ACP medicine, 3rd Edition

Gastroenterology

Diarrheal Diseases

Lawrence R. Schiller MD, FACP1

Clinical Professor of Internal Medicine

, University of Texas Southwestern Medical Center at Dallas, Attending Physician, Internal Medicine, Baylor University Medical Center

The author has received grants for educational activities from and served as an advisor for Novartis Pharmaceuticals Corp., GlaxoSmithKline, Romark Laboratories, Salix Pharmaceuticals, Inc., Santarus, Inc., and Takeda Pharmaceuticals North America, Inc.; has received grants for clinical research from Novartis Pharmaceuticals Corp. and GlaxoSmithKline; and has served as an advisor to TAP Pharmaceutical Products, Inc.

January 2006

Definition and Epidemiology

The word diarrhea is derived from the Greek words for “flowing through.” For most persons, diarrhea means the frequent passage of loose stools.1 This definition includes two major components: loose-stool consistency (pourable stools) and increased stool frequency (more than two bowel movements daily). Physicians often include a third component: increased stool weight (> 200 g/24 hr), but patients are poor estimators of stool output. In addition, some patients report diarrhea when they have fecal incontinence, even if stools are solid; therefore, every patient complaining of diarrhea should be asked about incontinence.

Diarrhea is a universal human experience. Most persons have had acute infectious diarrhea at some time during their lives. The incidence of acute diarrhea is roughly 5% to 7% annually in the United States.2 Infectious diarrhea is associated with contaminated food and water and typically is spread via fecal-oral transmission. Chronic diarrhea (i.e., lasting more than 4 weeks) is also common, with a prevalence of approximately 5% in the United States.3 It is less likely to be caused by infection and more likely to be a symptom of other disorders, such as inflammatory bowel disease, celiac disease, or lactose intolerance.

Pathophysiology and Classification

Diarrhea results from excess water in the stool.4 To understand the pathophysiology of diarrhea, it is necessary to briefly review how water is transported across the mucosa of the gastrointestinal tract. Water moves in response to osmotic gradients that are established by the absorption of salts (mainly sodium chloride but also potassium and bicarbonate salts) and nutrients (monosaccharides, amino acids, and fatty acids). Salts and nutrients move both passively in response to electrochemical gradients across the mucosa and actively in response to molecular pumps located in the enterocyte membranes.5

Each day, a typical person ingests about 2 L of fluid and produces 7 to 8 L of secretions (i.e., saliva, gastric juice, bile, pancreatic juice, and succus entericus). Thus, a total volume of 9 to 10 L enters the upper intestine daily. Most of the water is absorbed in the jejunum, along with nutrients. Absorption of residual nutrients and salts in the ileum results in a reduction of the volume of luminal contents entering the colon to only 1 to 1.5 L daily, a 90% reduction in the volume of fluid entering the intestine each day. The colonic mucosa can absorb salt against large electrochemical gradients and can reclaim 90% of the fluid passing the ileocecal valve each day, making the overall efficiency of small bowel and colonic water absorption about 99%.

Diarrhea develops if the overall efficiency of absorption declines by as little as 1%. This can occur under the following circumstances: the rate of intestinal nutrient and salt absorption decreases; net electrolyte secretion develops (an unusual circumstance except in cases of severe secretory diarrhea such as cholera, in which stool output can exceed 10 L/day); transit through the intestine speeds up, thereby limiting the time available for absorption; or poorly absorbable substances are ingested and increase intraluminal osmotic activity, causing the retention of water within the intestine.6

Common problems that primarily cause a reduction in the rate of intestinal nutrient and salt absorption include mucosal diseases, such as celiac disease; inflammatory diseases that disrupt the integrity of the intestinal mucosa (e.g., Crohn disease); and infections that cause diarrhea as the result of toxins that affect enterocyte function.

Isolated acceleration of intestinal transit is a poorly recognized mechanism of diarrhea, although historically, diarrhea was always attributed to it. Some patients with so-called functional diarrhea have rapid intestinal transit, which is likely to be important in the pathogenesis of their condition. Many patients with chronic idiopathic diarrhea have normal rates of fluid and electrolyte absorption when measured under perfusion conditions during which motility effects are neutralized, suggesting that motility must be playing a role in the pathogenesis of their diarrhea under ordinary circumstances.7 Accelerated transit is also a major factor in diarrhea that is associated with some endocrine diarrheas (e.g., hyperthyroidism, carcinoid syndrome, and other peptide-secreting tumors) or with irritable bowel syndrome.

Poorly absorbed substances that can induce osmotic diarrhea include lactose in lactose-intolerant individuals. Osmotic diarrhea can also occur with ingestion of excess quantities of other poorly absorbed carbohydrates (e.g., fructose and the sugar alcohols mannitol and sorbitol) and ions such as magnesium, phosphate, and sulfate.

Mechanisms that reduce the overall efficiency of absorption may coexist in various disease states. For instance, in celiac disease, loss of intestinal villi results in reduced salt and water absorption, as well as reduced nutrient absorption. Thus, increased stool water in this condition results from both a reduced rate of electrolyte absorption and the increased intraluminal osmotic activity of poorly absorbed substances. Intestinal transit may accelerate in many diarrheal states because of stimulation of peristalsis by increased intraluminal volumes.

FECAL OSMOTIC GAP

As the rate of intestinal salt absorption decreases, the concentration of salts in stool rises to the point at which the concentration approaches plasma osmolality (290 mOsm/kg), which is defined as the osmolality that intestinal contents must maintain beyond the proximal jejunum. If the rate of salt absorption is unimpaired but either nutrients are malabsorbed or poorly absorbable substances are ingested, fecal salt concentrations decrease because most of the available osmotic space is occupied by the poorly absorbed substance. This is the basis for calculation of the fecal osmotic gap [see Figure 1].8 In this calculation, the contribution of electrolytes to stool osmolality is estimated by doubling the concentration of sodium and potassium (the predominant cations in stool water) to account for unmeasured anions (mostly fatty anions, bicarbonate, or chloride). This value is then subtracted from 290 mOsm/kg (the putative osmolality of gut contents) to determine the contribution of nonelectrolytes to fecal osmolality. When electrolytes constitute most of luminal osmolality, the calculated fecal osmotic gap will be low (< 50 mOsm/kg). When poorly absorbable substances are present, the fecal osmotic gap will be large (> 100 mOsm/kg). Watery diarrhea with a low osmotic gap is classified as secretory diarrhea; diarrhea with a large fecal osmotic gap is classified as osmotic diarrhea. These categories are most helpful in the evaluation of patients with chronic diarrhea.

 

Figure 1. Fecal Electrolyte Concentrations in Diarrhea

Fecal electrolyte concentrations in secretory diarrhea (left column) and in osmotic diarrhea (right column). Note that most of the fecal osmolality can be attributed to fecal electrolytes in secretory diarrhea, whereas most of the osmolality in osmotic diarrhea results from the unmeasured (nonelectrolyte) osmoles. Calculation of the fecal osmotic gap allows an estimate of the contribution of unmeasured osmoles to fecal osmolality.82

CLASSIFICATION OF DIARRHEA

For clinical purposes, diarrhea can be classified as either acute (< 4 weeks' duration) or chronic (> 4 weeks' duration). Chronic diarrhea is further divided into watery, inflammatory, and fatty on the basis of stool characteristics.3 The value of this classification is that it allows the physician to direct evaluation and management more effectively, because diarrheal diseases can be distinguished by the duration of illness and the type of stools produced.

Acute Diarrhea

ETIOLOGY

Infectious Causes of Acute Diarrhea

Most forms of acute diarrhea (i.e., those lasting less than 4 weeks) are caused by infections and are self-limiting; the majority are caused by viruses (e.g., adenovirus, Norwalk agent, rotovirus), but some are caused by bacteria (e.g., Salmonella, Shigella, and Escherichia coli) and others by protozoa (e.g., Giardia, amebas) [see Table 1].2 The disease course of most viral and bacterial diarrheas lasts less than 1 week; therefore, infectious diarrhea lasting more than 7 days is more likely to be caused by protozoa.9

Table 1 Selected Infectious Diarrheas

Organism

Vehicle

Mechanism

Classic Characteristics

Complications

Campylobacter

Food (poultry); animal-to-person

Invasion; inflammation

Watery or blood diarrhea; ileitis and/or colitis, ulceration

Guillain-Barré syndrome; reactive arthritis

Salmonella

Food (poultry, eggs, seafood); animal-to-person

Invasion; inflammation

Gastroenteritis, ileitis, colitis; enteric fever (S. typhi)

Endovascular infection; osteomyelitis; sepsis

Shigella

Food (poultry); day care centers

Cytotoxin; inflammation

Two phases: enteritis (fever, cramps, diarrhea), followed by colitis (ulcers, inflammation)

Seizures, encephalopathy; reactive arthritis

E. coli O157:H7

Food (beef); fruit juices

Cytotoxin

Hemorrhagic colitis

Hemolytic-uremic syndrome

Enteroinvasive E. coli

Food (various); water

Invasion; inflammation

Colitis

Fever, sepsis

EnterotoxigenicE. coli

Food (various); water

Enterotoxin

Watery diarrhea

Dehydration, shock

Enteropathogenic and enteroadherentE. coli

Food (various); water

Contact with brush border

Watery diarrhea; may be prolonged

Dehydration

Vibrio cholerae

Water, seafood

Enterotoxin

Voluminous watery diarrhea

Dehydration, shock

Clostridium difficile

Person-to-person

Cytotoxin

Nosocomial infection; antibiotic-associated diarrhea; toxicity

Toxic megacolon; protein-losing enteropathy

Aeromonas,Plesiomonas

Water

Enterotoxin

Watery diarrhea; may be prolonged

 

Yersinia

Raw milk

Invasion; inflammation

Acute diarrhea or chronic ileocolitis-like Crohn disease

Reactive arthritis, extaintestinal infection, Guillain-Barré syndrome

Bacillus cereus

Fried rice

Exotoxin

Acute gastroenteritis

Fulminant liver failure

Staphylococcus

Fatty foods

Exotoxin

Acute gastroenteritis

 

Clostridiumperfringens

Fatty foods

Exotoxin

Acute gastroenteritis

Viruses

Person-to-person; water

Inflammation; ?toxins

Acute gastroenteritis; watery diarrhea

Giardia

Person-to-person; animal-to-person; water; day care

Contact

Watery diarrhea, dyspepsia

Cryptosporidium

Water; day care; animal-to-person

Contact

Watery diarrhea, may be prolonged; epidemics

Cyclospora

Imported fruit

Inflammation

Watery diarrhea, flatulence, pain, fatigue; may be prolonged

Entamoeba histolytica

Person-to-person

Invasion; inflammation

Variable: asymptomatic to dysentery; may mimic irritable bowel syndrome, inflammatory bowel disease

Liver abscess

Strongyloides

Larvae invade skin

Invasion; inflammation

Abdominal pain and diarrhea

Hyperinfection in immunosuppressed hosts

The epidemiology of acute infectious diarrhea depends on the circumstances of the infection and where one contracts the infection. For example, a history of recent travel, particularly to developing countries, makes a diagnosis of traveler's diarrhea likely. Previous antibiotic use and residence in an institution where antibiotic use is common (e.g., hospitals and nursing homes) are risk factors for Clostridium difficile infection. Children in day care facilities and their contacts, people engaging in promiscuous sexual activity, and users of illicit intravenous drugs are all at increased risk of contracting infectious diarrhea. Consumption of potentially contaminated food and drink is another risk factor for infectious diarrhea. With the globalization of commerce and mass processing of food, esoteric infections from overseas and large outbreaks of diarrhea have become more common.10

Pathogenic infections cause diarrhea by one of four mechanisms: (1) enterotoxins that subvert the regulatory mechanisms of enterocytes, (2) cytotoxins that destroy enterocytes, (3) adherence to the mucosa by organisms (so-called enteroadherent organisms) that alter enterocyte function as a result of physical proximity to the mucosa, and (4) invasion of the mucosa by organisms that provoke an inflammatory response by the immune system.11 In general, patients with cytotoxin-mediated diarrhea and those with invasive organisms experience more toxicity and have more abdominal pain than patients with enterotoxin-mediated diarrhea or enteroadherent infections.

Toxic Causes of Acute Diarrhea

Another mechanism for acute diarrhea is ingestion of a preformed toxin.12 Several species of bacteria, such as Staphylococcus aureus, Clostridium perfringens, and Bacillus cereus, can produce toxins that in turn cause so-called food poisoning (i.e., vomiting and diarrhea within 4 hours after ingestion). In such cases, the bacteria do not need to establish an intraluminal infection; ingestion of the toxin alone can produce the disease. Symptoms subside after the toxin is cleared, usually by the next day, and evidence of toxicity (e.g., fever) is minimal.

Other Causes of Acute Diarrhea

Other potential causes of acute diarrhea include food allergies and medication reactions. Food allergies are rarely recognized as causes of diarrhea in adults in the United States unless the diarrhea is associated with urticaria or other allergic symptoms. Medications often produce diarrhea as a side effect; this association is typically recognized by the patient because of the temporal relation between drug ingestion and diarrhea.

Finally, acute diarrhea may represent the initial stages of chronic diarrhea. However, patients with chronic diarrhea often do not seek help during the initial weeks of their illness unless the diarrhea is severe or is complicated by dehydration, symptomatic electrolyte disorders, or fever.

DIAGNOSIS

Medical History

A careful medical history is the key to the diagnosis of diarrhea. The acuity and severity of the process should be determined. Frequency of defecation is the easiest parameter for patients to relate, but frequency does not necessarily correlate with stool weight, which is a more meaningful measure of the physiologic impact of diarrhea. Manifestations of dehydration or volume depletion, such as orthostasis, thirst, decreased urine output, and weakness, suggest voluminous diarrhea. Acute weight loss can also be a guide to the severity of diarrhea; voluminous diarrhea produces substantial weight loss if rehydration efforts are suboptimal.

Stool characteristics are also quite important. The presence of blood or pus in the stool raises the issue of inflammatory diarrhea, such as that from colitis or enteroinvasive bacteria. Watery stools are more in keeping with a secretory process. The relationship of defecation to meals or fasting and the occurrence of nocturnal diarrhea, fecal urgency, or incontinence are other points of potential significance. Urgency and incontinence do not necessarily indicate voluminous diarrhea; more often, they reflect independent defects in the continence mechanisms. Additional symptoms of diarrhea that should be noted are abdominal pain or cramps; flatulence; bloating or distention; fever; and weight loss. A list of all prescription, over-the-counter, and herbal medications being taken by the patient should be compiled, and previous surgeries or radiation therapy should be discussed. The patient's diet should be scrutinized, and epidemiologic features (e.g., family members or other contacts with diarrhea, recent travel, water source, occupation, sexual activity, and illicit drug use) should be investigated.

Physical Examination

The physical examination is more useful for judging the severity of diarrhea than for determining its cause. Volume status should be assessed by looking for orthostatic change in blood pressure and pulse. Fever and other signs of toxicity should be recorded. A careful abdominal examination, with emphasis on bowel sounds and the presence of distention or tenderness, should be conducted.

Laboratory Testing

Blood tests

Extensive laboratory testing is not necessary for most patients with acute diarrhea; it should be reserved for those with toxicity, dehydrating diarrhea, or persistence of diarrhea for longer than would be expected, given its probable cause [see Figure 2]. In patients requiring extensive laboratory tests, a complete blood count should be obtained to assess for hemoconcentration, anemia, or leukocytosis. Patients with viral diarrhea typically have normal white blood cell (WBC) counts and differentials, although lymphocytosis may be seen. Invasive bacterial infections typically produce leukocytosis with many immature WBCs, but salmonellosis can induce leukopenia. Serum electrolytes and renal tests can define the metabolic impact of diarrhea.

 

Figure 2. Initial Evaluation of Acute Diarrhea

Initial evaluation of acute diarrhea.83

Stool tests

Stool testing is of value for patients with blood in their stools, dehydrating diarrhea, prolonged diarrhea, or dysentery and for patients who present as part of an outbreak of diarrhea. Stool cultures are sensitive and specific, but they are expensive. Some experts recommend obtaining stool cultures only for patients who have leukocytes (or the leukocyte marker lactoferrin) in the stool, because the yield of pathogenic bacteria will be higher in this group.13 Other researchers dispute this recommendation.14 Laboratories routinely test forSalmonella, Shigella, Campylobacter, and E. coli serotype O157:H7. Special cultures for tuberculosis, Yersinia, Aeromonas, or Plesiomonasmay need to be requested in appropriate patients. Polymerase chain reaction (PCR) testing with primers that are based on bacterial DNA is proving to be an accurate and sensitive technique for specific diagnosis.

Examination of stool for ova and parasites has variable utility, depending on the pretest probability of certain infections. For example, such testing might be very useful in a day care worker with diarrhea, but it would be of little help in a patient with hospital-acquired diarrhea. Enzyme-linked immunosorbent assay (ELISA) testing for giardiasis and serologic testing for amebiasis are more accurate tests for such specific infections in most settings. Patients who were treated with antibiotics during the 3 months before the onset of diarrhea or patients who develop diarrhea in institutional settings should have a stool sample analyzed for C. difficile toxin.

Imaging and Endoscopic Tests

In patients who have toxicity, blood in their stools, or persistent acute diarrhea, sigmoidoscopy or colonoscopy should be considered. In most patients without rectal bleeding, sigmoidoscopy is probably adequate as an initial evaluation, because most patients with colitis will have involvement of the left side of their colon. In patients with bleeding or those with AIDS and diarrhea, colonoscopy is preferable because some opportunistic infections and lymphomas are seen only in the right colon.15 Mucosal biopsies should be obtained in either case, particularly if the colon is grossly inflamed, because the pathologist can readily distinguish self-limited colitis from chronic ulcerative colitis even early on in the course of the disease.16 Patients with toxicity should undergo abdominal x-rays or computed tomography to confirm a diagnosis of colitis, to determine its extent, and to look for evidence of ileus or megacolon.

TREATMENT

Nonspecific Therapy

Because most cases of acute diarrhea are self-limited, most patients do not require specific therapy. Instead, judicious replacement of fluid and electrolyte losses is sufficient. This can be accomplished by intravenous fluids or oral rehydration solutions. Oral rehydration solutions are based on the concept that nutrient absorption accelerates sodium and fluid absorption by the jejunum.17 Initially, rehydration formulas used glucose as the absorbable nutrient; more recently, cereal-based oral rehydration solutions have been found to be more efficient. Oral rehydration solution does not reduce fecal losses (it may actually increase stool output); instead, it increases net fluid and electrolyte absorption. These solutions cannot be used if vomiting precludes ingestion; in such situations, intravenous rehydration must be used. Sports drinks (e.g., Gatorade) are designed to offset fluid and electrolyte losses from sweating and do not contain sufficient amounts of sodium to replace fecal losses. Solutions that more closely approximate World Health Organization rehydration solution are now commercially available (e.g., Rehydralyte, Resol, Ricalyte).

Diet

Most patients seek advice about altering their diets when suffering from diarrhea. Other than the provision of adequate water and salt, no specific instructions are needed. Some physicians routinely restrict dairy products in patients with diarrhea on the theory that these patients may have temporary lactase deficiency. This precaution is not necessary unless there is clinical evidence of lactose intolerance (e.g., exacerbation of diarrhea or flatus with ingestion of dairy products).

Antibiotics

Empirical antibiotic therapy for acute diarrhea may be appropriate under certain circumstances (e.g., diarrhea in travelers, outbreaks of bacterial or protozoan diarrhea, patient frailty, and patient toxicity). However, experts discourage routine use of empirical antibiotic therapy because of its lack of demonstrable efficacy in many infections and because of concerns about precipitating complications, such as hemolytic-uremic syndrome in patients with E. coli serotype O157:H7.18 A meta-analysis suggests that this latter point is not supported by the literature.19 When indicated, fluoroquinolones or trimethoprim-sulfamethoxazole is commonly used as empirical therapy. Rifaximin, a nonabsorbable antibiotic with activity against most bacterial enteric pathogens, is useful in patients with infections that are limited to the lumen (e.g., traveler's diarrhea), but it may not be effective against invasive organisms.20 In cases of persistent diarrhea in which protozoan infection is more likely, nitazoxanide, metronidazole, or tinadazole may be more appropriate.21

Nonspecific antidiarrheal agents, such as opiates, can reduce stool frequency and stool weight, and they may reduce associated symptoms, such as abdominal cramps.22 Concerns about slowing the clearance of pathogens from the intestine by reducing peristalsis have largely not been borne out. Intraluminal agents, such as bismuth subsalicylate (Pepto-Bismol) and adsorbents (e.g., kaolin), are also sometimes used [see Table 2].

Table 2 Nonspecific Treatment of Diarrhea

Category

Treatment

Typical Adult Dose

Rehydration

Intravenous fluid

1–5 L/24 hr

Oral rehydration solution

1–5 L/24 hr

Intraluminal agents

Adsorbents (kaolin-pectin)

15–60 ml q.i.d.

Bismuth subsalicylate

30 ml q.i.d.

Texture modifiers (psyllium)

18–30 g/24 hr

Drugs that inhibit transit

Opiates

 

Deodorized tincture of opium (10 mg morphine/ml)

5–20 drops q.i.d.

Paregoric (0.4 mg morphine/ml)

5–10 ml q.i.d.

Morphine sulfate (20 mg/ml)

2–10 drops q.i.d.

Codeine phosphate or sulfate

15–60 mg q.i.d.

Diphenoxylate with atropine

1–2 tablets q.i.d.

Difenoxin with atropine

1–2 tablets q.i.d.

Loperamide (2 mg)

1–2 tablets q.i.d.

Others

 

Clonidine

0.1–0.3 mg t.i.d.

Octreotide injection

50–200 mg t.i.d.

Therapy for Specific Infections and Syndromes

Campylobacter

A frequent cause of acute ileocolitis in the United States,23 Campylobacter is usually acquired by eating undercooked chicken; it has an incubation period of up to 1 week. Ulceration of the colonic mucosa and bloody diarrhea may occur with this infection. Antibiotics, such as erythromycin, shorten the course of the illness if given within the first few days of symptoms.

Salmonella enteritidis and S. choleraesuis

  1. enteritidisand S. choleraesuisare spread via contaminated food or water and cause acute gastroenteritis, ileocolitis, or colitis characterized by watery diarrhea.24 Antibiotic therapy with a fluoroquinolone, ampicillin, or trimethoprim-sulfamethoxazole should be reserved for severely ill patients or patients with compromised immunity (e.g., infants, elderly patients, pregnant women, and AIDS patients).25

Salmonella typhi

  1. typhicauses typhoid fever, a form of enteric fever.26The propensity of S. typhi to produce bacteremia distinguishes it from other enteric pathogens. When the infection is limited to the intestine of an otherwise healthy individual, no specific therapy is indicated, because antibiotics may paradoxically prolong excretion of the organism and increase relapses. When the infection becomes systemic and the patient is very ill, therapy is necessary, especially if the organism produces a metastatic endovascular infection. Fluoroquinolones are most often used. The diagnosis of a carrier state is made when stool cultures are positive for over 1 year.

Shigella

Shigella species are invasive organisms, but they also produce an enterotoxin that reduces water and electrolyte absorption.27 Shigellosis commonly causes a watery diarrhea initially (this watery diarrhea is most likely related to the enterotoxin). Watery diarrhea is followed by bloody diarrhea, which results from colitis produced by invasion of the colonic mucosa. Because of growing resistance to the fluoroquinolones in the United States, trimethoprim-sulfamethoxazole is the recommended initial treatment for most patients with shigellosis. Shigellosis contracted overseas is initially treated with fluoroquinolones, because those strains are more likely to be resistant to trimethoprim-sulfamethoxazole.

  1. coli serotype O157:H7

The O157:H7 organism has become a common cause of food-borne infection in the United States.28 It produces toxins similar to those produced by Shigella.29 Infection with this organism causes a hemorrhagic segmental colitis. The disease often occurs in large outbreaks from contamination of widely distributed foods, such as hamburger meat. Patients can become quite ill; hemolytic-uremic syndrome is a well-recognized complication. Antibiotics do not seem to improve the course of the illness and may cause hemolytic-uremic syndrome in children, although this theory is controversial.18,19

Clostridium difficile

  1. difficilehas become the most common cause of nosocomial diarrhea in many institutions.30In nonhospitalized adults, carriage rates for this organism are low, but it is spread easily from person to person by spores. Suppression of the normal bacterial flora of the colon can result in an overgrowth of C. difficile, if it is present. The organisms produce toxin A and toxin B; these cytotoxins inactivate small guanosine triphosphate (GTP)-binding proteins in the enterocytes, resulting in apoptosis.31 In institutional settings, the organism can be distributed efficiently to a large pool of susceptible persons by health care workers who do not wash their hands. The disease produced can range from a simple, self-limited diarrhea to a fulminant colitis.

Treatment for 2 weeks with metronidazole, 250 mg four times daily, or vancomycin, 125 to 500 mg four times daily, is effective against C. difficile. Relapses occur in up to 25% of patients, probably because of residual spores.32 Ingestion of probiotic bacteria or the nonpathogenic yeast Saccharomyces boulardii may reduce relapse rates.33 In most instances of relapse, longer periods of antibiotic therapy are indicated.

Other nosocomial diarrheas

Noninfectious causes of nosocomial diarrhea include medications (particularly elixirs that contain sorbitol or mannitol as noncaloric sweeteners and cancer chemotherapeutic drugs) and enteral feeding; in addition, nosocomial paradoxical diarrhea can occur in patients with fecal impaction. Infections with organisms other than C. difficile also occur in institutions, particularly extended-stay facilities. An important cohort of hospital patients that may develop infectious diarrhea are those who are immunocompromised by diseases such as AIDS or by drugs that are used to treat transplant rejection or inflammatory diseases. These patients are often infected with opportunistic pathogens, including viruses (e.g., cytomegalovirus and herpesvirus), bacteria (e.g., Mycobacterium avium complex), and parasites (e.g.,Cryptosporidium and Strongyloides).34,35 In addition, bone marrow transplant recepients may develop acute diarrhea from graft versus host disease.

Parasites

Acute diarrhea in noninstitutionalized patients can be caused by parasites.36 The likelihood of parasitic disease as a cause of acute diarrhea is profoundly influenced by geography and epidemiologic features. Giardiasis, for example, is a common infection in some areas but not others, probably because of variability in the effectiveness of water treatment. Ingestion of as few as a dozen cysts of G. lamblia may establish an infection, which accounts for the frequency of person-to-person transmission of this disease. ELISA for Giardia antigen is superior to microscopic inspection of stool (so-called ova and parasites testing) for the detection of giardiasis. Therapy with tinidazole, metronidazole, or nitazoxanide is effective in most patients, but reinfection can occur.37

Amebiasis is also common in some areas. Persons with amebiasis may be asymptomatic or may be extremely ill from invasion and spread of the organism to other organs, such as the liver.38 Diagnosis is typically made by microscopic examination of fresh stools, but ELISA shows promise in distinguishing the pathogenic species, Entamoeba histolytica, from nonpathogenic amebas. The colonoscopic appearance of amebiasis is often distinctive, and the organism can be identified in colonic biopsy specimens.

Cryptosporidiosis is a common but unappreciated cause of diarrhea.39 Cryptosporidium is resistant to chlorination, and it can cause large outbreaks when water supplies are contaminated. Microscopic inspection of stools has poor sensitivity for this organism, and many cases go undiagnosed. Treatment with nitazoxanide reduces the duration of diarrhea in children and adults with this infection.39

Other parasites that may cause acute diarrhea include Isospora, Cyclospora, Trichuris trichiura (whipworm), and Strongyloides. Special tests that may be necessary to identify these parasites include concentration of stool samples and mucosal biopsy. If these organisms are suspected, consultation with the laboratory staff allows use of the proper diagnostic tests.

Chronic Diarrhea

In contrast to acute diarrhea, in which infection is the overwhelmingly likely cause of illness, chronic diarrhea has an extensive and daunting list of possible causes [see Table 3].3 The simplest approach to making a diagnosis is to classify chronic diarrhea by the characteristics of the stools. Three categories of chronic diarrhea are recognized: watery, inflammatory, and fatty. Watery diarrhea can be subdivided further into osmotic and secretory diarrhea on the basis of stool analysis.

Table 3 Major Causes of Chronic Diarrhea

Osmotic diarrhea

   Osmotic laxative abuse

      Mg2+, SO42-, PO43-, lactulose, mannitol, sorbitol, PEG

   Carbohydrate malabsorption

      Lactose, fructose, others

Fatty diarrhea

   Malabsorption syndromes

      Mucosal diseases

      Short bowel syndrome

      Postresection diarrhea

      Small bowel bacterial overgrowth

      Mesenteric ischemia

   Maldigestion

      Pacreatic insufficiency

      Reduced luminal bile acid

Inflammatory diarrhea

   Inflammatory bowel disease

      Ulcerative colitis

      Crohn disease

      Diverticulitis

      Ulcerative jejunoileitis

Infections

   Invasive bacterial infection

   Clostridium, E. coli, tuberculosis, others

   Ulcerating viral infection

      Cytomegalovirus

      Herpes simplex

   Invasive parasites

      Amebiasis

      Strongyloides

Ischemic colitis

Radiation enterocolitis

Neoplasia

      Carcinoma of the colon

      Lymphoma

Secretory diarrhea

   Congenital chloridorrhea

   Chronic infections

   Inflammatory bowel disease

      Ulcerative colitis

      Crohn disease (ileum)

      Microscopic colitis

         Lymphocytic colitis

         Collagenous colitis

      Diverticulitis

   Drugs and poisons

      Stimulant laxative abuse

   Disordered regulation

      Postvagotomy

      Postsymphatectomy

      Diabetic neuropathy

      Irritable bowel syndrome

   Ileal bile acid malabsorption

   Endocrine diarrhea

      Hyperthyroidism

      Addison disease

   Neuroendocrine tumors

      Gastrinoma

      VIPoma

      Somatostatinoma

      Mastocytosis

      Carcinoid syndrome

      Medullary carcinoma of the thyroid

   Other neoplasia

      Colon carcinoma

      Lymphoma

      Villous adenoma

   Idiopathic secretory diarrhea

      Epidemic (Brainerd)

      Sporadic

WATERY DIARRHEA

Osmotic Diarrhea

Osmotic diarrhea results from ingestion of an osmotically active, poorly absorbable substance that necessitates the retention of water intraluminally to maintain isosmotic conditions.40 In practical terms, osmotic diarrhea is caused by ingestion of osmotic laxatives (magnesium, phosphate, and sulfate salts; sugar analogues, such as lactulose; sugar alcohols, such as mannitol or sorbitol; and polyethylene glycol) and carbohydrate malabsorption. The ingestion of osmotic laxatives may be purposeful [see Laxative Abuse, below] or accidental, as when excess magnesium is ingested as part of an antacid, mineral supplement, or multivitamin tablet. Carbohydrate malabsorption is most often the result of acquired lactase deficiency (a normal development in adult mammals) or mucosal disease, such as celiac sprue, that interferes with nutrient absorption.

Secretory Diarrhea

Secretory diarrhea has a much larger list of possible causes than does osmotic diarrhea [see Table 3].

Congenital chloridorrhea

Rarely, congenital absence of a transporter mechanism results in diarrhea. This is the case in congenital chloridorrhea, in which the chloride-bicarbonate exchanger in the ileum is not active.41 Under such conditions, chloride becomes poorly absorbable in the distal bowel and obligates water retention intraluminally.

Chronic infections

Some bacterial infections can last long enough to produce chronic secretory diarrhea.42 These include Aeromonas, Plesiomonas, enteropathogenic E. coli, C. difficile, M. tuberculosis, and Yersinia enterocolitica. A special situation is small bowel bacterial overgrowth syndrome, in which structural problems, such as jejunal diverticulosis, or motility problems, such as those seen in scleroderma, result in proliferation of bacteria in the jejunum.43 Although this bacterial overgrowth disrupts digestive processes and may produce fatty diarrhea, it also may reduce water and salt absorption, producing secretory diarrhea. Infection with parasites, such as G. lamblia, E. histolytica, andCryptosporidium, also can produce chronic diarrhea.44

Inflammatory bowel disease

Typically, inflammatory bowel diseases (e.g., ulcerative colitis and Crohn disease) produce inflammatory diarrhea, with blood and pus in the stool. Watery diarrhea can occur, especially when the distal colon is not involved. One form of inflammatory bowel disease that typically produces a watery diarrhea is microscopic colitis syndrome (lymphocytic colitis and collagenous colitis), in which the mucosa is inflamed but not ulcerated.45 Colonic diverticulitis is sometimes associated with a secretory diarrhea, which is probably mediated by inflammation-linked cytokines. Vasculitis and systemic inflammatory diseases may also be associated with secretory diarrhea.

Drugs

Drug therapy is a key cause of secretory diarrhea.46 Many drugs have diarrhea as a side effect. These include antibiotics; cardiovascular agents, such as beta-adrenergic antagonists, digitalis, and quinidine; cancer chemotherapy; nonsteroidal anti-inflammatory drugs (NSAIDs); and colchicine. Thus, in taking the history of a patient with chronic diarrhea, it is critical to formulate a detailed drug list, including over-the-counter and alternative medications. A special category of drug-induced secretory diarrhea is surreptitious ingestion of stimulant laxatives.

Other causes

Disordered motility or regulation can produce secretory diarrhea. Secretory diarrhea associated with disordered motility can occur in patients who have undergone vagotomy or sympathectomy, patients with autonomic neuropathy from diabetes or amyloidosis, and many patients with irritable bowel syndrome.47,48 In the United States, irritable bowel syndrome is the most common diagnosis made in patients with chronic diarrhea. This diagnosis is often incorrect, however, and may delay accurate diagnosis and treatment.

Malabsorption of bile acid in the ileum occurs in many diarrheal diseases as a result of ileal disease or resection and may be secondary to other processes, such as vagotomy, cholecystectomy, and rapid transit past the ileum. In a relatively small group of patients, idiopathic bile acid malabsorption is the cause of diarrhea.49

Endocrine causes of secretory diarrhea include hyperthyroidism, Addison disease, and a group of rare tumors of the endocrine cells of the gut, including gastrinomas, carcinoid tumors, vasoactive intestinal peptide tumors (VIPomas), somatostatinomas, and medullary carcinoma of the thyroid.50,51 These tumors produce peptides and other mediators that affect intestinal mucosal and muscle function and thereby produce diarrhea. In most cases, rapid intestinal transit seems to be the major mechanism producing diarrhea in these disorders, although this remains controversial.

Other tumors that produce secretory diarrhea include colon cancer (mechanism uncertain), villous adenoma of the rectum, lymphoma, and mastocytosis. Mastocytosis (and probably some lymphomas) produce diarrhea by release of histamine or other mediators that affect gut function. Infiltration of the mucosa also may play a role in some cases.

Secretory diarrhea can also be idiopathic.52 Idiopathic secretory diarrhea occurs in both sporadic and epidemic forms and may be caused by an as-yet unidentified infection.

INFLAMMATORY DIARRHEA

Inflammatory diarrhea is characterized by the presence of blood and pus in the stools, which usually occurs as a result of ulceration of the mucosa. Inflammatory bowel diseases, such as Crohn disease and ulcerative colitis, are in this category [see 4:IV Inflammatory Bowel Diseases]. Some patients with diverticulitis and diarrhea may have blood and pus in the stool, as do patients with the rare condition ulcerative jejunoileitis. Ulcerating infectious diseases may also produce inflammatory diarrhea. Such infections include pseudomembranous colitis from C. difficile infection; invasive bacterial infections, such as tuberculosis and yersiniosis; ulcerating viral infections, such as those caused by cytomegalovirus or herpesvirus; and invasive parasitic infections, such as amebiasis and Strongyloides. Inflammatory diarrhea also may be seen with ischemic colitis and radiation colitis, as well as colon cancer and lymphoma.

FATTY DIARRHEA

Fatty diarrhea may be caused by fat malabsorption resulting from mucosal diseases, such as celiac disease or Whipple disease; short bowel syndrome secondary to extensive surgical resection of the small intestine; small bowel bacterial overgrowth syndrome; and mesenteric ischemia. Fatty diarrhea also may be the consequence of maldigestion of fat caused by pancreatic exocrine deficiency or inadequate luminal bile acid concentration [see 4:XI Diseases Producing Malabsorption and Maldigestion].

Diagnosis

Medical history

An accurate medical history is even more important in cases of chronic diarrhea than in acute diarrhea. In addition to all the issues that should be discussed with patients who have acute diarrhea [see Acute Diarrhea, above], the history of patients with chronic diarrhea should include long-term trends in body weight, current appetite and food intake, review of previous medical problems and surgeries, potential secondary gains from illness, previous evaluations and treatments for diarrhea, and a detailed review of systems to look for clues to systemic illnesses [see Table 4].

Table 4 Steps in the Evaluation and Classification of Chronic Diarrhea3

Step

Elements

Findings/Considerations

History

Onset

Congenital, abrupt, gradual

Pattern

Continuous, intermittent

Duration

Epidemiologic features

Travel, food, water

Stool characteristics

Watery, bloody, fatty

Fecal incontinence

Abdominal pain

Occurs in inflammatory bowel disease, irritable bowel syndrome, ischemia

Weight loss

May be severe in malabsorption or neoplasm

Aggravating factors

Diet, stress

Mitigating factors

Diet, over-the-counter drugs, prescription drugs

Previous medical evaluation

Iatrogenic diarrhea

From drugs, radiation, surgery

Factitious diarrhea

Laxatives; may be surreptitious

Systemic disease

Diarrhea may complicate hyperthyroidism, diabetes mellitus, collagen vascular disease, tumor syndromes, AIDS, immunoglobulin deficiencies

Routine laboratory tests

CBC

Anemia, leukocytosis

Serum chemistry

Fluid/electrolyte status, nutritional status, serum protein/globulin

Stool analysis

Weight

Electrolytes

For calculating fecal osmotic gap

pH

Acid stools suggest carbohydrate malabsorption

Stool leukocytes

Found in inflammatory diarrhea

Fat output

Can be assessed by Sudan stain or quantitatively

Laxative screen

 

Categorization

Watery diarrhea (secretory or osmotic)

 

Inflammatory diarrhea

Fatty diarrhea

 

A principal diagnostic distinction in chronic diarrhea is between diarrhea associated with irritable bowel syndrome and diarrhea associated with other functional or organic problems. Irritable bowel syndrome is characterized by abdominal pain associated with defecation and an altered bowel habit.53 Variable stool consistency and intermittent constipation are common. Painless diarrhea should no longer be considered to be a type of irritable bowel syndrome; other causes of diarrhea should be sought in such cases.

Physical examination

The physical examination may provide clues to the diagnosis of chronic diarrhea. Characteristic skin changes may be seen in mastocytosis, glucagonoma, Addison disease, amyloidosis, carcinoid syndrome, Degos disease, and celiac disease. Amyloidosis may produce orthostatic hypotension and hepatosplenomegaly. Thyroid nodules or findings of hyperthyroidism may suggest medullary carcinoma of the thyroid or thyroid adenoma causing hyperthyroidism. Carcinoid syndrome may produce hepatosplenomegaly, edema, and a right-sided heart murmur in addition to flushing. Arthritis may be a clue to inflammatory bowel disease, Whipple disease, and some enteric infections. Lymphadenopathy could be present in patients with AIDS or lymphoma. The absence of peripheral arterial pulses or bruits suggests the possibility of mesenteric vascular disease. Rectal examination may disclose defective functioning of the anal sphincter or pelvic floor muscle, which could produce fecal incontinence. The physical findings that reflect the severity of diarrhea should also be recorded [see Acute Diarrhea, above].

Laboratory tests

As in acute diarrhea, routine laboratory testing is indicated to help determine the severity of chronic diarrhea [see Acute Diarrhea, above]. Unlike acute diarrhea, in which stool analysis is typically not used, stool analysis plays a key role in the assessment of chronic diarrhea by allowing adequate categorization of the type of diarrhea, thereby limiting the number of conditions to be considered.3 The stool analysis can be obtained on either a random sample or a timed collection. The value of a timed collection is that it allows the physician to quantitate stool output accurately. However, stool analysis obtained on a random sample can still provide many diagnostic clues.

Stool tests

Stool characteristics to measure include stool sodium and potassium concentrations, osmolality, and pH. Fecal occult blood testing and examination of stool for WBCs (or a surrogate chemical test, such as fecal lactoferrin concentration) should be conducted. Stool fat output should be measured quantitatively or assessed qualitatively with a Sudan stain of a fecal smear.

Measurement of stool electrolyte concentrations allows calculation of the fecal osmotic gap [see Fecal Osmotic Gap, above]. This can be used to identify watery diarrhea as being osmotic or secretory. Measurement of actual stool osmolality is only of value in detecting samples that have been contaminated with water or dilute urine and therefore have an osmolality less than 290 mOsm/kg. Stool osmolality rises rapidly in vitro because of bacterial fermentation, so the actual measurement should not be used to calculate the fecal osmotic gap. The pH of stool water can indicate whether or not carbohydrate malabsorption is present. Carbohydrates (or sugar alcohols) that are not absorbed in the small bowel and that reach the bacterial flora of the colon are fermented into short-chain fatty acids that reduce fecal pH, usually to less than 6. Thus, acid stools suggest carbohydrate malabsorption.8

Fatty diarrhea can be identified by measurement of stool fat, although careful interpretation of the results is sometimes necessary [seeSteatorrhea, below]. When appropriate, a laxative screen should be obtained. Measurement of laxatives by chemical or chromatographic methods can detect surreptitious laxative ingestion.

Completion of the stool analysis allows the clinician to characterize chronic diarrhea as being watery (whether secretory or osmotic diarrhea), inflammatory, or fatty. The subsequent evaluation depends on this categorization.

Evaluation of Watery Secretory Diarrhea

Secretory diarrhea is associated with many disorders; a thorough evaluation is therefore needed to identify the underlying cause [see Figure 3].

 

Figure 3. Evaluation of Chronic Secretory Diarrhea

Evaluation of chronic secretory diarrhea.3 Every test does not need to be done for every patient.

Stool tests

Infection should be excluded by stool culture for bacteria, stool assay for C. difficile toxin, and other tests for parasites, including ELISA for giardiasis. Biopsies of the small bowel or colon may be necessary to find the pathogens, especially in patients with AIDS or other immunodeficiencies. Small bowel aspirate for quantitative culture is the best test for detecting small bowel bacterial overgrowth.

Imaging and endoscopic tests

Structural diseases (e.g., short bowel syndrome or fistula, mucosal diseases, inflammatory bowel disease, and tumors) should be sought by radiographic and endoscopic testing. Small bowel radiography remains an important test in such cases. CT scans can detect small bowel and colonic disease, as well as problems extrinsic to the gut that may cause diarrhea, such as endocrine tumors. Inspection of the colonic mucosa by colonoscopy or sigmoidoscopy is essential in patients with secretory diarrhea, both to evaluate for gross changes and to obtain biopsy samples to look for evidence of microscopic colitis syndrome. Biopsies should be obtained even if the gross appearance of the colon is normal, because of the prevalence of microscopic colitis syndrome in patients with chronic watery diarrhea. A long endoscope that can reach the jejunum to obtain biopsy samples and aspirates is a valuable adjunct when other studies are unrevealing. The role of capsule endoscopy in the evaluation of patients with chronic diarrhea is under investigation; studies suggest that it may be helpful in detecting Crohn disease and, perhaps, celiac disease.54,55,56 However, capsule endoscopy does not allow for biopsy of abnormalities that are visualized during the procedure, which limits its utility. Double-balloon enteroscopy offers the possibility of visualizing and obtaining biopsies from the entire small intestine; this technique may find a place in the evaluation of patients with watery secretory diarrhea.57

Serum peptide measurement

Because diarrheagenic endocrine tumors are very rare, the measurement of serum peptides (e.g., gastrin, vasoactive intestinal polypeptide, calcitonin, and glucagons) or urinary excretion of secretagogue metabolites (e.g., 5-hydroxyindoleacetic acid or metanephrine) should be restricted to patients with symptoms consistent with tumor syndromes or those in whom a diagnosis remains elusive after initial testing.58More common endocrine problems, such as diabetes, hyperthyroidism, or Addison disease, should be excluded with appropriate blood tests.

Bile acid absorption measurement

Ileal resection or ileal disease can result in the escape of sufficient bile acid into the colon to increase luminal bile acid concentrations above 3 to 5 mmol. At these concentrations, bile acids reduce colonic mucosal water and electrolyte absorption; alternatively, they stimulate secretion, resulting in increased stool water. In most circumstances, bile acid malabsorption can be inferred from a history of ileal resection or disease. More controversial is the concept that bile acid malabsorption occurring in the absence of ileal resection or obvious ileal disease is responsible for idiopathic secretory diarrhea.59 Although bile acid malabsorption can be documented in many of these patients, administration of bile acid-binding resins does not always mitigate the diarrhea, casting doubts on bile acid malabsorption as the cause of the diarrhea.49 Therefore, in patients with secretory diarrhea that appears to be idiopathic, it is more practical to give a therapeutic trial of bile acid-binding resins than to measure bile acid malabsorption directly.

Evaluation of Watery Osmotic Diarrhea

Because osmotic diarrhea has fewer potential causes than secretory diarrhea, the evaluation is simpler [see Figure 4]. If stool water has low electrolyte concentrations (and therefore a high fecal osmotic gap), some other substance is taking up the osmotic space and is holding water in the lumen. In practice, this substance is usually magnesium ingestion or carbohydrate malabsorption.

 

Figure 4. Evaluation of Chronic Osmotic Diarrhea

Evaluation of chronic osmotic diarrhea.3 Every test does not need to be done for every patient.

Magnesium ingestion

Magnesium can be measured accurately in stool water. Excretion of more than 15 mmol (30 mEq) daily or concentrations greater than 45 mmol/L (90 mEq/L) strongly suggest magnesium-induced diarrhea.60 This diarrhea may be intentional (surreptitious laxative ingestion) or accidental (magnesium-containing antacids or mineral supplements).

Carbohydrate malabsorption

Carbohydrate malabsorption can occur from ingestion of poorly absorbable carbohydrates, such as lactose in someone with lactase deficiency, or from reduced carbohydrate absorption as a result of small bowel mucosal disease. In addition to ingestion of lactose, common causes of osmotic diarrhea include excessive ingestion of fructose (often used as a sweetener in commercial products),61 ingestion of poorly absorbed sugar alcohols (such as mannitol and sorbitol, which are used as low-calorie sweeteners), and use of inhibitors of carbohydrate absorption, such as acarbose. Because malabsorbed carbohydrate is rapidly fermented by colonic bacteria, gas and bloating are frequent symptoms. Diagnosis is made on the basis of a finding of low stool pH (typically less than 6) and a thorough dietary history.

Evaluation of Chronic Inflammatory Diarrhea

Patients with WBCs or blood in the stool are classified as having inflammatory diarrhea. Causes may include inflammatory bowel disease, infections, ischemia, radiation enteritis, and neoplasia [see Table 3]. Sometimes, these conditions produce a watery, secretory diarrhea without blood or pus in the stool; therefore, they must also be considered in the evaluation of that type of diarrhea [see Evaluation of Watery Secretory Diarrhea, above].

Imaging and endoscopic tests

Evaluation of patients with chronic inflammatory diarrhea should start with radiographic and endoscopic tests to look for structural problems [see Figure 5]. Sigmoidoscopy or colonoscopy should be considered first, because colitis is a common cause of inflammatory diarrhea. Biopsies should be performed to properly categorize colitis. CT has proved useful in many patients with inflammatory diarrhea because of the ability of CT to visualize inflammatory changes in the small bowel and colon and to identify complications of inflammation, such as abscess.

 

Figure 5. Evaluation of Chronic Inflammatory Diarrhea

Evaluation of chronic inflammatory diarrhea.3 Every test does not need to be done for every patient.

Infections that may produce chronic diarrhea, such as C. difficile, cytomegalovirus, amebiasis, and tuberculosis, need to be excluded by culture, biopsy, or serologic testing. It is important to realize that infection may complicate the courses of established problems, such as ulcerative colitis or Crohn disease. Patients with AIDS need an especially careful search for opportunistic infections.

Evaluation of Chronic Fatty Diarrhea

Steatorrhea

Excessive fat in the stool, or steatorrhea, implies a problem with fat solubilization, digestion, or absorption in the small intestine. Steatorrhea is usually defined as stool fat output of more than 7 g over 24 hours or daily output of more than 9% of the intake of fat. These criteria may not be valid in patients with diarrhea, however, because voluminous stools per se may increase fat excretion. In one study, artificially induced diarrhea produced mild steatorrhea of up to 14 g/24 hr in 35% of normal persons.62 Thus, in patients with diarrhea, fecal fat excretion of up to 14 g/24 hr has a low specificity for the diagnosis of defective fat absorption. The threshold for the diagnosis of steatorrhea also should be corrected for fat intake, because some patients with diarrhea have anorexia and some patients with steatorrhea have hyperphagia. When possible, fat intake should be estimated from diet diaries that are maintained during the collection period. Finally, measurement of fat excretion can be compromised by ingestion of poorly absorbed fat substitutes, such as olestra.

Qualitative estimation of fat excretion by Sudan stain of a fecal smear can be used when a timed collection or quantitative analysis is not possible. Semiquantitative methods employing assessment of the number and size of fat globules correlate well with quantitative analysis of fat excretion.

The fecal fat concentration may provide a clue to the etiology of steatorrhea. The major causes of steatorrhea are mucosal diseases (e.g., celiac disease), pancreatic exocrine insufficiency (e.g., chronic pancreatitis), and lack of bile acids (e.g., advanced biliary cirrhosis). Mucosal diseases are often associated with reduced fluid and electrolyte absorption; as a result, fat is diluted by unabsorbed water. Furthermore, in mucosal disease, fat still can be digested to fatty acids, which can inhibit water absorption in the colon. In contrast, diseases that alter fat solubilization or digestion typically do not alter mucosal water and electrolyte absorption; as a result, unabsorbed fat is disbursed in a smaller stool volume. Fecal fat concentrations of more than 9.5 g/100 g strongly suggest pancreatic or biliary steatorrhea. Assessment of patients with chronic fatty diarrhea should therefore begin with measurement of fecal fat excretion and concentration [seeFigure 6].

 

Figure 6. Evaluation of Chronic Fatty Diarrhea

Evaluation of chronic fatty diarrhea.3 Every test does not need to be done for every patient.

Imaging and endoscopic tests

If the cause of steatorrhea is not obvious from the patient's history and the results of fecal fat assessment, the next step is evaluation of the absorptive surface of the small intestine by endoscopic, histologic, and radiographic tests. During endoscopy, small bowel biopsies should be obtained for histologic analysis, and small bowel contents should be aspirated for quantitative culture to assess for small bowel bacterial overgrowth. Indirect tests, such as measurement of antigluten (antiendomysial) antibodies or tissue transglutaminase antibodies for the diagnosis of celiac disease or breath tests for bacterial overgrowth, have not displaced endoscopic testing as the gold standard for diagnosis of these conditions. Such tests, however, may be useful in some cases. Small bowel radiography and CT are valuable adjuncts for structural assessment in patients with steatorrhea.

If the absorptive surface is normal, attention should shift to luminal problems with fat solubilization or digestion. Testing for pancreatic exocrine insufficiency is rarely done, because of unwillingness to use duodenal intubation tests. An indirect test, such as measurement of stool chymotrypsin activity, has limited sensitivity and specificity. The best test for pancreatic exocrine insufficiency may be a therapeutic trial of pancreatic enzyme supplementation. If this is done, a large dose of enzymes should be administered and objective measurement of fat excretion should be monitored to assess the response to therapy. Likewise, testing for the adequacy of bile salt solubilization of fat is rarely done. If necessary, duodenal bile salt concentration can be measured.

TREATMENT

Nonspecific Therapy

Nonspecific therapy is used in patients with chronic diarrhea in three situations: (1) as a temporizing or initial therapy before diagnostic testing, (2) after diagnostic testing has failed to result in a diagnosis, and (3) when a diagnosis has been made, but no specific treatment is available or specific treatment has failed.22

Antibiotic therapy

Antibiotics are less useful in chronic diarrhea than in acute diarrhea because bacterial infection is less likely to be the cause of chronic diarrhea. Nevertheless, many clinicians try an empirical course of metronidazole or a fluoroquinolone before starting an extensive evaluation.

Symptomatic therapy with antidiarrheal drugs is often required in patients with chronic diarrhea [see Table 2]. Loperamide or diphenoxylate with atropine can be tried initially. In patients with chronic diarrhea, routine dosing (e.g., two tablets before each meal or at bedtime) is more effective than as-needed dosing after passing loose stools. More potent opiates, such as codeine, opium, and morphine, are underutilized in patients who do not respond to loperamide or diphenoxylate with atropine. Although these are controlled substances because of the possibility of abuse, abuse is unlikely in closely monitored patients with chronic diarrhea. Dosing should be started at a low level (e.g., codeine, 30 mg q.i.d.; deodorized tincture of opium, 3 drops q.i.d.; or morphine, 2 mg q.i.d.) and titrated up gradually to an effective dose. Stool-modifying agents, such as psyllium, can alter stool consistency but do not reduce stool weight. They may be of special help in patients with coexisting fecal incontinence.

Treatment of Specific Diseases and Syndromes

Osmotic diarrhea

Osmotic diarrhea should abate with fasting or elimination of the offending agent from the diet. This response may be incomplete if other diarrhea-producing mechanisms are still active, such as short bowel syndrome or diseases of small bowel mucosa.

Irritable bowel syndrome and functional diarrhea

Patients with chronic diarrhea in whom no other etiology is established are commonly diagnosed with irritable bowel syndrome or functional diarrhea. Irritable bowel syndrome is characterized chiefly by abdominal pain that is associated with altered bowel function, including constipation, diarrhea, or alternating diarrhea and constipation.53 A diagnosis of functional diarrhea is made when patients do not have prominent abdominal pain and have no evidence of other specific causes of diarrhea. Obviously, these diagnoses are only as firm as the evaluation that is used to exclude other causes of diarrhea. For example, most cases of diarrhea from malabsorption of bile acid or carbohydrates are characterized as functional diarrhea or irritable bowel syndrome because specific testing for those malabsorption disorders is not done. Thus, careful consideration of alternative diagnoses should precede a diagnosis of irritable bowel syndrome or functional diarrhea in patients with chronic diarrhea.

Nevertheless, there are certain clues to the diagnosis of irritable bowel syndrome or functional diarrhea that should be sought by the physician. Features that suggest a diagnosis of irritable bowel syndrome include a long history of diarrhea dating back to adolescence or young adulthood; passage of mucus; and exacerbation of symptoms with stress. Historical points that argue against irritable bowel syndrome include recent onset of diarrhea, especially in older individuals; nocturnal diarrhea; weight loss; blood in stools; voluminous stools (> 400 g/24 hr); and blood tests indicating anemia, leukocytosis, a low serum albumin concentration, or a high erythrocyte sedimentation rate.

New treatments for irritable bowel syndrome are being developed63 in response to current theories about the pathogenesis of this disorder; pathogenetic processes that may yield new treatment strategies include dysregulation by the enteric nervous system,64 food allergies,65small bowel bacterial overgrowth,66 and changes in the colonic bacterial flora.67

Microscopic colitis syndrome

Microscopic colitis syndrome, which subsumes the diagnoses of lymphocytic colitis and collagenous colitis, is a frequent cause of chronic diarrhea.45,68,69 This disorder is characterized by chronic watery diarrhea and microscopic evidence of mucosal inflammation in the presence of normal gross colonoscopic findings. Histologic findings in both lymphocytic colitis and collagenous colitis include intraepithelial lymphocytic infiltration and chronic inflammation in the lamina propria without crypt destruction. Collagenous colitis and lymphocytic colitis are distinguished by the presence or absence of a thickened subepithelial collagen layer.

The cause of microscopic colitis syndrome is uncertain. It is associated with many autoimmune disorders and immunologically mediated diseases, such as celiac disease, which suggests that immune dysregulation is important. Bacterial antigens within the colonic lumen may also play a role. NSAIDs have been implicated in some reports.

Women are more likely than men to have collagenous colitis; lymphocytic colitis is equally likely in men and women. Diarrhea is of moderate severity (typically, 500 to 1,000 g/24 hr) and is characteristically secretory in nature because it results from failure of the colonic mucosa to absorb water and salt. Diagnosis is made by obtaining biopsy material from normal-appearing mucosa at the time of sigmoidoscopy or colonoscopy.

Treatment options include budesonide, bismuth subsalicylate, 5-aminosalicylate drugs, prednisone, and azathioprine.45,68,69 Bile acid-binding drugs also have been reported to be successful in reducing diarrhea.70 Microscopic colitis can have a remitting and relapsing course, and symptomatic therapy with opiate antidiarrheal drugs may be all that is needed. There is no evidence that microscopic colitis is a risk factor for colon carcinoma, and no surveillance program is currently recommended.

Laxative abuse

Although rarely suspected, laxative abuse occurs regularly in four groups of patients: (1) those with anorexia or bulimia, (2) those who obtain a secondary gain from illness (e.g., disability payments, attention from relatives), (3) those with Munchausen syndrome, and (4) those who are dependent on others for their health care and who are poisoned by their caregivers (caregivers who do this are usually motivated by the desire to demonstrate their devotion to the patients).71 Physicians need to consider surreptitious laxative abuse in patients who confound diagnosis and who are in one of the categories.

Detection of laxative abuse depends on having a high index of suspicion. Clues include the presence of hypokalemia in a patient who is able to eat (suggesting stimulant laxative abuse or concurrent ingestion of diuretics), melanosis coli (brownish pigmentation in the colonic mucosa caused by ingestion of anthraquinone laxatives) in a patient being evaluated for chronic diarrhea, or a large fecal osmotic gap (seen with magnesium ingestion). Most laxatives can be detected in stool water by chemical techniques. Adulteration of stool by added water or hypotonic urine can be detected by finding a low measured stool osmolality (< 280 mOsm/kg). The addition of hypertonic urine can be detected by impossibly high stool osmolality (> 600 mOsm/kg) and the presence of a negative fecal osmotic gap resulting from high urinary sodium or potassium concentrations. Negative fecal osmotic gaps may also be calculated in patients ingesting laxatives containing phosphate or sulfate.

Before patients are confronted with the diagnosis of laxative abuse, testing should be confirmed on another stool specimen, and appropriate psychiatric consultation should be available, because some of these patients become suicidal when confronted, and all of them need counseling. In cases of laxative poisoning by a caregiver, legal proceedings need to be instituted to separate the patient from the caregiver. Outcome studies in laxative-abuse patients are few. One study suggested that nearly half of the patients sought further medical attention elsewhere for chronic diarrhea.72

Postsurgical diarrhea

Diarrhea can occur after several different kinds of operations. Peptic ulcer surgery is less common than it used to be, but new kinds of gastric operations, such as gastric bypass for obesity, produce similar complications. Dumping syndrome is the term used to describe a condition characterized by postprandial flushing, hypotension, diarrhea, and hypoglycemia.73 This syndrome results from unregulated gastric emptying, osmotic shifts of fluid into the gut, and the rapid release of peptide hormones from the small intestine. Dumping syndrome can occur after vagotomy (intentional or accidental), pyloroplasty, gastrojejunostomy, and gastric resection. It can be treated with dietary modifications, antidiarrheal drugs [see Table 2], and the somatostatin analogue octreotide. Gastric surgery may also predispose patients to bacterial overgrowth in the small intestine, abnormally rapid intestinal transit, bile acid malabsorption, and pancreatic exocrine insufficiency from inadequate stimulation of the pancreas.

Bowel resection can result in loss of surface area sufficient to impair absorption of nutrients or water and salt. Lesser degrees of resection can result in diarrhea if an area of specialized function is removed.74 For example, resection of the terminal ileum and right colon reduces bile acid absorption and the ability to absorb sodium against a large electrochemical gradient; these defects cannot be overcome by other areas of the intestine. With time, intestinal adaptation can overcome impaired electrolyte absorption, but intestinal adaptation cannot reverse loss of these specialized functions.

Ileostomy diarrhea is said to occur when stoma output exceeds 1,000 ml/24 hr. It may be caused by loss of absorptive surface area, if a substantial length of bowel has been resected; it may result from stomal stenosis, partial bowel obstruction, bacterial overgrowth, recurrent disease, medications, or intraperitoneal infection.75 A special situation occurs in patients with ulcerative colitis who have had an ileoanal anastomosis with creation of an ileal reservoir pouch. These patients may develop inflammation of the pouch (so-called pouchitis) caused by bacterial overgrowth or recurrent inflammatory bowel disease.76 Pouchitis can be treated with antibiotics such as metronidazole, anti-inflammatory drugs such as mesalamine, or ingestion of probiotic bacteria. Ordinary ileostomy diarrhea can be treated successfully with antidiarrheal opiate drugs.

Postcholecystectomy diarrhea occurs in as many as 20% of patients. It may be delayed in onset, and it is rarely severe. Diarrhea may occur as a result of ileal bile acid malabsorption at night, when the migrating motor complex may sweep bile acid past the absorptive sites in the terminal ileum, but some cases may have other causes.77 Postcholecystectomy diarrhea is best treated with bile acid-binding agents given at bedtime. Opiate antidiarrheal drugs may be needed in refractory cases.

Diabetic diarrhea

Up to 30% of patients with long-standing diabetes mellitus may experience chronic diarrhea.78 This diarrhea has been attributed to autonomic neuropathy and dysregulation of motility, but definitive evidence of neuropathy is not always evident. If steatorrhea is present, three conditions that occur with increased prevalence in diabetics should be considered: (1) small bowel bacterial overgrowth, (2) pancreatic exocrine insufficiency, and (3) celiac disease. Other causes that need to be considered are medications, such as acarbose, and ingestion of dietetic foods containing sugar alcohols (e.g., sorbitol or mannitol).

When watery diarrhea is present, treatment with clonidine, an alpha2-adrenergic agonist drug, may have special value. When clonidine cannot be tolerated because of its hypotensive effect or when it is not effective, opiate antidiarrheal drugs may be used. Fecal incontinence related to diabetic sensorimotor neuropathy may complicate diarrhea; this form of diarrhea needs to be evaluated, because therapies to mitigate incontinence, such as bio feedback training, may have a dramatic effect on quality of life.79

Diarrhea in patients with AIDS

Diarrhea in AIDS patients is likely to result from opportunistic infections or lymphoma. A careful search for the cause of diarrhea can result in targeted therapy that may cure the diarrhea.80 Colonoscopy is preferable to sigmoidoscopy because it allows visualization and biopsy of the right colon and ileum, which are often the sites of infection. It is possible that HIV-1 may directly produce diarrhea (so-called AIDS enteropathy), but in most cases, a specific infection can be identified.

Idiopathic secretory diarrhea

The diagnosis of idiopathic secretory diarrhea can be made when an exhaustive evaluation fails to reveal a cause of chronic secretory diarrhea. This condition often begins suddenly in previously normal individuals, and it is distinguished from the acute secretory diarrhea by its persistence for more than 4 weeks. It occurs in two forms, epidemic and sporadic.

Epidemic idiopathic secretory diarrhea occurs in outbreaks that are seemingly related to contaminated food or water.81 The initial description of this condition involved an epidemic of chronic diarrhea in Brainerd, Minnesota, and the condition has consequently become known as Brainerd diarrhea. Several outbreaks have been described in detail since the initial epidemic, and although the epidemiology suggests an infectious cause, no organism has been isolated.

Sporadic idiopathic secretory diarrhea affects individuals in an identical fashion as the epidemic form, but it does not seem to be acquired easily by family members or others.52 Many patients describe a history of travel to local lakes or recreational sites, but they are the only members of their parties that become ill.

Both forms of idiopathic secretory diarrhea begin abruptly and reach maximum intensity shortly thereafter. Fever is unusual. Weight loss of up to 20 lb characteristically occurs in the first few months of the illness, but it does not become progressive thereafter. Empirical trials of antibiotics and bile acid-binding drugs are ineffective, but nonspecific opiate antidiarrheal drugs provide some relief. Idiopathic secretory diarrhea is self-limited and usually disappears within 2 years of onset. The offset of diarrhea is gradual, occurring over 2 to 3 months.

Diarrhea of obscure origin

Diarrhea of obscure origin is said to be present when chronic diarrhea has evaded diagnosis in spite of an evaluation for structural problems. Patients are often referred commonly to centers interested in diarrheal diseases, where a specific cause for their diarrhea is often identified. Common diagnoses in these patients include fecal incontinence, drug-induced diarrhea, surreptitious laxative ingestion, microscopic colitis syndrome, bile acid-induced diarrhea, pancreatic exocrine insufficiency, carbohydrate malabsorption, sporadic chronic idiopathic secretory diarrhea, and, rarely, endocrine tumors. Most of these conditions can be recognized with a careful history, an appropriate index of suspicion, proper testing, or a well-conducted therapeutic trial. Failure to make a diagnosis is usually the result of not thinking through the differential diagnosis of chronic diarrhea and not appreciating the evidence at hand.

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Editors: Dale, David C.; Federman, Daniel D.