Diarrhea is a common clinical feature of inflammatory bowel diseases and may be accompanied by abdominal pain, urgency, and fecal incontinence. The pathophysiology of diarrhea in these diseases is complex, but defective absorption of salt and water by the inflamed bowel is the most important mechanism involved. In addition to inflammation secondary to the disease, diarrhea may arise from a variety of other conditions. It is important to differentiate the pathophysiologic mechanisms involved in the diarrhea in the individual patient to provide the appropriate therapy. This article reviews microscopic colitis, ulcerative colitis, and Crohn’s disease, focusing on diarrhea.
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About 80% of patients with inflammatory bowel diseases initially present with diarrhea.
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Defective fluid absorption by the inflamed bowel is the predominant pathophysiologic mechanism in many patients.
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Diarrhea may arise from a variety of conditions other than inflammation secondary to the disease.
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Careful assessment is required to allow treatment targeted at the underlying diarrheal mechanism(s).
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Uncritical interpretation of diarrhea as a consequence of inflammation caused by the disease can be detrimental and result in inadequate antiinflammatory therapy.
Introduction
Diarrhea is a prevalent symptom and sign of patients with inflammatory bowel diseases (IBDs) and affects most patients. It may represent the first perceived manifestation of intestinal inflammation that brings these patients to the attention of physicians and remain a relevant problem throughout the course of the disease. In a recent population-based study, 77% of patients with ulcerative colitis and 82% of patients with Crohn’s disease (CD) presented with diarrhea at onset of disease. In the microscopic colitis syndrome, diarrhea is present by definition. The severity of diarrhea in IBDs varies widely. Some patients pass slightly increased numbers of soft stools without major impact on activities of everyday life; for them, the symptoms may be merely an annoying nuisance. On the other end of the spectrum, the diarrhea can be so severe that substitution of water and electrolytes is required to compensate for enteral losses. More often, the diarrhea is not voluminous but it is persistent and associated with incapacitating and socially devastating urgency and fecal incontinence. In the typical patient, the diarrhea is intermittent, waxing and waning depending on the inflammatory activity of the disease.
Because diarrhea is so common and its severity is related to the intensity and extent of bowel inflammation, it is widely used as an index of disease activity and therapeutic response. Symptoms and signs pertaining to diarrhea (above all, stool frequency) are invariably present in scoring systems that gauge the clinical activity of IBDs. However, not all diarrhea is secondary to activated bowel inflammation. Particularly in patients with CD, conditions such as malabsorption of bile acids, fat, or carbohydrates, infection with Clostridium difficile , fistulas, a lack of absorptive surface because of previous resection, bacterial overgrowth or other causes may prevail, or add to the diarrhea caused by the disease per se. Moreover, defective function of the anal sphincter apparatus may aggravate symptoms and further complicate the clinical situation. Therefore, when a patient with IBD presents with diarrhea, careful assessment is warranted to define the causative mechanism(s) involved. Only then an individualized treatment plan can be tailored, targeting the pathophysiology relevant to the current problem. Uncritical interpretation of diarrhea as a consequence of inflammation caused by the disease can be detrimental because inadequate antiinflammatory therapy (eg, with steroids, or antibodies to tumor necrosis factor [TNF]) does not help and exposes patients to potentially dangerous side effects, and the unidentified cause of the problem (eg, an infective agent) is left untreated.
Brief review of normal intestinal fluid transport
Before discussing diarrheal diseases, it may be useful to briefly review some principal issues concerning normal physiology of gastrointestinal fluid transport.
Normal people ingest about 2 L of fluid per day with food and drink, but 8 to 10 L enters the small intestine. The additional volume originates from digestive secretion that reaches the lumen in the form of saliva, gastric juice, bile, or pancreatic juice. Further fluid is constantly secreted from cells of the intestinal crypts. Most of the water is absorbed in the small intestine and about 600 to 1500 mL passes the ileocecal valve. In the colon, almost all of the water that is not firmly bound to or associated with certain fecal solids (like undigested fiber and bacteria) is actively absorbed. Only 100 mL leaves the body with the stools. Thus, under normal conditions about 99% of the exogenous and endogenous fluid load is absorbed by the small bowel and the colon; if only 1 additional percent escapes absorption, excess water is likely to exist unbound to fecal solids, and stools become loose. When more than 1500 mL/d is delivered from the small bowel into the cecum, the colon can increase absorption up to 4 to 6 L per day, but individual differences in the maximal absorptive capacity of the colon may be substantial. The critical load of fluid to the cecum also depends on entry rate, and diarrhea may sometimes result from a sudden increase of ileal flow. In healthy individuals, a 250-mL bolus of fluid rapidly delivered to the colon produced no symptoms, whereas a 500-mL bolus resulted in loose stools.
Brief review of normal intestinal fluid transport
Before discussing diarrheal diseases, it may be useful to briefly review some principal issues concerning normal physiology of gastrointestinal fluid transport.
Normal people ingest about 2 L of fluid per day with food and drink, but 8 to 10 L enters the small intestine. The additional volume originates from digestive secretion that reaches the lumen in the form of saliva, gastric juice, bile, or pancreatic juice. Further fluid is constantly secreted from cells of the intestinal crypts. Most of the water is absorbed in the small intestine and about 600 to 1500 mL passes the ileocecal valve. In the colon, almost all of the water that is not firmly bound to or associated with certain fecal solids (like undigested fiber and bacteria) is actively absorbed. Only 100 mL leaves the body with the stools. Thus, under normal conditions about 99% of the exogenous and endogenous fluid load is absorbed by the small bowel and the colon; if only 1 additional percent escapes absorption, excess water is likely to exist unbound to fecal solids, and stools become loose. When more than 1500 mL/d is delivered from the small bowel into the cecum, the colon can increase absorption up to 4 to 6 L per day, but individual differences in the maximal absorptive capacity of the colon may be substantial. The critical load of fluid to the cecum also depends on entry rate, and diarrhea may sometimes result from a sudden increase of ileal flow. In healthy individuals, a 250-mL bolus of fluid rapidly delivered to the colon produced no symptoms, whereas a 500-mL bolus resulted in loose stools.
Microscopic colitis
Background and Definition
The recognition of microscopic colitis as a cause of diarrhea is rather novel and the associated terminology has been confusing. Thirty-six years ago, Lindström reported the case of a woman with chronic watery diarrhea and a grossly normal colon. Microscopy of rectal biopsy specimens revealed thick subepithelial collagenous deposits with plasmacytic infiltration in the lamina propria, and he named the condition collagenous colitis. Several years later, Read and colleagues described a group of patients with a similar clinical picture and nonspecific mucosal inflammation without a thickened collagen layer; they coined the term microscopic colitis to denote the fact that colonic mucosa appears normal to the naked eye. Subsequently, the term lymphocytic colitis was introduced to point out that the presence of lymphocytes in the epithelium of the colonic mucosa is the hallmark histologic feature in these patients. Currently, microscopic colitis is defined as a syndrome of watery diarrhea characterized by a normal colonoscopic appearance and histologic changes of lymphocytic-plasmacytic inflammation in the lamina propria and intraepithelial lymphocytosis, with or without thickening of the subepithelial collagen table. If a thickened collagenous band is present beneath the surface epithelium, the term collagenous colitis is used; if there is no thickened band, the condition is categorized as lymphocytic colitis. Because clinical presentation, disease course, and response to therapy are so similar, collagenous colitis and lymphocytic colitis are widely considered to represent 2 histologic subtypes of microscopic colitis.
Epidemiology
Microscopic colitis was once believed to be a rare disorder, but is has now become evident that it is a common cause of chronic diarrhea. At a tertiary referral center, the diagnosis was established in 10% of patients with this problem. In Olmsted county, 3.1 new cases per 100 000 inhabitants were recorded in 1 year for collagenous colitis and 5.5 for lymphocytic colitis, with a significant increase in the incidence of microscopic colitis over time. Similar results have been reported from Canada and Europe. Most of the studies showed a predominance of females, especially for collagenous colitis. The peak age of onset is in the sixth and seventh decade of life, yet all ages (even children) may be affected. Increased awareness of microscopic colitis by clinicians and pathologists may have contributed to the observed increase in incidence rates.
Cause
The cause of microscopic colitis is unknown. According to 1 hypothesis, a hitherto undefined noxious agent of dietary or microbiologic origin triggers or causes a chronic inflammation of the colonic mucosa in susceptible individuals. This view is supported by the presence of increased numbers of T lymphocytes in the epithelial lining of the colonic epithelium, which could reflect an immunologic reaction to that agent. In addition, when the fecal stream of patients with refractory collagenous colitis was diverted by an ileostomy, diarrhea ceased and the thickened subepithelial collagenous layer became normal. Clinical symptoms and the abnormal collagen layer recurred after restoration of intestinal continuity. Many patients with microscopic colitis also have autoimmune or rheumatologic diseases, further supporting involvement of the immune system. Microscopic colitis has also been related to the ingestion of different drugs, including aspirin, nonsteroidal antiinflammatory drugs (NSAIDs), proton pump inhibitors, ranitidine, sertraline, ticlopidine, acarbose, flutamide, and simvastatin. In some patients, withdrawal of the incriminated drug can lead to resolution of symptoms; in others, drug-induced diarrhea may have uncovered preexistent microscopic colitis. A further intraluminal factor is gluten. There exists a link between microscopic colitis and celiac sprue, with the concomitance of the 2 diseases being 50 times higher than expected in the general population ; 5.2% to 9% of patients with microscopic colitis also have celiac sprue. Several HLA-DQ loci have been identified to be linked with the occurrence of both microscopic colitis and celiac sprue, which suggests the possibility that similar immune mechanisms are involved. However, it is unlikely that gluten is the trigger of microscopic colitis.
Pathophysiology of Diarrhea
In vivo perfusion studies revealed that colonic ion transport is substantially impaired in patients with lymphocytic colitis and collagenous colitis. The predominant abnormality is a reduction of active and passive absorption of sodium and chloride, resulting in markedly depressed fluid absorption from the lumen of the colon. Recent in vitro experiments performed on colonic biopsy specimens from patients with collagenous colitis also showed reduced sodium and chloride absorption to be the main diarrheal mechanisms accompanied by altered diffusion and downregulation of tight junction molecules. Colonic fluid absorption and stool volume are dependent on the cellularity of the lamina propria but not on collagen table thickening ; the more inflammatory cells are present in the lamina propria, the less water and electrolytes are absorbed and the higher is the volume of diarrheal stools. These findings are most consistent with inflammation-driven genesis of diarrhea. Although not studied in detail in this setting, it is conceivable that abnormal ion transport is a consequence of the presence of increased local cytokines and other mediators released by the inflammatory process. Because colonic absorption is severely depressed and net secretion is not frequently noted, daily stool volume in microscopic colitis usually does not exceed the volume of fluid entering the colon each day (approximately 1000 mL) and averages about 500 mL. Stool volumes greater than 1000 mL/d or the presence of steatorrhea usually indicate the coexistence of celiac sprue.
In addition to inflammation, malabsorption of bile acids may also be present and aggravate diarrhea in some patients with collagenous colitis. However, bile acid malabsorption has been observed in many other diarrheal diseases and is an unlikely cause or main pathophysiologic mechanism of collagenous colitis. Treatment with bile acid–binding resins resulted in rapid symptomatic improvement in many of these patients but also in patients without bile acid wasting.
Clinical presentation
Chronic watery diarrhea is the main symptom in patients with microscopic colitis. Passage of blood, pus, or excess fat is atypical; in these situations, other causes should be sought. Severe abdominal pain and abdominal tenderness are also atypical, whereas cramping and abdominal discomfort associated with diarrhea are not unusual. Onset of symptoms can be insidious or sudden. When diarrhea abruptly occurs, it may suggest an infectious process, but microbiological evaluation of the stool remains negative. Daily stool weight typically amounts to 300 to 700 g, and may exceed 1500 g in severe cases. Dehydration is rare and the need for intravenous fluid substitution is exceptional. Stool frequency usually ranges between 3 and 10 bowel movements per day. Stools are watery or runny in 23% to 70% of patients ; the rest have decreased fecal consistency of various degrees, depending on diet and other factors. Many have nocturnal diarrhea. Urgency is often present and 9% to 60 % of patients suffer from fecal incontinence. Incontinence may be favored because the disease is more common in elderly women, in whom incontinence is also more prevalent. However, in a recent study, collagenous colitis was not associated with rectal hypersensitivity or disturbed anal function. On the contrary, when a balloon was distended in the inflamed rectum of these patients, they had a higher rectal pressure threshold and rectal volume at the feeling of first sensation. This finding is different from findings in patients with active ulcerative colitis, who typically have reduced rectal compliance.
Because these symptoms are nonspecific, they may erroneously be attributed to diarrhea-predominant irritable bowel syndrome (IBS), especially in younger women with mild disease. Other causes of watery diarrhea are listed in Box 1 .
Microscopic colitis
Malabsorption of carbohydrates and sugar alcohols
Lactose, fructose
Sorbitol
Laxative abuse
Magnesium, sulfate, phosphate, lactulose
Senna, bisacodyl, phenolphthalein, ricinoleic acid
Endocrine diarrhea
Diabetic diarrhea
Thyroid disease
Addison disease
Bile acid diarrhea
Amyloidosis
Mast cell disease
Small bowel bacterial overgrowth
Mesenteric ischemia
Iatrogenic diarrhea
Drugs
Postresection diarrhea
Radiation enteritis
Postvagotomy, postsympathectomy
Epidemic secretory diarrhea
Idiopathic secretory diarrhea
Poisons
Neoplasia
Colon carcinoma
Lymphoma
Villous adenoma
IBS
Giardiasis
Collagen-vascular diseases
Tuberculosis
Circulating secretagogues
Gastrin
Vasoactive intestinal polypeptide
Calcitonin
Somatostatin
Glucagon
Serotonin
Histamine
Lymphangiectasia
Ulcerative colitis
CD
Diagnosis
Diagnosis of microscopic colitis is usually straightforward, provided it is considered as a differential diagnosis. Because recognition of both lymphocytic and collagenous colitis is based entirely on histologic examination of colonic mucosa, it is essential that in patients presenting with chronic watery diarrhea, multiple biopsies (six to ten) are taken from different parts of the apparently normal colon. In most instances, the correct diagnosis can be established by initial use of sigmoidoscopy. Occasionally, initial samples are nondiagnostic as a result of discontinuous or patchy distribution of disease ; in this situation, full colonoscopy with biopsies taken from both the right and the left side of the colon should be performed. Depending on the clinical situation, colonoscopy is frequently performed initially to avoid false-negative results or to rule out other potential causes of the patient’s symptoms or coexisting carcinoma. It is also important that biopsy specimens are interpreted by a skilled pathologist who has been provided with information relevant to the case.
Treatment of microscopic colitis
Medical treatment options for microscopic colitis were analyzed in a recent Cochrane review. The results showed budesonide to be an effective treatment, and suggested that bismuth subsalicylate, prednisone, and mesalamine with or without cholestyramine may be beneficial. As an initial step in management of patients, NSAIDs and any other agents or dietary factors that might aggravate symptoms should be discontinued if possible; specific dietary recommendation or management is not available. To test for concurrent celiac sprue, serologic studies (tissue transglutaminase with an IgA level) can be performed. In patients with severe diarrhea, steatorrhea significant weight loss, unexplained iron deficiency anemia, or other signs of celiac disease, as well as in patients who are refractory to medical therapy, duodenal biopsies should be obtained.
Nonspecific Antidiarrheal Drugs
Antimotility medications, such as loperamide, are commonly prescribed first and often give satisfactory control of diarrhea in mild cases. In retrospective studies, a response was observed in 50% to 70% of patients. Resolution of diarrhea was less common (13%–23%).
Budesonide
Budesonide is the most thoroughly studied drug in the treatment of patients with microscopic colitis. Budesonide (9 mg/d) induces clinical and histologic response in both lymphocytic colitis and collagenous colitis, and maintains responses in collagenous colitis. Analysis of pooled data from controlled trials shows that after 6 to 8 weeks of treatment, a clinical response was noted in 81% of patients with collagenous colitis (placebo 17%) and in 86% of patients with lymphocytic colitis (placebo 40%). In collagenous colitis, continued treatment with budesonide at a lower dose (6 mg/d) could maintain response for 6 months in 75% of initial responders to induction therapy with 9 mg/d (placebo 25%). Discontinuation of therapy is frequently followed by relapse, but symptoms usually respond to reintroduction of budesonide. Many patients maintain remission on lower doses (3–6 mg/d). Patients on long-term therapy with budesonide need to be monitored for steroid side effects. Budesonide is considered the drug of first choice in patients with moderate to severe symptoms, or when symptoms persist despite other therapy.
Bismuth Subsalicylate
Bismuth subsalicylate has antiinflammatory and antibacterial effects. In 1 study, 90% of patients with microscopic colitis reached a clinical remission; in 80%, histologic improvement was noted. Similar results were obtained in a small controlled trial. Patients daily ingested 9 tablets of bismuth subsalicylate (262 mg each) in 3 divided doses. Response to bismuth subsalicylate usually occurs within 1 month of continuous treatment. In responders, the drug is usually given for a second month. Remission may last more than 2 years. Because bismuth subsalicylate is inexpensive and well tolerated, it can be tried initially in patients with mild or moderate diarrhea. In many countries, bismuth subsalicylate is not available because of concerns regarding long-term toxicity.
Cholestyramine
This anion-binding resin may alleviate diarrhea in patients with microscopic colitis with or without bile acid malabsorption. It has been speculated that the resin binds to an unknown offending agent that stimulates the inflammatory process. There have been several clinical observations, open-label studies, and 1 controlled trial suggesting clinical efficacy without constant improvement of inflammatory histology. The effective dose required for satisfactory control of diarrhea varies between patients (2–24 g/d), but most of those who respond need 4 to 12 g/d (1–3 packages of cholestyramine). Because of its taste and texture, it is difficult for many patients to ingest cholestyramine over longer periods. Nevertheless, cholestyramine may be helpful in patients with mild or moderate diarrhea and is an option in those resistant to steroid therapy.
5-Aminosalicylate Drugs
5-Aminosalicylate drugs have frequently been used in patients with microscopic colitis. In 1 unblinded study without placebo control, patients ingested mesalazine 800 mg 3 times daily alone or in combination with 4 g of cholestyramine for 6 months. Clinical and histologic remission reportedly occurred in 85% of patients with lymphocytic colitis and in 91% of patients with collagenous colitis, the latter benefitting more from additional cholestyramine. In uncontrolled series, a response was noted in less than half of the patients. Preliminary data from a randomized trial indicate that mesalazine is ineffective in collagenous colitis. At interim analysis clinical remission at 8 weeks was observed in 44% of patients treated with 3 g mesalazine granules; remission rates for placebo and budesonide (9 mg) were 59.5% and 80%, respectively.
Prednisolone
One small placebo-controlled trial showed a trend toward improvement in stool frequency after treatment with prednisolone 50 mg for 2 weeks. Systemic steroids are an option when budesonide fails, but responders are likely to relapse after discontinuation of therapy.
Azathioprine, 6-Mercaptopurine, and Methotrexate
These immunosuppressive drugs may be beneficial in steroid refractory or dependent patients. In 1 retrospective analysis of patients with collagenous colitis, treatment with methotrexate was followed by clinical improvement of symptoms in 16 of 19 cases. The median methotrexate dose was 7.5–10 mg and the dose range was 5–25 mg orally once a week.
Anti-TNF Drugs
According to recent small case series treatment with TNF-blockers (infliximab and adalimumab) was highly effective in inducing clinical remission in patients with refractory severe lymphocytic and collagenous colitis. In 1 study long term clinical remission (more than 1 year) was achieved in 3 of 4 patients. More data is required to define the role of anti-TNF therapy in this setting. The potential benefit of systemic steroids, immunosuppressives and anti-TNF drugs has to be weighed against the risks of drug-induced complications in the often elderly patients.
Most patients respond sufficiently to medical management. Surgery (ileostomy, with or without colectomy, or colectomy with ileal pouch-anal anastomosis) is reserved for those rare patients with debilitating diarrhea in whom all forms of medical therapy have been exhausted without success.
Ulcerative colitis and CD
Different from microscopic colitis, that has been considered a gentler and more subtle form of colitis, the classic IBDs (ulcerative colitis and CD) are characterized by more severe, macroscopically visible, inflammatory changes in the gut that usually entail destruction of the mucosal surface, with structures beyond the mucosa also being affected in CD. These 2 illnesses are more serious; they can be life-threatening and are associated with an increased risk of colorectal carcinoma.
Ulcerative colitis is a diffuse inflammation that primarily affects the colonic mucosa. It almost always involves the rectum and may extend proximally in a continuous fashion along a variable length of the colon. At initial presentation, disease is limited to the rectum in 30%, and does not reach beyond the splenic flexure in two-thirds of patients. In more than half of the patients, inflammation progresses with time to involve more proximal parts of the colon. Thus, topical therapy that reaches only distal parts of the colon may become inefficient in a patient with proximal progression of disease. The small bowel is not affected, with the exception of slight inflammation of the terminal ileum, which is referred to as backwash ileitis.
CD can involve any segment of the intestinal tube, from the mouth to the anus. Typically, the distal small bowel and the proximal colon are affected. About 25% of patients have colonic involvement only, and in about one-third of cases only the small intestine is inflamed. Distribution of inflammatory lesions is patchy and discontinuous, with normal-appearing segments of the intestine between affected areas. The behavior of CD can be inflammatory, stricturing, or penetrating, with progression to the penetrating variant with time.
Clinical presentation
Patients with ulcerative colitis present with a variable spectrum of symptoms and signs that are largely determined by the anatomic extent and intensity of inflammation in the colon. When the disease is limited to the rectum or rectosigmoid, recurrent or persistent rectal bleeding associated with the passage of mucus and small loose stools is common. In most patients with active disease, the number of bowel movements is increased. When the rectum is inflamed, many patients lose the ability to discriminate fecal matter from gas and experience a feeling of incomplete evacuation. Rectal compliance may be restricted, so that stool cannot be sufficiently withheld, and patients may be distressed by urgent defecation and incontinence. With more proximal extension of disease, diarrhea tends to become more severe and patients may pass more than 10 bloody stools per day. Abdominal cramps are often associated with the diarrhea. Nocturnal and postprandial diarrhea is common.
In CD, diarrhea is highly variable depending on gut segments affected and the diarrheal mechanisms involved. Patients with disease limited to the colon may have symptoms similar to patients with ulcerative colitis. When the small and the large intestine are inflamed, stool volume can be high because the diseased colon cannot fully compensate for increased fluid volumes delivered from the small intestine.
Not all patients with ulcerative colitis or CD present with diarrhea. One-third of patients with active proctitis or proctosigmoiditis may void pellets of hard stools. In CD, about 20% of patients initially present without diarrhea ; other symptoms, such as right lower abdominal pain or arthralgias, may dominate the clinical picture. Diarrhea often develops later, for example as a consequence of bowel resection.
Pathophysiology of diarrhea
The pathophysiology of diarrhea in IBD is multifactorial and complex. Inflammation clearly is the most important factor that finally results in abnormal intestinal ion transport and motor function. However, a variety of noninflammatory mechanisms may coexist, or precipitate diarrhea in the absence of inflammation.
Inflammation and defective intestinal ion transport
In ulcerative colitis, the principal disturbance that leads to the development of diarrhea is a profound decrease in the net absorption of sodium (and consequently of chloride and water) from the lumen of the colon. The failure to absorb salt and water is considered primarily a consequence of reduced activity of the Na+/K+-adenosine triphosphatase (ATPase) pump located in the basolateral membrane of colonocytes and of an impaired function of apical sodium channels. These channels are present in surface colonocytes located in the distal large bowel, where ulcerative colitis is invariably present. In addition, the epithelial barrier may be leaky because of apoptotic foci and altered tight junction structure, which is supposed to favor back leakage of absorbed fluid across the tight junctions into the lumen. By contrast, excessive active anion secretion, which is the underlying basis of several infectious diarrheal diseases (eg, cholera, enterotoxic Escherichia coli ) and of diarrhea caused by endogenous secretagogues (eg, vasoactive intestinal peptide ), does not seem to have major importance. This finding is in line with the observation that patients with the large bowel uncoupled by ileostomy do not have much discharge from the isolated colon, even although it may remain intensely inflamed.
Reduced net absorption of salt and water is also present in patients with CD of the large and small bowel. In addition to defective sodium absorption, active secretion may be important in the generation of diarrhea in some patients. Sodium transport has recently been shown to be reduced in colonocytes from the macroscopically noninflamed bowel of patients with small intestinal CD. Abnormal function of macroscopically normal intestine has also been noted in early perfusion studies, in which reduced sodium flux was detected in the radiologically normal small intestine of colectomized patients with CD. Thus, fluid absorption can be disturbed in areas of the intestine with an apparently normal morphology.
The changes in ion transport, as described earlier, are primarily a consequence of inflammation. A multitude of immune and inflammatory mediators are present in the intestinal mucosa of patients with IBD and are likely to alter colonocyte function and bowel motility directly or via endocrine cells and elements of the enteric nervous system. In experimental animals, proinflammatory cytokines such as TNF-α and interferon γ have been shown to impair the expression of sodium channels, reduce epithelial Na+/K+-ATPase activity, and increase mucosal permeability, leading to decreased intestinal sodium and water absorption. Therapeutic blockade of proinflammatory cytokines (eg, with antibodies to TNF) can reverse these effects and improve diarrhea in patients with IBD.
Inflammation also causes denudation of the epithelium, favoring leakage of plasmalike fluid and blood into the lumen, augmenting intestinal fluid load. In addition, the absorptive surface may be diminished because of ulcers. In some patients, the failure of the inflamed colon to salvage unabsorbed carbohydrates may have a role.
Diarrhea can also be accentuated by disturbances of intestinal motility. Although diarrhea in general goes along with accelerated intestinal transit, motor abnormalities may not be uniform but rather vary between segments of the gut. For example, many patients with active ulcerative colitis have proximal colonic stasis, whereas transit through the rectosigmoid region is rapid. Therefore, antidiarrheal drugs that further slow proximal colonic transit should be used with caution in these patients. The distal colon seems to be programmed to react to intraluminal contents by generating strong contractions that challenge the continence mechanism and cause frequent, urgent, and often painful defecation. In patients with CD, intestinal obstruction can impede normal flow of intestinal contents and cause diarrhea as a consequence of bacterial overgrowth (see later discussion).
Causes of diarrhea other than inflammation resulting from active disease
Not all diarrhea in patients with IBD originates from active inflammation caused by the disease. Especially in CD, a wide variety of potential mechanisms can interfere with normal absorption of nutrients and fluid. It is important to understand the pathophysiologic basis of these mechanisms to better identify the cause or causes responsible for the diarrhea in an individual patient ( Table 1 ).
| Cause | Diagnostic Approaches | Treatment |
|---|---|---|
| Inflammation caused by IBD | Blood chemistry Stool markers Endoscopy Radiologic imaging studies | Antiinflammatory medication Immunosuppressives Biologicals |
| Enteric infection | History of recent antibiotic therapy or previous infection with Clostridium difficile Microbiological stool tests Colonoscopy + biopsy (cytomegalovirus?) | Antimicrobial therapy |
| Malabsorption | Dietary history Breath tests Stool analyses [ 75 Se]Selena-homocholic acid conjugated with taurine, diagnostic trial with cholestyramine | Bile acids: binding resins Fat: low-fat diet, bile acid replacement Carbohydrate: avoid lactose and fructose |
| Bacterial overgrowth | Presence of predisposing abnormalities Bacterial culture from jejunal aspirate Breath tests | Antibiotics Dilatation of strictures Surgery |
| Postresection | Review of surgical history Radiologic imaging Endoscopy | Antidiarrheal medication Stool modifiers Frequent feedings, avoid caffeine Histamine 2 -receptor blockers, proton pump inhibitors Replacement of fluid and nutrients |
| Fistula | History of halitosis or fecal vomiting Radiologic imaging Endoscopy | Surgery |
| Medication | History | Discontinue offending agent |
| Food intolerance | History | Avoid offending diet |
| IBS | History Endoscopy, radiologic imaging and additional tests as required to exclude other causes | Fiber supplements Antispasmodics, antidiarrheal agents Tricyclic antidepressants |
Related posts:
Colorectal Normal Histology and Histopathologic Findings in Patients with Chronic Diarrhea
Bacterial Flora as a Cause or Treatment of Chronic Diarrhea
Diarrhea in the Immunocompromised Patient
Diarrhea Caused By Carbohydrate Malabsorption
Celiac Disease
Diarrhea in Chronic Inflammatory Bowel Diseases
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