ESSENTIALS OF DIAGNOSIS
Diarrhea present for longer than 4 weeks.
Before embarking on extensive workup, common causes should be excluded, including medications, chronic infections, and irritable bowel syndrome.
The causes of chronic diarrhea may be grouped into the following major pathophysiologic categories: medications, osmotic diarrheas, secretory conditions, inflammatory conditions, malabsorptive conditions, motility disorders, chronic infections, and systemic disorders (Table 15–6).
Numerous medications can cause diarrhea. Common offenders include cholinesterase inhibitors, SSRIs, angiotensin II receptor blockers, proton pump inhibitors, NSAIDs, metformin, allopurinol, and orlistat. All medications should be carefully reviewed, and discontinuation of potential culprits should be considered.
As stool leaves the colon, fecal osmolality is equal to the serum osmolality, ie, approximately 290 mOsm/kg. Under normal circumstances, the major osmoles are Na+, K+, Cl–, and HCO3–. The stool osmolality may be estimated by multiplying the stool (Na+ + K+) × 2. The osmotic gap is the difference between the measured osmolality of the stool (or serum) and the estimated stool osmolality and is normally less than 50 mOsm/kg. An increased osmotic gap (greater than 75 mOsm/kg) implies that the diarrhea is caused by ingestion or malabsorption of an osmotically active substance. The most common causes are carbohydrate malabsorption (lactose, fructose, sorbitol), laxative abuse, and malabsorption syndromes. Osmotic diarrheas resolve during fasting. Those caused by malabsorbed carbohydrates are characterized by abdominal distention, bloating, and flatulence due to increased colonic gas production.
Carbohydrate malabsorption is common and should be considered in all patients with chronic, postprandial diarrhea. Patients should be asked about their intake of dairy products (lactose), fruits and artificial sweeteners (fructose and sorbitol), processed foods and soft drinks (high-fructose corn syrup), and alcohol. The diagnosis of carbohydrate malabsorption may be established by an elimination trial for 2–3 weeks or by hydrogen breath tests.
Ingestion of magnesium- or phosphate-containing compounds (laxatives, antacids) should be considered in enigmatic chronic diarrhea. The fat substitute olestra also causes diarrhea and cramps in occasional patients.
Increased intestinal secretion or decreased absorption results in a high-volume watery diarrhea with a normal osmotic gap. There is little change in stool output during the fasting state, and dehydration and electrolyte imbalance may develop. Causes include endocrine tumors (stimulating intestinal or pancreatic secretion), bile salt malabsorption (stimulating colonic secretion), and microscopic colitis. Microscopic colitis is a common cause of chronic watery diarrhea in older adults (see Inflammatory Bowel Disease, below).
D. Inflammatory Conditions
Diarrhea is present in most patients with inflammatory bowel disease (ulcerative colitis, Crohn disease). A variety of other symptoms may be present, including abdominal pain, fever, weight loss, and hematochezia.
E. Malabsorptive Conditions
The major causes of malabsorption are small mucosal intestinal diseases, intestinal resections, lymphatic obstruction, small intestinal bacterial overgrowth, and pancreatic insufficiency. Its characteristics are weight loss, osmotic diarrhea, steatorrhea, and nutritional deficiencies. Significant diarrhea in the absence of weight loss is not likely to be due to malabsorption. The physical and laboratory abnormalities related to deficiencies of vitamins or minerals are discussed in Chapter 29.
F. Motility Disorders (Including Irritable Bowel Syndrome)
Irritable bowel syndrome is the most common cause of chronic diarrhea in young adults (see Irritable Bowel Syndrome, below). It should be considered in patients with lower abdominal pain and altered bowel habits who have no other evidence of serious organic disease (weight loss, nocturnal diarrhea, anemia, or gastrointestinal bleeding). Abnormal intestinal motility secondary to systemic disorders, radiation enteritis, or surgery may result in diarrhea due to rapid transit or to stasis of intestinal contents with bacterial overgrowth, resulting in malabsorption.
Chronic parasitic infections may cause diarrhea through a number of mechanisms. Pathogens most commonly associated with diarrhea include the protozoans Giardia, Entamoeba histolytica, and Cyclospora as well as the intestinal nematodes. Strongyloidiasis and capillariasis should be excluded in patients from endemic regions, especially in the presence of eosinophilia. Bacterial infections with C difficile and, uncommonly, Aeromonas and Plesiomonas may cause chronic diarrhea.
Immunocompromised patients are susceptible to infectious organisms that can cause acute or chronic diarrhea (see Chapter 31), including microsporidia, Cryptosporidium, CMV, Cystoisospora belli (formerly Isospora belli), Cyclospora, and Mycobacterium avium complex.
Chronic systemic conditions, such as thyroid disease, diabetes, and collagen vascular disorders, may cause diarrhea through alterations in motility or intestinal absorption.
The history and physical examination commonly suggest the underlying pathophysiology that guides the subsequent diagnostic workup (Figure 15–2). The clinician should establish whether the diarrhea is continuous or intermittent, its relationship to meals, and whether it occurs at night or during fasting. The stool appearance may suggest a malabsorption disorder (greasy or malodorous), inflammatory disorder (containing blood or pus), or a secretory process (watery). The presence of abdominal pain suggests irritable bowel syndrome or inflammatory bowel disease. Medications, diet, and recent psychosocial stressors should be reviewed. Physical examination should assess for signs of malnutrition, dehydration, and inflammatory bowel disease.
Decision diagram for diagnosis of causes of chronic diarrhea.
Because chronic diarrhea is caused by so many conditions, the subsequent diagnostic approach is guided by the relative suspicion for the underlying cause, and no specific algorithm can be followed in all patients. Prior to embarking on an extensive evaluation, the most common causes of chronic diarrhea should be considered, including medications, irritable bowel syndrome, and lactose intolerance. The presence of nocturnal diarrhea, weight loss, anemia, or positive results on FOBT are inconsistent with these disorders and warrant further evaluation. AIDS-associated diarrhea is discussed in Chapter 31.
A. Initial Diagnostic Tests
1. Routine laboratory tests
Complete blood count, serum electrolytes, liver chemistries, calcium, phosphorus, albumin, thyroid-stimulating hormone, vitamin A and D levels, prothrombin time with international normalized ratio (INR), erythrocyte sedimentation rate, and C-reactive protein should be obtained in most patients. Serologic testing for celiac disease with an IgA tissue transglutaminase (TG) test is recommended in the evaluation of most patients with chronic diarrhea even in the absence of signs of malabsorption. Anemia occurs in malabsorption syndromes (folate, iron deficiency, or vitamin B12) as well as inflammatory conditions. Hypoalbuminemia is present in malabsorption, protein-losing enteropathies, and inflammatory diseases. Hyponatremia and nonanion gap metabolic acidosis occur in secretory diarrheas. Increased erythrocyte sedimentation rate or C-reactive protein suggests inflammatory bowel disease.
Stool samples should be analyzed for ova and parasites, electrolytes (to calculate osmotic gap), qualitative staining for fat (Sudan stain), occult blood, and either leukocytes or fecal calprotectin or lactoferrin. Parasitic infections (Giardia, E histolytica, Cryptosporidia, and Cyclospora) may be diagnosed with stool multiplex PCR assays that test for a panel of pathogens within 1–5 hours, or, where PCR is unavailable, by microscopy with special stains. As discussed previously, an increased osmotic gap suggests an osmotic diarrhea or disorder of malabsorption. A positive fecal fat stain suggests a disorder of malabsorption. In patients with positive fecal fat or suspicion for chronic pancreatitis, a stool sample should be sent for measurement of pancreatic elastase, which is low with pancreatic insufficiency. The presence of fecal leukocytes or elevated calprotectin or lactoferrin may suggest inflammatory bowel disease.
3. Endoscopic examination and mucosal biopsy
Most patients with chronic persistent diarrhea undergo colonoscopy with mucosal biopsy to exclude inflammatory bowel disease (including Crohn disease and ulcerative colitis), microscopic colitis, and colonic neoplasia. Upper endoscopy with small bowel biopsy is performed when a small intestinal malabsorptive disorder is suspected (celiac disease, Whipple disease) from abnormal laboratory studies or a positive fecal fat stain. It may also be done in patients with advanced AIDS to document Cryptosporidium, microsporidia, and M avium-intracellulare infection.
If the cause of diarrhea is still not apparent, further studies may be warranted.
1. 24-hour stool collection quantification of total weight and fat
A stool weight of less than 200–300 g/24 h excludes diarrhea and suggests a functional disorder such as irritable bowel syndrome. A weight greater than 1000–1500 g suggests a significant secretory process, including neuroendocrine tumors. A fecal fat determination in excess of 10 g/24 h confirms a malabsorptive disorder. Fecal elastase less than 100 mcg/g may be caused by pancreatic insufficiency. (See Celiac Disease and specific tests for malabsorption, below.)
Calcification on a plain abdominal radiograph confirms a diagnosis of chronic pancreatitis, although abdominal CT and endoscopic ultrasonography are more sensitive for the diagnosis of chronic pancreatitis as well as pancreatic cancer. Small intestinal imaging with CT or MRI enterography is helpful in the diagnosis of Crohn disease, small bowel lymphoma, carcinoid, and jejunal diverticula. Neuroendocrine tumors may be localized using somatostatin receptor scintigraphy. Retention of less than 11% at 7 days of intravenous 75Se-homotaurocholate on scintigraphy suggests bile salt malabsorption.
A. SEROLOGIC TESTS FOR NEUROENDOCRINE TUMORS
Secretory diarrheas due to neuroendocrine tumors are rare but should be considered in patients with chronic, high-volume watery diarrhea (greater than 1 L/day) with a normal osmotic gap that persists during fasting. Measurements of the secretagogues of various neuroendocrine tumors may be assayed, including serum chromogranin A (pancreatic neuroendocrine tumors), vasoactive intestinal peptide (VIP) (VIPoma), calcitonin (medullary thyroid carcinoma), gastrin (Zollinger-Ellison syndrome), and urinary 5-hydroxyindoleacetic acid (5-HIAA) (carcinoid).
The diagnosis of small bowel bacterial overgrowth is suggested by a noninvasive breath tests (glucose or lactulose); however, a high rate of false-positive test results limits the utility of these tests. A definitive diagnosis of bacterial overgrowth is determined by aspirate of small intestinal contents for quantitative aerobic and anaerobic bacterial culture; however, this procedure is not available at most centers.
A number of antidiarrheal agents may be used in certain patients with chronic diarrheal conditions and are listed below. Opioids are safe in most patients with chronic, stable symptoms.
Loperamide: 4 mg orally initially, then 2 mg after each loose stool (maximum: 16 mg/day).
Diphenoxylate with atropine: One tablet orally three or four times daily as needed.
Codeine and deodorized tincture of opium: Because of potential habituation, these drugs are avoided except in cases of chronic, intractable diarrhea. Codeine may be given in a dosage of 15–60 mg orally every 4 hours; tincture of opium, 0.3–1.2 mL orally every 6 hours as needed.
Clonidine: Alpha-2-adrenergic agonists inhibit intestinal electrolyte secretion. Clonidine, 0.1–0.3 mg orally twice daily, or a clonidine patch, 0.1–0.2 mg/day, may help in some patients with secretory diarrheas, diabetic diarrhea, or cryptosporidiosis.
Octreotide: This somatostatin analog stimulates intestinal fluid and electrolyte absorption and inhibits intestinal fluid secretion and the release of gastrointestinal peptides. It is given for secretory diarrheas due to neuroendocrine tumors (VIPomas, carcinoid). Effective doses range from 50 mcg to 250 mcg subcutaneously three times daily.
Bile salt binders: Cholestyramine or colestipol (2–4 g once to three times daily) or colesevelam (625 mg, 1–3 tablets once or twice daily) may be useful in patients with bile salt-induced diarrhea, which may be idiopathic or secondary to intestinal resection or ileal disease.
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