Chronic Diarrhea - Clinical Gastroenterology and Hepatology

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2004;2:198 –206

Chronic Diarrhea: A Review on Pathophysiology and Management for the Clinical Gastroenterologist MICHAEL CAMILLERI Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.) Program, Gastroenterology Research Unit, Mayo Clinic and Mayo Foundation, Rochester, Minnesota

he objectives of this article are to provide a review for general gastroenterologists of the fluid fluxes in the normal human gut and the pathophysiological mechanisms that lead to chronic diarrhea, and to propose a practical approach to management. Most clinical disorders presenting as chronic diarrhea involve more than one physiological mechanism. The role of motility and functional disorders that result in chronic diarrhea will be emphasized, given the high prevalence of these conditions. There is a growing understanding of the roles of neurotransmitters and hormones in the development of functional gut disorders and intestinal motility and secretion; modulation of these mechanisms also provides a means for novel therapy.

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Physiology Intestinal Ion and Water Transport Ions and water can move bidirectionally across the intestinal mucosa, i.e., from luminal (mucosal) to blood (serosal) sides and vice versa. The difference between the 2 unidirectional fluxes, or the “net” ion flux, determines the direction of net transport. The active transport of ions (principally Na⫹, Cl⫺, and HCO3⫺) across the small intestinal epithelium provides the electrical and chemical forces that drive the coupled absorption of nutrients as well as the net absorption or secretion of water. A variety of absorptive and secretory agents, including local and systemic hormones, neurotransmitters,1 toxins released by enteric pathogens, and other molecules that gain access to the intestinal lumen, stimulate ion and water transport. Solutes are absorbed by active transport mediated by membrane-associated channels and transporters. In addition, solutes can traverse the intestinal epithelium through 2 other mechanisms, often collectively referred to as intestinal permeability. These are endocytotic uptake from the lumen, followed by exocytotic delivery to the basolateral compartment and intercellular transport through the tight junctions that separate enterocytes (the paracellular pathway). Although the traditional view is that 80% of water transport uses the

paracellular pathway, this transport is achieved by the creation of local osmotic gradients within the paracellular channels. Hence, specific enterocyte membrane transporters (e.g., GLUT 1) that induce solute transport ultimately drive absorption of water and ions. These transporters require energy and, hence, the use of the term active transport. Net movement of ions and fluid across the small intestinal epithelium in the basal state varies considerably along the length of the small intestine. What Are the Daily Fluid Fluxes in the Gastrointestinal Tract? Each day, 7– 8 L of fluid are secreted into the gastrointestinal tract or taken by mouth (Table 1). Oral intake and saliva contribute 1.5 L per day, bile and pancreatic secretion each 1 L, and gastric acid, pepsin, and other digestive enzymes add 1.5 L a day. However, fluxes of fluid during intestinal digestion contribute to the lumen a net 3.0 L of fluid, which flows along osmotic gradients through the highly permeable jejunal mucosa and results in the initial loss of fluids from the intravascular space into the lumen. Subsequently, small bowel reabsorption of water and electrolytes recovers much of the secreted fluid, so that only about 1.2 L of fluid enters the colon each day. Thus, the small bowel reabsorbs 5 L of fluid a day. Colonic reabsorption recovers 1 L of fluid, but the reserve absorptive capacity of the colon might recover up to 3 L per day.2 Thus, the stool volume rarely exceeds 200 mL per day in healthy individuals. The rate of fluid loading to the colon and regional transit rates can determine stool consistency.3 Careful studies with dye dilution marker techniques and triple lumen intubation methods4 have demonstrated that 7– 8 L per day enter the foregut and proximal midgut, and the rate has been estimated at 2.5 mL per © 2004 by the American Gastroenterological Association

1542-3565/04/$30.00 PII: 10.1053/S1542-3565(04)00003-5

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CLINICAL APPROACH TO CHRONIC DIARRHEA

Table 1. Daily Fluid Flux into Gastrointestinal Tract Oral intake Saliva Gastric secretions Bile Pancreatic secretion Small bowel secretion

1.5 L 0.5 L 1.0 L 1.0 L 1.0 L 3.0 L

minute during fasting and 5 mL per minute after meals. Similarly, the rate of flow fluid past the ileocecal valve is 0.3 mL per minute during fasting and double that rate postprandially.4 Experimentally, diarrhea can be induced by the infusion of normal saline. Even under such conditions, capacity for reabsorption of fluid and electrolytes in the small intestine and colon is vast. Thus, diarrhea occurs when infusion of the small intestine reaches approximately 17–22 mL per minute, or when infusion of the colon reaches 6 – 8 mL per minute. The capacity of the small intestine to absorb fluid reaches an average of about 5–7 mL per minute.4 Fasting or malnutrition might enhance fluid and ion transport responses to intestinal secretagogues, but they also enhance the effect of agents that stimulate intestinal ion absorption such as with Na⫹ coupled nutrients.5 Sodium and potassium fluxes occur along osmotic gradients and in response to the effects of “solvent drag” (the bulk flow of water along osmotic gradients drawing in ions with it) or specific coupled transport mechanisms. Similarly, the capacity of the colon to absorb fluid might reach 2.7 mL per minute, and this is 5–15 times the capacity of the small intestine per unit area, demonstrating the vast reserve capacity to absorb fluid in the colon. The colon is able to salvage much of the fluid that might be lost in small intestinal diseases; thus, moderate secretory states or malabsorption might not even result in chronic diarrhea. Motility of the Intestine and Colon The motor functions of the gut are intended to facilitate the digestion and orderly absorption of digesta and the fluids secreted during the digestive process. Thus, the stomach and small bowel participate in synchronized migrating motor complexes during fasting. Normally, it takes approximately 3 hours for solids or liquids to traverse the small bowel.6,7 The ileum empties into the colon the residual materials that do not require further salvage. Thus, the ileum acts like a reservoir that empties boluses of content, typically nondigestible residue and fluids, into the colon.8,9 Within the colon, there is irregular mixing, absorption, and transit, with the ascending and transit regions serving as reservoirs,10 facilitating the reabsorption of fluid and electrolytes. The

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ascending colon serves as a conduit, and the sigmoid and rectum serve as volitional reservoirs. Contractions recorded in the colon include segmenting or mixing contractions and occasional high-amplitude propagated contractions approximately 6 times per day in an average healthy person.11 These contractions occur most commonly early in the morning on awakening or after the ingestion of a meal. Altered transit might result from abnormal motility of the bowel, and this alteration in transit might influence absorption of fluid by increasing or decreasing the exposure of luminal content to the absorptive surface.

Pathophysiology of Chronic Diarrhea The causes of chronic diarrhea include inflammatory, osmotic, secretory, iatrogenic, motility, and functional diseases. In general, no single cause of chronic diarrhea is truly unifactorial from a perspective of pathophysiology. Thus, for example, prototype secretory disorders such as cholera might be associated with secretion and altered motility,12 and secretion, inflammation, and motility contribute to diarrhea caused by Clostridium difficile toxin.13,14 Inﬂammatory Chronic Diarrhea Inflammatory diseases cause chronic diarrhea with exudative, secretory, or malabsorptive components. The pathogenesis of IBD is increasingly understood in terms of the molecular mechanisms that result in changes in both innate and acquired immunity.15 The response of the gut to bacteria and other antigens in the lumen results from the interaction between the host, the genetic environment, dietary, and bacterial antigens. Inflammatory causes of chronic diarrhea might present with features that suggest malabsorption or rectal bleeding. The nature of the malabsorption depends on the regions affected (e.g., proximal vs. distal small bowel), and rectal bleeding is usually a manifestation of colonic or rectal ulcerations. The presence of an inflammatory cause of chronic diarrhea is suggested by the presence of mucus and blood in the stool, by concomitant abdominal pain, or by symptoms referable to the skin, eyes, and joints. Typically, bowel imaging and tissue biopsies provide the diagnosis of the condition. Inflammatory chronic diarrhea is rapidly diagnosed when associated with rectal bleeding or malabsorption. In the case of microscopic colitis, a therapeutic trial might be needed to determine whether it is the cause of the chronic diarrhea when no other cause is identified. Thus, although anti-inflammatory agents, including bismuth subsalicylate16 or other

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more potent anti-inflammatory medications, appear to benefit patients with microscopic or collagenous colitis, other data in the literature suggest that simply slowing down transit through the bowel with loperamide results in an equivalent therapeutic benefit.17 It is still unclear whether this entity is a primary bowel disorder or secondary to another mechanism that results in microscopic inflammation, such as bile acid malabsorption or effects of analgesics.18 Osmotic Chronic Diarrhea In osmotic diarrheas, osmotically active substances draw fluids from the plasma into the jejunum along the osmotic gradients through the highly permeable jejunal epithelium. Examples of chronic diarrhea due to an osmotic cause include malabsorption states such as celiac disease, bacterial overgrowth, osmotic laxatives (including salts, polyethylene glycol, and lactulose), and maldigestion as occurs commonly in disaccharidase deficiency, and pancreatic exocrine insufficiency. Osmotic diarrheas might result in steatorrhea and azotorrhea (passage of fat and nitrogenous substances into the stool), but typically they do not cause any rectal bleeding.19 With osmotic diarrheas, the volume of stool is reduced during fasting, but the osmotic gap of the stool is greater than 50 mOsm/kg. Measured osmolality of the water from a fresh stool sample is a useful measurement to identify such an osmotic gap. Normally, the stool water is electroneutral, that is, an equivalent number of anions and cations are present. Thus, measurement of the sodium and potassium concentrations multiplied by 2 should be almost equivalent to the osmolality of plasma (280 mOsm/kg). When the measured osmolality exceeds 2 times the sodium and potassium concentration by more than 50 mOsm/kg, an osmotic factor is contributing to the diarrhea. When the stool water pH is below 5 and the osmotic gap is more than 50 mOsm/kg, the osmotic factor is likely to be a disaccharide that has undergone bacterial fermentation in the colon to produce acid residues that reduce stool water pH. Thus, a high osmotic gap with stool water pH of less than 5 is indicative of disaccharidase deficiency.19 Secretory Chronic Diarrhea In secretory diarrheas, there is secretion of isoosmolar fluid into the intestine. In this situation, other electrolyte abnormalities might coexist. Thus, hypokalemia and acidosis are associated with Verner-Morrison syndrome or VIPoma.20 Examples of secretory diarrheas include congenital abnormalities such as congenital chloridorrhea, in which an abnormality in the genetic control of chloride-bicarbonate exchange in the ileum results in

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 2, No. 3

the loss of chloride into the stool. Another example is the loss of ␣2-adrenergic function in enterocytes of patients with autonomic neuropathy caused by diabetes mellitus.21 Colonic secretion might occur as a result of bile acid malabsorption or the effects of hormones secreted by neuroendocrine tumors including VIP, gastrin, serotonin, calcitonin, prostaglandins, and others. The literature is replete with examples of exogenous infusions of these substances resulting in intestinal secretion. More recently, the effects of the secretagogues have also been demonstrated on explants of human intestinal epithelium.22 Secretory diarrhea might be associated with altered motor functions induced by the hormone or transmitter produced by the tumor, as in carcinoid diarrhea.23 Typically, secretory diarrhea caused by neuroendocrine tumors has been identified by radioimmunoassay-based measurements of plasma levels of the hormone or its metabolite in urine. Examples include measurements of VIP, gastrin, or calcitonin in plasma or 24-hour collections of urine for 5-hydroxyindoleacetic acid. With the advances in imaging including magnetic resonance imaging or endoscopic ultrasound, endocrine tumors can be identified without the need for selective sampling of the portal venous circulation or selective angiography of the pancreas.23 The typical features of secretory diarrhea include the persistence of the diarrhea with fasting and the absence of steatorrhea, azotorrhea, or blood per rectum. Hypokalemia and acidosis typically suggest VIPoma syndrome, and the measured osmotic gap of stool is less than 50 mOsm/kg. Among hormonal diarrheas, carcinoid syndrome provides an example illustrating that the neuroendocrine tumor cells produce substances such as serotonin, substance P, and prostaglandins that can also affect motor function of the gut. von der Ohe et al.23 demonstrated the motor component of carcinoid diarrhea including accelerated small bowel and proximal colonic transit times and changes in the colon’s capacitance or reservoir function and the motor response to ingestion of a meal (Figure 1). Colonic secretion might result from the effects of unabsorbed fats, fatty acids, and bile acids on colonic epithelium. This form of secretory diarrhea might result from surface-active (e.g., detergent) effects of these compounds.24 –26 Iatrogenic Causes of Chronic Diarrhea Chronic diarrhea might follow abdominal surgery. After cholecystectomy, about 5%–10% of patients develop diarrhea; the mechanism is still not completely understood.27,28 Some of these patients respond to sequestering bile acid with cholestyramine, but this is not

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Figure 1. Carcinoid diarrhea causing rapid colonic transit of isotope. Note that in 2 hours, isotope has moved from cecum to rectum. (Reprinted with permission from von der Ohe et al.23 Copyright © 1993 Massachusetts Medical Society. All rights reserved.) Inset above: Note the H&E appearance of carcinoid tumors with sheets of well-defined cells. Inset below: Note the chromogranin-positive cells demonstrating the presence of secretory granules within the carcinoid tumor cells.

a universal response. Chronic diarrhea might result from vagal injury and ileal resection. In current practice, vagal injury results from fundoplication or gastric bypass procedures. Testing for vagal malfunction includes the pulse rate and electrocardiographic R to R interval response to deep breathing or measurement of pancreatic polypeptide in plasma in response to modified sham feeding.29 The D cells in the pancreas (source of pancreatic polypeptide) are under control by vagal cholinergic neurons, and sham feeding stimulates the vagal nuclei in the brainstem. Thus, heart period response to deep breathing should be greater than 10 per minute, although there are variations as a result of age and gender. With abdominal vagal injury caused by surgery, the cardiac index of vagal function is usually normal. Pancreatic polypeptide response to modified sham feeding should increase by more than 25 pg/mL (or pg/L) if there is an intact vagal function.30 There are, however, pitfalls in the interpretation of the pancreatic polypeptide response to sham feeding. For example, there might be an inadequate sham feeding stimulus because of failure to follow instructions or high baseline levels of pancreatic polypeptide as a result of uremia. More importantly, false negatives result from increased plasma levels of pancreatic polypeptide induced by swallowed food, which activates the enteric phase of pancreatic polypeptide secretion. Iatrogenic chronic diarrhea might also follow ileal resection. The extent of resection determines the mech-

anisms and manifestations. Poley and Hofmann31 showed that, with resections of less than 100 cm, there is colonic secretion induced by di-␣-hydroxy bile acids, which increase mucosal permeability25 and stimulate intracellular cyclic AMP.32 When resections are greater than 100 cm long, chronic depletion of bile acids occurs because of the loss of the active transport mechanism in the terminal ileum, resulting in poor micellar formation and chronic diarrhea as a result of the malabsorbed fat.31 Malabsorbed fatty acids might also serve as colonic secretagogues. Motility Disorders Causing Chronic Diarrhea Rapid transit delivers fluid secreted during digestion to the distal small bowel or colon; this prevents reabsorption of normally secreted fluid in the small bowel, or it overwhelms the reabsorption capacity of the colon. On the other hand, reduced motility leading to slow transit might result in bacterial overgrowth with bile acid deconjugation, poor micelle formation, and steatorrhea. The clinical manifestations of chronic diarrhea caused by motility disorders include steatorrhea, usually up to 14 g per day.33 Experimentally, intestinal secretion induced by means of an osmotic laxative results in acceleration of transit through the bowel, and this is associated with up to 14 g of fat in the stool.33 On the other hand, the presence of more than 14 g per day of fat in the stool might suggest the presence of bacterial overgrowth

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or associated disease such as celiac disease. Celiac disease is rarely associated with diabetes mellitus,34 which might also cause diarrhea as a result of dysmotility. Motility disorders causing chronic diarrhea are usually not associated with any blood loss per rectum. On the other hand, the clinical features suggest a neuropathic or myopathic underlying disease. The prototype disease examples are diabetes mellitus and scleroderma. Systems review might identify symptoms caused by the classic triopathy of diabetes mellitus (peripheral neuropathy, retinopathy, and nephropathy) or the peripheral manifestations associated with collagenoses (e.g., affecting skin, eyes, mouth, joints). Diabetes is associated with a number of diseases that cause diarrhea and steatorrhea. These include exocrine pancreatic insufficiency, celiac sprue,34 small bowel bacterial overgrowth, and, rarely, bile acid malabsorption.35 Other reasons for diarrhea in patients with diabetes are the loss of ␣2-adrenergic tone in enterocytes, small bowel or colonic dysmotility, and incontinence manifesting as diarrhea caused by anorectal dysfunction.35 Patients with incontinence might present as diarrhea, and the anorectal dysfunction might result from sensory neuropathy, sympathetic neuropathy causing weakness of the internal anal sphincter, or pudendal neuropathy causing weakness of the external anal sphincter.36,37 In patients with systemic sclerosis, chronic diarrhea might occur because of small bowel dilatation, widemouthed diverticulosis, or bacterial overgrowth.38 Pneumatosis intestinalis occurs in a minority of patients, but the diarrhea might also be associated with incontinence, typically nocturnal because of the weakness of the internal anal sphincter when the volitional external sphincter cannot compensate during sleep. Bacterial overgrowth and diverticulosis require aspirate or breath tests and small bowel follow-through with upright images to demonstrate air fluid levels or a computed tomographic scan with careful evaluation for air fluid levels in the horizontal position. Transit measurements are often undertaken in patients with suspected motility disorders as a screening test for dumping syndrome (accelerated gastric emptying) and fast or slow transit at all levels of the gut. Transit measurements evaluate the severity of the motor abnormality. However, it is important to realize that fast transit might be a result of an underlying disease, not only a primary neuromuscular disorder. For example, disease of the mucosa, such as celiac disease, might also result in accelerated transit.


Functional Diarrhea and Irritable Bowel Syndrome Functional diarrhea and diarrhea associated with irritable bowel syndrome affect 3%–5% of people in Western communities.39 The cause of these 2 disorders of gastrointestinal function is unknown, although the pathophysiology (e.g., colonic transit, motility, and rectal hypersensitivity) has been well characterized. These 2 disorders might overlap in the same patient over time, depending on the prominence of pain in the patient’s symptom complex. Clinically, it is useful to distinguish the passage of repetitive, small, but normal consistency stools from an increased stool frequency with changes in stool consistency. Visual aids such as the Bristol stool form scale40 describe the consistency of bowel movements, but few clinicians use this visual aid in clinical practice. It is also useful to identify the relationship between feeding and the development of urgency and diarrhea. A number of patients with functional diarrhea experience aggravation of their abdominal cramping, urgency, and bowel movements with meals.41 The main clinical complaint in these patients is often the urgency and repeated call to stool, but daily stool output is usually normal. Passage of stool relieves the sensations of pain and urgency. Irritable bowel syndrome is a chronic condition in which abnormal gut sensation and motility have been well documented.42 The proportion of patients with hypersensitivity appears to be approximately 60%,43 and recent data suggest that rectal sensory thresholds might be useful to differentiate patients with irritable bowel syndrome from those with other functional conditions such as constipation and dyspepsia.44 In earlier studies of rectal sensory thresholds, it was demonstrated that the patients with diarrhea-predominant irritable bowel syndrome were more likely to have rectal hypersensitivity.45 This hypersensitivity might be important in eliciting the urge to defecate or the sensation of incomplete rectal evacuation. Motor dysfunction in diarrhea-predominant irritable bowel syndrome is characterized by rapid movement of radioisotope in scintigraphic studies46,47 and increased frequency of high-amplitude propagated contractions after a meal.48 The pathophysiology of irritable bowel syndrome is still not completely understood, but disturbances affecting 1 or more levels of the neural control (from brain to visceral nerves) and the gut itself contribute to the disorder.42 Putative neurotransmitter dysfunctions in visceral nociception and abnormal motility occurring in

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Table 2. Identifying Key Issues in the Clinical History Is the consistency of the stool altered, or are stools of normal consistency passed more frequently? Does the patient have diarrhea or incontinence? Is incontinence at daytime or nighttime? Does the diarrhea alternate with constipation? What is the diurnal frequency and periodicity of the symptom? Specifically, does the diarrhea occur at nighttime? Does the patient pass blood per rectum with or without diarrhea? Are there features suggestive of steatorrhea (oily, undigested food, difficult to flush, or weight loss)? Are there other features to positively diagnose irritable bowel syndrome: relationship with abdominal pain, sense of incomplete rectal evacuation? Medications, past medical/surgical history. Relationship of diarrhea to meals or dietary factors. Symptoms referable to skin, eyes, joints.

irritable bowel syndrome include changes in serotonin, CCK, and neurokinins.49,50 Incontinence: The Unspoken Symptom Continence requires contractions of the puborectalis muscle, maintenance of the anorectal angle, and normal rectal sensation, as well as contraction of the anal sphincter. In contrast, defecation requires relaxation of the puborectalis, straightening of the anorectal angle, and relaxation of the anal sphincter to allow the stool to be passed through the pelvic floor down to the rectum under the propulsive force of the colonic contractions as well as the raised pressure induced in the abdomen by the Valsalva maneuver.51 It is important to remember that many patients with incontinence of stool will report incontinence as chronic diarrhea because of embarrassment rather than because they have any real difficulty distinguishing diarrhea from incontinence.52 Physicians should address this possibility by direct questioning while eliciting the history. The first physiological test that must be done in patients with chronic diarrhea is the rectal examination, during which the strength of the anal sphincter at rest and during squeeze should be evaluated. A low anal sphincter tone at rest might suggest a reason why the patient’s “diarrhea” appears to be nocturnal. Nocturnal incontinence occurs when the internal sphincter tone is unable to prevent stool seepage. In contrast, the presence of diarrhea with urgency or aggravation of incontinence by stress or physical activity suggests that the squeeze (external) sphincter pressure is too low to oppose the flow of stool from the lower rectum. In some patients with functional diarrhea, diarrhea with irritable bowel syndrome, or in the elderly, incontinence might be related to urgency or inability to reach the toilet in


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time, even though anal sphincter pressures are normal. In these patients, voluntary anal sphincter contraction cannot be sustained for a sufficient length of time to resist the colonic propulsive forces associated with urgency.

Clinical Appraisal of the Patient The common causes of diarrhea encountered in clinical practice are disorders of gastrointestinal function (or irritable bowel syndrome), IBD, and, when associated with features suggestive of steatorrhea, celiac disease, pancreatic insufficiency, and small bowel bacterial overgrowth. The clinical appraisal should specifically search features suggestive of these diseases. History The first step is to identify what the patient means by diarrhea. Identifying several specific positive or negative features is key to the overall appraisal of these patients.53,54 The key issues are listed in the form of questions in Table 2 and form the basis for the algorithm in Figure 2. An increased frequency of bowel movements of normal consistency, “rabbity” or small-caliber stools, abdominal discomfort before and relieved by having a bowel movement, bloating, mucus in the stool, and a sense of incomplete evacuation are quite characteristic of irritable bowel syndrome. Some patients also report frequent urges to defecate, passage of soft stool, or flatus, but there is no increase in stool water loss. The syndrome should be positively sought by direct questioning to elicit this cluster of symptoms.42 Disturbance of sleep by urge to defecate suggests an organic disease rather than irritable bowel syndrome. Although classic textbooks associate nocturnal diarrhea with diabetes or bacterial overgrowth, it is really a nonspecific symptom of organic disease.

Figure 2. Initial management algorithm based on features accompanying diarrhea. p.r., per rectum; IBS, irritable bowel syndrome.

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Table 3. Physical Examination Are there general features to suggest malabsorption, such as anemia, edema, or clubbing? Are there features to suggest underlying autonomic neuropathy or collagen vascular disease, in the pupils, orthostasis, skin, hands, or joints? Is there abdominal mass or tenderness? Are there any abnormalities of rectal mucosa, rectal defects, or altered anal sphincter functions?

The presence of blood in the stool in patients with diarrhea should suggest mucosal disease. It is regarded as an alarm feature that should not be attributed to associated conditions such as hemorrhoids or colonic diverticulosis. Clinical features also facilitate identification of malabsorption, such as the presence of foul-smelling, light-colored, floating stool or undigested foods in the stool. Similarly, objective findings such as anemia, edema, malnutrition, short stature, or clubbing suggest malabsorption. However, these objective abnormalities are relatively infrequent in the patients with chronic diarrhea presenting to clinical gastroenterologists. Careful questioning is also necessary to differentiate diarrhea from incontinence, the often unvoiced symptom. The history should identify the duration and periodicity of diarrhea, aggravating dietary factors, relationship to medications, or a medical history of a disorder or surgery that might cause diarrhea. Physical Examination Table 3 summarizes the main features to be assessed during the physical examination. The presence of abdominal mass or tenderness should alert the clinician to the possibility of IBD or a neoplasm. However, it is also common to find cecal or sigmoid tenderness in patients with irritable bowel syndrome. Hepatomegaly with nodularity might be the only finding in patients with carcinoid diarrhea, although flushing is also present in about 80% of patients by the time the tumor burden causes diarrhea. Rectal examination is mandatory to assess the mucosa, wall defects (e.g., rectocele), or occult intussusception that might cause overflow diarrhea and to assess the anal continence mechanism. Perianal excoriation or moisture and a patulous anus might be signs of sphincter weakness. Very rarely in adults, diarrhea results from retention with overflow incontinence, but this is more common as encopresis in childhood or in the geriatric age group. Retention might be the result of internal mucosal prolapse, intussusception, or puborectalis spasm, which can also be suggested by the finding of a tender bar of muscle posteriorly that fails to relax during the digital


examination of the rectum.51 Excessive perineal descent or “ballooning” of the perineum during straining reflects a long history of excessive straining for constipation, ultimately resulting in stretch of the pudendal nerves and development of sphincter weakness and incontinence because of a pudendal neuropathy. Tests and Therapies The algorithm in Figure 2 provides a practical approach to select patients for specific testing. To avoid unnecessary, costly, or potentially dangerous investigations in patients with suspected functional diarrhea, it is important to use positive symptom diagnosis and relatively inexpensive screening tools, and to introduce therapeutic trials in the management process.42 A limited series of initial investigations is necessary to exclude organic, structural, metabolic, or infectious diseases. These include hematology and chemistry tests; stool examination for occult blood, ova, and parasites; tissue transglutaminase (as screen for celiac disease); flexible sigmoidoscopy; and, in those older than 40 years of age or with a first-degree relative with colon polyps or cancer, a barium enema or colonoscopy. The presence of abnormal hemoglobin, mean corpuscular volume, potassium, calcium, or albumin necessitates further investigation to exclude malabsorption or a secretory/hormonal diarrhea. The follow-up (rather than initial screening) tests (Figure 3) include stool fat, small bowel aspirate and biopsy, and measurement of hormones in plasma (such as VIP, gastrin, calcitonin), or urine 5-hydroxyindoleacetic acid. The finding of colitis or other mucosal lesions in the colon at endoscopy or barium enema clearly requires further assessment and specific therapy. We do not routinely obtain stool fat measurement in patients with

Figure 3. Algorithm for management when abnormal findings are identified on limited screen for organic disease. Hb, hemoglobin; Alb, albumin; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; OSM, osmolality.

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chronic diarrhea and normal initial test results because experience suggests that the stool fat is infrequently elevated in these patients, and because stool fat measurements of up to 14 g/day might result from accelerated transit or an osmotic laxative (i.e., the stool fat in the range of 7–14 g/day has a low specificity for malabsorption). A more detailed dietary history might identify factors that might be aggravating or, indeed, causing those symptoms, such as intolerance of lactose, fructose, or sorbitol. Some centers perform a colonic biopsy routinely at flexible sigmoidoscopy to detect microscopic or collagenous colitis in patients with unexplained diarrhea. If the left side of the colon shows a macroscopically normal appearance, we do not routinely biopsy the mucosa because, in studies of patients with suspected irritable bowel syndrome, it was shown not to contribute any clinically useful information55 other than the nonspecific effects of the phosphate enemas used to cleanse the lower colon. The initial biochemical, hematologic, and stool evaluations will have excluded organic disease in the vast majority of patients. Once organic, structural, or biochemical disorders are excluded, the patient might be reassured about these normal findings and that symptomatic treatment is usually effective. Such chronic diarrhea should be treated symptomatically with antidiarrheal agents such as loperamide up to 16 mg/day in divided doses, including preprandial dosing. In patients with negative initial test results who do not respond to treatment with opioids, stool osmolality, chemistry, and a screen for laxatives are helpful in identifying disaccharide or other malabsorption, and screening for surreptitious laxative abuse. If these studies are negative, hormonal diarrhea needs to be excluded, and small bowel and colonic transit studies are used when available to assess the severity of accelerated transit.47 This provides the basis for further efforts to slow transit or control secretory diarrhea56 by means of higher doses of loperamide, up to 16 to 24 mg/day,35 clonidine 0.1 mg twice a day57 orally or by patch, alosetron 1 mg twice a day, or octreotide 50 –100 ␮g three times a day before meals. An empiric trial of cholestyramine 4 g three times a day might be helpful especially with limited ileal resections.31,58

Conclusion Chronic diarrhea is a symptom that is frequently encountered in clinical practice. The vast majority of patients have functional or motility disorders, rather than inflammatory, malabsorptive, or secretory diseases. Positive diagnosis of irritable bowel syndrome or func-


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tional diarrhea is the first step, followed by careful history and rectal examination. The nature of the symptoms should inform the clinician on the choice of initial tests. Subsequent management is directed to positively identified diagnosis or empiric trials with motility inhibitors. This approach should reduce the costs incurred in the management of patients with chronic diarrhea.59

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Address requests for reprints to: Michael Camilleri, M.D., Mayo Clinic, Charlton 8-110, 200 First Street S.W., Rochester, Minnesota 55905. e-mail: [email protected]. Supported in part by grants RO1-DK54681 and K24-DK-02638 from the National Institutes of Health.