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With a complaint of
"diarrhea," the physician must establish if this represents a
change in the patient's bowel habit and if the complaint arises from a
perception of increased frequency of stool, increased volume or both.
If the diarrhea is acute (i.e., lasting less than two
weeks), the malabsorption of fluid and electrolytes probably has an
infectious or toxic cause (Table
8). When diarrhea lasts for a longer period of time, other
explanations need to be considered. In the absence of prior gastric
surgery, the four most common causes of chronic diarrhea are (1) the
irritable bowel syndrome; (2) inflammatory bowel disease; (3)
malabsorption; and (4) carcinoma of the colon. The physician also must
consider altered bowel function due to drug or alcohol abuse (see Section
11). Bacteria (toxin-mediated,
cytotonic) Viruses Protozoa Parasites Associated tenesmus,
urgency or a sense of incomplete evacuation suggests involvement of the
rectum or sigmoid colon. The passage of blood, pus and mucus suggests
bowel inflammation, ischemic bowel disease or cancer. Malassimilation
syndromes (discussed in the previous section) are suspect if there is
passage of food and oil droplets, or if the patient develops symptoms
suggestive of nutrient deficiency, particularly weight loss.
In Western societies, stool weight is approximately 200
g/day. Since stools are 70-90% water, regardless of their consistency,
excess fecal water must accompany diarrheal diseases with elevated stool
weight. This concept leads directly to consideration of the mechanisms
responsible for the malabsorption or stimulated secretion of water.
Two caveats need to be remembered. First, fecal bulk
varies with the diet, being influenced most notably by the content of
indigestible carbohydrates (dietary fiber). Stools are smaller in
developed countries than they are among societies whose members regularly
ingest large amounts of dietary fiber. Second, disease of the distal colon
or rectum can lead to the frequent, often painful passage of small stools
(due to limited capacity as a reservoir), yet there may be little fecal
water and no increase in stool weight. In fact, "constipation"
may be common in patients with proctitis.
Acute diarrhea is thus defined as stool weight > 200 g/day for less
than 14 days' duration. It always will represent a change in bowel habit
for the individual and will often be associated with an increased
frequency of bowel movements. Most enteric infections are
self-limiting and resolve in less than two weeks. Acute bacterial
diarrheas can be classified into toxigenic types, in which an
enterotoxin is the major pathogenic mechanism, and invasive types,
in which the organism penetrates the enterocyte as a primary event,
although an enterotoxin may be produced as well. Enterotoxins are either cytotonic
(producing intestinal fluid secretion by activation of intracellular
enzymes, without damage to the epithelial surface) or cytotoxic
(causing injury to the enterocyte as well as inducing fluid secretion).
Three major clinical syndromes caused by bacterial infections are (1) food
poisoning, (2) infectious gastroenteritis and (3) traveler's diarrhea. 10.1.1 FOOD POISONING The food poisoning syndrome
characteristically features the development of a brief but explosive
diarrheal illness in subjects following exposure to a common food source
contaminated with bacteria or bacterial toxins. Staphylococcus aureus,
Salmonella, Clostridium perfringens and Bacillus cereus are responsible
for 90% of these outbreaks.
Staphylococcus aureus produces a heat-stable, odorless
and tasteless enterotoxin that is generated in poorly refrigerated
desserts and seafoods. Ingestion of the preformed enterotoxin causes
nausea, vomiting and profuse diarrhea within 4 to 8 hours. Spontaneous
resolution occurs within 24 hours. No specific therapy is available or
necessary.
Clostridium perfringens produces a preformed toxin from
spores that germinate in contaminated meats cooked to less than 50ºC.
Symptoms are diarrhea and crampy abdominal pain without vomiting,
beginning 8 to 24 hours after the meal. The illness lasts less than 24
hours. No specific therapy is indicated.
Bacillus cereus produces either a diarrheal syndrome or
a vomiting syndrome, depending upon the enterotoxin. The vomiting syndrome
is always associated with ingestion of rice and is caused by a preformed
toxin that is elaborated when rice is left to cool unrefrigerated.
Flash-frying later does not generate enough heat to destroy the toxin. The
diarrheal syndrome occurs after ingestion of the organism itself. Both
illnesses are short-lived and require no specific therapy.
The diagnosis of food poisoning is usually made by
history. Except in special circumstances (e.g., botulism), isolation of
the toxin is not cost-effective. 10.1.2 GASTROENTERITIS The organisms responsible
for bacterial gastroenteritis exert their predominant effects by invading
and destroying the intestinal epithelium or by producing various
enterotoxins. 10.1.2.1
Toxin-mediated, cytotoxic bacterial gastroenteritis Vibrio cholerae is the
prototypic cause of toxigenic diarrhea. The Vibrio cholerae organisms
elaborate a toxin that attaches to the inner cell membrane and activates
adenylate cyclase (formerly "adenyl cyclase"). The presence of
adenylate cyclase then elevates cyclic AMP (cAMP) levels. Cyclic AMP then
stimulates the enterocyte to secrete fluid and electrolytes while at the
same time impairing their absorption. Stool output can exceed 1 L/hour.
Treatment is based on restoring fluid and electrolyte balance and
maintaining intravascular volume. Even though fluid and electrolyte
transport is impaired, glucose transport is intact. Since glucose
absorption carries Na+ (and thus water with it), an oral
rehydration solution containing glucose, sodium and water will enhance
water absorption during the profound dehydration stage of cholera.
Several types of Escherichia coli (E. coli) are
intestinal pathogens. Each exerts its effects through different mechanisms
(Table 9). Invasive forms of E. coli may cause colitis that
resembles colitis from other bacterial infections and also may resemble
ischemia clinically, endoscopically and histologically.
Enterotoxigenic E. coli (ETEC) colonizes the upper
small intestine after passing through the acid barrier of the stomach. The
organisms colonize the surface without penetrating the mucus layer. Like
cholera, ETEC causes no mucosal damage and no bacteremia. Two types of
enterotoxins are produced by ETEC: the heat-labile toxin (also called
"labile toxin" or LT) and the heat- stable toxin (also called
"stable toxin" or ST). ETEC can elaborate LT only, ST only, or
both toxins. ST produces diarrhea by stimulating intestinal secretion
through guanylate cyclase and subsequently cyclic GMP. LT produces
diarrhea by a similar mechanism, except that it acts through adenylate
cyclase and cyclic AMP. After a 24- to 48-hour incubation period, the
disease begins with upper abdominal distress followed by watery diarrhea.
The infection can be mild (with only a few loose movements) or severe
(mimicking cholera). Treatment is symptomatic. Antibiotic therapy is
ineffective and favors the emergence of resistant ETEC strains.
Vibrio parahaemolyticus causes acute diarrheal disease
after consumption of seafood: raw fish or shellfish. The common factor in
most outbreaks appears to be storage of the food for several hours without
proper refrigeration. Explosive, watery diarrhea is the cardinal
manifestation, along with abdominal cramps, nausea and vomiting. Fever and
chills occur in 25% of cases. The duration of illness is short, with a
median of three days. Treatment is symptomatic; there is no role for
antimicrobial therapy.
After ingestion, Shigella dysenteriae organisms attack
the colon, sparing the stomach and small bowel. Shigella organisms adhere
to the mucosal surface, penetrate the mucosal surface, and then multiply
within epithelial cells, moving laterally through the cytoplasm to
adjacent cells by filopodium-like protrusions. Shigella organisms rarely
penetrate below the intestinal mucosa and almost never invade the
bloodstream. Both attached and intracellular organisms elaborate toxic
products.
Even a small inoculum of 200 organisms (as contrasted
with Salmonella, which requires greater than 107 organisms)
will lead to crampy abdominal pain, rectal burning and fever associated
with multiple small-volume bloody mucoid bowel movements. Intestinal
complications include perforation and severe protein loss. Extraintestinal
complications include respiratory symptoms, meningismus, seizures, the
hemolytic uremic syndrome, arthritis and rashes. Ampicillin 500 mg q.i.d.
or co-trimoxazole 2 tablets b.i.d. for 5 days is the treatment of choice.
Amoxicillin, interestingly, is not effective therapy for shigellosis.
Salmonella food poisoning has been attributed to an
enterotoxin similar to that of Staphylococcus aureus, but none has been
clearly identified. Within 12 to 36 hours after ingestion of contaminated
foods (usually poultry products), there is a sudden onset of headaches,
chills and abdominal pain, with nausea, vomiting and diarrhea. These
symptoms may persist for one to four days before subsiding. Antibiotic
therapy of nontyphoidal Salmonella gastroenteritis fails to alter the rate
of clinical recovery. In fact, antibiotic therapy will increase the
duration of intestinal carriage of the Salmonella and is thus
contraindicated.
Campylobacter jejuni-induced diarrhea is more common
than diarrhea from either Salmonella or Shigella. Infection is from
consumption of improperly cooked or contaminated foodstuffs. Campylobacter
attaches to the mucosa and releases an enterotoxin that destroys the
surrounding epithelia. Clinically, there is often a prodrome of
constitutional symptoms along with headache and generalized malaise. A
prolonged diarrheal illness follows - often with a biphasic character,
with initial bloody diarrhea, slight improvement, then increasing
severity. The illness usually lasts less than one week, although symptoms
can persist for a longer period, and relapses occur in as many as 25% of
patients. Erythromycin 500 mg q.i.d. for 7 days is optimal therapy.
Yersinia enterocolitica is often transmitted to humans
from pets or food sources. The organism invades epithelial cells and
produces an enterotoxin. Clinically, the spectrum of illness ranges from
simple gastroenteritis to invasive ileitis and colitis. This organism
causes diarrheal illness most frequently in children less than 5 years of
age. Children over 5 years of age develop mesenteric adenitis and
associated ileitis, which mimic acute appendicitis. Yersinia is less
likely to cause disease in adults; if it does, the illness is an acute
diarrheal episode that may be followed two to three weeks later by joint
symptoms and a rash (erythema nodosum). Treatment is symptomatic. There is
no evidence that antibiotics alter the course of the gastrointestinal
infection.
Clostridium difficile causes antibiotic-associated
colitis (Section 10.4). 10.1.2.2 Invasive bacterial gastroenteritis Certain strains of E. coli are invasive, producing an
illness indistinguishable from shigellosis. Isolates of E. coli 0157:H7
have been identified in the stools of patients with a diarrheal illness
clinically designated as "hemorrhagic colitis." Infection has
been traced to contaminated hamburger meat obtained from a variety of
sources, including large national restaurant chains.
Ingestion of this organism results in severe crampy
abdominal pain and fever, followed within 24 hours by bloody diarrhea that
lasts five to seven days. Since the organism is shed in the stool for only
a short period of time, early stool collections are critical for the
diagnosis. Treatment is symptomatic, as antibiotics do not appear to alter
the disease course. In severe cases with possible toxic megacolon,
systemic antibiotics may be in order.
Approximately 1,700 serotypes and variants of
Salmonella are potential pathogens for humans. A dose of approximately 107-109
organisms is required to produce a clinical illness. Salmonella organisms
invade the mucosa of the small intestine and (particularly) the colon.
This form of gastroenteritis produces nausea and vomiting followed by
abdominal cramps and diarrhea that lasts three to four days and then
gradually subsides. In 10% of the cases bacteremia of the Salmonella
organism occurs, and in approximately 5% there are disseminated infections
to bones, joints and meninges. Certain conditions increase the risk of
salmonellosis: hemolytic anemia, malignancy, immunosuppression,
achlorhydria and ulcerative colitis. With uncomplicated Salmonella
gastroenteritis, treatment is symptomatic. In fact, antibiotic therapy
increases the duration of intestinal carriage of these organisms. Patients
with complicated Salmonella gastroenteritis (e.g., those with predisposing
conditions or sepsis, or who are very young or very old) should be treated
with ampicillin or co-trimoxazole. 10.1.2.3 Bacterial gastroenteritis of unknown
mechanism Enterohemorrhagic E. coli-induced diarrhea tends to
occur in neonates and young children. Only occasionally does it affect
older children and adults. The pathogenic mechanism of this diarrhea is
unclear; adherence of the organism to the intestinal epithelial cell seems
to cause intestinal damage. There is no indication for specific treatment
except for neonates in a nursery epidemic. In this case, oral
nonabsorbable aminoglycosides should be used. 10.1.3 TRAVELER'S DIARRHEA Traveler's diarrhea is a syndrome characterized by an
increase in frequency of unformed bowel movements, typically four to five
loose stools per day. Associated symptoms include abdominal cramps,
nausea, bloating, urgency, fever and malaise. Traveler's diarrhea usually
begins abruptly, during travel or soon after returning home, and is
generally self-limiting, lasting three to four days. Ten percent of cases
persist longer than one week, approximately 2% longer than one month and
very few beyond three months. Enterotoxigenic E. coli (ETEC) is the most
common causative agent of traveler's diarrhea. These organisms adhere to
the small intestine, where they multiply and produce an enterotoxin that
causes fluid secretion and hence diarrhea. Salmonella gastroenteritis,
Shigella dysentery, and viral enteric pathogens (rotavirus and
Norwalk-like virus) are less common causes of traveler's diarrhea.
Since traveler's diarrhea is usually mild and
self-limiting, with complete recovery even in the absence of therapy,
therapy should be considered optional (Table
10). TABLE 10. Traveler's diarrhea: recommendations for treatment General Specific To decrease severity of acute attack:
Prophylaxis: The value of prophylaxis for travelers is unclear.
Bismuth preparations are helpful, but their use is limited by the large
volumes necessary and by their taste. Antibiotic prophylaxis can reduce
the likelihood of developing diarrhea, but carries its own risks. At least two groups of
viruses are capable of producing an acute diarrheal illness. 10.2.1 NORWALK VIRUS The Norwalk virus causes a
self-limiting syndrome that affects children and adults, mainly in winter.
An incubation period of 24 to 48 hours is followed by a variable
combination of fever, anorexia, nausea, vomiting, myalgia, abdominal pain
and diarrhea. Spontaneous recovery occurs two to three days later. Immune
electron microscopy of fecal filtrates demonstrates a characteristic 27 nm
viral particle (the Norwalk agent). No specific treatment is available.
The vomiting represents delayed gastric emptying; there are no morphologic
features of gastritis. 10.2.2 ROTAVIRUSES Rotaviruses are the most
common causes of acute nonbacterial gastroenteritis in infancy and
childhood. Rotaviruses invade mucosal epithelial cells. The resulting
illness is more severe than that caused by the Norwalk virus. Rotavirus
infection commonly requires hospital admission and intravenous fluids.
Infection occurs mainly in children from 6 to 24 months old, and almost
always in winter. Virus excretion is maximum three to four days after the
onset of symptoms and disappears after a further three to four days. The
stability of the virus and the large number of viral particles excreted
make environmental contamination inevitable, with a high risk of secondary
infection in susceptible contacts. For example, 20% of the rotavirus
infections diagnosed in pediatric hospitals are acquired in the hospital.
Most older children and adults have antibodies to rotaviruses, so any
subsequent infection is generally mild. The parasites that infect
the intestine may be divided into three broad groups. These include
protozoa, roundworms and flatworms. The flatworms may be further divided
into cestodes (tapeworms) and trematodes (flukes). This chapter will focus
upon only a few relevant protozoa. 10.3.1 GIARDIA LAMBLIA Giardia lamblia is endemic
in many areas of the world, including Canada. Some patients with
giardiasis present with an abrupt, self-limiting illness that develops one
to three weeks after infection and lasts three to four days. Others may
develop chronic and episodic diarrhea associated with bloating and, at
times, steatorrhea and a malabsorption syndrome clinically like celiac
disease. Diagnosis is made by recovery of the organism; it is found in the
stool of approximately 50% of patients and in 90% of histologically
examined smear preparations obtained from small bowel biopsy specimens (Figure
16A, B)
. The treatment of choice in both asymptomatic and symptomatic patients is
metronidazole 250 mg t.i.d. for 7 days. Repeat therapy will occasionally
be needed to totally eradicate the organism. Quinacrine 100 mg t.i.d. for
7 days also is effective. 10.3.2 AMEBIASIS This is an acute and
chronic disease caused by the organism Entamoeba histolytica. Although
there are numerous species of ameba that inhabit the human intestinal
tract, E. histolytica seems to be the only variety that is pathogenic for
humans. Its manifestations vary from the asymptomatic carrier state to a
severe fulminating illness with mucosal inflammation and ulceration.
Asymptomatic patients harbor only cysts in their stools and have no
evidence of tissue invasion. Since the cysts are resistant to the outside
environment, the disease can be transmitted by individuals unaware of
their infective potential. This is in contrast to patients with acute or
chronic invasive disease, who harbor a trophozoite that cannot survive
outside the host.
The acute illness is characterized by diarrhea with the
passage of blood and mucus, and by variable degrees of abdominal pain. In
its most severe form it may mimic fulminating ulcerative colitis and may
progress to a toxic dilation (toxic megacolon) and perforation of the
colon. During the acute illness, trophozoites may be recovered in the
stool, from biopsies of shallow ulcers in the rectum, or from smears of
rectal mucus.
Chronic infectious features may develop many years
after the patient has left an endemic area. Patients present with
nonspecific bowel complaints and may show radiologic changes in the distal
small bowel and colon that mimic Crohn's disease, cancer or tuberculosis.
Diagnosis necessitates recovering trophozoites from the stool. As an
adjunct, the indirect hemagglutination test can help detect patients with
invasive disease.
Intestinal complications of amebiasis include massive
intestinal hemorrhage, which is rare; ameboma formation in any part of the
colon, which may lead to obstruction or intussusception; permanent
stricture formation during the healing stage; and postdysenteric colitis,
which usually resolves over several weeks or months without specific
therapy.
Systemic dissemination of the ameba may involve other
organs, such as the brain, lung, pericardium and liver. Liver abscess is
the most common extraintestinal infection by the ameba.
Therapeutic agents used for the treatment of amebiasis
act at selected sites: intraluminally, intramurally or systemically.
Treatment must therefore be individualized to the location of the disease.
Asymptomatic carriers are treated with iodoquinol 650 mg t.i.d. for 20
days; this effective agent acts against amebas located intraluminally.
Acute or chronic intestinal disease is treated with metronidazole 750 mg
t.i.d. for 10 days. However, because metronidazole is less effective
against organisms within the bowel lumen, iodoquinol (650 mg t.i.d. for 20
days) must be added. 10.3.3 CRYPTOSPORIDIA Cryptosporidia are a genus
of protozoa classified within the subclass Coccidia. Cryptosporidia
infection has been recognized as a diarrheal disease in humans only since
1979. In immunocompetent persons it presents as a transient, self-limiting
diarrheal state lasting from one to seven days. Adults are less commonly
affected than young children. In most, the illness is mild and medical
help is not sought. With immunological incompetence (e.g., AIDS, neoplasia,
hypogammaglobulinemia or concurrent viral infection), a persistent chronic
watery diarrhea may occur. Diagnosis is made by demonstrating
Cryptosporidia oocysts in the stool or, better still, by mucosal biopsy
and examination of the microvillus border for embedded Cryptosporidia
oocysts (Figure 17).
A successful treatment for Cryptosporidia has not yet
been found. Spiramycin and hyperimmune bovine colostrum remain
experimental. Since almost every drug can cause diarrhea, the first
question to ask a patient is "What medications, both prescribed and
over-the-counter, are you currently taking?" Discontinuing the drug
is often the only therapeutic move required in nonantibiotic diarrhea;
even in patients with antibiotic-associated diarrhea, with or without
colitis, this may be the only step necessary. Although many drugs can
cause diarrhea, little is understood about the ways in which they do so.
The common causes of drug-induced diarrhea with pathogenic mechanisms
follow. 10.4.1 ANTIBIOTIC-ASSOCIATED DIARRHEA AND
PSEUDOMEMBRANOUS COLITIS Antibiotics are the most common cause of drug-induced
diarrhea. In many cases, the condition is self-limiting. The development
of pseudomembranous colitis (PMC) in association with antibiotics may be a
serious and sometimes life-threatening condition.
PMC secondary to antibiotics was first recognized
during the 1950s. Initially, it was thought to be caused by overgrowth
with Staphylococcus aureus, but later research revealed that the colitis
was usually caused by an enterotoxin produced by Clostridium difficile.
PMC can follow virtually any antibiotic use. It may
occur months after antibiotic exposure, and may rarely occur without a
past history of antibiotic use. The frequency of diarrhea or colitis does
not appear to be related to dose or route of administration. Symptoms can
occur while the patient is on the antibiotic or within six weeks following
its discontinuation. Only increasing age is clearly identifiable as a risk
factor. The diarrhea is usually loose with a blood-streaked mucus. Frank
bleeding is uncommon. The diarrhea can be devastating, with up to 30 bowel
movements in a 24-hour period. The diarrhea may be associated with varying
degrees of abdominal pain and low-grade fever. Depending on the severity
of the diarrhea and the amount of fluid loss, hypotension, shock and even
death have been reported. In many patients the problem is self-limiting
and resolves spontaneously with discontinuation of the antibiotic. Further
investigation is required in those patients who have severe diarrhea
associated with systemic symptoms and those whose diarrhea persists
despite discontinuing the implicated antibiotic.
An accurate history is usually sufficient to suggest
the diagnosis of PMC, and a sigmoidoscopy may be all that is required for
confirmation. The presence of copious amounts of mucus and typical raised
white pseudomembrane plaques are characteristic features on sigmoidoscopy.
Biopsies help confirm the diagnosis (Figure
18A, B)
. The distal colon is involved in most cases so that sigmoidoscopy is
usually adequate. Lesions may be restricted to the right colon,
necessitating colonoscopy.
Isolation of C. difficile plus toxin in the stools
provides the diagnosis. If it is certain that there can be no other cause
for the diarrhea, treatment can be undertaken while awaiting assay
results. Treatment depends upon the condition of the patient. If symptoms
are resolving with discontinuance of the antibiotic, no further therapy
may be indicated. In mild cases, metronidazole 250 mg p.o. t.i.d. for 14
days is effective. In severe hospitalized cases the drug of choice is
vancomycin 125 mg p.o. q.i.d. for 14 days. Vancomycin is poorly absorbed
and central nervous system and renal toxic effects are uncommon. The high
cost of this medication limits its use, even though the eradication rate
is quite high. If oral therapy cannot be used, as with severe ileus or
recent surgery, parenteral metronidazole is preferred. Some 20% of treated
patients will have a recurrence of symptoms, PMC or C. difficile, usually
within 4 to 21 days of stopping treatment. In this case, another course of
metronidazole or vancomycin should be given. Cholestyramine (Questran®)
binds the toxin and can provide symptomatic relief even though it will not
eliminate the microorganism. 10.4.2 MAGNESIUM-CONTAINING ANTACIDS Usually, the osmotic diarrhea produced by Mg++
is mild; it may even be welcomed by previously constipated patients. A
change to a magnesium-free aluminum-containing antacid is all that is
required to control the situation in some. (Magnesium can be used to
induce diarrhea by the rare patient with the Münchausen syndrome seeking
medical attention for self-induced problems.) 10.4.3 ANTIARRHYTHMIC DRUGS The antiarrhythmic drugs most commonly associated with
diarrhea include quinidine, procainamide and disopyramide. The mechanism
involved is unknown. Changing the antiarrhythmic drug may halt the
diarrhea. 10.4.4 OTHER MEDICATIONS Colchicine, often administered for acute gout, produces
diarrhea as a common side effect. It resolves with discontinuance of the
medication. The mechanism of the diarrhea is unknown, but may relate to an
intestinal cytotoxic effect of colchicine. Antimetabolites (e.g.,
methotrexate) often cause diarrhea as a result of damage to the small or
large bowel mucosa. This type of diarrhea can be devastating and difficult
to control. Except for rehydration and stopping the drug, little can be
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