UEU-co logo

MD Consult: Books: Goldman: Cecil Medicine: Chapter 143 – APPROACH TO THE PATIENT WITH DIARRHEA AND MALABSORPTION

Goldman: Cecil Medicine, 23rd ed.

Copyright © 2007 Saunders, An Imprint of Elsevier


Carol E. Semrad

Don W. Powell


Normal stool frequency ranges from three times a week to three times a day. Although individuals rarely cite increases in frequency alone as the definition of diarrhea, a decrease in stool consistency (increased fluidity) and stools that cause urgency or abdominal discomfort are likely to be termed diarrhea. Consistency is defined as the ratio of fecal water to the water-holding capacity of fecal insoluble solids, which are composed of bacterial mass and dietary fiber. One half of the dry weight of stool is bacteria. Because it is difficult to measure stool consistency and because stool is predominantly (60 to 85%) water, stool weight becomes a reasonable surrogate of consistency.

Physicians often define diarrhea as a physical sign, 24-hour stool excretion by weight or volume, rather than as a symptom. Daily stool weights of children and adults are less than 200 g, and greater stool weights are an objective definition of diarrhea; however, this definition misses 20% of diarrheal symptoms in patients with loose stools less than this daily weight.

Acute diarrheas are those lasting less than 2 to 3 weeks or, rarely, 6 to 8 weeks. The most common cause of acute diarrhea is infection. Chronic diarrheas are those lasting at least 4 weeks, and more usually 6 to 8 weeks or longer. There are three categories of chronic diarrhea: osmotic (malabsorptive) diarrhea, secretory diarrhea, and inflammatory diarrhea.


Diarrhea is the second leading cause of mortality worldwide and is particularly problematic for children younger than 5 years of age in developing nations. In the United States, the elderly are susceptible to death from diarrheal disease: more than 1600 deaths occur annually among those older than 74 years of age. It is estimated that approximately 5% of the U.S. population suffer from chronic diarrhea and that about 40% of these individuals are older than 60 years of age.

In the United States, the complaint of diarrhea accounts for more than 7 million outpatient visits by 4 million patients per year. The combination of non–food-borne gastroenteritis, food-borne illness, irritable bowel syndrome, chronic diarrhea, and inflammatory bowel diseases accounts for about 250,000 hospital admissions, 2.6 million emergency room visits, and 12.7 million physician visits. Total costs for diarrheal diseases are about $1.2 billion in direct (health care) costs and $5.4 billion in indirect costs (days lost from work).


Abnormalities of Fluid and Electrolyte Transport

Diarrhea previously was thought to be caused principally by abnormal gastrointestinal motility. It is now clear that most diarrheal conditions are due primarily to alterations of intestinal fluid and electrolyte transport and less to smooth muscle function.

Each 24 hours, 8 to 10 L of fluid enters the duodenum with 800 mEq sodium (Na+), 700 mEq chloride (Cl-), and 100 mEq potassium (K+). The diet supplies 2 L of this fluid; the remainder comes from salivary, stomach, liver, pancreatic, and duodenal secretions. The small intestine normally absorbs 8 to 9 L of this fluid and presents 1.5 L to the colon for absorption. Of the remaining fluid, the colon absorbs all but approximately 100 mL, which contains 3 mEq, 8 mEq, and 2 mEq of Na+, K+, and Cl-, respectively. Diarrhea can result from decreased absorption or increased secretion by either the small intestine or the colon. If deranged electrolyte transport or the presence of nonabsorbable solutes in the intestinal lumen reduced the absorptive capacity of the small intestine by 50%, the volume of fluid presented daily to the normal colon (50% of 10 L, or 5 L) would exceed its maximum daily absorptive capacity of 4 L. Stool excretion of 1000 mL would result, which by definition is diarrhea. Alternatively, if the colon is deranged so that it cannot absorb even the 1.5 L normally presented to it by the small intestine, a stool volume of greater than 200 mL in 24 hours would result, again defined as diarrhea.

At the cellular level, excess intraluminal fluid volumes occur when there is a derangement of electrolyte transport capabilities of the small or large intestine or when osmotic solutes in the bowel lumen create an adverse osmotic gradient that the normal electrolyte absorptive mechanisms cannot overcome. Na+ transport by the epithelium from lumen to blood (by Na+-coupled sugar and amino acid transport in the small intestine, by Na+:H+ exchange proteins in the small intestine and proximal colon, and by aldosterone-regulated Na+ channels in the distal colon) creates a favorable osmotic gradient for absorption ( Fig. 143-1 A and B ). Oral rehydration solutions (ORS), which are used extensively to replace diarrheal fluid and electrolyte losses, are effective because they contain Na+, sugars, and, often, protein (amino acids). If unabsorbable or poorly absorbable solutes (e.g., lactose in lactase-deficient individuals, polyethylene glycol in colon-cleansing solutions, or magnesium [Mg2+] citrate in cathartics) are present in the lumen, the Na+-absorbing mechanisms are incapable of creating an osmotic gradient favorable for absorption; as a result, fluid remains in the lumen and is the basis of osmotic or malabsorptive diarrhea.

FIGURE 143-1  Mechanisms of intestinal transport of water and electrolytes. A, Intestinal sodium absorption. Sodium is actively absorbed in villus cells of the small intestine and surface cells of the colon. The sodium-potassium adenosine triphosphatase (Na+,K+-ATPase) present on the cell basolateral membrane maintains a low intracellular Na+ concentration and an electronegative cell interior favoring Na+ movement across the apical membrane from lumen into cell. In the small intestine, glucose and galactose are taken up with sodium and water at the apical membrane by the sodium-glucose ligand transporter (SGLT1). Several different sodium-dependent amino acid carriers, some with overlapping substrate specificities, transport cationic, anionic, and neutral amino acids into villus cells. Dipeptides and tripeptides are transported by a hydrogen-coupled oligopeptide carrier, PepT1, that is driven by luminal hydrogen ions generated by the epithelial Na+/H+ exchanger. Fructose is taken up by the facilitative glucose transporter (GLUT5). B, Sodium also is absorbed by nutrient-independent transport processes in the small intestine and colon. The Na+/H+ (NHE) and Cl-/HCO3- (DRA) exchangers are inhibited by agents that elevate intracellular cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), or calcium. C, Chloride secretion by intestinal crypt cells. Chloride can be secreted actively throughout the small intestine and colon. Intracellular mediators of secretion (cAMP, cGMP, Ca2+) open apical Cl- channels (cystic fibrosis transmembrane conductance regulator [CFTR], calcium-activated chloride channel [CaCC]) and basolateral K+ channels. Chloride moves from crypt cells into the intestinal lumen, favoring movement of Cl- from the blood into cells by the Na+/K+/2Cl- cotransporter (NKCC1). Bicarbonate (HCO3) also may be secreted via the CFTR channel. D, Regulation of intestinal water and electrolyte transport. Normally, the intestine is in a net absorptive state under the control of extrinsic adrenergic nerves from the sympathetic nervous system. Guanylin, the natural ligand for the Escherichia coli stable-toxin receptor (membrane-bound guanylyl cyclase [GC-C]), may be important in regulating local chloride secretion. The normal tone of the intestine is modified by the enteric nervous system, endocrine and inflammatory cells in the intestinal mucosa, and circulating hormones. The enteric nervous system releases a variety of neurotransmitters, some that stimulate chloride secretion (e.g., vasoactive intestinal peptide [VIP], acetylcholine) and others that promote sodium absorption (e.g., enkephalins, neuropeptide Y). Hormones produced locally from enterochromaffin cells (ECC) in the intestinal epithelium and inflammatory mediators released from immune cells directly affect enterocytes and nearby nerves. Circulating hormones (e.g., aldosterone, glucocorticoids) enhance sodium absorption in the intestine. Glucocorticoids also inhibit release of arachidonic acid and production of prostaglandin by inflammatory cells.

Active Cl- secretion or inhibited Na+ absorption also creates an osmotic gradient favorable for the movement of fluids from blood to lumen and is the basis of the secretory diarrheas. Agents that increase enterocyte cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), or intracellular ionized calcium (Ca2+), such as cholera toxin, Escherichia coli enterotoxins, prostaglandin, and vasoactive intestinal peptide (VIP), all inhibit Na+ absorption and stimulate Cl- secretion ( Table 143-1 ; see Fig. 143-1 C ). Secretion is controlled by neurotransmitters, hormones, and inflammatory mediators (see Fig. 143-1 D ).

TABLE 143-1   — 

Laxatives Phenolphthalein, anthraquinones, bisacodyl, oxyphenisatin, senna, aloe, ricinoleic acid (castor oil), dioctyl sodium sulfosuccinate; endogenous laxatives such as dihydroxy bile acids and long-chain fatty acids
Medications/drugs Diuretics (furosemide, thiazides); coffee, tea, and cola (caffeine and other methylxanthines); asthma medication (theophylline); thyroid preparations; type II diabetes drug (metformin)
Cholinergic drugs, glaucoma eye drops, and bladder stimulants (acetylcholine analogues or mimetics); myasthenia gravis medication (cholinesterase inhibitors); cardiac drugs (quinidine and quinine); gout medication (colchicine); antihypertensives (angiotensin-converting enzyme inhibitors); histamine 2 blocker (ranitidine); proton pump inhibitors; antidepressants (selective serotonin reuptake inhibitors); antineoplastic drugs; chenodeoxycholic acid
Prostaglandins (misoprostol); di-5-aminosalicylic acid (azodisalicylate); gold (also may cause colitis)
Protease inhibitors
Human immunodeficiency virus (HIV)
Toxins Metals (arsenic); plants (e.g., mushroom Amanita phalloides); organophosphates (insecticides and nerve poisons); seafood toxins (ciguatera, scombroid poisoning, and paralytic, diarrhetic, or neurotoxic shellfish poisoning); monosodium glutamate
Bacterial enterotoxins Vibrio cholerae, toxigenic Escherichia coli (heat-labile and heat-stable toxins), Campylobacter, Yersinia, Klebsiella, Clostridium difficile, Staphylococcus aureus (toxic shock syndrome), Clostridium perfringens, Clostridium botulinum, Bacillus cereus
Hormone-producing tumors VIPoma and ganglioneuromas; medullary carcinoma of thyroid (calcitonin and prostaglandins); mastocytosis (histamine); villous adenoma (prostaglandins)
Inflammatory conditions Allergy and anaphylaxis (histamine, serotonin, platelet-activating factor, prostaglandins); infection (reactive oxygen metabolites, platelet-activating factor, prostaglandins, histamine); idiopathic inflammation; inflammatory bowel disease, celiac disease
Ischemic colitis

Adapted from Powell DW: Approach to the patient with diarrhea. In Yamada T, Alpers DH, Owyang C, et al (eds): Textbook of Gastroenterology, 3rd ed. Philadelphia, Lippincott-Raven, 1999.


To understand the three general categories of diarrhea—malabsorption (osmotic diarrheas), secretory diarrheas, and inflammatory diarrheas—it is necessary to understand how the normal intestine handles fluid and solutes in health and disease. Regardless of whether a subject ingests a hypotonic meal, such as a steak, or a hypertonic meal, such as milk and a doughnut, the volume of the meal is augmented by gastric, pancreatic, biliary, and duodenal secretions. The permeable duodenum then renders the meal approximately isotonic with an electrolyte content similar to that of plasma by the time it reaches the proximal jejunum. As the chyme moves toward the colon, the Na+ concentration in the luminal fluid remains constant, but Cl- is reduced to 60 to 70 mmol/L, and bicarbonate (HCO3-) is increased to a similar concentration as the result of Cl- and HCO3- transport mechanisms in the enterocyte and HCO3- secretion in the ileum (see Figs. 143-1B and 143-1C ). In the colon, K+ is secreted, and the Na+ transport mechanism of the colonocyte, together with the low epithelial permeability, extract Na+ and fluid from the stool. As a result, the Na+ content of stool decreases to 30 to 40 mmol/L; K+ increases from 5 to 10 mmol/L in the small bowel to 75 to 90 mmol/L; and poorly absorbed divalent cations, such as Mg2+ and Ca2+, are concentrated in stool to values of 5 to 100 mmol/L. The anion concentrations in the colon change drastically because bacterial degradation of carbohydrate (i.e., unabsorbed starches, sugars, and fiber) creates short-chain fatty acids that attain concentrations of 80 to 180 mmol/L. At colonic pH, these are present as organic anions, such as acetate, propionate, and butyrate. Depending on the concentrations generated, these fatty acids/anions may decrease stool pH to 4 or lower. The osmolality of the stool is approximately that of plasma (280 to 300 mOsm/kg H2O) when it is passed.

With ingestion of a poorly absorbable or unabsorbable solute (e.g., Mg2+, polyethylene glycol) or an unabsorbed carbohydrate (e.g., lactulose or, in lactase-deficient individuals, lactose), a considerable proportion of the osmolality of stool results from the nonabsorbed solute. This gap between stool osmolality and the sum of the electrolytes in the stool causes osmotic diarrhea.

Inflammatory diarrheas are characterized by enterocyte damage and death, villus atrophy, and crypt hyperplasia. The enterocytes on rudimentary villi of the small intestine are immature cells with poor disaccharidase and peptide hydrolase activity, reduced or absent Na+-coupled sugar or amino acid transport mechanisms, and reduced or absent sodium chloride absorptive transporters. Conversely, the hyperplastic crypt cells maintain their ability to secrete Cl- (and perhaps HCO3-). If the inflammation is severe, immune-mediated vascular damage or ulceration allows protein to leak (exudate) from capillaries and lymphatics and contribute to the diarrhea. Activation of lymphocytes, phagocytes, and fibroblasts releases various inflammatory mediators that induce intestinal chloride secretion (see Fig. 143-1 D ). Interleukin-1 (IL-1) and tumor necrosis factor also are released into the blood, causing fever and malaise.


Clinical Manifestations

Approximately 80% of acute diarrheas are due to infections with viruses, bacteria, helminths, and protozoa. The remainder are secondary to the ingestion of medications, poorly absorbed sugars (fructose polymers or sorbitol), fecal impaction, pelvic inflammation (e.g., acute appendicitis [ Chapter 145 ]), or intestinal ischemia ( Chapter 146 ).

Sporadic, Food-Borne, and Water-Borne Infectious Diarrhea

Most infectious diarrheas are acquired through fecal-oral transmission from water, food, or person-to-person contact ( Table 143-2 ). Patients with infectious diarrhea often complain of nausea, vomiting, and abdominal pain and have watery, malabsorptive, or bloody diarrhea and fever (dysentery) ( Chapters 325 through 333 , 357 , 358 , 371 373 , 377 , 378 , 402 , and 403 ). As documented using polymerase chain reaction methods of diagnosis, most outbreaks of nonbacterial acute gastroenteritis in the United States and other countries are caused by caliciviruses (Norwalk agent). Rotavirus predominantly causes diarrhea in infants, usually in the winter months, but also may cause nonseasonal acute diarrhea in adults, particularly the elderly. Mechanisms for diarrhea include decreased fluid absorption due to destruction of villus enterocytes and stimulation of fluid secretion by NSP4 rotatoxin and viral activation of the enteric nervous system.

TABLE 143-2   — 

Vehicle Classic Pathogens
Water (including foods washed in such water) Vibrio cholerae, caliciviruses (Norwalk agent), Giardia, Cryptosporidium
  Poultry Salmonella, Campylobacter, Shigella species
Beef, unpasteurized fruit juice Enterohemorrhagic Escherichia coli
Pork Tapeworm
Seafood and shellfish (including raw sushi and gefilte fish) V. cholerae, Vibrio parahaemolyticus, and Vibrio vulnificus; Salmonella and Shigella species; hepatitis A and B viruses; tapeworm; anisakiasis
Cheese, milk Listeria species
Eggs Salmonella species
Mayonnaise-containing foods and cream pies Staphylococcal and clostridial food poisonings
Fried rice Bacillus cereus
Fresh berries Cyclospora species
Canned vegetables or fruits Clostridium species
Sprouts Enterohemorrhagic E. coli, Salmonella species
Animal-to-person (pets and livestock) Salmonella, Campylobacter, Cryptosporidium, and Giardia species
Person-to-person (including sexual contact) All enteric bacteria, viruses, and parasites
Daycare center Shigella, Campylobacter, Cryptosporidium, and Giardia species; viruses, Clostridium difficile
Hospitalization, antibiotics, or chemotherapy C. difficile
Swimming pool Giardia and Cryptosporidium species
Foreign travel E. coli of various types; Salmonella, Shigella, Campylobacter, Giardia, and Cryptosporidium species; Entamoeba histolytica

Adapted from Powell DW: Approach to the patient with diarrhea. In Yamada T, Alpers DH, Owyang C, et al (eds): Textbook of Gastroenterology, 3rd ed. Philadelphia, Lippincott-Raven, 1999.

Some of the short-lived watery diarrheas ascribed to “viral gastroenteritis” are likely to be mild, sporadic, food-borne bacterial infections. In addition to enteric infections, certain systemic infections (e.g., hepatitis, listeriosis, legionellosis) and emerging infections (e.g., Hanta virus, severe acute respiratory syndrome [SARS], avian influenza) may cause or manifest with substantial diarrhea.

Food-borne illness affects one in four people in the United States, and the incidence is estimated to be 76 million cases per year, with 325,000 hospitalizations and 5000 deaths annually. The incidence may be underestimated, because most patients present with sporadic diarrhea rather than as part of a clear epidemic, and most endemic diarrheas are not reported. Data suggest that fewer than 11% of these infections are reported to the Centers for Disease Control and Prevention (CDC). Emerging food-borne diseases in the United States include the enteritidis serotype of Salmonella, Campylobacter jejuni, E. coli O157:H7, and Cyclospora infections. Recent outbreaks of E. coli O157:H7 have been associated with petting zoos. Fish can become contaminated in their own environment (especially the filter-feeding bivalve mollusks, such as mussels, clams, oysters, and scallops) or by food handlers. Organisms that are specific for seafood include Vibrio parahaemolyticus, which causes either watery or bloody diarrhea, and Vibrio vulnificus, which causes watery diarrhea and, especially in patients with liver disease, a fatal septicemia. Ingestion of meat contaminated by anthrax ( Chapter 317 ) causes fever, diffuse abdominal pain, and bloody stool or vomitus. Anthrax invades the intestinal mucosa; the organism, or anthrax toxin, causes inflammation, ulceration, and necrosis. Ascites develops, and death results from blood loss, dehydration and electrolyte imbalance, intestinal perforation, or toxemia.

Food-Borne and Water-Borne Poisonings

Food poisoning occurs with environmental chemicals, such as monosodium glutamate (used in Asian food), heavy metals (arsenic from rat poison), insecticides (organophosphates and carbamates), and natural toxins found in mushrooms and seafood (fin fish or shellfish). Most of these toxins cause varying combinations of gastrointestinal and neurologic symptoms. Arsenic ( Chapter 20 ) also induces cardiovascular collapse at higher, acute doses; one form of mushroom (Amanita) poisoning ( Chapter 111 ) can cause acute liver and kidney failure.

Diarrhea and neurologic symptoms (tingling and burning around the mouth, facial flushing, sweating, headache, palpitations, and dizziness) of seafood poisoning may be caused by histamine release from the decaying flesh of blood fish (mahi-mahi, tuna, marlin, or mackerel) after it is caught. This form of seafood poisoning is called scombroid. Plankton, algae, or dinoflagellates ingested by tropical fish (amberjack, snapper, grouper, or barracuda) produce a toxin (ciguatoxin) that causes seafood poisoning called ciguatera. Fish from the Albemarle-Pamlico estuary (eastern United States) ingest toxic dinoflagellates that cause Pfiesteria piscicida poisoning. The dinoflagellate toxins cause nausea; vomiting; abdominal pain; diarrhea; neurologic symptoms such as weakness, pruritus, circumoral paresthesias, and temperature reversal (hot drinks taste cold and vice versa); and psychiatric abnormalities and memory loss. Shellfish poisonings are also caused by algae or dinoflagellates ingested by bivalve mollusks; these different toxins can cause predominantly neurologic symptoms (paralytic, neurotoxic, or amnestic shellfish poisonings), which are occasionally severe, or predominantly gastrointestinal symptoms (diarrhetic shellfish poisoning). Puffer fish poisoning (tetrodotoxin) causes neurologic symptoms, respiratory paralysis, and death.

Antibiotic-Associated Diarrheas

Diarrhea occurs in 20% of patients receiving broad-spectrum antibiotics; about 20% of these diarrheas are due to Clostridium difficile ( Chapter 319 ). Recently, hypervirulent, fluoroquinolone-resistant strains have emerged, causing an increase in the incidence and severity of C. difficile infections, including fulminant C. difficile colitis that can lead to colectomy or even death. The A and B toxins produced by C. difficile can cause diarrhea. In animal models, IL-8, substance P, and leukotriene B4 were found to mediate toxin A–stimulated intestinal fluid secretion. C. difficile can cause severe diarrhea, pseudomembranous colitis, or toxic megacolon. Patients may have a relapsing course after seemingly successful therapy with metronidazole or vancomycin. Non–C. difficile antibiotic-induced diarrhea is generally mild and self-limited, and it usually clears spontaneously or in response to cholestyramine therapy. North American travelers to developing countries and travelers on airplanes and cruise ships where errors in food preparation occur are at high risk for acute infectious diarrhea. Environmental sanitation inspections of cruise ships can decrease diarrheal outbreaks in passengers. Bacterial agents account for 85% of traveler’s diarrhea. Enterotoxic E. coli is the most common cause. E. coli heat-stable toxin binds to guanylate cyclase in the enterocyte brush-border membrane, resulting in elevation of intracellular cGMP. E. coli heat-labile toxin, similar to cholera toxin, binds to the monosialoganglioside GM1 in the brush-border membrane, resulting in the activation of adenylate cyclase and elevation of intracellular cAMP. cAMP and cGMP stimulate intestinal chloride secretion (see Fig. 143-1 C ) and inhibit nutrient-independent absorption of sodium and chloride (see Fig. 143-1 B ). Sodium-glucose absorption is not affected; hence, the basis for ORS therapy. Cholera toxin permanently binds to adenylate cyclase (until the natural turnover of the intestinal epithelium, in 5 to 7 days), resulting in persistent secretion and severe diarrhea. Of the 10 to 15 cases of cholera reported in the United States each year, about 60% are travel associated.

Sexually Transmitted and Aids-Related Diarrheas

Men who have sex with men and prostitutes develop infectious diarrhea through the oral-fecal route. The incidence of infectious diarrhea among men who have sex with men (“gay bowel syndrome”) has decreased markedly, but the decline has been more than offset by the high incidence and seriousness of enteric infections in patients with acquired immunodeficiency syndrome (AIDS) ( Chapter 413 ). In patients with human immunodeficiency virus (HIV) disease who are receiving highly active antiretroviral therapy, diarrhea is more likely to be due to protease inhibitors than enteric infection.

Daycare Diarrhea

More than 6 million children in the United States attend daycare, and diarrhea from organisms that colonize at a low inoculum dose (e.g., Shigella, Giardia, Cryptosporidium) or organisms that are spread easily (e.g., rotavirus, astrovirus, adenovirus) is extremely prevalent in this setting. The secondary attack rate for parents and siblings is 10 to 20%.


The differential diagnosis of acute watery diarrhea includes food toxins, infections, medications, and diseases ( Fig. 143-2 ; see Table 143-2 ) ( Chapters 326 through 334 , 358 , 359 , 373 , 374 , 378 , 379 , 400 , 403 , and 404 ). The use of the laboratory to make the diagnosis of infectious diarrhea can be reduced if the evaluation focuses on Campylobacter, Salmonella, Shigella, and C. difficile and if only liquid stools are cultured. Organisms that can cause diarrhea but are not sought routinely by most clinical microbiology laboratories unless specifically requested include Yersinia, Plesiomonas, enterohemorrhagic E. coli serotype O157:H7, Aeromonas, Cryptosporidium, Cyclospora, Microsporidia, and noncholera Vibrio. Parasites such as Giardia and Strongyloides and enteroadherent bacteria can be difficult to detect in stool but may be diagnosed by intestinal biopsy. Even with the use of all available laboratory techniques, the cause of 20 to 40% of all acute infectious diarrheas remains undiagnosed.

FIGURE 143-2  Algorithm for the diagnostic approach to acute diarrhea. AIDS = acquired immunodeficiency syndrome; C. difficile = Clostridium difficile; CMV = cytomegalovirus; E. coli = Escherichia coli; IV therapy = intravenous rehydration; M. avium = Mycobacterium avium complex; ORS = oral rehydration solution; WBCs = white blood cells.  (Adapted in 2006 with permission from Thielman NM, Guerrant RL: Acute infectious diarrhea. N Engl J Med 2004;350:38-47. Copyright 2004, Massachusetts Medical Society. All rights reserved.)


The treatment of diarrhea can be symptomatic (fluid replacement and antidiarrheal agents) or specific (antimicrobial therapy) or both. Because death in acute diarrhea is caused by dehydration, the first task is to assess the degree of dehydration and replace fluid and electrolyte deficits. Severely dehydrated patients should be rehydrated with intravenous Ringer’s lactate or saline solution, to which additional K+ and NaHCO3- may be added as necessary. Alert patients should be given ORS, which is equally effective in repairing fluid and electrolyte losses. In mild-to-moderate dehydration, ORS can be given to infants and children in volumes of 50 to 100 mL/kg over 4 to 6 hours; adults may need to drink 1000 mL/hr. Reduced-osmolarity ORS solutions (Na+ 75 mmol/L, osmolarity 245 mmol/L versus Na+ 90 mmol/L, osmolarity 311 mmol/L in standard solutions) are better tolerated and effective in non-cholera diarrhea but may cause hyponatremia in patients with high-volume diarrhea. Glucose-based ORS, although effective in rehydrating the patient, may worsen the diarrhea. In contrast to glucose-based solutions, rice-based ORS decrease diarrhea in cholera victims; rice is digested to many glucose monomers that aid in the absorption of intestinal secretions. These solutions may not decrease stool output in acute diarrheas, but they will effectively rehydrate the patient despite continued diarrhea. After the patient is rehydrated, ORS are given at rates equaling stool loss plus insensible losses until the diarrhea ceases.

Bismuth subsalicylate (Pepto-Bismol, 525 mg orally every 30 minutes to 1 hour for five doses, may repeat on day 2) is safe and efficacious in bacterial infectious diarrheas. Because of the possibility of worsening the colonization or invasion of infectious organisms by paralyzing intestinal motility, and because of evidence that the use of motility-altering drugs may prolong microorganism excretion time, neither opiates nor anticholinergic drugs are recommended for invasive bacterial infectious diarrheas. However, loperamide (2 mg orally four times a day for 3 to 7 days, maximal dose 16 mg daily) can be useful and safe in acute or traveler’s diarrhea, provided that it is not given to patients with dysentery (high fever, with blood or pus in the stool), and especially when administered concomitantly with effective antibiotics. A combination of loperamide (2 mg orally four times a day) plus simethicone (125 mg orally four times a day) may reduce the abdominal cramps and duration of traveler’s diarrhea. Racecadotril (100 mg orally three times a day in adults, 1.5 mg/kg of body weight orally three times a day in children), an intestinal enkephalinase inhibitor that is antisecretory but does not paralyze intestinal motility, is effective in the treatment of acute diarrhea in children and adults.

Anxiolytics (e.g., diazepam 2 mg orally two to four times daily) and antiemetics (e.g., promethazine 12.5 to 25 mg orally once or twice daily) that decrease sensory perception may make symptoms more tolerable and are safe. Some foods or food-derived substances (green bananas, pectins [amylase-resistant starch], zinc) lessen the amount and/or duration of diarrhea in children. Unabsorbed amylase-resistant starches are metabolized in the colon to short-chain fatty acids that enhance fluid absorption. Zinc supplementation (20 mg of elemental zinc orally once a day) is effective in preventing recurrences of diarrhea in malnourished children. Copper deficiency is a potential complication of prolonged zinc therapy.

Probiotics are live, nonpathogenic, human microorganisms that provide a health benefit. Level 1 evidence has been reported for the therapeutic use of probiotics. Most species are lactic acid bacteria. Lactobacillus GG (1010 colony-forming units [CFU]/250 mL ORS daily until diarrhea stops) added to an ORS decreases the duration of diarrhea in children with acute diarrhea, particularly with rotavirus infection. Saccharomyces boulardii, lactobacillus GG,[1] and other organisms (Lactobacillus reuteri, Enterococcus faecium, Lactobacillus acidophilus, Streptococcus thermophilus, bifidobacteria) also may be effective in the prevention of antibiotic-associated diarrhea and C. difficile diarrhea in children and adults. Their role in the treatment of acute infectious and antibiotic-associated diarrheas in adults is less clear. Saccaromyces boulardii (500 mg orally two times a day for 30 days) may be effective in preventing recurrent C. difficile infection. Some commercially available probiotic preparations contain dead microorganisms and may not be effective.

Certain infectious diarrheas should be treated with antibiotics, including those associated with shigellosis ( Chapter 330 ), cholera ( Chapter 325 ), pseudomembranous enterocolitis ( Chapter 319 ), parasitic infestations ( Chapter 371 through 373 and 378), and sexually transmitted diseases ( Chapter 307 ). For traveler’s diarrhea, ciprofloxacin (500 mg orally two times a day for 5 days) is an effective treatment. A newly licensed, nonabsorbable antibiotic, rifaximin (200 mg taken orally once a day for 2 weeks), is safe and effective for treatment of traveler’s diarrhea in Mexico, but it may not be effective against Campylobacter and Shigella infections, so fluoroquinolones remain the first line of treatment for traveler’s diarrhea. Antibiotics are not usually indicated in case of viral diarrhea or cryptosporidiosis, because they are not effective. Treatment of E. coli serotype O157:H7 infection is not recommended at present, because current antibiotics do not seem to be helpful, and the incidence of complications (hemolytic-uremic syndrome) may be greater after antibiotic therapy. Regardless of the cause of infectious diarrhea, patients should be treated if they are immunosuppressed; have valvular, vascular, or orthopedic prostheses; have congenital hemolytic anemias (especially if salmonellosis is involved); or are extremely young or old.

While the clinician is awaiting stool culture results to guide specific therapy ( Chapter 309 ), the fluoroquinolones (e.g., ciprofloxacin 500 mg orally two times a day for 5 days) are the treatment of choice. Trimethoprim-sulfamethoxazole is second-line therapy. If the symptom complex suggests Campylobacter infection, azithromycin (500 mg orally one time a day for 3 days) should be added. If C. difficile is suspected on an epidemiologic basis, metronidazole (250 mg orally four times a day or 500 mg orally three times a day for 10 days) should be prescribed. Fluoroquinolone-resistant and trimethoprim-sulfamethoxazole–resistant strains of Shigella, E. coli, Salmonella, Campylobacter, and C. difficile have emerged. Azithromycin, 500 mg orally on day 1 and 250 mg orally one time a day for 4 days, may be an effective alternative treatment for resistant strains of Shigella and Campylobacter and for traveler’s diarrhea acquired in Mexico.


Travelers should be vigilant in avoiding ingestion of contaminated food or water. An oral cholera vaccine against recombinant toxin B subunit and killed whole-cell (rBS-WC) is effective in preventing infection from the O1 El Tor strain and partially effective against enterotoxigenic E. coli strains.[2] Cholera vaccination is recommended for relief workers and health professionals who work in endemic countries and for individuals who are immunocompromised or have chronic illnesses or hypochlorhydria. Rifaximin (200 mg orally per day for 2 weeks) is safe and effective for preventing traveler’s diarrhea in Mexico, [3] and the combination of rifaximin plus loperamide is better than either one alone.[4] Bismuth subsalicylate (525 mg orally four times a day for up to 3 weeks) is also effective.

Nosocomial Hospital Diarrheas

Diarrhea is either the first or the second most common nosocomial illness among hospitalized patients and residents in long-term care facilities. Fecal impaction and medications are common causes. Magnesium-containing laxatives and antacids, sulfate and phosphate laxatives, and lactulose cause osmotic diarrheas. Colchicine, neomycin, para-aminosalicylic acid, and cholestyramine damage the enterocyte and/or bind bile salts, resulting in malabsorption. Radiation therapy and drugs such as gold cause intestinal inflammation and diarrhea. Liquid formulations of any medication can cause diarrhea (elixir diarrhea) because of the high content of sorbitol used to sweeten the elixir. Patients prescribed liquid medications through feeding tubes may receive more than 20 g of sorbitol daily. An important but poorly understood cause of diarrhea is enteral (tube) feeding ( Chapter 235 ), particularly in critically ill patients, who often develop diarrhea. Dysmotility, increased intestinal permeability, and low sodium content in enteral formulas may be contributing factors. The diarrhea often can be managed with pectin or, if there are no contraindications, with loperamide, and diarrhea is not a reason to stop tube feeding unless stool volumes exceed 1 L/day.

Patients in mental institutions and nursing homes have high incidences of nosocomial infectious diarrheas (e.g., hemorrhagic E. coli, C. difficile). Infectious diarrhea (mostly caused by C. difficile) is also common in acute-care hospitals, accounting for more than 20% of nosocomial infections and being second only to respiratory infections on pediatric wards and in intensive care units. Severe C. difficile infection has also been reported in the community and among peripartum women. The likelihood of a nosocomial infection caused by Salmonella, Shigella, or parasites in the hospital is now so low that routine evaluation for these agents is not indicated except in patients with neutropenia, HIV infection, or signs of enteric infection. Immunosuppressed patients are susceptible to nosocomial diarrhea, especially viral infections (rotavirus, astrovirus, adenovirus, and coxsackievirus).

The incidence of acute, mild diarrhea with cancer chemotherapy or radiation therapy is high, approaching 100% with some agents, such as amsacrine, azacitidine, cytarabine, dactinomycin, daunorubicin, doxorubicin, floxuridine, 5-fluorouracil, 6-mercaptopurine, methotrexate, plicamycin, and irinotecan (CPT-11). IL-2 therapy, resveratrol, and the combination of 5-fluorouracil plus leucovorin are frequent causes of severe watery diarrhea. Current treatment for chemotherapy-induced and radiation-induced diarrhea is symptomatic and includes loperamide (2 mg orally four times a day) and nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., naproxen 250 to 500 mg orally twice daily). In patients with severe diarrhea, octreotide may be an effective treatment.

Runner’s Diarrhea

Gastrointestinal disturbances including anorexia, heartburn, nausea, vomiting, cramps, urgency, and diarrhea occur in 10 to 25% of persons who exercise vigorously, particularly women marathon runners and triathletes. The pathophysiology in runner’s diarrhea is unclear but may involve release of intestinal secretogogues or hormones by ischemia. Loperamide and NSAIDs are taken prophylactically by many runners, but it is not clear whether they are effective.


The goal in evaluating a patient with chronic diarrhea is to make a definitive diagnosis as quickly and inexpensively as possible ( Fig. 143-3 ). In 25 to 50% of cases, expert history and physical examination may be sufficient. The addition of stool culture and examination for ova and parasites, determination of stool fat, and flexible sigmoidoscopy with biopsy raises the diagnostic rate to about 75%. The remaining 25% of patients with severe or elusive chronic diarrhea may need extensive testing and perhaps hospitalization.

FIGURE 143-3  Approach to the evaluation of chronic diarrhea. CBC = complete blood count; FOBT = fecal occult blood test; O&P = ova and parasites; WBCs = white blood cells.  (Adapted from Powell DW: Approach to the patient with diarrhea. In Yamada T, Alpers DH, Owyang C, et al [eds]: Textbook of Gastroenterology, 3rd ed. Philadelphia, Lippincott-Raven, 1999.)

   Prolonged, Persistent, and Protracted Infectious Diarrheas

Stool culture and examination may detect organisms that often cause protracted infectious diarrhea in adults: enteropathogenic (enteroadherent) E. coli, Giardia, Entamoeba, Cryptosporidium, Aeromonas, and Yersinia enterocolitica. If none of these organisms is found, a therapeutic trial of metronidazole or trimethoprim-sulfamethoxazole may be indicated. Persistent infectious diarrhea lasting longer than 3 to 4 weeks occurs in 3% of returned travelers; if trimethoprim-sulfamethoxazole or the fluoroquinolones have been unsuccessful, tetracycline or metronidazole should be tried.

After documented infectious diarrhea, 25% of patients experience pain, bloating, urgency, a sense of incomplete evacuation, and loose stools for 6 months or longer. This syndrome of infectious diarrhea–induced irritable bowel syndrome, also called Brainerd’s diarrhea if it is particularly prolonged and accompanied by severe diarrhea, is initiated by unidentified organisms. Some patients respond to cholestyramine. Celiac disease also may manifest after intestinal infections, so patients should be screened for it in this setting.

Visitors who reside in the tropics for 1 to 3 months may develop tropical sprue (see later discussion). A severe postinfectious diarrhea syndrome (severe protracted diarrhea) may develop in infants and children in developing nations and can occur in milder forms (postenteritis syndrome) in infants and children in developed countries. Malnutrition and death (mortality rate, 50%) can occur with severe disease. Treatment includes dietary lactose exclusion in mild disease or total parenteral nutrition for severely affected patients. Metronidazole, tetracycline, trimethoprim-sulfamethoxazole, folic acid, and zinc therapy also may help.

   Malabsorptive Syndromes

Malabsorption is caused by many different diseases, drugs, or nutritional products that impair intraluminal digestion, mucosal absorption, or nutrient delivery to the systemic circulation ( Fig. 143-4 ; Tables 143-3 and 143-4 [3] [4]). Dietary fat is the nutrient most difficult to absorb. Fat is predominantly insoluble in the aqueous milieu of the intestine and critically depends on all phases of digestion, absorption, and delivery for its assimilation. Steatorrhea (excess fat in the stool) is the hallmark of malabsorption; a stool test for fat is the best screening test for malabsorption. Malabsorption does not always cause diarrhea. Clinical signs of vitamin or mineral deficiencies may occur in the absence of diarrhea ( Table 143-5 ). A careful history is crucial in guiding further testing to confirm the suspicion of malabsorption and to make a specific diagnosis (see Fig. 143-4 ). The goals of treatment are to correct or treat the underlying disease and to replenish water, electrolyte, and nutritional losses.

FIGURE 143-4  Approach to the diagnosis of malabsorption.

TABLE 143-3   — 

Mechanism of Malabsorption Conditions
Impaired mixing Partial gastrectomy with gastrojejunostomy
Gastric bypass surgery
Impaired lipolysis Chronic pancreatitis
Pancreatic cancer
Congenital pancreatic insufficiency
Congenital colipase deficiency
Impaired micelle formation Severe chronic liver disease
Cholestatic liver disease
Bacterial overgrowth
Crohn’s disease
Ileal resection
Impaired mucosal absorption Congenital, primary, and secondary lactase deficiency
Congenital enterokinase deficiency
Celiac disease
Tropical sprue
AIDS-related (infections, enteropathy)
Radiation enteritis
Graft-versus-host disease
Whipple’s disease
Eosinophilic gastroenteritis
Megaloblastic gut
Collagenous sprue
Ulcerative jejunitis
Bacterial overgrowth
Short-bowel syndrome
Impaired nutrient delivery Congenital intestinal lymphangiectasia
Constrictive pericarditis
Severe congestive heart failure
Unknown Hypoparathyroidism
Adrenal insufficiency
Carcinoid syndrome

AIDS = acquired immunodeficiency syndrome.

TABLE 143-4   — 

Drug Mechanism Nutrient Malabsorbed
Cholestyramine Bile salt binder Iron and cobalamin
High fiber, phytates Chelator Iron, calcium, magnesium
Tetracycline Chelator Calcium
Antacids Chelator Calcium, phosphate
Olestra Nonabsorbable fat (lipophilic) Fat-soluble vitamins
Orlistat Lipase inhibitor Fat, fat-soluble vitamins
Metformin ?? Glucose, cobalamin, folate
Acarbose Competitive inhibitor of intestinal α-glucosidases Carbohydrate
Colchicine ?Altered membrane trafficking Carbohydrate, fat, cobalamin
Neomycin Inhibitor of protein synthesis, binds bile salts Carbohydrate, fat, protein
Methotrexate Villus blunting Carbohydrate, fat, protein
Phenytoin Decreases folate absorption Folate
Sulfasalazine Inhibits folate hydrolase, ?inhibits folate transporter Folate

TABLE 143-5   — 

Nutrient Malabsorbed Clinical Manifestation
Protein Wasting, edema
Carbohydrate and fat Diarrhea, abdominal cramps and bloating, weight loss/growth retardation
Fluid and electrolytes Diarrhea, dehydration
Iron Anemia, cheilosis, angular stomatitis
Calcium/vitamin D Bone pain, fractures, tetany
Magnesium Paresthesias, tetany
Vitamin B12/folate Anemia, glositis, cheilosis, paresthesias, ataxia (vitamin B12 only)
Vitamin E Paresthesias, ataxia, retinopathy
Vitamin A Night blindness, xerophthalmia, hyperkeratosis, diarrhea
Vitamin K Ecchymoses
Riboflavin Angular stomatitis, cheilosis
Zinc Dermatitis, hypogeusia, diarrhea
Selenium Cardiomyopathy
Essential fatty acids Dermatitis
   Conditions That Impair Intraluminal Digestion

Most digestion and absorption of nutrients occurs in the small intestine ( Fig. 143-5 ). Pancreatic proteases (trypsinogen, chymotrypsinogen, proelastase, and procarboxypeptidases) are secreted from acinar cells in inactive forms. The cleavage of trypsinogen to trypsin by the duodenal brush-border peptidase enteropeptidase (enterokinase) allows trypsin to cleave the remaining trypsinogen and other proteases to their active form. Neutralization of acid in the small intestinal lumen by bicarbonate secreted from pancreatic duct cells is physiologically important because pancreatic enzyme activity and bile salt micelle formation is optimal at a luminal pH of 6 to 8.

FIGURE 143-5  Phases of intestinal digestion and absorption of dietary fat, protein, and carbohydrate. a.a. = amino acids; ApoB, A = apolipoproteins B and A; Chol = cholesterol; FA = fatty acids; MG = monoglycerides; TG = triglycerides.

Carbohydrates and most dietary proteins are water soluble and readily digested by pancreatic enzymes. Most dietary lipids (long-chain triglycerides, cholesterol, phosphatidylcholine [lecithin], and fat-soluble vitamins) are water insoluble and must undergo lipolysis and incorporation into mixed micelles before they can be absorbed across the intestinal mucosa. Pancreatic lipase, in the presence of its cofactor, colipase, cleaves long-chain triglycerides into fatty acids and monoglycerides. The products of lipolysis interact with bile salts and phospholipids to form mixed micelles, which also incorporate cholesterol and fat-soluble vitamins (D, A, K, and E) in their hydrophobic centers.

   Impaired Mixing

Surgical alterations, such as partial gastrectomy with gastrojejunostomy (a Billroth II anastomosis) or gastrointestinal bypass surgeries for morbid obesity, result in the release of biliary and pancreatic secretions into the intestine at a site remote from the site of entry of gastric contents into the jejunum. This imbalance can result in impaired lipolysis and impaired micelle formation, with subsequent fat malabsorption. Absorption of iron, calcium, and cobalamin is impaired as well. Rapid transit through the jejunum contributes to the malabsorption of nutrients. Individuals with these conditions also have surgical anastomoses that predispose to bacterial overgrowth.

   Impaired Lipolysis

A deficiency in pancreatic lipase may be caused by the congenital absence of pancreatic lipase or by destruction of the pancreatic gland due to alcohol-related pancreatitis, cystic fibrosis, or pancreatic cancer. Pancreatic lipase also can be denatured by excess secretion of gastric acid (e.g., Zollinger-Ellison syndrome; Chapter 205 ).

   Chronic Pancreatitis

Chronic pancreatitis ( Chapter 147 ) is the most common cause of pancreatic insufficiency and impaired lipolysis. In the United States, chronic pancreatitis most commonly results from alcohol abuse; in contrast, tropical (nutritional) pancreatitis is most common worldwide. Malabsorption of fat does not occur until more than 90% of the pancreas is destroyed.

Clinical Manifestations

Individuals typically present with bulky, fat-laden stools (usually >30 g of fat per day), abdominal pain, and diabetes, although some present with diabetes in the absence of gastrointestinal symptoms. Stools usually are not watery, because undigested triglycerides form large emulsion droplets with little osmotic force and, in contrast to fatty acids, do not stimulate water and electrolyte secretion in the colon. Deficiency of fat-soluble vitamins is seen only rarely, presumably because gastric and residual pancreatic lipase generates enough fatty acids for some micelle formation. Clinical manifestations of carbohydrate and protein malabsorption also are rare in pancreatic insufficiency. In severe disease, subclinical protein malabsorption, manifested by the presence of undigested meat fibers in the stool, and subclinical carbohydrate malabsorption, manifested by gas-filled, floating stools, can occur. Weight loss, when it occurs, is most often caused by decreased oral intake to avoid abdominal pain or diarrhea and less commonly by malabsorption.


Between 30 and 40% of individuals with chronic pancreatitis secondary to alcohol abuse have calcifications on abdominal radiographs. A qualitative or quantitative test for fecal fat is positive in individuals whose pancreas is more than 90% destroyed. Noninvasive tests of pancreatic function are not sensitive enough to detect mild to moderate insufficiency, so the secretin stimulation test is preferred ( Table 143-6 ).

TABLE 143-6   — 

Test Comments
Quantitative stool fat test Gold standard test of fat malabsorption, with which all other tests are compared. Requires ingestion of a high-fat diet (100 g) for 2 days before and during the collection. Stool is collected for 3 days. Normally, <7 g/24 hr is excreted on a high-fat diet. Borderline abnormalities of 8–14 g/24 hr may be seen in secretory or osmotic diarrheas that are not caused by malabsorption. There are false-negative findings if fat intake is inadequate. False-positive results can occur if mineral oil laxatives or rectal suppositories (e.g., cocoa butter) are given to the patient before stool collection.
Qualitative stool fat test Sudan stain of a stool sample for fat. Many fat droplets per medium-power (40×) field constitute a positive test result. The NMR method determines the percentage of fat in the stool (normal, <20%). The test depends on an adequate fat intake (100 g/day). There is high sensitivity (90%) and specificity (90%) with fat malabsorption of >10 g/24 hr. Sensitivity drops with stool fat in the range of 6–10 g/24 hr.
Acid steatocrit Reliable screening test for fat malabsorption that is inexpensive and easy to perform. Centrifugation of acidified stool in a hematocrit capillary yields solid, liquid, and fatty layers. Results are expressed as volumetric percentages (lipid phase on solid phase); normal, <10%. High sensitivity (100%) and specificity (95%) compared with the 72-hr stool quantitative fat test. Depends on adequate fat intake (100 g/day).
D-Xylose test A test of small intestinal mucosal absorption, used to distinguish mucosal malabsorption from malabsorption due to pancreatic insufficiency. An oral dose of D-xylose (25 g/500 mL water) is administered, and D-xylose excretion is measured in a 5-hr urine collection. Normally, >4 g of D-xylose is excreted in the urine over 5 hr. The test also may be positive in bacterial overgrowth owing to metabolism of D-xylose by bacteria in the intestinal lumen. False-positive test results occur with renal failure, ascites, and an incomplete urine collection. Blood levels at 1 and 3 hr improve sensitivity. May be normal with mild or limited mucosal disease.
Hydrogen breath test Most useful in the diagnosis of lactase deficiency. An oral dose of lactose (1 g/kg body weight) is administered after measurement of basal breath H2 levels. The sole source of H2 in the mammal is bacterial fermentation; unabsorbed lactose makes its way to colonic bacteria, resulting in excess breath H2. A late peak (within 3–6 hr) of >20 ppm of exhaled H2 after lactose ingestion suggests lactose malabsorption. Absorption of other carbohydrates (e.g., sucrose, glucose, fructose) also can be tested.
Secretin stimulation test The gold standard test of pancreatic function. Requires duodenal intubation with a double-lumen tube and collection of pancreatic juice in response to IV secretin. Allows measurement of bicarbonate (HCO3-) and pancreatic enzymes. A sensitive test of pancreatic function, but labor intensive and invasive.
Fecal elastase-1 test Stool test for pancreatic function. Equal sensitivity to the secretin stimulation test for the diagnosis of moderate-to-severe pancreatic insufficiency. More specific than the fecal chymotrypsin test. Unreliable with mild insufficiency. False-positive results occur with increased stool volume and intestinal mucosal diseases.
Quantitative culture of small intestinal aspirate Gold standard test for bacterial overgrowth. Greater than 105 colony-forming units (CFU)/mL in the jejunum suggests bacterial overgrowth. Requires special anaerobic sample collection, rapid anaerobic and aerobic plating, and care to avoid oropharyngeal contamination. False-negative results occur with focal jejunal diverticula and when overgrowth is distal to the site aspirated.
Hydrogen breath test The 50-g glucose breath test has a sensitivity of 90% for growth of 105 colonic-type bacteria in the small intestine. If bacterial overgrowth is present, increased H2 is excreted in the breath. An early peak (within 2 hr) of >20 ppm exhaled H2 suggests bacterial overgrowth. False-negative results occur with non–hydrogen-producing organisms.
14C-D-xylose breath test This test uses 1 g of carbon 14–labeled D-xylose. It has a sensitivity and specificity >90% for growth of 105 colonic-type bacteria in the small intestine. Bacteria metabolize D-xylose with release of 14CO2, which is absorbed and exhaled. Non-degraded D-xylose is absorbed in the small bowel and does not reach the colon, yielding a greater specificity than the H2 breath test. A nonradioactive13C-D-xylose breath test is suitable for children and pregnant women.
Small-bowel biopsy Obtained for a specific diagnosis when there is a high index of suspicion for small intestinal disease. Several biopsy specimens (4–5) must be obtained to maximize the diagnostic yield. Distal duodenal biopsy specimens are usually adequate for diagnosis, but occasionally enteroscopy with jejunal biopsy specimens is necessary. Small intestinal biopsy provides a specific diagnosis in some diseases (e.g., intestinal infection, Whipple’s disease, abetalipoproteinemia, agammaglobulinemia, lymphangiectasia, lymphoma, amyloidosis). In other conditions, such as celiac disease and tropical sprue, the biopsy specimens show characteristic findings, but the diagnosis is made on improvement after treatment.
Permeability studies These tests of mucosal integrity are gaining favor as screening tests for small intestinal disease and for monitoring response to treatment. The study is performed by administering an oral dose of nonabsorbable markers (e.g., mannitol/lactulose, lactulose/51Cr-EDTA) and measuring urinary excretion. Currently a research tool.
Schilling test A test of vitamin B12 absorption. Performed as part I, followed by parts II, III, and IV if needed
  Part I: A saturating dose (1 mg IM) of vitamin B12 is given, followed by an oral dose of 0.5–2 μg radioactive cyanocobalamin). Urine is collected for 24 hr because of a poorly understood delay in the passage of cobalamins across ileal cells. Part I is abnormal in all individuals with vitamin B12 deficiency except those with dietary deficiency and food-cobalamin malabsorption.
Part II: The test is repeated with a dose of intrinsic factor. Distinguishes lack of intrinsic factor from other causes of vitamin B12 malabsorption.
Part III: The test is repeated with pancreatic enzymes. Can be used as a test for pancreatic insufficiency. In such individuals, administration of exogenous enzymes frees cyanocobalamin from R-proteins, reverting the Schilling test to normal.
Part IV: The test is repeated with antibiotics. When values for parts I and II are low, bacterial overgrowth can be distinguished from ileal disease by repeating the test after a 5-day course of antibiotics.

51Cr-EDTA = chromium 51–labeled ethylenediamine tetraacetic acid; NMR = nuclear magnetic resonance.

* Not all of these tests are readily available. A strong suspicion for any disease may warrant foregoing an extensive work-up and obtaining the test with highest diagnostic yield. In some cases, empirical treatment, such as removing lactose from the diet of an otherwise healthy individual with lactose intolerance, is warranted without any testing.


Pancreatic enzyme replacement and analgesics are the mainstays of treatment. It is difficult to correct fat malabsorption completely with exogenous pancreatic enzymes because of their inactivation by acid and pepsin in the stomach. Normally, 28,000 U of lipase is present in the duodenal lumen with each meal. A high lipase–containing pancreatic enzyme preparation (25,000 to 40,000 U of lipase in the form of uncoated enzymes or enteric-coated, pH-sensitive microspheres) should be prescribed with each meal. Minimicrosphere preparations (e.g., 20,000 U of lipase taken orally with each meal) may be best tolerated owing to their small capsule size. Pancreatic proteases present in enzyme preparations may reduce abdominal pain by inactivating cholecystokinin (CCK)-releasing factor in the duodenum. Uncoated preparations may be more effective in pain relief, because coated preparations release enzymes predominantly distal to the duodenum. An histamine 2 receptor antagonist (e.g., ranitidine, 150 mg orally taken two times a day) or a proton-pump inhibitor (e.g., Prevacid [lansoprazole], 15 to 30 mg orally once a day) should be added to uncoated pancreatic enzyme replacement therapy in patients with a poor response.

   Impaired Micelle Formation


Bile salt concentrations in the intestinal lumen can fall to less than the critical concentration (2 to 3 mmol/L) needed for micelle formation because of decreased bile salt synthesis (severe liver disease), decreased bile salt delivery (cholestasis), or removal of luminal bile salts (bacterial overgrowth, terminal ileal disease or resection, cholestyramine therapy, acid hypersecretion). Fat malabsorption resulting from impaired micelle formation is generally not as severe as malabsorption resulting from pancreatic lipase deficiency, presumably because fatty acids and monoglycerides can form lamellar structures, which to a certain extent can be absorbed. Malabsorption of fat-soluble vitamins (D, A, K, and E) may be marked, however, because micelle formation is required for their absorption.

Decreased Bile Salt Synthesis and Delivery

Malabsorption can occur in individuals with cholestatic liver disease or bile duct obstruction. The clinical consequences of malabsorption are seen most often in women with primary biliary cirrhosis because of the prolonged nature of the illness. Although these individuals can present with steatorrhea, bone disease is the most common presentation. Osteoporosis is more common than osteomalacia. The cause of bone disease in these patients is poorly understood and often is not related to vitamin D deficiency. Bone disease is treated with calcium supplements (and vitamin D if a deficiency is documented), weight-bearing exercise, and a bisphosphonate (e.g., alendronate 10 mg orally once daily or 70 mg orally once weekly).

Intestinal Bacterial Overgrowth

In health, only small numbers of lactobacilli, enterococci, gram-positive aerobes, or facultative anaerobes can be cultured from the upper small bowel lumen. Motility and acid are the most important factors in keeping the number of bacteria in the upper small bowel low. Any condition that produces local stasis or recirculation of colonic luminal contents allows development of a predominantly “colonic” flora (coliforms and anaerobes, such as Bacteroides and Clostridium) in the small intestine ( Table 143-7 ). Anaerobic bacteria cause impaired micelle formation by releasing cholylamidases, which deconjugate bile salts. The unconjugated bile salts, with their higher pKa, are more likely to be in the protonated form at the normal upper small intestinal pH of 6 to 7 and can be absorbed passively. As a result, the concentration of bile salts decreases in the intestinal lumen and can fall to less than the critical micellar concentration, causing malabsorption of fats and fat-soluble vitamins. Vitamin B12 deficiency and carbohydrate malabsorption also can occur with generalized bacterial overgrowth. Anaerobic bacteria ingest vitamin B12 and release proteases that degrade brush-border disaccharidases. Lactase is the disaccharidase normally present in lowest abundance and is the first affected. Although anaerobic bacteria use vitamin B12, they synthesize folate. Individuals with bacterial overgrowth usually have low serum vitamin B12 levels but normal or high folate levels; this helps distinguish bacterial overgrowth from tropical sprue, in which vitamin B12 and folate levels are usually low because of decreased mucosal uptake.

TABLE 143-7   — 

  Afferent loop dysfunction after gastrojejunostomy
Ileocecal valve resection
Surgical loops (end-to-side intestinal anastomoses)
  Duodenal and jejunal diverticula
Strictures (Crohn’s disease, radiation enteritis)
Adhesions (postsurgical)
Gastrojejunocolic fistulas
Diabetes mellitus
Idiopathic pseudo-obstruction
Atrophic gastritis
Proton-pump inhibitors
Acquired immunodeficiency syndrome
Acid-reducing surgery for peptic ulcer disease
Immunodeficiency states
Chronic renal failure
Clinical Manifestations

Individuals with bacterial overgrowth can present with diarrhea, abdominal cramps, gas and bloating, weight loss, and signs and symptoms of vitamin B12 and fat-soluble vitamin deficiency. Watery diarrhea occurs because of the osmotic load of unabsorbed carbohydrates and stimulation of colonic secretion by unabsorbed fatty acids.


The diagnosis of bacterial overgrowth should be considered in the elderly and in individuals with predisposing underlying disorders (see Table 143-7 ). Bacterial overgrowth may be associated with the irritable bowel syndrome ( Chapter 139 ). The identification of greater than 105 CFU/mL in a culture of small intestinal aspirate remains the gold standard in diagnosis. The noninvasive tests with a sensitivity and specificity comparable to intestinal culture are the glucose hydrogen breath test and the 14C- or 13C-D-xylose breath test; in individuals with low vitamin B12 levels, a Schilling test before and after antibiotic therapy can be diagnostic (see Table 143-6 ).


The goals of treatment are to correct the structural or motility defect, if possible; to eradicate offending bacteria, and to provide nutritional support. Acid-reducing agents should be stopped if possible. Treatment with antibiotics should be based on culture results whenever possible; otherwise, empirical treatment is given. Tetracycline (250 to 500 mg orally four times a day) or a broad-spectrum antibiotic against aerobes and enteric anaerobes (ciprofloxacin, 500 mg orally twice a day; amoxicillin/clavulanic acid, 250 to 500 mg orally three times a day; cephalexin, 250 mg orally four times a day with metronidazole, 250 mg three times a day) should be given for 14 days. The nonabsorbable antibiotic rifaximin (400 mg orally three times a day) is also effective,[5] but less so in individuals with an excluded (blind) intestinal loop. Prokinetic agents such as metoclopramide (10 mg orally four times a day) or erythromycin (250 to 500 mg orally four times a day) can be tried to treat small bowel motility disorders, but often they are not efficacious. Octreotide (50 μg subcutaneously every day) may improve motility and reduce bacterial overgrowth in individuals with scleroderma. If the structural abnormality or motility disturbance cannot be corrected, the patient is at risk for malnutrition and deficiencies of vitamin B12 and fat-soluble vitamins. Cyclic treatment (1 week out of every 4 to 6 weeks) with rotating antibiotics may be required in these patients to prevent recurrent bouts of bacterial overgrowth. If supplemental calories are needed, medium-chain triglycerides should be given, because they are not dependent on micelle formation for their absorption. Monthly treatment with vitamin B12 should be considered, along with supplemental vitamins D, A, K, and E and calcium.

   Ileal Disease or Resection

Disease of the terminal ileum is most commonly due to Crohn’s disease (which also may lead to ileal resection), but it also can be caused by radiation enteritis, tropical sprue, tuberculosis, Yersinia infection, or idiopathic bile salt malabsorption. These diseases cause bile salt wasting in the colon.

The clinical consequences of bile salt malabsorption are related directly to the length of the diseased or resected terminal ileum. In an adult, if less than 100 cm of ileum is diseased or resected, watery diarrhea results because of stimulation of colonic fluid secretion by unabsorbed bile salts. Fat absorption remains normal, because increased bile salt synthesis in the liver compensates for bile salt losses and micelle formation is preserved. Bile acid diarrhea responds to cholestyramine (2 to 4 g taken at breakfast, lunch, and dinner). If more than 100 cm of ileum is diseased or resected, bile salt losses (>3 g/day) in the colon exceed the capacity for increased bile salt synthesis in the liver, the bile salt pool shrinks, and micelle formation is impaired. As a result, steatorrhea ensues, and fatty acid–induced intestinal secretion synergizes with the bile acid–induced secretion to cause diarrhea. Treatment is with a low-fat diet, vitamin B12 (300 to 1000 μg subcutaneously once every month or 2 mg orally once a day), dietary supplements of calcium (500 mg orally two to three times a day, monitor 24-hour urine calcium for adequacy of dose), and a multiple vitamin-mineral supplement. An antimotility agent should be given for diarrhea. Bile salt binders may worsen diarrhea. Screening for fat-soluble vitamin deficiencies (vitamins A and E, 25-(OH) vitamin D, and prothrombin time) and bone disease (bone densitometry, serum calcium, intact parathyroid hormone, 24-hour urine for calcium) should be done.

Three long-term complications of chronic bile salt wasting and fat malabsorption are renal stones, bone disease (osteoporosis and osteomalacia), and gallstones. Oxalate renal stones occur as a consequence of excess free oxalate absorption in the colon. Free oxalate is generated when unabsorbed fatty acids bind luminal calcium, which is then unavailable for binding oxalate. Renal oxalate stones sometimes can be avoided with a low-fat, low-oxalate diet and calcium supplements. Bone disease is caused by impaired micelle formation with a resulting decrease in absorption of vitamin D; year-round sun exposure reduces this complication. Vitamin D (50,000 U orally one to three times a week) and calcium supplements (500 mg orally two to three times a day) should be given to susceptible individuals, but vitamin D levels and serum and urinary calcium must be monitored for response to treatment, because excess vitamin D can be toxic. The mechanism of gallstone formation in these individuals is unclear; pigmented gallstones are most common.

   Conditions That Impair Mucosal Absorption


Nutrients are absorbed along the entire length of the small intestine, with the exception of iron and folate, which are absorbed predominantly in the duodenum and proximal jejunum, and bile salts and cobalamin, which can be absorbed only in the distal ileum. The efficiency of nutrient uptake at the mucosa is influenced by the number of villus absorptive cells, the presence of functional hydrolases and specific nutrient transport proteins on the brush-border membrane, and transit time. Transit time determines the contact time of luminal contents with the brush-border membrane and influences the efficiency of nutrient uptake across the mucosa.

Fatty Acids

Long-chain fatty acids are transported across the microvillus membrane of villus epithelial cells by the fatty acid transport protein FATP4; are resynthesized into triglycerides; and combine with cholesterol ester, fat-soluble vitamins, phospholipid, and apoproteins to form chylomicrons. The bile salts from mixed micelles remain in the intestinal lumen and are absorbed in the distal ileum by sodium-dependent cotransport.

Oligosaccharides and larger oligopeptides (products of pancreatic enzyme digestion), sucrose and lactose, are hydrolyzed further by enzymes present in the brush-border membrane of villus epithelial cells before they are absorbed. Although only sugar monomers (glucose, galactose, fructose) can be taken up at the apical epithelial cell membrane, dipeptides and tripeptides are readily taken into the cell. Defects in amino acid uptake in Hartnup’s disease and cystinuria are characterized by renal and intestinal malabsorption of neutral and basic amino acids. In the intestine, these defects are offset by the absorption of these amino acids as dipeptides and tripeptides.


Water-soluble vitamins are readily absorbed throughout the small intestine. Fat-soluble vitamins, minerals, and cobalamin are more difficult to absorb because of the requirement for micelle formation (vitamins D, A, K, and E), a divalent charge (magnesium, calcium, iron), or selected sites of uptake in the intestine (iron, cobalamin). Calcium is absorbed best in the proximal small intestine by a vitamin D–dependent uptake process. Magnesium from the diet and endogenously secreted magnesium from biliary, gastric, and pancreatic juices are absorbed by the small intestine (throughout its length) by a poorly understood mechanism. Ferrous iron is transported into intestinal epithelial cells by a proton-coupled metal-ion transporter (Nramp2) that has specificity for Fe2+ and other divalent cations (Zn2+, Mn2+, Co2+, Cd2+, Cu2+, Ni2+, and Pb2+). The absorption of calcium and nonheme iron is enhanced by solubilization with hydrochloric acid. Intraluminal compounds such as oxalate, phytates, and long-chain fatty acids bind to calcium and magnesium, decreasing their absorption. Individuals with severe mucosal disease or short-bowel syndrome with high fecal fluid outputs lose magnesium and zinc from endogenous secretions.

Mucosal malabsorption can be caused by specific (usually congenital) brush-border enzyme or nutrient transporter deficiencies or by generalized diseases that damage the small intestinal mucosa or result in surgical resection or bypass of small intestine. The nutrients malabsorbed in these general malabsorptive diseases depend on the site of intestinal injury (proximal, distal, or diffuse) and the severity of damage. The main mechanism of malabsorption in these conditions is a decrease in surface area available for absorption. Some conditions (infection, celiac disease, tropical sprue, food allergies, and graft-versus-host disease [GVHD]) are characterized by intestinal inflammation and villus flattening; others are characterized by ulceration (ulcerative jejunitis, NSAIDs diarrhea), infiltration (amyloidosis), or ischemia (radiation enteritis, mesenteric ischemia).


Folates ( Chapters 170 and 237 ) are both taken in the diet and produced by bacteria in the colon. Deficiency can be caused by poor intake or malabsorption secondary to intestinal disease or drugs. Dietary folates are absorbed in the proximal small intestine. A reduced folate carrier (RFC1), expressed in the small intestine and colon, suggests that folate might be absorbed in the colon and the small intestine.


The cobalamins ( Chapters 170 and 237 ) are high-molecular-weight, water-soluble molecules that contain a porphyrin-like corrin ring with a cobalt atom in its center. The supplemental form contains a cyanide group attached to the cobalt atom; hence the name cyanocobalamin (vitamin B12). The cobalamins are readily abundant in foods containing animal proteins (e.g., meat, seafood, eggs, milk), so cobalamin deficiency in industrialized countries is rarely due to poor dietary intake but rather reflects the inability to absorb cobalamin. This inability may be caused by a lack of intrinsic factor, consumption of cobalamin by overgrowth of anaerobic bacteria in the small bowel lumen, ileal disease or resection, or defective transcobalamin II. Large amounts of cobalamin are present in the liver (2 to 5 mg), and cobalamin is reabsorbed from bile via the enterohepatic circulation, limiting daily losses to only 0.5 to 1 μg. It usually takes 10 to 12 years for cobalamin deficiency to develop after it is eliminated from the diet, but deficiency can occur more rapidly (2 to 5 years) with malabsorptive syndromes. If lack of gastric acid causes food-cobalamin malabsorption, treatment with oral cyanocobalamin is curative.

   Lactase Deficiency


Acquired lactase deficiency is the most common cause of selective carbohydrate malabsorption. Most individuals, except those of northern European descent, begin to lose lactase activity by the age of 2 years. The prevalence of lactase deficiency is highest (85 to 100%) in Asians, blacks, and Native Americans.


The persistence/nonpersistence of lactase activity is associated with a single nucleotide polymorphism C/T-13910 that is found upstream of the lactase gene on chromosome 2q21-22. Hypolactasia is associated with the C/C-13910 genotype in diverse ethnic groups. The mechanism by which this variant downregulates the lactase gene is not known, but functional studies suggest genotype-dependent alterations in levels of messenger RNA.

Clinical Manifestations

Adults with lactase deficiency typically complain of gas, bloating, and diarrhea after the ingestion of milk or dairy products but do not lose weight. Unabsorbed lactose is osmotically active, drawing water followed by ions into the intestinal lumen. On reaching the colon, bacteria metabolize lactose to short-chain fatty acids, carbon dioxide, and hydrogen gas. Short-chain fatty acids are transported with sodium into colonic epithelial cells, facilitating the reabsorption of fluid in the colon. If the colonic capacity for the reabsorption of short-chain fatty acids is exceeded, an osmotic diarrhea results (see later discussion of carbohydrate malabsorption in watery diarrheas).


The diagnosis of acquired lactase deficiency can be made by empirical treatment with a lactose-free diet, which results in resolution of symptoms; by the hydrogen breath test after oral administration of lactose; or by genetic testing. Many intestinal diseases cause secondary reversible lactase deficiency, including viral gastroenteritis, celiac disease, giardiasis, and bacterial overgrowth.

Congenital Enteropeptidase (Enterokinase) Deficiency

Enteropeptidase is a brush-border protease that cleaves trypsinogen to trypsin, triggering the cascade of pancreatic protease activation in the intestinal lumen. The rare congenital deficiency of enteropeptidase results in inability to activate all pancreatic proteases and leads to severe protein malabsorption. It manifests in infancy as diarrhea, growth retardation, and hypoproteinemic edema.


Formation and exocytosis of chylomicrons at the basolateral membrane of intestinal epithelial cells are necessary for the delivery of lipids to the systemic circulation. One of the proteins required for assembly and secretion of chylomicrons is the microsomal triglyceride transfer protein, which is mutated in individuals with abetalipoproteinemia. Children with this disorder have fat malabsorption and the consequences of vitamin E deficiency (retinopathy and spinocerebellar degeneration). Biochemical tests show low plasma levels of apoprotein B, triglyceride, and cholesterol. Membrane lipid abnormalities result in red blood cell acanthosis (burr cells). Intestinal biopsy is diagnostic; the tissue is characterized by engorgement of epithelial cells with lipid droplets. Calories are provided by treatment with a low-fat diet containing medium-chain triglycerides. Medium-chain fatty acids are easily absorbed and released directly into the portal circulation, bypassing the defect of abetalipoproteinemia. Poor absorption of long-chain fatty acids sometimes can result in essential fatty acid deficiency. High doses of fat-soluble vitamins, especially vitamin E, often are needed. Mutations in the apolipoprotein B gene (hypobetalipoproteinemia) and intracellular retention of chylomicrons (Anderson’s disease) cause a similar although less severe clinical syndrome.

   Celiac Disease

Definition and Epidemiology

Celiac disease, also called celiac sprue, nontropical sprue, and gluten-sensitive enteropathy, is an inflammatory condition of the small intestine precipitated by the ingestion of wheat, rye, and barley in individuals with certain genetic predispositions. Screening studies for the antigliadin (AGA), antiendomysial (EMA), and anti-tissue transglutaminase (anti-tTG) antibodies that are associated with celiac disease suggest a prevalence in Caucasian populations of about 1%, with the highest prevalence in Northern Ireland. High-risk groups for celiac disease include first-degree relatives and individuals with type I diabetes mellitus, autoimmune thyroid disease, primary biliary cirrhosis, Turner’s syndrome, and Down syndrome. About 10% of patients diagnosed with irritable bowel syndrome or with microscopic (lymphocytic) colitis have celiac disease.


Environmental and genetic factors are important in the development of celiac disease. The alcohol-soluble protein fraction of wheat gluten, the gliadins, and similar prolamins in rye and barley trigger intestinal inflammation in susceptible individuals. Oat grains, which have prolamins rich in glutamine but not proline, are rarely toxic. Gliadins and similar prolamins with high proline content are relatively resistant to digestion by human proteases. A 33-mer peptide that is a natural digestion product of α2-gliadin may be important in the pathogenesis of celiac disease. This peptide resists terminal digestion by intestinal brush-border proteases and contains three previously identified antigenic epitopes. It also reacts with tissue transglutaminase and stimulates human leukocyte antigen (HLA) DQ2–restricted intestinal T-cell clones from individuals with celiac disease.

Approximately 15% of first-degree relatives of affected individuals are found to have celiac disease. Predisposition to gluten sensitivity has been mapped to the HLA-D region on chromosome 6. More than 90% of individuals with celiac disease have the DQ2 heterodimer encoded by alleles DQA1★0501 and DQB1★0201, compared with 20 to 30% of controls. A smaller celiac group carries HLA DQ8. Genome-wide searches support a strong susceptibility locus for celiac disease in the HLA-D region. Non-HLA loci have been suggested but not yet identified. The DQ2 protein expressed on antigen-presenting cells has positively charged binding pockets; tTG (the autoantigen recognized by EMA) may enhance intestinal inflammation by deamidation of select glutamine residues in gliadin to negatively charged glutamic acid. In the deamidated form, most gliadin peptides have a higher binding affinity for DQ2 and are more potent stimulants of gluten-sensitized T cells. Villous atrophy may be caused by inflammation that is triggered by γ-interferon released from DQ2- or DQ8-restricted CD4 T cells in the lamina propria. Alternatively, intraepithelial lymphocytes may directly kill intestinal epithelial cells under the influence of IL-15 released from stressed enterocytes.

Clinical Manifestations

Celiac disease usually manifests early in life at about 2 years of age (after wheat has been introduced into the diet) or later in the second to fourth decades of life, but it can occur at any age. Breast-feeding and the time of introduction of wheat in the diet (4 to 6 months of age) may lessen the risk or delay the onset of celiac disease in children at risk. About half of adults with celiac disease in the United States present with anemia or osteoporosis without diarrhea or other gastrointestinal symptoms. These individuals most likely have proximal disease that impairs iron, folate, and calcium absorption but an adequate surface area in the remaining intestine for absorption of other nutrients. Other extraintestinal manifestations of celiac disease include rash (dermatitis herpetiformis), neurologic disorders (peripheral neuropathy, ataxia, epilepsy), psychiatric disorders (depression, paranoia), reproductive disorders (infertility, spontaneous abortion), short stature, dental enamel hypoplasia, chronic hepatitis, or cardiomyopathy.

Individuals with significant mucosal involvement present with watery diarrhea, weight loss or growth retardation, and the clinical manifestations of vitamin and mineral deficiencies (see Table 143-5 ). All nutrients, most notably carbohydrate, fat, protein, electrolytes, fat-soluble vitamins, calcium, magnesium, iron, folate, and zinc, are malabsorbed. Cobalamin deficiency is more common (10% of patients) than previously thought and usually corrects itself on a gluten-free diet. Symptomatic individuals require supplementation of vitamin B12. Diarrhea is caused by many mechanisms, including a decreased surface area for water and electrolyte absorption, the osmotic effect of unabsorbed luminal nutrients, an increased surface area for chloride secretion (crypt hyperplasia), and the stimulation of intestinal fluid secretion by inflammatory mediators and unabsorbed fatty acids. Some individuals have impaired pancreatic enzyme secretion caused by decreased mucosal cholecystokinin release or bacterial overgrowth that may contribute to diarrhea.


The diagnosis of celiac disease is made by characteristic changes found on a small intestinal biopsy specimen and improvement when a gluten-free diet is instituted (Figs. 143-6 and 143-7 [6] [7]). Mucosal flattening may be observed endoscopically as reduced duodenal folds or duodenal scalloping. Characteristic features found on intestinal biopsy include the absence of villi, crypt hyperplasia, increased intraepithelial lymphocytes, and infiltration of the lamina propria with plasma cells and lymphocytes. In some individuals, the only abnormal biopsy finding is increased intraepithelial lymphocytes.

FIGURE 143-6  Intestinal biopsy appearance of flattened villi, hyperplastic crypts, and increased intraepithelial lymphocytes.  (Courtesy of John Hart, MD.)

FIGURE 143-7  Regeneration of villi after initiation of a gluten-free diet.  (Courtesy of John Hart, MD.)

Serologic markers for celiac disease are useful in supporting the diagnosis, in screening first-degree relatives, and in monitoring the response to a gluten-free diet. AGA immunoglobulin A (IgA) and IgG antibodies are sensitive but not specific and should not be used for screening of adults. EMA IgA antibodies, detected by indirect immunofluorescence, are highly sensitive (90%) and specific (90 to 100%) for active celiac disease in skilled laboratory testing. An enzyme-linked immunosorbent assay (ELISA) test to detect antibodies against tTG has equal sensitivity to the EMA test and is less operator dependent. Anti-tTG and EMA IgA antibodies tests are negative in individuals with selective IgA deficiency (present in up to 2.6% of individuals with celiac disease). In these patients, anti-tTG IgG antibodies may be helpful in diagnosis. A new dot blot assay against recombinant human tTG reacts to IgA and IgG antibodies, increasing the specificity to almost 100%. Patients with mild disease may have negative antibody studies. In equivocal cases (negative serology and equivocal biopsy or positive serology and normal biopsy), HLA genotyping is useful to exclude the diagnosis of celiac disease in those who lack the DQ2 or DQ8 gene.


Treatment consists of a lifelong gluten-free diet. Wheat, rye, and barley grains should be excluded from the diet. Rice and corn grains are tolerated. Oats (if not contaminated by wheat grain) are tolerated by most. Early referral to a celiac support group is often helpful in maintaining dietary compliance. Owing to secondary lactase deficiency, a lactose-free diet should be recommended until symptoms improve. All individuals with celiac disease should be screened for vitamin and mineral deficiencies and have bone densitometry performed. Of individuals with celiac disease, 70% have osteopenia. Documented deficiencies of vitamins and minerals should be replenished ( Table 143-8 ), and women of childbearing age should take folic acid supplements.

TABLE 143-8   — 

Vitamin Oral Dose Parenteral Dose
Vitamin A[*] Water-soluble A, 25,000 U/day[]  
Vitamin E Water-soluble E, 400–800 U/day[]
Vitamin D[] 25,000–50,000 U/day
Vitamin K 5 mg/day
Folic acid 1 mg/day
Calcium[§] 1500–2000 mg elemental calcium/day  
Calcium citrate, 500 mg calcium/tablet[]
Calcium carbonate, 500 mg calcium/tablet[]
Magnesium Liquid magnesium gluconate[] 2 mL of a 50% solution (8 mEq) both buttocks IM
1–3 tbsp (12–36 mEq magnesium) in 1–2 L of ORS or sports drink sipped throughout the day
Magnesium chloride hexahydrate[] 100–600 mg elemental magnesium/day
Zinc Zinc gluconate[]  
20–50 mg elemental zinc/day   
Iron 150–300 mg elemental iron/day Iron sucrose[#]
Polysaccharide-iron complex[] Sodium ferric gluconate complex[#]
Iron sulfate or gluconate Iron dextran (as calculated for anemia (IV or IM; Chapter 163 )[]
B-complex vitamins 1 megadose tablet/day  
Vitamin B12 2 mg/day 1 mg IM or SC/mo[**]

ORS = oral rehydration solution.

* Monitor serum vitamin A level to avoid toxicity, especially in patients with hypertriglyceridemia.
Form best absorbed or with least side effects.
Monitor serum calcium and 25-OH vitamin D levels to avoid toxicity.
§ Monitor 24-hr urine calcium to assess adequacy of dose.
If intestinal output is high, additional zinc should be given. Monitor for copper deficiency with high doses.
Parenteral therapy should be given in a supervised outpatient setting because of the risk of fatal reactions.
# Decreased risk of fatal reactions when compared with iron dextran.
** For vitamin B12 deficiency, 1 mg IM or SC twice a week for 4 wk, then once a month.


Of patients with celiac disease treated with a gluten-free diet, 90% experience symptomatic improvement within 2 weeks. The most common cause of a poor dietary response is continued ingestion of gluten. Other possibilities include a missed diagnosis (intestinal infection, agammaglobulinemia), bacterial overgrowth, pancreatic insufficiency, microscopic colitis, or other food allergies (cow’s milk, soy protein). For a small percentage of patients on a strict gluten-free diet, enteropathy persists and no other diagnosis is found; this is so-called refractory sprue. Rarely, collagen deposition is found beneath the surface epithelium (collagenous sprue), or a hypoplastic mucosa shows villus and crypt atrophy. Some patients have antienterocyte antibodies indicative of autoimmune enteritis. Others have ulcerative jejunitis or a monoclonal population of intraepithelial T cells with an aberrant phenotype or clonal T-cell receptor-γ gene rearrangements predictive of enteropathy-associated T-cell lymphoma. Although patients with collagenous sprue or autoimmune enteritis may respond to steroid treatment, a hypoplastic mucosa indicates irreversible (end-stage) intestinal disease. Individuals with celiac disease are at increased risk for intestinal T-cell lymphoma, gastrointestinal tract carcinomas (small bowel adenocarcinoma, esophageal and oropharyngeal squamous carcinomas), and increased mortality; a strict gluten-free diet for life may lessen these risks. Intestinal lymphoma should be suspected in individuals who have abdominal pain, recurrence of symptoms after initial response to a gluten-free diet, or refractory sprue.

   Tropical Sprue

Tropical sprue is an inflammatory disease of the small intestine associated with the overgrowth of predominantly coliform bacteria. It occurs in residents or travelers to the tropics, especially India and Southeast Asia. Individuals classically present with diarrhea and megaloblastic anemia secondary to vitamin B12 and folate deficiency, but some have anemia only. Intestinal biopsy characteristically shows subtotal and patchy villus atrophy in the proximal and distal small intestine, which may be caused by the effect of bacterial toxins on gut structure or by the secondary effects of vitamin B12 deficiency on the gut (megaloblastic gut). Diagnosis is based on history, documentation of vitamin B12 and/or folate deficiency, and the presence of an abnormal small intestinal biopsy report. Treatment is a prolonged course of broad-spectrum antibiotics, oral folate, and vitamin B12 injections until symptoms resolve. Relapses occur mainly in natives of the tropics.


   Giardia lamblia

Giardia lamblia infection, the most common protozoal infection in the United States, can cause malabsorption in individuals infected with many trophozoites, especially the immunocompromised or IgA-deficient hosts. Malabsorption occurs when many organisms cover the epithelium and cause mucosal inflammation, which results in villus flattening and a decrease in absorptive surface area. Stool for ova and parasites at this stage of infection is often negative because of the attachment of organisms in the proximal small intestine. Diagnosis can be made by a stool antigen-capture ELISA test but may require duodenal aspiration and biopsies.

   Human Immunodeficiency Virus

Diarrhea, malabsorption, and wasting are common in individuals with AIDS but are seen less frequently with improved antiretroviral therapy ( Chapter 413 ). Malabsorption is usually due to infection with cryptosporidia, Mycobacterium avium-intracellulare complex, Isospora belli, or microsporidia. An organism can be identified by stool examination or intestinal biopsy about 50% of the time. AIDS enteropathy (a term used if no organism is identified) also can cause malabsorption. Mechanisms of malabsorption and diarrhea include villus atrophy, increased intestinal permeability, rapid small bowel transit (in patients with protozoal infection), and ultrastructural damage of enterocytes (in AIDS enteropathy). Among individuals with AIDS and diarrhea, results of fecal fat and D-xylose absorption are frequently abnormal. Serum albumin, vitamin B12, and zinc levels are often low. Low serum levels of vitamin B12 also have been reported in HIV-infected individuals without AIDS. Vitamin B12 deficiency is caused mainly by ileal disease, but low intrinsic factor (IF) and decreased transcobalamin (TC) II may be contributing factors. Management of malabsorption should focus on restoring the immune system by treating the underlying HIV infection with antiviral therapy. If possible, the offending organism should be treated with antibiotics. If the organism cannot be eradicated, chronic diarrhea and malabsorption result; treatment in these cases consists of antimotility agents and a lactose-free, low-fat diet. Pancreatic enzyme replacement therapy can be tried in HIV-infected individuals who are taking highly active antiretroviral therapy or nucleoside analogues and who have fat malabsorption of obscure origin. If supplemental calories are needed, liquid oral supplements that are predigested and high in medium-chain triglycerides (semi-elemental) are tolerated best. Vitamin and mineral deficiencies should be screened for and treated.

   Whipple’s Disease

Whipple’s disease, a rare cause of malabsorption, manifests with gastrointestinal complaints in association with systemic symptoms, such as fever, joint pain, or neurologic manifestations. About one third of patients have cardiac involvement, most commonly culture-negative endocarditis. Occasionally, individuals present with ocular or neurologic disease without gastrointestinal symptoms. Men are affected more commonly than women, particularly white men. The organism responsible for causing Whipple’s disease is a gram-positive actinomycete, Tropheryma whippelii. The epidemiology and pathogenesis of Whipple’s disease are poorly understood. The prevalence of the disease is higher in farmers compared with other workers, which suggests that the organism lives in the soil. Using the polymerase chain reaction, T. whippelii has been detected in sewage and in duodenal biopsy specimens, gastric juice, saliva, and stool of individuals without clinical disease. Whether the latter represents a carrier state or the presence of nonpathogenic organisms is not known. Immunologic defects and an association with the HLA-B27 gene may be disease factors. Small intestinal biopsy shows villus blunting and infiltration of the lamina propria with large macrophages that stain positive with the periodic acid–Schiff method and are filled with the organism. It is important to distinguish these macrophages from macrophages infected with M. avium-intracellulare complex, which stain positive on acid-fast staining and are found in individuals with AIDS. Treatment is with a prolonged course of broad-spectrum antibiotics (e.g., parenteral penicillin G 1.2 U every day and streptomycin 1.0 g every day for 10 to 14 days, plus 160 mg of trimethoprim and 800 of sulfamethoxazole orally two times a day for 1 year or 160 mg of trimethoprim and 800 of sulfamethoxazole orally two times a day for 1 year). Relapses are common, but initial treatment with parenteral penicillin and streptomycin may lessen the relapse rate.

   Graft-versus-Host Disease

Diarrhea occurs frequently after allogeneic bone marrow or stem cell transplantation. Immediately after transplantation, diarrhea is caused by the toxic effects of cytoreductive therapy on the intestinal epithelium. At 20 to 100 days after transplantation, diarrhea is usually due to GVHD or infection. Patients with GVHD present clinically with a skin rash, buccal mucositis, anorexia, nausea, vomiting, abdominal cramps, and diarrhea. The diagnosis of GVHD in the gastrointestinal tract can be made on biopsy of the stomach, small intestine, or colon. In mild cases, the mucosa appears normal on inspection at endoscopy, but apoptosis of gastric gland or crypt cells can be found on biopsy. In severe cases, denudation of the intestinal epithelium results in diarrhea and malabsorption and often requires parenteral nutritional support. Octreotide (50 to 250 μg subcutaneously three times a day) may be helpful in controlling voluminous diarrhea. Treatment of GVHD is with steroids and antithymocyte globulin combined with parenteral nutritional support until intestinal function returns.

   Short-Bowel Syndrome

Malabsorption caused by small bowel resection or surgical bypass is called the short-bowel syndrome. The most common causes in the United States are Crohn’s disease, radiation enteritis, and mesenteric ischemia, but massive resection due to adhesions, volvulus, or ischemia after intra-abdominal surgery or gastric bypass surgery are increasingly common causes. The severity of malabsorption depends on the site and extent of resection, the capacity for bowel adaptation, and the function of the residual bowel. Adaptive changes to enhance absorption in the remaining bowel include hyperplasia, dilation, and elongation. Mechanisms of malabsorption after small bowel resection include a decreased absorptive surface area, decreased luminal bile salt concentration, rapid transit, and bacterial overgrowth. Limited jejunal resection usually is tolerated best, because bile salt and vitamin B12 absorption remain normal. Ileal resection is less well tolerated because of the consequences of bile salt-wasting and the limited capacity of the jejunum to undergo adaptive hyperplasia.

When fewer than 100 cm of jejunum remain, the colon takes on an important role in caloric salvage and fluid reabsorption. Malabsorbed carbohydrates are digested by colonic bacteria to short-chain fatty acids, which are absorbed in the colon. Parenteral nutrition may be avoided by a diet rich in complex carbohydrates, ORS, and an antimotility agent. In comparison, individuals with fewer than 100 cm of jejunum and no colon have high jejunostomy outputs and often require intravenous fluids or parenteral nutrition to survive. These individuals waste sodium, chloride, bicarbonate, magnesium, zinc, and water in their ostomy effluent. Dietary modifications should include a high-salt, nutrient-rich diet given in small meals. An ORS with a sodium concentration greater than 90 mmol/L is absorbed best. Oral vitamin and mineral doses higher than the usual U.S. recommended daily allowances are required (see Table 143-8 ). Vitamin B12 should be given parenterally. Magnesium deficiencies are often difficult to replenish with oral magnesium because of its osmotic effect in the intestinal lumen. A liquid magnesium preparation added to an ORS and sipped throughout the day may minimize magnesium-induced fluid losses. Potent antimotility agents, such as tincture of opium, often are needed to slow transit and maximize contact time for nutrient absorption. High-volume jejunostomy outputs can be lessened by inhibiting endogenous secretions with a proton-pump inhibitor and, in severe cases, octreotide. The benefit of octreotide may be offset by its potential to inhibit intestinal adaptation and impair pancreatic enzyme secretion with doses greater than 300 μg/day. In the most severe cases, supplemental calories must be provided by nocturnal tube feeding or parenteral nutrition. Treatment with growth hormone (0.1 mg/kg/day subcutaneously) with or without glutamine (30 g once a day orally) for 4 weeks may reduce parenteral nutrition requirements in patients who have had massive intestinal resections.[1] A glucagon-like peptide 2 analogue that stimulates adaptive hyperplasia in remnant intestine after resection is in clinical trials. Long-term complications include bone disease, renal stones (oxalate stones if the colon is present, urate stones with a jejunostomy), gallstones, bacterial overgrowth, fat-soluble vitamin deficiencies, essential fatty acid deficiency, and D-lactic acidosis. Small bowel transplantation should be considered for individuals who require parenteral nutrition to survive and then develop liver disease or venous access problems.

   Conditions That Impair Nutrient Delivery to the Systemic Circulation

Insoluble lipids (present in chylomicrons) are exocytosed across the basolateral membrane of epithelial cells into the intestinal lymphatics. From there, they enter the mesenteric lymphatics and the general circulation via the thoracic duct. Sugar monomers, amino acids, and medium-chain fatty acids are transported across the basolateral membrane of intestinal epithelial cells into capillaries and into the portal circulation. Sugar monomers are transported across the basolateral membrane by the facilitative glucose transporter isoform (GLUT2) and amino acids by facilitative amino acid carriers (see Fig. 143-1A ).

   Impaired Lymphatic Drainage

Diseases that cause intestinal lymphatic obstruction, such as primary congenital lymphangiectasia (malunion of intestinal lymphatics), and diseases that result in secondary lymphangiectasia (lymphoma, tuberculosis, Kaposi’s sarcoma, retroperitoneal fibrosis, constrictive pericarditis, severe heart failure) result in fat malabsorption. The increased pressure in the intestinal lymphatics leads to leakage and sometimes rupture of lymph into the intestinal lumen, with the loss of lipids, gamma globulins, albumin, and lymphocytes. The diagnosis of lymphangiectasia can be made by intestinal biopsy, but the specific cause may be more difficult to identify. Individuals with lymphangiectasia malabsorb fat and fat-soluble vitamins and have protein loss into the intestinal lumen. The most common presentation is hypoproteinemic edema. Nutritional management includes a low-fat diet and supplementation with medium-chain triglycerides, which are absorbed directly into the portal circulation. Fat-soluble vitamins should be given if deficiencies develop.


See Figures 143-8 and 143-9 [8] [9] for algorithms concerning evaluation of watery diarrheas.

FIGURE 143-8  Approach to the evaluation of watery diarrheas. IBS = irritable bowel syndrome; PE = physical examination.  (Adapted from Powell DW: Approach to the patient with diarrhea. In Yamada T, Alpers DH, Owyang C, et al [eds]: Textbook of Gastroenterology, 3rd ed. Philadelphia, Lippincott-Raven, 1999.)

FIGURE 143-9  Approach to the evaluation of severe or elusive diarrheas. CA = cancer; 5-HIAA = 5-hydroxyindoleacetic acid; IBD = inflammatory bowel disease; VIP = vasoactive intestinal polypeptide; WDHA = watery diarrhea hypokalemia achlorhydria.  (Adapted from Powell DW: Approach to the patient with diarrhea. In Yamada T, Alpers DH, Owyang C, et al [eds]: Textbook of Gastroenterology, 3rd ed. Philadelphia, Lippincott-Raven, 1999.)

   Ingestion of Nonabsorbable Solutes: Magnesium and Sodium Phosphate/Sulfate Diarrheas

Individuals ingesting significant amounts of Mg2+-based antacids or high-potency multimineral/multivitamin supplements and individuals surreptitiously taking Mg2+-containing laxatives or nonabsorbable anion laxatives, such as Na2PO4 (neutral phosphate) or Na2SO4 (Glauber’s or Carlsbad salt), may develop significant osmotically induced, watery diarrhea.

   Carbohydrate Malabsorption

   Sorbitol and Fructose Diarrhea

Chewing gum and elixir diarrhea may result from the chronic ingestion of dietetic foods, candy, chewing gum, or medication elixirs that are sweetened with unabsorbable carbohydrates such as sorbitol. Excessive consumption of pears, prunes, peaches, and apple juice, which also contain sorbitol and fructose, can result in diarrhea. Fructose may be malabsorbed if ingested in high concentrations, and an occasional patient may have diarrhea related to ingestion of large volumes of fruit juice or soft drinks that are sweetened with fructose-containing corn syrup.

   Rapid Intestinal Transit

Approximately 25% of the normal 200-g carbohydrate diet may be unabsorbed by the normal small intestine. When passed into the colon, it is metabolized to osmotically active short-chain fatty acids by colonic flora. Diets that are high in carbohydrate and low in fat may allow rapid gastric emptying and rapid small intestinal motility, leading to carbohydrate malabsorption and osmotic diarrhea. Rapid orocecal transit time also occurs in thyrotoxicosis. Because carbohydrate is metabolized also to H2 and CO2 by colonic bacteria, the symptoms of excess flatus, abdominal bloating, and cramping abdominal pain may be important clues to the diagnosis of carbohydrate malabsorption.

   Glucose-Galactose Malabsorption and Disaccharidase Deficiencies

Lactase deficiency and congenital absence of enterocyte brush-border carbohydrate hydrolases and transport proteins may cause diarrheas. Lactase deficiency should be considered in cases of unexplained watery diarrhea, especially if accompanied by abdominal cramps, bloating, and flatus (see earlier discussion). Patients with symptoms on ingestion of mushrooms may have trehalase deficiency.

   Prior Surgery: Bile Acid Diarrhea

There are three types of bile acid-induced diarrhea. Type 1 results from severe disease (e.g., Crohn’s disease), resection, or bypass of the distal ileum, which allows dihydroxy bile salts to escape absorption (see earlier discussion). Type 2 bile acid diarrhea, or primary bile acid malabsorption, may be congenital or acquired. This form of diarrhea often responds to cholestyramine, 2 to 4 g given orally two to four times daily. Type 3 bile acid diarrhea is caused by measured increases in fecal bile acids in patients with postcholecystectomy diarrhea. It is unclear why interruption of gallbladder storage leads to increased bile acid wastage. Although many patients respond to cholestyramine, some do not. Another cause of type 3 bile acid diarrhea is truncal vagotomy combined with a drainage procedure (postvagotomy diarrhea), after which 20 to 30% of patients develop diarrhea. Many patients do not respond to cholestyramine, but motility-altering drugs such as opiates (e.g., loperamide 2 to 4 mg orally two to four times daily) and anticholinergics (e.g., hyoscyamine sulfate 0.125 to 0.250 mg orally two to four times daily) may be of benefit. Celiac disease also may appear first after gastric surgery or vagotomy.

   Functional Watery Diarrheas (Irritable Bowel Syndrome)

About 25% of patients with irritable bowel syndrome have a symptom complex of predominantly painless diarrhea ( Chapter 139 ), but many patients are discovered to have other conditions, such as occult lactose intolerance, celiac disease (antibody screening is recommended), collagenous or microscopic/lymphocytic colitis, rapid transit with carbohydrate-wasting diarrhea, malabsorption of fructose or sorbitol, or even primary bile acid malabsorption (type 2). Many of these patients’ symptoms begin with an enteric infection (see Prolonged, Persistent, and Protracted Infectious Diarrheas), and many of these patients have an idiopathic bacterial overgrowth syndrome.


See Figure 143-9 .

   Endocrine Tumor Diarrheas

   Carcinoid Syndrome

Patients with metastatic carcinoid tumors of the gastrointestinal tract or, rarely, primary nonmetastatic carcinoid tumors of the bronchial epithelium may develop a watery diarrhea and cramping abdominal pain in addition to other symptoms ( Chapter 251 ). Because one third of these patients do not have other symptoms at the time the diarrhea begins, carcinoid should be considered in patients with secretory diarrhea.


Diarrhea occurs in one third of patients with Zollinger-Ellison syndrome ( Chapter 205 ), may precede the ulcer symptoms, and in about 10% of patients it is the major pathophysiologic manifestation. The diarrhea is caused by high volumes of hydrochloride secretion (which can be reduced by nasogastric aspiration or effective antisecretory therapy) and by maldigestion of fat due to pH inactivation of pancreatic lipase and precipitation of bile acids.

   Vipoma or Watery Diarrhea Hypokalemia Achlorhydria Syndrome

Non–beta cell pancreatic adenomas may secrete various peptide secretagogues, including VIP, that produce all of the symptoms of this disease ( Chapter 205 ). Patients with this syndrome have secretory diarrhea, with 70% of patients having more than 3 L of stool per day and almost all having more than 700 mL/day. Stool electrolyte losses account for the dehydration, hypokalemia, and acidosis that give this syndrome its name.

   Medullary Carcinoma of the Thyroid

Medullary carcinoma of the thyroid may occur in sporadic form, or it may manifest as part of the multiple endocrine neoplasia type II syndrome with pheochromocytomas and hyperparathyroidism in 25 to 50% of cases ( Chapter 250 ). Watery (secretory) diarrhea is caused by secretion of calcitonin by the tumor; however, these tumors also elaborate other secretogogues, such as prostaglandins, VIP, and serotonin. By the time watery diarrhea occurs, the tumor has metastasized, and this symptom portends a poor prognosis.

   Nonendocrine Malignancies

   Villous Adenomas

Large (4 to 10 cm) villous adenomas of the rectum or rectosigmoid may cause a secretory form of diarrhea (500 to 3000 mL/24 hours) characterized by hypokalemia, chloride-rich stool, and metabolic alkalosis. Secretogogues such as prostaglandins have been found in the tumor and rectal effluent of patients, and indomethacin administration reduces the diarrhea in some.

   Systemic Mastocytosis

The diarrhea of systemic mastocytosis ( Chapter 276 ) may be malabsorptive, secondary to mast cell infiltration of the mucosa with resulting villous atrophy, or intermittent and secretory. Histamine or another mast cell mediator may be the secretogogue responsible for these symptoms and for the secretory diarrhea, either by stimulating gastric acid secretion (such as in Zollinger-Ellison syndrome) or by having a secretory effect on the intestine. Antihistamines (H1 blockers), H2 blockers, proton-pump inhibitors, and cyclooxygenase inhibitors may be helpful. Blockade of mast cell degranulation with disodium cromoglycate may reduce all the symptoms and the diarrhea, but not the steatorrhea, which may be treated better with corticosteroids.

   Factitious Diarrhea

Approximately 15% of patients referred to secondary or tertiary centers for diarrhea and 25% of patients with proven secretory diarrheas are found to be ingesting either laxatives or diuretics surreptitiously. These patients present with severe chronic watery, often nocturnal, diarrhea and may have abdominal pain, weight loss, nausea, vomiting, hypokalemic myopathy, acidosis, or protein-losing enteropathy. Patients may have 10 to 20 bowel movements per day, with 24-hour stool volumes in the range of 300 to 3000 mL. Ingestion of bisacodyl, anthraquinone (senna, cascara, aloe, rhubarb, frangula, and danthron), or osmotic laxatives (neutral phosphate, epsom salts, and magnesium citrate) can cause this syndrome. Some patients ingest large quantities of diuretics, such as furosemide or ethacrynic acid.

More than 90% of patients are women, and two different clinical syndromes are most common: (1) women younger than 30 years of age, in whom eating disorders such as anorexia nervosa or bulimia may be part of the psychic abnormality, and (2) middle-aged to elderly women, who have extensive medical histories and are more likely to be health care workers. Factitious diarrhea is sufficiently common to warrant laxative screening to exclude this syndrome before initiation of extensive medical evaluation for the other causes of diarrhea.

   Chronic Idiopathic Diarrhea and Pseudopancreatic Cholera Syndrome

Patients in whom extensive evaluation for a cause of secretory diarrhea is negative are said to have either chronic idiopathic diarrhea or pseudopancreatic cholera syndrome, depending on whether the fasting stool volumes are less than or greater than 700 mL/24 hours. If no diagnosis is found after thorough testing and a search for surreptitious laxative abuse, a therapeutic trial with bile salt–binding drugs (e.g., cholestyramine 4 g orally before meals three times a day), NSAIDs (e.g., naproxen 250 mg orally twice daily), or opiates (e.g., loperamide 2 mg orally four times a day, maximum dose 16 mg a day) is warranted. Follow-up studies suggest that the diarrhea is usually self-limited and disappears spontaneously in 6 to 24 months.

   Diabetic Diarrhea

Of young to middle-aged diabetics with type 1 diabetes, particularly men between 20 and 40 years of age whose diabetes has been poorly controlled for more than 5 years, 20% have a profuse watery, urgent diarrhea, often occurring at night with incontinence. These patients usually have concomitant neuropathy, nephropathy, and retinopathy. Exocrine pancreatic insufficiency is sometimes the cause, and bacterial overgrowth occasionally is present because of the motility disturbance of the autonomic neuropathy. Patients with type 1 diabetes must have an appropriate evaluation to exclude other causes of diarrhea, especially celiac disease. If no other cause is found, clonidine may be helpful. Patients with neuropathy frequently have impaired anal sphincter function, and high-dose loperamide may improve the incontinence. A common cause of diarrhea in type 2 diabetics is therapy with metformin or, less commonly, acarbose.

   Alcoholic Diarrhea

Binge drinking of alcohol causes a brief episode of diarrhea that usually lasts less than 1 day. Chronic alcoholics often have a severe watery diarrhea that persists for days or weeks after hospitalization. Various physiologic abnormalities have been described in alcoholics as a cause of diarrhea, but none has been proven. With abstinence, renourishment, and replenishment of vitamin deficiencies, the diarrhea slowly improves.


See Figure 143-10 for an algorithm for evaluation of inflammatory diarrheas.

FIGURE 143-10  Approach to the evaluation of inflammatory diarrheas. ESR = erythrocyte sedimentation rate; Hx = history; IBD = inflammatory bowel disease; UC = ulcerative colitis.  (Adapted from Powell DW: Approach to the patient with diarrhea. In Yamada T, Alpers DH, Owyang C, et al [eds]: Textbook of Gastroenterology, 3rd ed. Philadelphia, Lippincott-Raven, 1999.)

   Inflammatory Bowel Disease

Patients with Crohn’s disease or ulcerative colitis have diarrhea with stool volumes usually less than 1 L/24 hours ( Chapter 144 ). Occasional patients with severe ulcerative colitis have more severe diarrhea, with water and electrolyte secretion in the unaffected small intestine, suggesting the presence of circulating secretogogues originating from the inflamed colon. Pouchitis (inflammation of the ileal reservoir) is a common cause of diarrhea in patients who have ulcerative colitis with an ileoanal anastomosis after colectomy. The cause is unknown. Antibiotic therapy is effective, but relapses are common. A probiotic compound containing lactobacilli, bifidobacteria, and Streptococcus thermophilus may be effective at preventing relapses.

   Eosinophilic Gastroenteritis

Infiltration of various layers of the gastrointestinal tract with eosinophils is a recognized clinical entity that is accompanied by diarrhea in 30 to 60% of patients. Peripheral eosinophilia is present in 75% of these patients. The disease may involve the entire gastrointestinal tract from esophagus to anus, or it may be isolated to a segment. Abdominal pain, nausea, vomiting, weight loss, steatorrhea, and protein-losing enteropathy are other prominent signs and symptoms of this disease. The cause of eosinophilic gastroenteritis is unknown, but approximately 50% of patients have atopic (allergic) histories, and food allergy is suspected. Corticosteroids (prednisone 20 to 40 mg orally once a day for 7 to 10 days) are the mainstay of therapy; disodium cromoglycate (200 mg orally four times daily) may be useful. Infestation with nematodes must be excluded before this diagnosis is made.

   Milk and Soy Protein Intolerance and Food Allergy

Intolerance to cow’s milk and soy protein is a well-established cause of enterocolitis in infants ( Chapter 274 ). Approximately 50% of patients who are allergic to one of these proteins are also allergic to the other. The role of food allergy in causing diarrhea in adults is less clear. Commonly suspected allergens include milk, eggs, seafood, nuts, artificial flavors, and food coloring.

   Collagenous and Lymphocytic Colitis

These two conditions, collectively known as microscopic colitis, may or may not be the same disease or variants of the same disease. Lymphocytic colitis is equally prevalent in men and women, whereas collagenous colitis occurs 10 times more often in middle-aged or elderly women. These conditions may be associated with autoimmune disease or with NSAID use. There is an increased prevalence (15%) of microscopic colitis among individuals with celiac sprue. These diseases may be categorized as either inflammatory or secretory diarrheas. An epidemiologic relationship to medications such as NSAIDs, H2-receptor blockers, proton-pump inhibitors, selective serotonin reuptake inhibitors (SSRIs) and others has been reported, and increased luminal prostaglandin levels may cause the diarrhea. Enteric infections, food hypersensitivity, or intraluminal bile has been proposed as a trigger for prostaglandin release from lymphocytes. The disease disappears with fecal stream diversion. Antidiarrheal agents such as loperamide (2 mg orally four times a day) are the mainstay of therapy. Budesonide (9 mg orally once a day), bismuth subsalicylate therapy (eight chewable 262-mg tablets orally once a day), and 5-aminosalicylates (e.g., mesalamine 400 to 800 mg orally three times daily) may be useful. Those with refractory disease may require corticosteroids (e.g., prednisone 40 mg orally once a day).

   Protein-Losing Enteropathy

Severe protein loss through the gastrointestinal tract caused by ulceration, obstructed lymphatics, or immune-related vascular injury occurs in a variety of disease states: bacterial or parasitic infection, gastritis, gastric cancer, collagenous colitis, inflammatory bowel disease, congenital intestinal lymphangiectasia, sarcoidosis, lymphoma, mesenteric tuberculosis, Ménétrier’s disease, sprue, eosinophilic gastroenteritis, systemic lupus erythematosus, chronic peritoneal dialysis, and food allergies. The condition usually responds to corticosteroids (e.g., prednisone 10 to 60 mg orally once daily) or immunosuppressive therapy (e.g., 6-mercaptopurine in carefully titrated doses).

   Radiation Enteritis

Patients receiving pelvic radiation for malignancies of the female urogenital tract or the male prostate may develop chronic radiation enterocolitis 6 to 12 months after total doses of radiation greater than 40 to 60 Gy ( Chapters 18 and 145 ). Symptoms can develop 20 years after treatment, however. In irradiated animal models, early abnormalities include an increase in inflammatory mediators, an increase in cholinergic stimulation of intestinal tissue, and endothelial cell apoptosis that precedes epithelial cell apoptosis. The last finding suggests that vascular injury is the primary event. Vascular endothelial growth factor, basic fibroblast growth factor, and IL-11 protect animal intestine from radiation damage. Diarrhea may be caused by bile acid malabsorption if the ileum is damaged, by bacterial overgrowth if radiation causes small intestinal strictures or bypass, or by radiation-induced chronic inflammation of the small intestine and colon. Rapid transit also may contribute to malabsorption and diarrhea. Treatment is often unsatisfactory. Anti-inflammatory drugs (sulfasalazine, corticosteroids) and antibiotics have been tried with little success. Cholestyramine (4 g orally three times a day) and NSAIDs (e.g., naproxen 250 to 500 mg orally twice daily) may help, as may opiates (loperamide 2 mg orally four times a day or loperamide-N-oxide 3 mg orally two times a day).

   Miscellaneous Diseases

Although acute mesenteric arterial or venous thrombosis manifests as an acute bloody diarrhea, chronic mesenteric vascular ischemia may manifest as watery diarrhea. Gastrointestinal tuberculosis and histoplasmosis manifest as diarrhea that may be either bloody or watery, as do certain immunologic diseases, such as Behçet’s syndrome or Churg-Strauss syndrome. All of these diseases may be misdiagnosed as inflammatory bowel disease. Diarrhea, the hallmark of acute GVHD after allogeneic bone marrow transplantation, manifests with the triad of dermatitis, hepatic cholestasis, and enteritis (see earlier discussion). Neutropenic enterocolitis, an ileocolitis that occurs in neutropenic leukemic patients, sometimes is caused by C. difficile infection.

Diagnosis of Chronic Diarrheas

History and Physical Examination

A detailed history, physical examination, and certain screening tests lead to a diagnosis in 75% of patients with watery diarrheas (see Table 143-1 and Figs. 143-3 and 143-8 [3] [8]). A history of 10 to 20 bowel movements per day suggests secretory diarrhea (see Fig. 143-9 ). A history of peptic ulcer should suggest gastrinoma or systemic mastocytosis. Physical examination is helpful only if the thyromegaly of medullary carcinoma, the cutaneous flushing of the neuroendocrine tumors and systemic mastocytosis, the dermatographism of systemic mastocytosis, or the migratory necrolytic erythema of glucagonoma is evident. Scars from previous surgery may suggest postvagotomy diarrhea or terminal ileal resection with bile acid diarrhea. Autonomic dysfunction (e.g., postural hypotension, impotence, gustatory sweating) is almost invariably present in diabetic diarrhea.

Evaluation for malabsorption begins with a careful history of bowel habits, weight loss, travel, food or milk tolerance, underlying gastrointestinal or liver diseases, abdominal surgery, radiation or chemotherapy treatments, family history, and drug and alcohol use. Patients with malabsorption can present with a variety of gastrointestinal or extraintestinal manifestations (see Table 143-5 ). Significant malabsorption of fat and carbohydrate usually causes chronic diarrhea, abdominal cramps, gas, bloating, and weight loss. Steatorrhea (fat in the stool) manifests as oily, foul-smelling stools that are difficult to flush down the toilet. Stools may be large and bulky (e.g., pancreatic insufficiency) or watery (e.g., bacterial overgrowth, mucosal diseases). Individuals with malabsorption also can present with manifestations of vitamin and mineral deficiencies. Dyspnea can be caused by anemia from iron, folate, or vitamin B12 deficiency. Cheilosis, angular stomatitis, or a scaly rash can be caused by many vitamin and mineral deficiencies or essential fatty acid deficiency (see Table 143-5 ). Dermatitis herpetiformis is a blistering, burning, itchy rash on the extensor surfaces and buttocks that is associated with celiac disease. Manifestations of calcium, magnesium, or vitamin D malabsorption include paresthesias and tetany due to hypocalcemia or hypomagnesemia and bone pain due to osteomalacia or osteoporosis-related fractures. Paresthesias and ataxia are manifestations of cobalamin and vitamin E deficiency.

The important clinical manifestations of inflammatory diarrheas are the signs and symptoms of inflammation and/or the effects of severe chronic protein loss (see Fig. 143-10 ). Diarrhea in these inflammatory diseases may be meager (e.g., the pseudodiarrhea of proctitis), or it may be fairly severe (e.g., as in GVHD). Systemic manifestations of inflammatory bowel disease include oral aphthous ulcers, polymigratory arthritis, uveitis, erythema nodosum, pyoderma gangrenosum, and the palpable purpura of vasculitis.

Blood Tests

Blood measurements (see Fig. 143-3 ) of iron, folate, vitamin B12, vitamin D, or prothrombin time (vitamin K) help evaluate malabsorption. Although serum carotene levels may be low simply from poor intake, values lower than 50 μg/dL suggest malabsorption. Peripheral blood findings of leukocytosis, eosinophilia, elevated erythrocyte sedimentation rate, hypoalbuminemia, or low total serum protein suggests an inflammatory diarrhea, whose hallmark is the presence of blood, either gross or occult, and leukocytes in the stool. There are no bedside screening tests to establish the diagnosis in watery diarrheas.


Radiographic imaging should be viewed as an adjunct to the diagnosis of diarrheal diseases and not a primary test. Malabsorption may be suggested by a flat plate of the abdomen that shows pancreatic calcification. Some diseases (e.g., previous gastric surgery, gastrocolic fistulas, blind loops from previous intestinal anastomoses, small intestine strictures, multiple jejunal diverticula, abnormal intestinal motility that could lead to bacterial overgrowth) may be shown by computed tomography or magnetic resonance imaging of the abdomen after administration of oral contrast agents or by a traditional upper gastrointestinal radiographic series with small intestine follow-through. Certain diseases may manifest radiographically as uniform thickening of the intestinal folds (e.g., amyloidosis, lymphoma, Whipple’s disease); others, such as lymphoma or lymphangiectasia, show uniform or patchy abnormalities. Patients with celiac disease show dilation of the small intestine, with little mucosal abnormality, and segmentation of the barium column as a result of precipitation or flocculation of the barium. Routine contrast radiographs of the gastrointestinal tract usually are not helpful in the diagnosis of watery diarrheas, unless they show a previous vagotomy, extensive small bowel resection or cholecystectomy, the presence of a tumor (carcinoid or villous adenoma), or a bowel filled with fluid (endocrine tumor). Abdominal contrast imaging may show diagnostic evidence of inflammatory bowel disease or changes suggestive of eosinophilic gastroenteritis or radiation enterocolitis. Early or mild gut inflammation may be missed entirely by radiography. Somatostatin receptor scintigraphy with indium 111–labeled octreotide can be useful in localizing gastrinomas, pancreatic endocrine tumors, and carcinoid tumors.

Endoscopy and Biopsy

Upper endoscopy with distal duodenal biopsy should be undertaken if serologic tests for celiac disease are positive or diagnostic clues suggest small bowel mucosal malabsorption. Some patients may have patchy mucosal disease and require enteroscopy with jejunal biopsies for diagnosis. Patients with severe watery or elusive diarrhea should have a flexible sigmoidoscopy or, preferably, a colonoscopy to exclude villous adenomas of the rectosigmoid and biopsy to exclude microscopic or collagenous colitis, mastocytosis, or early inflammatory bowel disease. Colonoscopy and biopsy also may reveal melanosis coli secondary to chronic use of anthracene laxatives. Terminal ileal biopsy may indicate inflammatory bowel disease. Newly developed, longer, flexible push endoscopes and wireless video capsule endoscopy ( Chapter 136 ) are increasingly used to diagnose small bowel diseases.

Other Laboratory Tests


If chronic diarrhea is the presenting symptom, a stool examination for ova and parasites and a stool antigen-capture ELISA test for Giardia should be obtained. A stool test for fat is the best available screening test for malabsorption (see Table 143-6 ). If the fecal fat test result is negative, selective carbohydrate malabsorption or other causes of diarrhea should be considered. If the fecal fat test result is positive ( Fig. 143-11 ), further testing should be based on clinical suspicion for particular diseases. If pancreatic insufficiency is suspected, imaging studies of the pancreas should be performed. If proximal mucosal damage is suspected, multiple small intestinal biopsy specimens should be obtained. If there are no clues as to the cause of malabsorption, a D-xylose test may help to distinguish mucosal disease from pancreatic insufficiency. The D-xylose test result also can be abnormal in individuals with bacterial overgrowth; if this condition is suspected, culture of an intestinal aspirate or a breath test should be obtained (see Table 143-6 ). Small bowel contrast imaging is useful in detecting ileal disease and structural abnormalities that predispose to bacterial overgrowth. Some individuals with celiac disease present with selective nutrient deficiencies without diarrhea. In these cases, tTG antibody tests and intestinal biopsy should be performed. If malabsorption is suspected in patients hospitalized for severe diarrhea or malnutrition, a more streamlined evaluation usually includes a stool for culture, ova and parasites, and fat; an abdominal imaging study; and a biopsy of the small intestine.

FIGURE 143-11  Sudan stain of stool for fat. The positive stain (left) shows larger globules of unabsorbed fat (arrows).

Watery Diarrhea

Breath tests to measure the respiratory excretion of labeled CO2 after oral administration and metabolism of radioactive carbon–labeled substrates, or of H2 after administration of carbohydrates, can assess fat, carbohydrate, and bile salt malabsorption or bacterial overgrowth (see Table 143-6 ).

The diagnosis of endocrine tumors, such as carcinoids, gastrinoma, VIPoma, medullary carcinoma of the thyroid, glucagonoma, somatostatinoma, and systemic mastocytosis, is made by showing elevated blood levels of serotonin or urinary 5-hydroxyindoleacetic acid and serum levels for gastrin, VIP, calcitonin, glucagon, somatostatin, histamine, or prostaglandins ( Chapter 205 ). Somatostatin receptor scintigraphy has proved to be sensitive and useful in the diagnosis and evaluation of Zollinger-Ellison syndrome ( Chapter 205 ).

Inflammatory Diarrhea

Video capsule endoscopy ( Chapter 136 ) of the small bowel may detect inflammation not evident by upper or lower endoscopy or conventional barium contrast radiography. Fecal white blood cells can be detected in stool smears with a methylene blue stain. Stool excretion of lactoferrin (a constituent of leukocytes) also may be used as a quantitative index of fecal leukocyte loss. The most sensitive test for certain inflammatory diarrheas is measurement of intestinal protein loss by 24-hour stool excretion or clearance of chromium 51–labeled albumin or α1-antitrypsin.

Elusive Diarrhea

An important adjunct to diagnosing the cause of diarrhea is to look at the stool. The greasy, bulky stool of steatorrhea and the bloody stool of gut inflammation are distinctive. Patients with steatorrhea sometimes also have severe watery diarrhea, however. Qualitative tests on outpatient spot stool collections and quantitative tests (stool fat, electrolytes, and osmolality) on 48- to 72-hour stool collections can help define the causes of diarrhea, especially severe or elusive diarrheas (see Table 143-6 and Fig. 143-9 ). Stool collections can be analyzed for appearance, weight, quantitative fecal fat, electrolytes (Na+, K+, and, if necessary, Cl-, PO42- and Mg2+), osmolality, fecal pH, and laxative screen. Stool or urine can be analyzed for emetine (a component of ipecac), bisacodyl, castor oil, or anthraquinone. Stool SO42-, PO42-, and Mg2+ analysis detects factitious diarrheas caused by osmotic cathartics.

Carbohydrate malabsorption lowers stool pH because of colonic fermentation of carbohydrate to short-chain fatty acids. Stool pH less than 5.3 usually means pure carbohydrate malabsorption, whereas, in the generalized malabsorptive diseases, stool pH is greater than 5.6 and usually greater than 6.0.

The normal stool osmotic gap, which is the difference between stool osmolality (or 290 mOsm) and twice the stool Na+ and K+ concentrations, is 50 to 125. In secretory diarrheas, the solutes causing the movement of water from blood to bowel lumen are the secreted Na+ and K+ ions; stool Na+ concentrations are usually greater than 90 mmol/L, and the osmotic gap is less than 50. In osmotic diarrhea, the ingestion of nonabsorbable (or nonabsorbed) solutes displaces Na+ from the stool and causes the osmotic gap and the diarrhea (see Pathophysiology); stool Na+ is less than 60 mmol/L, and the osmotic gap is greater than 125. Stools with Na+ concentration between 60 and 90 mmol/L and calculated osmotic gaps between 50 and 100 can result from either secretory or malabsorptive abnormalities. Patients with Mg2+-induced diarrhea may be diagnosed by fecal Mg2+ values greater than 50 mmol/L. Sodium anion–induced diarrheas mimic secretory diarrhea because the stool Na+ content is high (>90 mmol/L), and there is no osmotic gap; this diarrhea may be diagnosed by determining stool Cl- concentration, because these anions displace stool Cl-, and the resulting stool Cl- value is usually less than 20 mmol/L.

Treatment of Chronic Diarrheas

Antidiarrheal Therapy

Antidiarrheal agents are of two types: those that are useful for mild-to-moderate diarrheas and those that are helpful in secretory and other severe diarrheas. The bulk-forming agents (kaolin-pectin, psyllium, and methylcellulose) increase the consistency of stool and have no antisecretory activity. Pectin has been shown to have proabsorptive activity. Other antidiarrheal agents have only mild proabsorptive or antisecretory action, and most have antidiarrheal activity by altering the intestinal motility. Bismuth salicylates, opiates, loperamide, clonidine, phenothiazine, and somatostatin have mild antisecretory activity but also cause dilation of the small intestine and colon and decrease peristalsis. The opiates also increase anal sphincter tone. The therapeutic mechanism of these drugs is to trap fluid within the intestine and put it in contact with the mucosa for a longer period, allowing more complete absorption.

The opiates may be symptomatically useful in mild diarrheas. Paregoric, deodorized tincture of opium, codeine, and diphenoxylate with atropine largely have been supplanted by loperamide. Loperamide does not pass the blood-brain barrier and has a high first-pass metabolism in the liver; it has a high therapeutic-to-toxic ratio and is essentially devoid of addiction potential. It is safe in adults, even in total doses of 24 mg/day. The usual dose is 2 to 4 mg two to four times daily. When opiates are given, stool output is not a reliable gauge for replacing fluid losses, because the antimotility effects of opiates cause fluid to sequester in the bowel lumen (third space). The antimotility effects are a problem in infectious diarrheas, because stasis may enhance bacterial invasion and delay clearance of microorganisms from the bowel, increasing carriage time. Opiates and anticholinergics also are dangerous in severe inflammatory bowel disease, where they may precipitate megacolon. Racecadotril does not seem to affect motility, so it may prove to be a useful, opiate-like antidiarrheal.

The use of drugs with potentially serious side effects can be justified for treatment of severe secretory diarrheas. The somatostatin analogue octreotide has its major antisecretory effect in carcinoid syndrome and in neuroendocrine tumors, because it inhibits hormone secretion by the tumor. Newer, long-acting preparations are now available, easing its use. Octreotide may be of only limited usefulness in short-bowel syndrome and AIDS diarrhea. Agents such as phenothiazine, calcium-channel blockers, or clonidine can have serious side effects but may be tried if octreotide fails. Clonidine can be useful in the diarrhea of diarrhea-predominant irritable bowel syndrome, opiate withdrawal, and, occasionally, in patients with diabetic diarrhea. Serotonin-3 receptor antagonist (alosetron) therapy may be justified for severe diarrhea-predominant irritable bowel syndrome.[7] Indomethacin, a cyclooxygenase blocker that inhibits prostaglandin production, occasionally may be useful in neuroendocrine tumors, irritable bowel syndrome, and food allergy and is most useful in patients with diarrhea caused by acute radiation, AIDS, or villous adenoma of the rectum or colon. Cyclooxygenase blockers may be harmful in inflammatory bowel disease. Glucocorticoids reduce prostaglandin and leukotriene production in inflammatory bowel disease and have a proabsorptive effect on the intestine that is demonstrable by 5 hours after administration. The new anti–tumor necrosis factor antibodies are useful in Crohn’s disease and in ulcerative colitis that is unresponsive to conventional therapy ( Chapter 144 ).

Email to Colleague Print Version

Copyright © 2007 Elsevier Inc. All rights reserved. –

Leave a Reply

Time limit is exhausted. Please reload the CAPTCHA.


apply_now Pepperstone Group Limited