006;55:191–6. [53] Bueno L, de Ponti F, Fried M, et al. Serotonergic and non-serotonergic targets in the pharmacotherapy of visceral hypersensitivity. Neurogastroenterol Motil 2007;19(1 Suppl): 89–119.
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[54] O’Mahony L, McCarthy J, Kelly P, et al. A randomized, placebo-controlled, double-blind comparison of the probiotic bacteria lactobacillus and bifidobacterium in irritable bowel syndrome (IBS): symptom responses and relationship to cytokine profiles. Gastroenterology 2005;128:541–51. [55] Liebregts T, Adam B, Bredack C, et al. Immune activation in patients with irritable bowel syndrome. Gastroenterology 2007;132:913–20. [56] Dinan TG, Quigley EM, Ahmed SM, et al. Hypothalamic–pituitary–gut axis dysregulation in irritable bowel syndrome: plasma cytokines as a potential biomarker? Gastroenterology 2006;130:304–11. [57] Spiller RC. Role of nerves in enteric infection. Gut 2002;51:759–62. [58] Khalif IL, Quigley EM, Konovitch EA, et al. Alterations in the colonic flora and intestinal permeability and evidence of immune activation in chronic constipation. Dig Liver Dis 2005;37:838–49. [59] Bradley HK, Wyatt GM, Bayliss CE, et al. Instability in the faecal flora of a patient suffering from food-related irritable bowel syndrome. J Med Microbiol 1987;23:29–32. [60] Si JM, Yu YC, Fan YJ, et al. Intestinal microecology and quality of life in irritable bowel syndrome patients. World J Gastroenterol 2004;10:1802–5. [61] Malinen E, Rinttila T, Kajander K, et al. Analysis of the fecal microbiota of irritable bowel syndrome patients and healthy controls with real-time PCR. Am J Gastroenterol 2005; 100:373–82. [62] Matto J, Maunuksela L, Kajander K, et al. Composition and temporal stability of gastrointestinal microbiota in irritable bowel syndrome—a longitudinal study in IBS and control subjects. FEMS Immunol Med Microbiol 2005;43:213–22. [63] King TS, Elia M, Hunter JO. Abnormal colonic fermentation in irritable bowel syndrome. Lancet 1998;352:1187–9. [64] Dear KL, Elia M, Hunter JO. Do interventions which reduce colonic bacterial fermentation improve symptoms of irritable bowel syndrome? Dig Dis Sci 2005;50:758–66. [65] Pimentel M, Chow EJ, Lin HC. Eradication of small bowel bacterial overgrowth reduces symptoms of irritable bowel syndrome. Am J Gastroenterol 2000;95:3503–6. [66] Pimentel M, Chow E, Lin H. Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome: a double-blind, randomized, placebocontrolled study. Am J Gastroenterol 2003;98:412–9. [67] Nucera G, Gabrielli A, Lupascu A, et al. Abnormal breath tests to lactose, fructose and sorbitol in irritable bowel syndrome may be explained by small intestinal bacterial overgrowth. Aliment Pharmacol Ther 2005;21:1391–5. [68] Cuoco L, Salvagnini M. Small intestine bacterial overgrowth in irritable bowel syndrome: a retrospective study with rifaximin. Minerva Gastroenterol Dietol 2006;52:89–95. [69] Cuoco L, Cammarota G, Jorizzo R, et al. Small intestinal bacterial overgrowth and symptoms of irritable bowel syndrome. Am J Gastroenterol 2001;96:2281–2. [70] Pimentel M, Soffer EE, Chow EJ, et al. Lower frequency of MMC is found in IBS subjects with abnormal lactulose breath test, suggesting bacterial overgrowth. Dig Dis Sci 2002;47: 2639–43. [71] Jones MP, Craig R, Olinger E. Small intestinal bacterial overgrowth is associated with irritable bowel syndrome: the cart lands squarely in front of the horse. Am J Gastroenterol 2001;96:3204–5. [72] Mishkin D, Mishkin S. Re: Pimentel et al. Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel syndrome. Am J Gastroenterol 2001;96: 2505–6. [73] Riordan SM, McIver CJ, Duncombe VM, et al. Small intestinal bacterial overgrowth and the irritable bowel syndrome. Am J Gastroenterol 2001;96:2506–8. [74] Hasler WL. Lactulose breath testing, bacterial overgrowth, and IBS: just a lot of hot air? Gastroenterology 2003;125:1898–900. [75] Simre´n M, Stotzer P-O. Use and abuse of hydrogen breath tests. Gut 2006;55:297–393.
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[76] Parisi G, Leandro G, Bottona E, et al. Small intestinal bacterial overgrowth and irritable bowel syndrome. Am J Gastroenterol 2003;98:2572. [77] Walters B, Vanner SJ. Detection of bacterial overgrowth in IBS using the lactulose H2 breath test: comparison with 14C-d-Xylose and healthy controls. Am J Gastroenterol 2005;100: 1566–70. [78] Posserud I, Stotzer PO, Bjornsson E, et al. Small intestinal bacterial overgrowth in patients with irritable bowel syndrome. Gut 2006;56:802–8. [79] Quigley EM. Germs, gas and the gut; the evolving role of the enteric flora in IBS. Am J Gastroenterol 2006;101(2):334–5. [80] Sharara AI, Aoun E, Abdul-Baki H, et al. A randomized double-blind placebo-controlled trial of rifaximin in patients with abdominal bloating and flatulence. Am J Gastroenterol 2006;101:326–33. [81] Pimentel M, Park S, Mirocha J, et al. The effect of a nonabsorbed antibiotic (rifaximin) on the symptoms of the irritable bowel syndrome: a randomized trial. Ann Intern Med 2006;145: 557–63. [82] Drossman DA. Treatment for bacterial overgrowth in the irritable bowel syndrome. Ann Intern Med 2006;145:626–8. [83] Quigley EMM, Flourie B. Probiotics in irritable bowel syndrome: a rationale for their use and an assessment of the evidence to date. Neurogastroenterol Motil 2007;19:166–72. [84] Hamilton-Miller JMT. Probiotics in the management of irritable bowel syndrome: a review of clinical trials. Microb Ecol Health Dis 2001;13:212–6. [85] Kim HJ, Camilleri M, McKenzie S, et al. A randomized controlled trail of a probiotic, VSL#3 on gut transit and symptoms in diarrhoea-predominant IBS. Aliment Pharmacol Ther 2003;17:895–904. [86] Tsuchiya J, Barreto R, Okura R, et al. Single-blind follow-up study on the effectiveness of a symbiotic preparation in irritable bowel syndrome. Chin J Dig Dis 2004;5:169–74. [87] Kim HJ, Vazquez Roque MI, Camilleri M, et al. A randomised controlled trial of probiotic combination VSL#3 and placebo in IBS with bloating. Neurogastroenterol Motil 2005;17:687–96. [88] Kajander K, Hatakka K, Poussa T, et al. A probiotic mixture alleviates symptoms in irritable bowel syndrome patients: a controlled 6-month intervention. Aliment Pharmacol Ther 2005;22:387–94. [89] Bittner AC, Croffut RM, Stranahan MC. Prescript-Assist probiotic-prebiotic treatment for irritable bowel syndrome: a methodologically oriented, 2-week, randomized, placebocontrolled, double-blind clinical study. Clin Ther 2005;27:755–61. [90] Drisko J, Bischoff B, Hall M, et al. Treating irritable bowel syndrome with a food elimination diet followed by food challenge and probiotics. J Am Coll Nutr 2006;25:514–22. [91] Whorwell PJ, Altinger L, Morel J, et al. Efficacy of an encapsulated probiotic Bifidobacterium infantis 35624 in women with irritable bowel syndrome. Am J Gastroenterol 2006;101:326–33. [92] Rousseaux C, Thuru X, Gelot A, et al. Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors. Nat Med 2007;13:35–7. [93] Wingate DL, Hongo M, Kellow JE, et al. Disorders of gastrointestinal motility: towards a new classification. J Gastroenterol Hepatol 2002;17:S1–S14. [94] Quigley EM. Disturbances of motility and visceral hypersensitivity in irritable bowel syndrome: biological markers or epiphenomenon. Gastroenterol Clin North Am 2005;34: 221–33. [95] Tornblom H, Lindberg G, Nyberg B, et al. Full-thickness biopsy of the jejunum reveals inflammation and enteric neuropathy in irritable bowel syndrome. Gastroenterology 2002;123: 1972–9. [96] Quigley EM. Irritable bowel syndrome and inflammatory bowel disease: interrelated diseases? Chin J Dig Dis 2005;6:122–32.
Gastroenterol Clin N Am 36 (2007) 749–763
GASTROENTEROLOGY CLINICS OF NORTH AMERICA
Gastrointestinal Motility Disorders in Adolescent Patients: Transitioning to Adult Care Manu R. Sood, FRCPCH, MD*, Colin D. Rudolph, MD, PhD Division of Pediatric Gastroenterology and Nutrition, Medical College of Wisconsin, 9000 West Wisconsin Avenue, Milwaukee, WI 53226, USA
ESOPHAGEAL DISORDERS Motor Disorders of the Esophagus Esophageal motor disorders are uncommon in children [1]. Symptoms of dysphagia, odynophagia, and vomiting are more often associated with inflammatory disorders of the esophagus, especially eosinophilic esophagitis. This disorder presents with retrosternal discomfort and dysphagia in 20% to 67% of affected children [2]. Diagnosis is made when endoscopy and biopsy reveal eosinophilic infiltrates in the esophageal mucosa, with more than 20 eosinophils per high power field. Children are also at risk for mechanical obstructions from esophageal stricture, congenital webs, duplications, and tumor. These possibilities are usually excluded with a radiographic contrast study, which is also the most common modality for initial recognition of an esophageal motor disorder in childhood. Of the primary esophageal motor disorders, achalasia is the most common in pediatric patients but less then 5% of patients who have achalasia present during childhood. The estimated incidence of achalasia in children is 0.4 to 1.1 per 100,000 population and the prevalence is 7.9 to 12.6 per 100,000 population [1,3]. Older children usually present with symptoms such as dysphagia and vomiting, but infants and younger children are less able to describe symptoms so they may present with prolonged mealtimes, nighttime cough, and aspiration of esophageal contents. Because these disorders are uncommon in childhood, other diagnoses are often considered; pediatric patients may be misdiagnosed with disorders such as anorexia nervosa [4], bulimia, or rumination [5], which all present with vomiting or weight loss. The differential diagnosis of esophageal achalasia includes Esophageal stricture Leiomyomas
*Corresponding author. E-mail address:
[email protected] (M.R. Sood). 0889-8553/07/$ – see front matter doi:10.1016/j.gtc.2007.07.015
ª 2007 Elsevier Inc. All rights reserved. gastro.theclinics.com
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Anorexia nervosa Rumination Chagas’ disease Candida esophagitis
Childhood achalasia is usually idiopathic, but autosomal recessive inheritance has been reported in a small number of children and is more common in those of consanguineous parents [6]. Children presenting with achalasia in early childhood require evaluation for Allgrove’s or triple-A syndrome [7,8]. In this condition, achalasia is associated with adrenal insufficiency and alacrima. It is inherited in an autosomal-recessive manner, with the involved gene on chromosome 12q13. Alacrima is present from birth and adrenal insufficiency usually manifests as hypoglycemia or addisonian skin pigmentation before 5 years of age. Neurologic abnormalities, including hyper-reflexia, muscle weakness, dysarthria, and ataxia, have also been reported. In children with Rozycki syndrome, achalasia is associated with deafness, short stature, vitiligo, and muscle wasting. This condition is also inherited in an autosomal-recessive manner [1]. Diagnosis of achalasia is usually made by barium swallow that shows a dilated esophagus with tapering at the distal end, absent peristalsis, or tertiary contractions. Manometry can be performed in specialized centers and findings are similar to those in adults. Drug treatment with isosorbide dinitrate or nifedipine has been used in childhood, but these are generally not well tolerated by children [1]. Botulinum toxin injection into the lower esophageal sphincter provides only transient relief [9]. Pneumatic dilation can lead to prolonged relief of symptoms in some patients. A review of all published pediatric series including 151 patients showed overall improvement with dilation in 58% of the patients [10]. Dysphagia persisted in 20% and myotomy was required in 25% because of unsuccessful dilatation. In contrast, reports from large pediatric series following open or laparoscopic myotomy report that almost 75% of children improve with this procedure [1,10–12]. The incidence of postmyotomy reflux ranges from 7% to 50%, and the requirement for antireflux surgery at the time of myotomy remains controversial. All pediatric patients should be monitored for potential gastroesophageal reflux disease (GERD), which is common following achalasia treatment, but no guidelines are available regarding the advisability of routine endoscopic examination. As in adults, symptoms of dysphagia persist despite therapy. Fluids are generally better tolerated than solids. During periods of rapid growth, such as adolescence, the use of high-calorie liquid supplements may be required to ensure adequate caloric intake for growth. Tracheoesophageal Fistula and Atresia Tracheoesophageal fistula (TEF) is commonly associated with esophageal atresia (EA). Primary surgical repair is performed in early infancy in most cases. The less common ‘‘H-type’’ TEF without EA may go undiagnosed for months, years, or even decades. Adolescents with an undiagnosed H-type fistula present with bouts of coughing after drinking, retrosternal pain, recurrent pneumonitis,
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and hemoptysis [13]. A carefully performed radiographic swallow study and bronchoscopy is usually sufficient to establish the diagnosis. Esophageal peristalsis, assessed by manometry, is abnormal in 75% to 100% of children and young adults with a history of EA [14,15]. Many children with repaired EA/TEF need to eat slowly, and may need to avoid meats. Dysphagia is a commonly reported symptom in adolescents and adults; 13% to 20% report daily dysphagia and 53% to 92% occasional dysphagia [13]. Choking episodes during meals are also common in adults who had EA/TEF repair in childhood [13,16,17]. Some patients may require repeated removal of esophageal food impactions. GERD is extremely common in this population, occurring in up to 35% to 58% of the children and up to 46% of the adults [18]. GERD appears to be caused by intrinsic motor dysfunction and a shortened intra-abdominal segment of the esophagus. Histologically proven esophagitis is present in 20% and Barrett esophagus in 6% of adults [14]. About one half of patients who have EA/TEF and GERD improve with medical therapy but the rest require antireflux surgery [18]. All patients who undergo esophageal replacement with either a gastric ‘‘pull-up’’ or colonic interposition are at a substantially increased risk for pulmonary complications of GERD because the usual reflux protective mechanisms are absent. Patients should be instructed to limit meal ingestion to several hours before bedtime and to sleep with the head of bed elevated to reduce nighttime reflux episodes. GASTRIC AND INTESTINAL MOTILITY DISORDERS Gastric Emptying Disorders Gastroparesis may occur in children, but similar symptoms may be caused by gastric outlet obstruction, particularly in younger children, where a congenital or acquired anatomic anomaly, such as hypertrophic pyloric stenosis, antral and duodenal webs, and pyloric duplication cysts, may present similarly. Postviral gastroparesis due to cytomegalovirus and Epstein-Barr virus has been reported in children but are more likely to resolve with time, compared with adults [19]. As in adults, metabolic and endocrine disorders delay gastric emptying [20]. Gastric surgery, such as fundoplication, may result in either rapid or delayed gastric emptying [21]. Pyloroplasty is occasionally performed with a fundoplication, potentially resulting in more severe dumping that persists life long. Chronic Intestinal Pseudo-Obstruction Syndrome Chronic intestinal pseudo-obstruction syndrome (CIP) is a rare, severe, disabling disorder characterized by repetitive episodes, or continuous symptoms and signs, of bowel obstruction, including radiographic documentation of dilated bowel with air fluid levels, in the absence of a fixed, lumen-occluding lesion. Based on a strict definition, CIP should only be diagnosed when mechanical obstruction has been excluded. More than 50% of pediatric patients develop symptoms in the neonatal period and 40% have associated intestinal malrotation. In contrast to adult
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CIP, where the disorder is usually acquired and associated with a secondary disorder, pediatric patients are more likely to have a primary motility disorder because of disordered development of intestinal nerves, muscles, or interstitial cells of Cajal (ICC) [22,23]. Mouse models demonstrate that various mutations that impact on neural crest differentiation result in disorders of the enteric nervous system and it is likely that similar mutations in humans cause congenital neuropathic CIPS [24]. Abnormal or delayed development of the ICC may also present with CIP [25]. In infants, motility may improve over time, but if CIP persists past the second year of life, further improvement is unlikely (Box 1). Some patients have smooth muscle pathology due to abnormalities in actin expression, whereas other muscle disorders result from mitochondrial disorders. One of the well-recognized disorders in children is mitochondrial
Box 1: Causes of pediatric chronic intestinal pseudo-obstruction Myopathies Familial Nonfamilial Actin subtype deficiencies Acquired Scleroderma Diabetes Amyloidosis Myositis (autoimmune) Mitochondrial disorders ICC cell deficiency Neuropathies Familial Nonfamilial Neuronal dysplasia Acquired Diabetes Amyloidosis Chagas Viral infection (Epstein-Barr virus, cytomegelovirus) Drugs (vincristine) Mitochondrial disorders Autoimmune neuropathy Eosinophilic enterocolitis
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neurogastrointestinal encephalopathy, characterized by intestinal dysmotility, peripheral neuropathy, ophthalmoplegia, and features of mitochondrial myopathy on muscle biopsy [26,27]. The disease may first manifest during adolescence, and pseudo-obstruction usually precedes the onset of the symptomatic neuropathy. MRI shows white matter abnormalities and ragged-red fibers are present in muscle biopsy specimens. In another distinct CIP and abnormal small bowel motility and late development of neurologic symptoms in children has been associated with deficiency of oxidative phosphorylation enzymes [28]. Inflammatory disorders such as eosinophil-induced myositis or ganglionitis can cause CIP symptoms [29]. Acquired aganglionosis from a T-cell–mediated inflammatory response against enteric neurons and myocytes, leading to CIP, has also been reported with pediatric onset CIP [30]. In these disorders, symptoms may improve with immunosuppressive therapy. In-utero exposure to toxins such as alcohol [31] is associated with neonatal pseudo-obstruction, and viral infections such as cytomegalovirus, herpes zoster, and Epstein-Barr have also been linked with early onset CIP [32]. The most common presenting symptoms of CIP in childhood are abdominal distention and vomiting. Other symptoms in CIP patients include chronic constipation, abdominal pain, failure to thrive, and diarrhea. About 40% of pediatric patients have bladder dysfunction. In most children with congenital disease, the clinical course has an illness plateau with intermittent increases in acuity. Triggers for acute decompensation include intercurrent infections, general anesthesia, psychologic stress, and poor nutrition. Diagnosis of pseudo-obstruction symptoms in childhood is usually based on radiographic findings of dilated bowel in the absence of a mechanical obstruction, but antroduodenal or colon manometry may be used to aid in diagnosis and to differentiate neuropathic from myopathic pseudo-obstructive disorders [33–35]. In neuropathic CIP, the migrating motor complex is either absent or abnormal (Fig. 1), whereas in myopathic CIP, it is present but the amplitude of contractions is markedly reduced. Although manometry helps to differentiate neuropathic from myopathic pseudo-obstruction, it does not identify the cause of the neuropathy or myopathy, which is potentially identified with full-thickness rectal and small bowel biopsies. These biopsies may be particularly useful in identifying treatable causes of CIP due to inflammatory disorders. The management of children with CIPS is individualized because severity and regional involvement vary. The major principles are to use the bowel for nutrition whenever possible, ensure normal growth, and relieve pain. Venting gastrostomies and ostomies may relieve discomfort and provide access for alternative feeding routes [36]. Children who require parenteral nutrition should be challenged intermittently with trials of minimal amounts of enteral feeding because even small volumes of enteral feeding may prevent total parenteral nutrition–associated liver disease [37]. Pain can be managed by bowel decompression and treatment with tricyclic antidepressants and gabapentin [36,38]. Small bowel bacterial overgrowth is common [39] and cycles of oral
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Fig. 1. (A) Antroduodenal manometry showing normal fasting motility and the migrating motor complex. (B) Fasting antroduodenal manometry in visceral neuropathy; the contraction amplitudes are normal but motility is disorganized.
antibiotic treatment are often useful. In addition, during acute episodes of severe abdominal pain, the possibility of volvulus must be considered because the massively dilated loops of bowel can occasionally twist around the elongated, stretched mesentery [40].
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The quality of life for children with CIP and their parents is worse than for most other chronic diseases of childhood [38]. Mortality rates of up to 40% are reported for children with myopathic CIP within the first decade of life because of complications of the disease, whereas a lower rate of 25% is seen in children with neuropathic disease [41]. As children with CIP progress toward adulthood, central venous access for total parenteral nutrition administration can be challenging because of a loss of appropriate sites for central line access because of recurrent thrombosis of the major veins. Referral for intestinal transplantation should occur before line access becoming overly challenging. Those patients who develop liver cirrhosis and failure due to parenteral nutrition– induced liver disease may require a liver transplant in addition to a small bowel transplant. The results of intestinal transplantation performed for motility disorders are comparable to those experienced with other causes of intestinal failure. Newer immunosuppressive protocols with pretreatment/induction with antilymphocyte conditioning and steroid-free posttransplantation tacrolimus monotherapy have shown improved graft survival, and lower complications rates; patient/ graft survivals of 81% to 76% at 1 year, 62% to 60% at 3 years, and 61% to 51% at 5 years have now been reported, and continuing therapy refinements have recently led to even more impressive graft survival results in the 85% range [42]. Patients who have motility disorders have additional complicating factors, including difficulty determining the extent of the disease process (which may involve any part of the gastrointestinal tract), associated urologic anomalies, and the requirement for multivisceral organ transplantation, but survival rates are similar [43]. The transplanted bowel appears to have a normal migratory motor complex in most patients, but postprandial activity changes are not observed [44]. Despite the improving results, the persistent high morbidity and mortality associated with small bowel transplantation requires careful consideration before transplantation because a reasonable lifestyle can be achieved for many patients with the native, but dysfunctional, bowel and nutritional supplementation.
MOTILITY DISORDERS OF THE COLON AND DEFECATION Childhood Constipation and Implications for Colon Motility Disorders in Adults Constipation is very common problem in children and accounts for 3% of pediatric outpatient visits and 10% to 25% of pediatric gastroenterology outpatient visits [45]. Constipation in childhood is defined either as infrequent or uncomfortable bowel movements which are usually associated with large hard stools. Repeated experiences of painful or unpleasant defecation can lead to a maladaptive, age-appropriate behavioral strategy of avoiding or delaying defecation. Therefore, children, instead of responding to each defecatory urge with pelvic floor relaxation and bearing down, contract the pelvic floor and gluteal muscles to delay or avoid defecation. Children may adapt various
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‘‘retentive’’ postures, such as arching their backs and squeezing their bottoms. Some children can go without having a bowel movement for 2 or 3 weeks. Some of these children develop fecal incontinence, where liquid stool seeps around the rectal fecal mass and leaks out. Treatment with a stool softener, parent education, and behavioral modification therapy including toilet training, is successful in most. Almost 30% of children who start with chronic constipation and fecal retentive behavior suffer from relapses or have persistent symptoms, despite medical therapy into adolescent and adult life [46]. Some of these patients grow up to develop irritable bowel syndrome–like symptoms [47]. In one adult study, 98% of the patients who had idiopathic megarectum (n ¼ 21), 74% who had idiopathic megarectum and megacolon (n ¼ 23), and 61% who had megacolon (n ¼ 18) reported onset of constipation in childhood [48]. All patients who had idiopathic megarectum continued to have fecal incontinence into adult life. Treatment with laxatives or enema was successful in 68% and the rest required surgery. Abnormal colon transit has also been reported in 39% to 58% of children with chronic constipation [49,50]. Because the most common delay is at the level of the rectum, it is thought to be indicative of megarectum, from a reluctance to have a bowel movement because of anticipated pain. This finding is akin to that of an outlet obstruction with adult defecation disorders. A small case series reported normalization of colon motility abnormalities after colon decompression in a small proportion of children with chronic intractable constipation [51]. Slow colon transit has been reported in adults who had idiopathic megarectum, with onset of symptoms in childhood [52]. Autonomic and sensory neuropathy has been reported in adults with slow transit constipation (STC), and these patients often have a positive family history of severe constipation [53]. Studies examining the innervation of the colon in children have reported excessive production of nitric oxide in the myenteric plexus of the colon in patients who have STC [54]. One large series showed reduced substance P fibers in children with STC [55]. Decreases in enteric neural elements (neurons or neurofilaments) and ICC have also been reported [56]. The role of ICC as the intestinal pacemaker has been established in experimental animal models, where lack of ICC leads to absence of slow waves and is associated with delayed or absent intestinal motility [57,58]. Decreases in c-kit mRNA and c-kit protein are present in patients who have STC; therefore, a decreased ICC function might impair colon contractile response and cause delayed transit in STC patients [59]. It seems likely that some patients have underlying neuromuscular abnormalities of the colon that manifest first in childhood and then persist as adults, but no predictive factors are known to aid in determining which pediatric patient will have ongoing problems. Management as adults is similar to management during childhood. Treatment with osmotic and stimulant laxatives and prokinetic agents is preferable to surgical therapies.
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Hirschsprung’s Disease Hirschsprung’s disease (HD) is a relatively common disorder of neural crest migration that typically presents in the early neonatal period. Aganglionosis of the bowel can affect varying segments; in almost 80% of children, the rectosigmoid area is affected, and in the remaining 20%, varying lengths of the colon and sometimes small bowel are aganglionic [60]. HD may present in adults, with more than 200 adult cases being reported [61,62]. Late diagnosis is usually preceded by decades of constipation requiring laxatives, enemas, and hospitalizations. Confirmatory diagnosis of HD requires a rectal biopsy at least 5 cm above the anus. Including part of the submucosa in the biopsy sample is important. In older children and adults with chronic constipation, a surgically performed biopsy may be required to obtain an adequate tissue sample, whereas a suction biopsy is generally sufficient in infants and younger children. At least 100 tissue sections must be void of neuron cell bodies (ganglion cells) to confirm the diagnosis. HD is a male-predominant disease with a male-to-female ratio of 4:1 in children with short-segment disease [63,64]. The population risk of developing HD is 0.02% and the occurrence risk for siblings of a child with HD is 4% [64]. As the length of aganglionic segment increases, the recurrence risk to siblings increases and the male predominance decreases [64]. HD has also been associated with chromosomal abnormalities, other birth defects, and syndromes with mendelian patterns of inheritance (Table 1).
Table 1 Selected abnormalities associated with Hirschsprung’s disease Anomaly Down syndrome Deletion 13q (partial) Dandy-Walker malformation with microcephaly Bardet-Biedl syndrome Cartilage hair hypoplasia Ondine’s curse Familial dysautonomia MEN 2A MEN 2B Neurofibromatosis I Smith-Lemli-Opitz syndrome Waardenburg syndrome type 4
Mode of inheritance/ genetic locus or gene
Incidence in Hirschsprung’s disease
Chromosomal/trisomy 21 Chromosomal Unknown
2%–15% Unknown 3.6%–3.9%
Autosomal recessive/multiple Autosomal recessive/9q13 Variable/RET, GDNF, EDN3 Autosomal recessive/9q21 Autosomal dominant/RET Autosomal dominant/RET Autosomal dominant/NFI Autosomal recessive Autosomal dominant/SOX10
Unknown Unknown 1.8%–1.9% Unknown 2.5%–5% Unknown Unknown Unknown Unknown
Autosomal recesiive/EDNRB, EDN3
Unknown
Abbreviations: EDN3, endothelin-3; EDNRB, endothelin receptor B; GDNF, glial cell line-derived neurotrophic factor; MEN, meningioma gene; NFI, nuclear factor I gene; RET, REarranged during Transfection gene; SOX10, SRY-box containing gene 10.
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Mutations in the REarranged during Transfection (RET) gene are responsible for approximately one half of familial cases and a smaller fraction of sporadic cases. RET gene on chromosome 10q encodes a receptor tyrosine kinase expressed in cells of neural crest origin. It transduces extracellular signals that influence cell proliferation, migration, differentiation, and programmed cell death. Many of the mutations identified in RET [65–68] in individuals with HD are heterozygous loss-of-function mutations distributed throughout the gene. The penetrance of RET mutations is estimated to be 50% to 70%. The RET mutations are much more likely to be identified in familial cases of HD (50%) than in sporadic cases (15%–35%) [69–71]. Mutations in the RET ligands, glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN), have been identified in a small minority of cases of HD [72,73]. Endothelin receptor B (EDNRB) is a G-protein–coupled receptor activated by 21 amino acid peptides known as endothelins. Patients who have homozygous mutation of this gene often have pigmentation defects of skin and hair and sensorineural hearing loss, referred to as WaardenburgShah syndrome [74]. Mutations in human SOX10 have also been identified in patients who have HD and Waardenburg-Shah syndrome [75]. Other features associated with Waardenburg-Shah syndrome include progressive ataxia, growth failure, hypotonia with mental retardation, and autonomic abnormalities. Treatment of HD is surgical [60]. The aganglionic bowel and the transition zone need to be resected and various operative procedures are performed to reestablish bowel continuity [60]. During the procedure, the surgeon must confirm the presence of ganglion in the remaining bowel. Generally, it is useful to ensure that several centimeters of ganglion-containing bowel are resected, to ensure that the remaining bowel has a normal-functioning enteric neural plexus. Treating HD diagnosed in adults is no different than treating HD in children. Primary pull-through procedures without preliminary diversion have gained popularity in recent decades and are the preferred method of repair for most pediatric surgeons. Postsurgery, 60% to 70% of children have continuing difficulties with defecation [76]. Persistent constipation following HD surgery can result from fecal retention, neuropathy proximal to the aganglionic segment, and hypertensive anal sphincter. It can be difficult to distinguish among these conditions when they follow HD surgery. Colon and anorectal manometry can clarify the diagnosis and help with the treatment planning. Although the aganglionic segment is resected and the remaining histology appears healthy, children with neuropathy proximal to the aganglionic segment have abnormal colon manometry. Hypertensive anal sphincter affects about 5% of children with constipation after HD surgery [76]. The recto-anal inhibitory reflex is absent in HD and elevated resting anal sphincter pressure produces a high-pressure zone that cannot be overcome by the high-amplitude colon contractions. Diagnosis requires anal manometry and, if hypertensive anal sphincter is identified, treatment with botulinum toxin injection into the muscular sphincter may be efficacious [76,77].
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Fig. 2. (A) Normal colon motility. The high amplitude propagating contractions do not propagate into the rectum. (B) Colon manometry in a child with fecal incontinence following pullthrough surgery for HD. The high amplitude peristaltic contraction propagate into the rectum and give very little warning to the child before the stool leaks out.
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In some patients, the botulinum toxin injection only works transiently and, if repeated injections are necessary, surgical anal sphincterotomy can be considered. About one half of patients who have had successful surgery have difficulties with fecal soiling that may last into adult life. The most common reasons for soiling is that high-amplitude propagating contractions, which normally end in the sigmoid (Fig. 2A), continue to propagate through the neorectum to the anus (Fig. 2B). Fast colon transit time assessed using sitzmarkers, and reduced anal sphincter pressure, have also been reported in children with fecal incontinence [78]. Colon manometry clarifies the reasons for constipation and soiling following successful HD surgery [76]. In patients who have fecal soiling due to highamplitude propagating contractions through the neorectum, drugs such as loperamide and amitriptyline often firm up the stools and reduce soiling episodes and provide relief from the crampy pain associated with attempts to avoid soiling. SUMMARY Pediatric motility disorders present challenges like most other chronic diseases of childhood. The goal is to optimize medical care and ensure the adequate nutritional status essential for neurocognitive and psychosocial development of the child. During adolescence, the drive for independence and peer acceptance offers its own challenges. The need for enteral or parenteral nutrition support, not being able to eat certain kinds of food, and the risk of fecal incontinence can have a huge impact on the quality of life. As in other children and young adults, the educational and job opportunities available to these patients may be restricted. Multidisciplinary care from specialists, including gastroenterologists, psychologists, and pain specialists, is often required to optimize the lives of these patients. References [1] Sood MR, Rudolph CD. Achalasia and other motor disorders. In: Wylie R, Hyams JS, editors. Pediatric gastrointestinal and liver disease. 3rd edition. Philadelphia: Elsevier Inc.; 2006. p. 327–38. [2] Noel RJ, Rothenberg ME. Eosinophilic esophagitis. Curr Opin Pediatr 2005;17(6):690–4. [3] Azizkhan RG, Tapper D, Eraklis A. Achalasia in childhood: a 20-year experience. J Pediatr Surg 1980;15(4):452–6. [4] Duane PD, Magee TM, Alexander MS, et al. Oesophageal achalasia in adolescent women mistaken for anorexia nervosa. BMJ 1992;305(6844):43. [5] MacKalski BA, Keate RF. Rumination in a patient with achalasia. Am J Gastroenterol 1993;88(10):1803–4. [6] Dayalan N, Chettur L, Ramakrishnan MS. Achalasia of the cardia in sibs. Arch Dis Child 1972;47(251):115–8. [7] Grant DB, Barnes ND, Dumic M, et al. Neurological and adrenal dysfunction in the adrenal insufficiency/alacrima/achalasia (3A) syndrome. Arch Dis Child 1993;68(6):779–82. [8] Weber A, Wienker TF, Jung M, et al. Linkage of the gene for the triple A syndrome to chromosome 12q13 near the type II keratin gene cluster. Hum Mol Genet 1996;5(12):2061–6. [9] Hurwitz M, Bahar RJ, Ament ME, et al. Evaluation of the use of botulinum toxin in children with achalasia. J Pediatr Gastroenterol Nutr 2000;30(5):509–14.
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