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DIARRHEA

The differential diagnosis of diarrhea may be approached from either an anatomic or a physiologic basis.
The anatomic approach is used in Table 22. In the stomach and duodenum, pernicious anemia and
ZollingerEllison syndrome are prominent causes. A carcinoma may form a fistula with the transverse colon
and cause diarrhea. Viral gastroenteritis, and Giardia infection may also be prominent causes.

DIARRHEA
Liver and biliary tract diseases of all types may cause diarrhea (steatorrhea) by decreasing the secretion of
bile. Ampullary carcinoma and cirrhosis are illustrated here, but one should not forget the diarrhea of chronic
cholecystitis. The pancreas is the source of important digestive enzymes; as a result, chronic pancreatitis
and pancreatic carcinomas may be associated with diarrhea (steatorrhea) in adults, whereas cystic fibrosis
should be considered in children. The pancreatic islet cell tumors may secrete gastrin or vasoactive
intestinal peptide, causing diarrhea.
Most of the lesions causing diarrhea are in the small intestine. Thus, cholera, Salmonella, Staphylococci,
typhoid, and tuberculosis attack here. The carcinoid syndrome, various polyps (especially PeutzJeghers),
and regional ileitis are also important causes. Toxins and drugs (Table 22) are common causes acting here,
as are pellagra and other vitamin deficiencies and food allergies. Systemic autoimmune diseases such as
scleroderma and Whipple disease are also important. Mesentery artery insufficiency or obstruction should
be considered both here and in the colon.
TABLE 22. DIARRHEAANATOMIC CLASSIFICATION

Degener
Vascula

Inflammat

Neopla

ory

sm

ative

Intoxication

and

and

Deficien

Idiopathic

Congen
ital

Autoimmu
ne
Allergic

Trau
ma

Endocrine

cy

Carcin
Stoma
ch and
Duode
num

oma

Surg

Viral

with

Pernicio

gastroent

fistula

us

eritis

into

anemia

Uremia

intestin

ery

Zollinger

(e.g.

Ellison

blind

syndrome

loop)

es

Iron
Parasite

deficienc

Antacid

Neopla
Liver
and

Chronic

sm

cholecystit obstruc

Biliary

is and

ting

Tract

lithiasis

bile

Cirrhosis

Cirrhosis

ducts

Pancre
as

Chronic
pancreatiti
s

Pancre
atic
carcino
ma

Radiation

Cystic

Pancreatic

fibrosis

cholera

Degener
Vascula

Inflammat

Neopla

ory

sm

ative

Intoxication

and

and

Deficien

Idiopathic

Congen
ital

Autoimmu
ne
Allergic

Trau
ma

Endocrine

cy

Islet
cell
adeno
ma

Peutz

Mesent
Small

eric

Intestin

artery

insuffici

Jehgers
Cholera

Carcin
oid

Pellagra

Sprue

divertic

Regional

Fistul

Hypoparathy

ulum

ileitis

roidism

(Meckel

ency

Pyridoxi
Botulism

Polyp

ne
deficienc

Cathartic

Whipple

Hyperthyroidi

disease

sm

Scleroder

Addison

ma

disease

Staphyloc

Sarco

occus

ma

Salmonell

Lymph

oma

Escherichi

Mercurial

Reserpine

Antibiotic

Degener
Vascula

Inflammat

Neopla

ory

sm

ative

Intoxication

and

and

Deficien

Idiopathic

Congen
ital

Autoimmu
ne
Allergic

cy

a coli

Parasites

Alcohol

Tuberculo

Other

sis

drugs

Mesent
Large

eric

Intestin

artery

insuffici

Shigella

Polyp

Mucus
colitis

Familial
polypos
is

Ulcerative
colitis

ency

Carcin
oma
Amebiasis

and

Diverticulo

other

sis

neopla

Granulom
atous
colitis

sms

Other
parasites

Antibiotic

Hypervitam

Food
allergy

Trau
ma

Endocrine

Degener
Vascula

Inflammat

Neopla

ory

sm

ative

Intoxication

and

and

Deficien

Idiopathic

Congen
ital

Autoimmu
ne
Allergic

Trau
ma

Endocrine

cy

inosis

Uremia

A wide variety of etiologic agents cause diarrhea by their action on the colon.
1.
2.
3.
4.
5.
6.
7.
8.
9.

VVascular diseases include ischemic colitis.


IInfectious agents such as bacillary dysentery (Shigella), Escherichia coli, Campylobacter,
Yersinia, and amebiasis may ulcerate or inflame the colon.
NNeoplasms such as carcinomas and polyps cause chronic irritation and exudates from the
colon with hypermotility and diarrhea.
DDegenerative lesions of the muscularis that cause diverticulosis and allow overgrowth of
bacteria and chronic inflammation may lead to diarrhea, but this may be classified under the
idiopathic category as well.
IIntoxicating substances, osmotic cathartics, and antibiotics (by allowing overgrowth of
bacteria and fungi) may involve the colon (e.g., pseudomembranous colitis). Mucous colitis or
irritable bowel syndrome may best be classified as idiopathic.
CCongenital lesions of the colon include the solitary diverticulum of the cecum, malrotation
(more frequently associated with intestinal obstruction), and familial polyposis.
AAutoimmune disease of the colon is common and includes both ulcerative colitis and
granulomatous colitis.
TTrauma is not a common cause of diarrhea anywhere in the intestinal tract, but certainly
surgically induced fistulas may occur in the colon or anywhere else.
EEndocrine disorders do not usually affect the colon directly.

Having considered the local causes of diarrhea, do not forget reflex diarrhea from diseases of other organs,
such as pyelonephritis, salpingo-oophoritis, and central nervous system diseases.
Using Table 23, the reader can develop the differential diagnosis of diarrhea with physiology. Diarrhea may
result from increased intake of fluids or bulk foods; hyposecretion of enzymes necessary for digestion of
food; hypersecretion of gastrointestinal fluids and enzymes; malabsorption of various substances,
particularly protein and fat; exudations of pus induced by granulomatous or ulcerative colitis and
Salmonella or Shigella infections; hypermobility from stimulation by cathartics, various hormones (e.g.,

vasoactive intestinal peptides and gastrin), and hypomobility from autonomic dysfunction as occurs in
diabetic neuropathy.
TABLE 23. DIARRHEAPHYSIOLOGIC CLASSIFICATION

Hyposecretio Hypersecretio Hypomobilit


n

Gastric

Pernicious
anemia

Hypermobility

Primary
Malabsorption

Zollinger
Ellison

Dumping syndrome

syndrome

Iron
deficiency

Gastric
resection

Duodenal

Lactase

Blind loop

deficiency

syndrome

Secretion-induced

Sucrase
deficiency

Biliary

Liver

Cholecystokinin

Cholecystokini

disease

induced

n-induced

Obstructive

Regional ileitis

jaundice

Pancreati

Cystic

Pancreatic

fibrosis

cholera (islet
cell adenoma

Gastrin

Exudative

Hyposecretio Hypersecretio Hypomobilit


n

Hypermobility

Primary
Malabsorption

Exudative

with
vasoactive
intestinal
peptide)

Small
Intestine

Chronic

Vasoactive

pancreatitis

intestinal peptide

Cholera (e.g.,
Escherichia
coli)

Diabetic
diarrhea

Drugs

Coffee

Celiac sprue

Serotonin-induced

Tropical sprue

Cathartic

Regional
ileitis

Salmonellosi
s

Whipple
disease

Parasympathomime

Intestinal

tic

lymphoma

Extensive
resection

Protein-losing
Large

enteropathy

Intestine

(e.g., villous
adenoma)

Shigella

Hyposecretio Hypersecretio Hypomobilit


n

Hypermobility

Primary
Malabsorption

Exudative

Ulcerative
colitis

Amebiasis

Approach to the Diagnosis


Whichever method is applied (anatomic or physiologic), most causes of diarrhea can be recalled before
interviewing the patient. Then one can proceed to ask the right questions to eliminate each suspected
cause. Combinations of symptoms and signs will assist greatly in narrowing the differential diagnosis. For
example, chronic diarrhea and copious mucous without blood suggests irritable bowel syndrome. Chronic
diarrhea with mucous and blood suggests ulcerative colitis.
Physical examination is often unrewarding but it may disclose a hepatic, rectal, or pelvic source for the
diarrhea; it may also indicate that the diarrhea is a sign of a systemic disease (e.g., scleroderma or
hyperthyroidism). Rectal examination may reveal a fecal impaction. A warm stool examination for pus, pH
(acid stool suggests lactase deficiency), fat and meat fibers, blood, ova, and parasites is most essential. A
stool culture is done. Proctoscopy (immediately if there is blood) followed by colonoscopy, barium enema,
and upper gastrointestinal (GI) series is usually necessary in all cases.

Other Useful Tests


1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.

CBC (malabsorption syndrome)


Cathartic stool examination (intestine parasites)
Small-bowel series (malabsorption syndrome)
Duodenal aspiration (giardiasis, Strongyloides)
Lactose tolerance test (lactase deficiency)
d-Xylose absorption test (malabsorption syndrome)
Serum gastrin (gastrinoma)
Urine 5-hydroxyindoleacetic acid (5-HIAA) (malabsorption syndrome, carcinoid tumor)
Mucosal biopsy (malabsorption syndrome)
Colonoscopy and biopsy (ulcerative colitis, amebic colitis, granulomatous colitis)
Stool for Giardia antigen (giardiasis)
HIV antibody titer (AIDS)
Angiogram (ischemic colitis)
Culture for Clostridium difficile (pseudomenbranous colitis)
Glucose tolerance test (diabetic enteropathy)

Diarrhea
Lonny M. Hecker, M.D., David R. Saunders, M.D., and David Losh, M.D.

1.0 Introduction
Diarrhea affects most individuals at some time during their lives. The occasional
loose or watery stool is so common that few individuals seek medical advice,
unless the diarrhea is persistent. In this chapter diarrhea is divided into acute and
chronic categories based on whether it has been present for less than or greater
than four weeks.
This chapter will present evidenced based recommendations for the evaluation
and treatment of diarrhea in adults. The information provided is not necessarily
applicable to children and should not be used to guide pediatric practice. It
includes important papers published prior to 1990 and those accessed via a
MEDLINE search, 1990 - 1998, using the MeSH headings Diarrhea, acute, and
diarrhea, chronic. Other headings searched included malabsorptive syndrome,
and Fordtran, JS, whose research group has made so many contributions to the
subject.
2.0 Physiology and Pathophysiology
Diarrhea results when the remarkable efficiency of the gut for absorbing water,
electrolyte, and nutrients is impaired. About 9-10 liters of water and electrolyte
enter the upper jejunum daily, of which one liter is delivered to the cecum, and
one-tenth of a liter is delivered to the outside world. Decreasing this efficiency
from 99% to 98% would double fecal water to produce potentially a wetter stool.
A great variety of drugs, toxins, pathogens, and food stuffs can impair the
efficiency of salt and water absorption.
The chief contribution of the stomach to digestion and absorption is metered
delivery of food and drink to the small intestine so that the absorptive capacity of
the upper small intestine is not overwhelmed.
Carbohydrate and protein in the small and large intestines are especially
important in increasing the efficiency of sodium and water absorption. Soluble
starches are digested by pancreatic amylase into small chains of glucose
molecules which, together with the ingested disaccharides (lactose and sucrose),
are hydrolyzed to monomers by brush border enzymes.
Absorption of sodium (and water) is coupled to the absorption of glucose and
galactose, especially in the duodenum and jejunum. Much of the available sugars
have been absorbed when chyme arrives in the ileum, where sodium absorption
relies on sodium/hydrogen and chloride/bicarbonate exhangers. Carbohydrate

which escapes absorption in the small intestine is fermented by colonic bacteria


to short-chain fatty acids whose colonic absorption enhances sodium (and water)
transport and provides nutrients for colonic absorptive cells. By the time feces
reach the left colon, most of the available carbohydrate has been fermented so
that sodium absorption becomes dependent on exhangers and on sodium channels.

Dietary protein also enhances sodium and water absorption by mechanisms


similar to those described for carbohydrate. Amino acids and sodium are
absorbed by coupled transport, and short-chain fatty acids derived from amino
acids in the right colon enhance sodium (and water) absorption.

Colonic bacteria do not salvage appreciable amounts of unabsorbed long-chain


fatty acids (LCFA). In fact, the double bonds of dietary LCFA may be
hydroxylated so that the excreted LCFA bears little resemblance to the dietary
LCFA,

and they may become more potent inhibitors of colonic absorption.

A final consideration is the mouth-to-anus transit time which can be derived by


measuring the transit of the head of the meal (HOMTT), or of the whole meal
(WMTT). WMTT involves ingesting a number of radio-opaque, or isotopicallylabeled pellets whose average mouth-to-anus transit time is calculated. WMTT is
48-72 hours in normal subjects [Cummings, 1976], [Metcalf, 1987]. Pellets have
the longest residence in the colon, and fecal weights are inversely proportional to
the time of colonic residence [Vassallo, 1992]. Head of meal transit time
(HOMTT) is measured with a poorly-absorbed colored substance, and it is the
time between ingestion and the first appearance of the color in the stools.
HOMTT averaged 36 hours after 14 healthy subjects ingested carmine red with
an English breakfast [Read, 1980]; diarrhea ensued when the HOMTT was
experimentally reduced to less than 12 hours [Read, 1980].
The punch-line: the overall balance for the absorption of sodium is 99%; of
starch, 99%; of protein, 95%; and of LCFA, 95%, and these remarkable
efficiencies depend on adequate lumenal digestion, absorptive cell surface, and
transit time.
Mechanistically, absorption may be impaired by poorly absorbed, osmotically
active solutes in the intestinal lumen, by alteration in absorptive cell function, by
increases in crypt cell secretion, and by too rapid transit of intestinal contents.
Most often, absorption is impaired by mechanisms acting in concert. For
example, excessive volume of intestinal contents can speed intestinal transit;
cytokines from mural inflammatory cells can enhance cryptal secretion, and can
influence the enteric nervous system to speed transit; bile salts, and long-chain
fatty acids, malabsorbed in the small intestine, can block water and electrolyte
absorption in the colon.
The colon employs several mechanisms to ensure it delivers to the rectosigmoid
a formed stool, probably the most important factor in fecal continence. The colon
has reserve capacity by which it can absorb 2-3 extra liters of water and
electrolyte delivered from the small intestine in a day [Debongnie, 1978].
Colonic bacteria ferment soluble carbohydrate and protein, which escaped small
intestinal absorption, into absorbable gases and short-chain fatty acids.
Otherwise, these unfermented, unabsorbable solutes would be osmotically active
in colonic contents, and would cause diarrhea.
3.0 Acute Diarrhea
Acute diarrhea may be defined clinically as any sudden and significant increase
in the frequency or decrease in the consistency of the stool lasting less than four
weeks. Acute enteric illness is preferable to gastroenteritis, since the
underlying pathophysiology may not involve any inflammation [Guerrant, 1985].
Most patients presenting with acute diarrhea will improve spontaneously without
any specific tests or treatment. These patients must be readily distinguished from

those at risk who require urgent intervention. It is, therefore, incumbent on the
primary care provider to carefully select both diagnostic tests and therapeutic
modalities. This is one area of clinical medicine where careful history and
physical are still of paramount importance.
3.1 Background
3.1.1 Incidence
The overall incidence of acute diarrhea in adults is difficult to determine. Most
episodes are self-limited and probably do not involve the health care provider.
Epidemiologists have examined the impact of acute diarrheal disease on the
health care system by looking at the number of adult patients hospitalized with
the diagnosis of diarrhea using the International Classification of Diseases, Ninth
revision (ICD-9) codes for both infectious and presumed non-infectious
diarrhea. One study, in the southeast United States found that, of a total 4.06
million hospitalizations in 1985, 2.1% listed diarrhea among the top threedischarge diagnoses [Gangarosa, 1992]. Diarrhea was strongly associated with
9% of all hospitalizations of children and 1.5% of hospitalizations of adults.
Certain circumstances are associated with an especially high incidence of acute
diarrheal disease. Operation Desert Shield involved the deployment of 200,000
US military personnel in Saudi Arabia. The rate of diarrheal disease in this group
soared to as much as 100 cases per 1000 soldiers per week in some units
[Hyams, 1991]. 57% of surveyed troops reported at least one episode of diarrhea
and 20% reported to be temporarily disabled due to diarrhea. Enterotoxigenic
E. coli, Shigella and Norwalk virus appeared to be the most common etiological
agents.
3.1.2 Morbidity and Mortality
Diarrhea is a major cause of childhood disease in the developing world. Global
mortality estimates from diarrhea and its complications range from 1.5 to 5.1
million deaths per year for children under the age of five [Bern, 1992]. Acute
diarrheal illness is also associated with adult mortality in the United States. In
fact, age over 70 years is the most important risk factor for death related to
diarrhea.
The National Center for Health Statistics data indicates more than 25,000
persons died of diarrhea in the US between 1979 and 1987 [Lew, 1991].
Seventy-eight per cent of these individuals were 55 years of age or older. Being
white, female and residing in a nursing home were independent risk factors for
death among the elderly.
3.1.3 Foodborne Disease

Foodborne-disease is a very important cause of acute diarrheal illness. It is


difficult to reliably estimate the true incidence, because most episodes are not
reported. The Centers for Disease Control maintains a surveillance program to
track the occurrence of foodborne-disease outbreaks (FBDOs), defined as the
occurrence of two or more cases of a similar illness resulting from the ingestion
of a common food [Bean, 1996].
Between 1988 and 1992 a total of 2,423 FBDOs were reported. The etiology was
determined in only 41% of all outbreaks. Many of those without a defined cause
may have been viral because appropriate testing may not have been available.
The CDC also tracks the vehicle of transmission for FBDOs where the most
common single sources are chicken, eggs, and salads made of poultry, fish or
eggs. Recent outbreaks and the increasing reliance on commercially prepared
foods with nationwide distributions have contributed to increased concern with
food safety [Hedberg, 1994].
3.1.4 Costs
The economic impact is considerable as well. The Food and Drug Administration
estimated that in 1985 acute intestinal infection causing vomiting, diarrhea, or
both, resulted in more than $1 billion in medical costs and more than $20 billion
in lost productivity [Garthright, 1988].
3.2 Differential Diagnosis
The differential diagnosis of acute diarrhea in adults is listed in (Table 1). The
differential diagnosis can be narrowed based on the predominant symptoms at
presentation. The three major symptom complexes are as follows:
o
o
o

Watery diarrhea associated with nausea and vomiting


Noninflammatory diarrhea
Inflammatory diarrhea

Acute diarrhea occurring in travelers and persons with AIDS warrants certain
special considerations and will be discussed later.
3.2.1 Acute Watery Diarrhea with Nausea and Vomiting
Acute watery diarrhea associated with nausea and vomiting is typically called
gastroenteritis. Most cases are infectious, due to either bacteria or viruses.
3.2.1.1 Staphylococcus aureus
Staphylococcus aureus infection is characterized by the sudden onset of
abdominal pain, nausea, vomiting, and diarrhea and in a minority of cases fever
(Table 2). Symptoms are due to ingestion of preformed toxin which is usually in

foods which are cooked and then improperly stored at room temperature
[Holmberg, 1984]. Antimicrobial therapy is not recommended for S. aureus
associated diarrhea because symptoms are due to preformed toxin and are selflimited.
3.2.1.2 Viral Gastroenteritis
Acute diarrhea, vomiting and fever are the hallmarks of viral gastroenteritis,
which accounts for 30-40% of all acute diarrheal illness in the US (Table 2).
Symptoms result from reduced absorptive surface in the small intestine due to
viral mediated lysis of enterocytes. Most viral gastroenteritis is caused by one of
five viruses. Rotavirus accounts for 30-60% of all severe watery diarrhea in
infants and young children and is a major cause of morbidity and mortality
worldwide. Rotavirus, enteric Adenovirus, Calcivirus and Astrovirus are
uncommon causes of diarrhea in adults in the United States. Norwalk virus,
however, is much more common in adults and older children. It is more common
during the winter and may be found in contaminated drinking or swimming water,
poorly cooked shellfish, and contaminated foods [Kohn, 1995]. Norwalk virus has
been responsible for nearly 40% of all outbreaks of acute vomiting and diarrhea
in schools, camps, hospitals, nursing homes and on cruises [Blacklow, 1991].
The virus is spread via the fecal-oral route, though airborne transmission has
also been suggested. Norwalk virus infection causes vomiting, cramps headache
and diarrhea beginning 1-2 days after exposure and usually lasting 1-2 days.
Norwalk viral infection is associated with marked delayed gastric emptying and
small intestinal mucosal damage causing both carbohydrate and fat
malabsorption. Symptoms may persist for 2 weeks. Specific diagnostic tests
remain research tools at the present time. Symptoms are self-limited and there is
no effective or recommended anti-viral therapy.
3.2.1.3 Non-Infectious Causes of Acute Diarrhea and Vomiting
There are also non-infectious causes of watery diarrhea and vomiting. For
example, acute heavy metal poisoning due to ingestion of copper, zinc, iron or
cadmium may cause nausea, vomiting, cramps and diarrhea occurring 5 to 60
minutes after ingestion [Bishai, 1993].
3.2.2 NonInflammatory Diarrhea
The hallmark of noninflammatory diarrhea or watery nonbloody diarrhea, is large
volume stools. Upper gastrointestinal symptoms including nausea, vomiting and
cramps may occur but significant abdominal pain and fever are usually absent.
Acute noninflammatory diarrhea is usually associated with small bowel infections.
Leukocytes are typically absent from the stool. Bacterial enteric pathogens,
which cause acute nonbloody diarrhea in adults, include Vibrio cholerae,
enterotoxigenic E. coli (ETEC), Clostridium perfringens and Bacillus cereus.
Commonly implicated protozoa include Giardia lamblia, Cryptosporidium parvum,

Cyclospora and Dientamoeba fragilis (Table 3). Frequent noninfectious causes of


acute nonbloody watery diarrhea include medications, poorly absorbed
carbohydrates (lactose, sorbitol, xylitol), caffeine, and alcohol.
3.2.2.1 Vibrio cholera
Vibrio cholera is a gram-negative bacteria found in marine or brackish waters.
Seafood, especially crabs, oysters and shrimp, is a natural reservoir. Cholera
toxin binds to mucosal cells causing a secretory diarrhea mediated by cyclic
AMP. Symptoms may range from asymptomatic infection to profuse watery
diarrhea. Individuals with impaired gastric acid secretion are at increased risk.
The syndrome of "cholera gravis" is characterized by "rice water" stool with
volumes over 1L/hour leading to rapid dehydration and death. Fortunately, cases
of mild to moderate disease are 4 - 5 times more common [Morris, 1985].
Rehydration is the mainstay of treatment although antibiotics may shorten the
duration of symptoms and excretion of bacteria [Farthing, 1996].
3.2.2.2 Vibrio parahaemolyticus
Vibrio parahaemolyticus causes hemolysis associated with acute self-limited and
sometimes bloody diarrhea, vomiting and fever. Vibrio vulnificus may cause
diarrhea but is far more commonly reported as a cause of primary septicemia in
individuals with underlying liver disease [Klontz, 1988]. Other noncholera vibrios
have also been reported causes of food poisonings and travelers diarrhea.
3.2.2.3 Enterotoxigenic E. coli (ETEC)
Enterotoxigenic E. coli (ETEC) is the leading bacterial cause of travelers
diarrhea. It can also be a cause of domestic outbreaks. ETEC infection is
transmitted by ingestion of contaminated food or water. Disease results from
adherence and colonization of the small intestine and the subsequent elaboration
of two distinct enterotoxins (heat-labile, LT and heat-stable, ST). ETEC is
responsible for the classical syndrome of travelers diarrhea including watery
diarrhea, nausea, abdominal cramps and low grade fever [Levine, 1987].
Definitive diagnosis remains largely confined to research laboratories. It requires
identification of a specific toxin by EIA (enzyme immunoassay) or DNA probe of
the toxin gene. Empiric therapy, in the appropriate setting, is very common but
often unwarranted.
3.2.2.4 Clostridium perfringens
Clostridium perfringens is a spore forming, enterotoxin producing, gram positive
bacillus. It is a frequent cause of food poisoning in institutions serving cooked but
improperly stored meats [Lund, 1990]. It has also been reported as a cause of
sporadic and nosocomial diarrhea. Symptoms are often mild but may include
watery diarrhea and abdominal pain lasting 12-24 hours. The diagnosis depends

on detection of enterotoxin in the stool. Antimicrobial therapy is generally not


recommended.
3.2.2.5 Bacillus cereus
Bacillus cereus is an aerobic gram positive rod which can produce two different
toxins responsible for two distinct clinical syndromes. The emetic syndrome
associated with ingestion of preformed toxin causes sudden onset of nausea,
vomiting and abdominal pain. Improperly stored rice and pasta are the most
commonly reported sources. B. cereus emetic toxin has also been associated
with fulminant liver failure and death [Mahler, 1997]. The diarrheal syndrome, in
contrast, is due to elaboration of toxin within the lumen of the small intestine. This
toxin causes profuse watery diarrhea and abdominal cramps lasting
approximately 24 hours. Antimicrobial therapy is not recommended for B. cereus
infections.
3.2.2.6 Giardia lamblia
Giardia lamblia is the most common intestinal protozoal pathogen in the industrial
world causing 7% of all cases of acute diarrhea [Farthing, 1993]. The
trophozoites localize in the small intestine and cause diarrhea. Contaminated
food, water or direct person to person contact may transmit Giardia. Fecal-oral
spread is prevalent in day care centers and residential institutions [Pickering,
1984]. Most infections are clinically inapparent though symptoms may include
watery diarrhea, nausea, anorexia and bloating. Chronic infection may present
with symptoms that mimic irritable bowel syndrome. The sensitivity of the
microscopic examination of stool for ova and parasites is unacceptably low. A
commercially available ELISA for the detection of G. lamblia associated antigens
has sensitivity and specificity of >90% and has emerged as the test of choice
[Addiss, 1991]. Treatment with metronidazole 250mg qid for 7 days is generally
recommended [DuPont, 1997].
3.2.2.7 Cryptosproridium parvum
Cryptosproridium parvum, a coccidian protozoa became recognized as a
worldwide pathogen after its description in patients with AIDS. Improved
diagnostic techniques have lead to a marked increase in the frequency of
diagnosis in both healthy and immunocomprimised individuals. Groups at
increased risk include day care age children [Tangermann, 1991], travelers
[Jokipii, 1985] and the elderly [Bannister, 1989]. In 1993 a large outbreak of acute
watery diarrhea was traced to Cryptosporidium transmitted through the water
supply due to inadequate filtration [MacKenzie, 1994]. Since then four foodborne
outbreaks have been reported associated with either fresh pressed apple cider or
chicken salad. The potential for outbreaks is significant, because the oocysts are
fastidious and only a small inoculum (100 organisms) is needed to produce
disease. Cryptosporidiosis has been associated with relentless and sometimes

fatal diarrhea in AIDS. Healthy persons infected with cryptosporidium develop


self-limited watery diarrhea, cramps, and nausea. Associated symptoms may
include fatigue, low-grade fever, myalgias and headaches. The incubation period
(median of one week) is similar to Giardia but the duration of illness is
considerably shorter. Diagnosis is based on the finding of oocysts on acid-fast
stains of concentrated stool. Commercially available enzyme immunoassays
(EIA) to detect Cryptosporidium specific antigen promise improved sensitivity and
specificity [Dagan, 1995]. No antimicrobial has proven efficacious though,
paromomycin has been used successfully in persistent cases and in
immunocomprimised hosts [Bissuel, 1994].
3.2.2.8 Cyclospora
Cyclospora, another coccidian protozoa, was first positively identified as a human
enteric pathogen in 1993 [Ortega, 1993]. Cyclospora is similar to
Cryptosporidium in its morphological appearance, staining characteristics and
effect on small bowel mucosa. Cyclospora is distinguished from Cryptosporidium
by its larger size. Both cause self limited diarrhea in healthy individuals and
intractable diarrhea in persons with AIDS [Dagan, 1995]. The first reported
outbreak of diarrheal illness due to Cyclospora occurred among housestaff
physicians living in a hospital dormitory who were exposed to contaminated tap
water [Huang, 1995]. Symptoms included explosive watery diarrhea, cramps, and
myalgias and less frequently nausea, vomiting and low grade fevers. Cycles of
remission and relapse often last several weeks. Treatment with trimethoprimsulphamethoxazole for 7 days has been shown to be effective in a doubleblinded randomized controlled trial [Hoge, 1995].
3.2.2.9 Dientamoeba fragilis
Dientamoeba fragilis, another protozoa previously thought to be harmless is now
recognized as a true diarrheal pathogen. Symptoms typically include diarrhea
and abdominal pain. Microscopic examination of 3 fresh stools preserved
immediately with polyvinyl alcohol fixative and stained appropriately has a
sensitivity of 70-85% [Butler, 1996]. D. fragilis infection is highly associated with
and probably transmitted by Enterobius vermicularis or pinworm. Positive
identification of D. fragilis should prompt one to look for and treat E. vermicularis.
Diiodohydroxyquin, is often recommended though metronidazole and tetracycline
are also effective [Butler, 1996].
3.2.2.10 Nonpathogenic Organisms
Normally the stool contains many nonpathogenic organisms. Some have
suggested that Candida species when present in high concentration may cause
watery diarrhea. Several reports have presented cases wherein individuals with
diarrhea and no other identifiable enteric pathogen are cured after eradication of
Candida with antifungal medications [Gupta, 1990]. Blastocystis hominis

similarly has often been presented as a cause of diarrhea when large numbers
are present in the stool. To date there is insufficient evidence to definitively
implicate either of these organisms as causes of diarrhea [Shlim, 1995].
3.2.3 Acute Inflammatory Diarrhea
Acute inflammatory diarrhea typically presents as frequent bowel movements
often accompanied by blood, left lower quadrant cramping, abdominal pain and
urgency. Fecal leukocytes are often present. The typical pathogens associated
with inflammatory diarrhea include Salmonella, Shigella, Campylobacter jejuni,
enterohemorrhagic E. coli 0157:H7 (EHEC), enteroinvasive E. coli (EIEC) and
Clostridium difficile. Less common causes include Yersinia, E. histolytica,
Aeromonas species and Plesiomonas shigelloides (Table 4).
3.2.3.1 Salmonella
Salmonella species are gram-negative rod shaped bacteria. S. typhi is the
principal cause of enteric or typhoid fever causing fever, delirium and abdominal
pain. Typhoidal salmonella is not a particularly important cause of diarrhea. The
nontyphoidal Salmonella species, however include some of the most important
causes of foodborne illness in the U.S. [Chalker, 1988]. They may account for
more than 25% of all reported cases of FBDO and 50% of all FBDO deaths in
which an organism can be identified [Bean, 1996] (Table 5). Approximately
40,000 cases of nontyphoidal Salmonella are reported to the CDC annually,
probably representing only a small fraction of the actual incidence. Most
transmissions have been traced to raw or partially cooked eggs, poultry, beef,
pork or milk. Documented sources have also included contaminated medical
equipment, marijuana, and pets. Salmonella infections cause diarrhea principally
by direct invasion of both small and large intestinal mucosa, however an
enterotoxin, which causes secretory diarrhea, has also been described.
Salmonella enteritis usually presents with watery diarrhea and abdominal pain.
Grossly bloody diarrhea is surprisingly uncommon. Constitutional symptoms
including headache, fever, chills and malaise may occur [Baird-Parker, 1990].
Salmonella enteritis is usually self-limited with resolution of diarrhea within one
week. While fecal leukocytes are common, the diagnosis is based upon
isolation of Salmonella from the stool. Antibiotic therapy has not been proven to
shorten the course of the acute illness and may prolong excretion and thereby
transmission of the organism [Neill, 1991]. Antibiotic treatment is therefore not
recommended for healthy persons with mild symptoms. Antimicrobial therapy is
reserved for patients who are bacteremic or at increased risk of the
consequences of bacteremia including extremes of age and those with sickle cell
disease, AIDS, cancer, prosthetic valves or other serious underlying disease
[DuPont, 1997].
3.2.3.2 Shigella

Shigellae include the four species; S. dysenteraie, S. flexneri, S. boydii and S.


sonnei. Shigellae are gram negative bacilli found in contaminated food and
water. Fecal-oral and person to person transmission is common. High rates of
infection are associated with poor sanitation and overcrowding. Day-care
facilities are a frequent location of outbreaks in the US with S. sonnei as the
predominate species. A very low inoculum is required to transmit infection and an
attack rate of up to 20% of household contacts has been reported. Shigellosis is
the classic example of bacillary dysentery characterized by fever, abdominal
cramps and watery diarrhea rapidly progressing to bloody mucoid stool, fecal
urgency and tenesmus. Shigella causes disease by invasion and destruction of
colonic mucosa. Its cytotoxic activity is likely related to elaboration of an
enterotoxin. S. dysenteriae serotype 1 is the most severe and has been
associated with hemolytic-uremic syndrome. Shigellosis is typically self-limited
but may be associated with severe complications particularly in infants and those
with altered immune status. Microscopic stool examination will typically reveal
sheets of polymorphonuclear leukocytes. Sigmoidoscopy may reveal nonspecific
signs of colitis with increased rectal erythema, friability, and sometimes
ulceration. Definitive diagnosis depends on stool culture. Though caution should
be exercised, recent evidence suggests antimotility agents such as loperamide
may be used safely in patients with dysentery [Murphy, 1993]. Antibiotic therapy
is always indicated for confirmed Shigellosis in order to shorten the duration of
illness and the likelihood of transmission. Trimethoprim/sulfamethoxazole is
adequate if the infection is acquired in the US but because of high levels of
resistance, a quinolone (Table 14) is necessary for persons acquiring the
disease elsewhere [DuPont, 1997], [Tauxe, 1990].
3.2.3.3. Campylobacter
Campylobacter are mobile gram-negative rods. Campylobacter jejunii is a
common cause of diarrhea in the United States [Blaser, 1983]. Most cases occur
following ingestion of incompletely cooked chicken or cross contamination of
other foods because of improper handling of raw chicken. Person to person
transmission and outbreaks in day-care centers are uncommon. The mechanism
of disease is believed to be direct tissue invasion of the small and large intestine
causing a nonspecific enterocolitis. Several enterotoxins have been described
but their pathogenic significance is unknown. The most common clinical
manifestations include fever, abdominal pain and diarrhea, which may be loose,
watery, or bloody. The illness generally lasts up to a week. Complications are
uncommon but relapses can occur [Skirrow, 1990]. Fecal leukocytes are
common and sigmoidoscopy will typically reveal changes of acute colitis. The
diagnosis is made on stool culture. Antibiotic treatment is recommended to
reduce the duration of symptoms. Erythromycin is recommended though
azithromycin may be effective as well [DuPont, 1997], [Kuschner, 1995].
Significant quinolone resistance has been reported.
3.2.3.4 Escherichia coli

There are six major groups of diarrheagenic Escherichia coli. Enteropathogenic


E. coli (EPEC) causes watery diarrhea in infants and children.
Enterohemorrhagic (EHEC) and enteroinvasive (EIEC) strains both produce
bloody diarrhea (see below). enterotoxigenic E. coli (ETEC) is the major cause
of travelers diarrhea (see below). Less common enteroaggregative E. coli
(EaggEC) and enteroadherent E. coli (EAEC) have been reported as causes of
travelers diarrhea and AIDS associated diarrhea.
3.2.3.4.1 Escherichia coli O157:H7 (EHEC)
Escherichia coli O157:H7 was first recognized as a cause of diarrhea in
humans in 1982 [Riley, 1983]. It is now well known as one of the most common
bacterial causes of diarrhea. Numerous outbreaks have occurred with potentially
devastating complications, especially in young children. The term
enterhemorrhagic E. coli (EHEC) is used to describe E. coli serotype O157:H7
because of its propensity to produce hemorrhagic colitis . The pathogenesis of E.
coli O157:H7 is due to the production of a Shiga-like toxin, which causes a
vasculitis responsible for the colitis and the hemolytic-uremic syndrome (HUS).
In one study E. coli O157:H7 was the most commonly isolated organism from
stool specimens that were visibly bloody [Slutsker, 1997]. Outbreaks have
occurred related to poorly cooked meat in fast-food restaurants, unpasteurized
apple cider, swimming in public pools and lakes, day care centers and
consumption of raw vegetables including potatoes and alfalfa sprouts [Su, 1995].
Person to person transmission during outbreaks is common particularly in day
care centers and nursing homes. The clinical manifestations of E. coli O157:H7
typically include the sudden onset of abdominal cramps followed by watery
diarrhea, which becomes bloody. Diarrhea usually lasts 2 to 14 days. The clinical
presentation, endoscopic findings and histology of mucosal biopsies are identical
to that of ischemic colitis. Nausea, vomiting and fever are common. HUS
characterized by microangiopathic hemolytic anemia, thrombocytopenia and
renal failure complicates 2 - 7 % of E. coli O157:H7 cases [Griffin, 1991].
Progression to HUS and thrombocytopenic thrombotic purpura occurs
predominantly in young children. Only very recently, have most clinical
laboratories begun to identify E.coli O157:H7 routinely on stool cultures.
Antimicrobials have not been shown to be effective and are not recommended.
3.2.3.4.2 Enteroinvasive E. Coli (EIEC)
Enteroinvasive E. coli (EIEC) is distinguished by the presence of a plasmid
containing genes that code for Shiga-like toxin which permits invasion,
proliferation and ultimately destruction of epithelial cells. EIEC is contracted by
ingestion of contaminated food or water. Though it has been responsible for
outbreaks in both adults and children, it is much less common than either ETEC
or EHEC. The clinical presentation closely resembles that of Shigellosis with
fever, abdominal cramps, tenesmus and bloody diarrhea lasting 5 to 7 days. Most

clinical laboratories do not test for EIEC which can be identified by culture and
specialized serogrouping, or PCR. Treatment recommendations are identical to
that proposed for Shigellosis. No controlled trials have examined the role of antimicrobial therapy though use of trimethoprim and sulfamethoxazole has been
suggested [DuPont, 1997].
3.2.3.5 Clostridium difficile
Clostridium difficile associated diarrhea accounts for only 15-20% of all
antibiotic associated diarrhea [Kelly, 1994]. In fact, most antibiotic associated
diarrhea is mild, self limited and not associated with C. difficile [Fekety, 1997]. C.
difficile is a spore forming obligate anaerobic bacillus found ubiquitously in soil,
water and health care institutions. C. difficile rarely invades intestinal mucosa.
Instead, it causes intestinal damage via the elaboration of 2 toxins which adhere
to the mucosal surface. Most strains of C. difficile elaborate both toxins A and B.
The two toxins vary in potency, however both act to cause disease.
Approximately 8% of all patients admitted to the hospital are asymptomatic
carriers of C. difficile [McFarland, 1990]. C. difficile associated diarrhea occurs
sporadically and in outbreaks. Almost every antibiotic has been associated with
C. difficile diarrhea. The most frequently involved are ampicillin, other penicillin
derivatives, cephalosporins, and clindamycin. Even metronidazole and
vancomycin have been implicated as causes of C. difficile diarrhea. C. difficile
associated diarrhea may not manifest itself until 6-8 weeks after the
discontinuation of antibiotics. It has also been associated with chemotherapeutic
agents and less frequently with underlying leukemia and lymphoma without prior
exposure to antibiotics or chemotherapy. Patients typically present with cramps
and watery diarrhea. Occult bleeding may be noted, but significant hematochezia
is rare [Kelly, 1994]. Colitis more commonly involves the left colon but isolated
right sided colitis may occur and can cause marked right sided abdominal pain
and tenderness with little diarrhea. The term "C. difficile associated diarrhea" may
be used to describe the entire spectrum of disease from a purely secretory
diarrhea to colitis with or without pseudomembranes and even fulminant colitis.
Complications may include dehydration, electrolyte disturbances, reactive
arthritis, toxic megacolon and colonic perforation. Clinical signs and symptoms
can include fever, abdominal tenderness, and profound leukocytosis. Flexible
sigmoidoscopy may reveal a nonspecific colitis. Pseudomembranes, when
present, appear as yellowish plaques which may become confluent.

3.2.3.5.1 C. difficile Diagnosis


The gold standard for the diagnosis is the stool cytotoxin test with sensitivities of
94-100% and specificities of 99% [Doern, 1992]. This is a tissue culture assay
wherein toxin B in stool causes cell lysis. Several commercially available simple,
rapid and inexpensive test have become available for the detection of C. difficile
in the stool. Enzyme immunoassays (EIA) detect toxins A and/or B in the stool.
Sensitivities reported range from 60% -95%, depending on the individual lab
[Jacobs, 1996]. Most studies have compared EIA to clinical or endoscopic
diagnosis rather than to stool cytotoxin tests. EIA tests may fail to diagnose on
the average 10% (range 5-33%) of clinically apparent C. difficile diarrhea [Fekety,
1997], [Jacobs, 1996]. The latex agglutination test detects glutamate
dehydrogenase produced by C. difficile. It does not detect toxin A or B and
therefore cannot distinguish between toxigenic and nontoxigenic strains of C.
difficile [DiPersio, 1991]. Stool culture for C. difficile is not recommended
because the frequency of nontoxigenic C. difficile may approach 25%. Difficulties
arise because tests are reported simply as positive or negative and clinical
decisions are commonly made without knowledge of the assay used or the

sensitivities and specificities in the particular laboratory performing the test.


False negative C. difficile tests may occur with any of the available methods.
Recently published practice guidelines recommend additional stool specimens be
submitted for the same or other testing methods if the initial test is negative and
the clinical suspicion is strong. This approach may have clinical merit but there
are no available studies evaluating its utility. Overall, stool testing for C. difficile in
hospitalized patients with acute diarrhea has a much higher yield (20%) than
either stool culture for enteric pathogens or examination for ova and parasites (13%).
There is abundant clinical experience regarding the utility of sigmoidoscopy in the
diagnosis of C. difficile associated diarrhea. Flexible sigmoidoscopy in a patient
without enema preparation may reveal the characteristic appearance of
pseudomembranous colitis and allow a rapid diagnosis when sensitive stool
testing is either delayed or unavailable. The utility of sigmoidoscopy compared to
stool testing has not been subjected to scientific study, however.
The diagnosis of C. difficile associated diarrhea should be suspected in anyone
who was recently hospitalized or received antibiotics. Data regarding the
epidemiology of community acquired C. difficile associated diarrhea is limited. A
recent retrospective cohort study by the Harvard Community Health Plan found
an overall incidence of 7.7 cases/100,000 person years [Hirschhorn, 1994]. The
overall risk was <1 in 10,000 antibiotic prescriptions and 82% of cases were
treated as outpatients. Risk factors included increasing age, and exposure to
more than one antibiotic. Several well designed studies have demonstrated C.
difficile associated diarrhea is a nosocomial infection. A prospective
comprehensive study of 487 patients admitted to a general medicine ward found
29/428 (7%) of patients had positive C. difficile cultures on admission. 21%
acquired C. difficile while in the hospital and of those 31% developed antibiotic
associated diarrhea [McFarland, 1990]. Diarrhea, fever, leukocytosis and fecal
leukocytes were often absent even in the most severe cases. Risk factors for
the acquisition of C. difficile associated diarrhea by hospitalized patients included
increasing age, severity of underlying illness, use of cephalosporins, penicillins,
enemas, gastrointestinal stimulants and stool softeners.
Recently published practice guidelines advise testing for C. difficile in anyone
who has received antibiotics within the prior two months and/or whose diarrhea
began 72 hours or more after hospitalization [Fekety, 1997] (Table 6). The use of
a two month time limit for prior antibiotic exposure appears to be reasonable
based on clinical experience, however there is insufficient evidence to support
this as a strict cutoff. The recommendation that C. difficile be considered only in
those with diarrhea beginning 72 hours after hospitalization does not appear to
be supported by available studies.
3.2.3.5.2 C. difficile Treatment

Diarrhea may resolve obviating the need for specific treatment if antibiotics can
be discontinued. Similarly, mild C. difficile associated diarrhea may resolve
spontaneously and does not need to be treated. Moderate to severe diarrhea
should be treated with oral metronidazole (250mg qid for 10 days). Oral
vancomycin (125 mg qid for 10 days) is more expensive and should be reserved
for pregnant women, children under age ten and patients who are critically ill due
to pseudomembranous colitis [Fekety, 1997]. It may also be prescribed for
patients who do not respond, cannot tolerate or are infected with organisms that
are resistant to metronidazole.
Clinical relapse will occur in 10 to 20% of patients who have initially responded to
therapy. Relapse will usually occur within three weeks after completion of
therapy. Relapses should be confirmed with repeat stool C. difficile toxin assay.
Asymptomatic patients should not be retested. Positive toxin tests in patients
without symptoms do not need to be treated [Kelly, 1994]. If possible, antibiotics
should be discontinued and avoided for at least two months. Relapses are
usually due to incomplete eradication or reinfection rather than the development
of resistance. Metronidazole should also be the treatment of choice for relapses.
Though there are few randomized placebo controlled trials, treatment
approaches for patients with multiple relapses include the following: 1- 2 months
of either oral metronidazole or oral vancomycin every other day with a gradual
taper; oral vancomycin plus rifampin; oral yogurt, lactobacillus preparations,
cholestyramine or Saccharomyces boulardii [Fekety, 1997].
Prevention of C. difficile associated diarrhea depends primarily upon proper
handwashing by hospital personnel and avoidance of unnecessary and
potentially high risk antibiotics [Pear, 1994]. Saccharomyces boulardii, a
nonpathogenic yeast was evaluated in a double blind-blind placebo controlled
randomized trial for the prevention of antibiotic associated diarrhea [McFarland,
1995]. Patients receiving new -lactam antibiotic prescriptions were randomized
to placebo or S. boulardii (500 mg po bid) beginning within 72 hours of antibiotic
initiation and continuing until 3 days after the antibiotic was discontinued.
Significantly fewer patients taking S. boulardii developed antibiotic associated
diarrhea (RR = 0.29 95% CI = 0.08,0.98). S. boulardii does not appear to have
any side effects.
3.2.3.6 Amebiasis
Amebiasis is one of the most common parasitic diseases worldwide. Infection is
acquired by ingestion of protozoal cysts of Entamoeba histolytica. The
trophozoite produced in the small bowel invades the epithelium of the colon
causing ulceration.

Risk factors in the United States include sexual promiscuity and colonic irrigation.
Amebiasis is unlikely to be contracted during short-term foreign travel though
high rates of infection exist in the Indian subcontinent, southern and western
Africa, the Far East and South and Central America. The clinical presentation of
acute amebiasis includes abdominal pain, tenesmus, and frequent loose to
watery stools with blood and mucus. Rarely fulminant colitis may intervene with
rapid onset of severe bloody diarrhea, fever and abdominal tenderness
progressing to colonic perforation and death. The diagnosis is complicated by the
recent discovery of 2 distinct but morphologically identical species, E. dispar and
E. histolytica. E. dispar is noninvasive, only associated with an asymptomatic
carrier state and 10 times more common worldwide. It is nonpathogenic even in
patients with AIDS [Ravdin, 1995]. The pathogenic and nonpathogenic species
cannot be distinguished under the microscope unless one identifies E. histolytica
trophozoites, which have engulfed erythrocytes.
Virtually all patients with acute amebic colitis have fecal occult blood tests, but
fecal leukocytes are rare due to the phagocytic activity of the parasite
[Gonzalez-Ruiz, 1994]. Serum anti-amebic antibodies are usually present but
cannot distinguish between past and present infection. A negative antibody test,
however is very helpful is eliminating acute amebic colitis from the differential
diagnosis in a patient with acute bloody diarrhea [Ravdin, 1990]. Colonoscopy
with biopsy of the ulcer edge and histological demonstration of ameba remains
the definitive test for the diagnosis of amebic colitis. Recommended treatment of
invasive colitis is metronidazole 750 mg po tid for 10 days. Less severe colitis
may be treated with tetracycline 250 mg po tid for 10 days or erythromycin 500
mg po qid for 10 days. All treatments should be followed by diiodohydroxyquin
650mg po tid for 20 days to eliminate all residual cysts [Ravdin, 1995].
3.2.3.7 Aeromonas and Plesiomonas
Aeromonas hydrophilia, Aeromonas sobria and Plesiomonas shigelloides
are gram negative facultative anaerobic bacteria, which are likely but not
universally, accepted causes of acute diarrhea. The most common source of
Aeromonas is untreated drinking water and patients typically present within one

week of exposure with watery diarrhea, abdominal cramps and sometimes


vomiting [Ravdin, 1990], [Holmberg, 1986]. Blood in the stool associated with the
sigmoidoscopic appearance of non-specific colitis has been described [Deutsch,
1997]. Plesiomonas infection is associated with eating raw shellfish and causes
an illness characterized by severe abdominal cramps and diarrhea, which can be
bloody. Antimicrobial therapy is generally not needed, although Aeromonas and
Plesiomonas are both sensitive to quinolones.
3.2.3.8 Yersinia enterocolitica
Yersinia enterocolitica is a gram negative bacteria that is an uncommon cause of
acute diarrhea in adults in the United States. It is an invasive organism and
though enterotoxins have been described their role is not yet well established.
Transmission of the disease may occur via a fecal-oral route from contaminated
food and water. The most frequent source in the US in recent years has been
consumption of raw pork intestines (chitterlings). Children under five will typically
present with inflammatory diarrhea [Lee, 1991]. Older children may develop
mesenteric adenitis and inflammation of the terminal ileum clinically mimicking
acute appendicitis. Adults rarely develop clinically apparent Yersinosis which may
include self-limited diarrhea followed by arthritis and erythema nodosum.
Antimicrobial therapy has not been shown to be effective.
3.3 Traveler's Diarrhea
The ease with which people can move around the world has dramatically
increased the frequency of travelers diarrhea, now affecting up to one third of
individuals who travel to a developing area. Travelers diarrhea has been defined
as the passage of at least three unformed stools in a 24-hour period during travel
or during the first seven to ten days after returning home. Associated symptoms
may include nausea, vomiting, abdominal pain, fecal urgency, tenesmus, and
bloody or mucoid stools. Individuals at highest risk include young children, adults
ages 15-29 years, and those with high gastric pH (achlorhydria, postgastrectomy,
and proton-pump inhibitor use). The spectrum of infectious agents varies from
country to country, but overall, the most common pathogens in order of
decreasing frequency include enterotoxigenic Escherichia coli (ETEC),
enteroaggregrative E coli (EAEC), Shigella species, Campylobacter jejuni,
Rotavirus, Aeromonas species, Plesiomonas shigelloides, Salmonella species,
noncholera Vibrios, and Noravirus [Jiang, 2002]. Giardia, Cryptosporidium, and
Microsporidia are less frequent causes of travelers diarrhea but may cause
prolonged symptoms. Cyclospora may also be an important cause of prolonged
traveler's diarrhea particularly for those traveling to Nepal. However, in ~40% of
travelers with severe diarrhea, no cause of infection is found even with
sophisticated microbial testing [Jiang, 2002]. Severity of travelers diarrhea is
mostly independent of the organism recovered, with the possible exception of
Campylobacter, which leads to more systemic symptoms and a more prolonged
course than other common pathogens [Sanders, 2002]. Most travelers fear

contaminated water as the source of disease, but contaminated food may be a


much more common vehicle of transmission for both bacteria and viruses.
3.3.1 Prophylaxis
Education of travelers in the adage "boil it, peel it, cook it or forget it" may be
one of our best first-line defenses. Prophylactic use of fluoroquinolones in low
doses (250 mg ciprofloxacin, or 400 mg norfloxacin per day is 90% effective in
preventing diarrhea when traveling in areas where the resident bacteria have not
become resistant to these drugs (Southeast Asia, particularly Thailand, for
example). [Rendi-Wagner, 2002]. Bismuth subsalicylate has been demonstrated
to have 65% effectiveness when taken prophylactically, in a dose of 2 tablets 4
times daily [Graham, 1983], [DuPont, 1987]. Prophylaxis with antibiotics may be
effective, but is not recommended for healthy travelers because of the risk of side
effects and the increasing problem of drug resistance. Exceptions are usually
made for those with serious underlying medical conditions and occasionally for
those travelers unable or unwilling to risk a brief illness.
3.3.2 Treatment of Traveler's Diarrhea
The evaluation and approach to the treatment of travelers diarrhea should be
similar to that employed in other causes of acute diarrhea, as discussed below.
Most persons have mild symptoms, which are self-limited and require only
attention to oral hydration. Nonantibiotic therapies including bismuth
subsalicylate and loperamide may reduce stool frequency, liquidity and the
duration of illness (Table 7). In general, oral rehydration plus bismuth
subsalicylate or loperamide are adequate therapy for mild to moderate diarrhea
(less than four stool per day). Antibiotics should generally be reserved for
persons with travelers diarrhea who have moderate to severe symptoms. Double
blind randomized studies have demonstrated the efficacy of several antibiotic
regimens in treating acute travelers diarrhea: single doses of either levofloxacin
500 mg or azithromycin 1000 mg, or twice-daily dosing of rifaximin 200 mg or
ciprofloxacin 500 mg, for three days, appear to be roughly equivalent [DuPont,
2001], [Adachi, 2003]. In countries where bacteria are likely to be resistant to
fluoroquinolones, azithromycin or rifaximin should be used for empiric treatment.
Over half of enteric bacterial isolates from patients with travelers diarrhea are
resistant to Trimethoprim -sulfamethoxazole, which has limited utility for
treatment of travelers diarrhea.
Download a PowerPoint Presentation to learn more about Traveler's Diarrhea.
3.4 Diarrhea in Patients with AIDS
Diarrhea is one of the most common manifestations of acquired
immunodeficiency syndrome (AIDS). AIDS associated diarrhea is typically
chronic, however it is also usually infectious and therefore inclusion in this

discussion of acute diarrhea is warranted. An exhaustive review of the causes


and treatment of diarrhea in AIDS is however, beyond the scope of this review
and appears elsewhere [Lew, 1997]. Diarrhea associated with HIV infection
differs most notably by the fact that multiple etiologic agents may be present
simultaneously [Antony, 1988]. Though some infectious agents remain without
proven effective treatment, evaluation is justified by studies which demonstrate
the benefit of specific therapy [Smith, 1992], [Smith, 1988]. Bacterial agents
including Salmonella species, Shigella flexneri and Campylobacter jejunii may
cause chronic watery diarrhea with blood and mucus. These infections occur
more frequently in persons infected with HIV and may often be chronic, recurrent
and associated with bacteremia. Various strains of E. coli have also been
identified as important cause of diarrhea in AIDS. Mycobacterium avium
complex causes diarrhea usually in association with disseminated disease. Some
parasites including Cryptosporidia, Microsporidia and Isospora belli may
cause profuse watery diarrhea and weight loss in persons with AIDS. Giardia
lamblia and E histolytica do not appear to be more frequent or severe in HIV
infected patients [Albrecht, 1995]. Blastocystis hominis is probably not an
enteric pathogen, even in severely immunocompromised hosts. Adenovirus may
also cause watery diarrhea with increased stool frequency in association with
HIV infection. Cytomegalovirus [See Figure 7A ] can cause either an enteritis
or more commonly a colitis with bloody diarrhea, fever, and weight loss. Herpes
simplex virus may cause perianal disease and proctitis [ Figure 7B ]

but is much less frequently a cause of significant diarrhea [Smith, 1988].


Indications for specific antibiotic therapy are listed in (Table 8). A stepwise
approach to the diagnostic evaluation of nonbloody diarrhea in persons with
AIDS has been suggested [Smith, 1993]. An initial approach which includes only
a stool culture appears to be the most cost effective when subjected to medical
decision analysis [Johanson, 1990]. When necessary, further workup should
include stool culture, C. difficile toxin, and microscopic examination for ova and
parasites using saline, iodine, trichrome and acid-fast preparations. A complete
evaluation including colonoscopy and esophagogastroduodenoscopy with

multiple biopsies should be reserved for those patients in whom a specific agent
cannot be identified, and significant symptoms persist despite nonspecific
therapy.
3.5 Diagnostic Evaluation
3.5.1 History
The initial evaluation of the adult patient presenting with acute diarrhea should
focus on the setting, nature and severity of the acute diarrheal illness as well as
the patient's age and overall health status. Early intervention is warranted for
individuals who are elderly (>70 years), debilitated or immunocompromised.
Even previously healthy adults with acute diarrhea should see their health care
provider early if they experience dehydration, fever, gastrointestinal bleeding,
abdominal pain or neurologic symptoms.
Recently published practice guidelines recommend prompt medical evaluation in
those patients who present with dehydration, bloody stools, profuse watery
diarrhea, fever greater than 38.5 C (101.3 F), severe abdominal pain, >6
unformed stools during a 24 hr period, or duration of illness of >48 hours
[DuPont, 1997]. These guidelines are derived from available scientific evidence
but in this case they are largely based upon consensus. The impact of >6
unformed stools or duration of illness >48 hours on either the likelihood of a
positive stool culture or the ultimate clinical outcome of the patient has not been
studied.
The patient should be asked if they have noted any symptoms of dehydration
including lightheadedness, dizziness, dry mouth, excessive thirst, decreased
urine output, increased heart rate or changes in mental status. Initial history
should also elicit any associated nausea, vomiting, fever, shaking chills or signs
of significant upper or lower gastrointestinal bleeding (coffee ground emesis,
hematemesis, melena, hematochezia), joint pain or a new skin rash. If this initial
assessment does not indicate anything requiring immediate intervention, the
evaluation can proceed to focus on the character of the illness, the setting in
which it began, and other factors which may point to a specific diagnosis.
In order to assess the severity the diarrhea one should ask specifically about the
frequency, consistency and volume of the stool. Patients should be asked to
quantify the number of bowel movements in a 24-hour period. It may be helpful to
stratify the severity of diarrhea. Mild diarrhea be defined as less than three
unformed bowel movements in a 24 hour period. Moderate diarrhea is three or
four per day and severe diarrhea is more than four unformed bowel movements
per day. In the absence of a specific diagnosis, the type of empiric treatment
(bismuth subsalicylate, loperamide or antimicrobials) may be predicated on this
type of stratification scheme [Gorbach, 1997]. A report of >6 stools is a sign of
severity and should prompt one to pursue further medical evaluation. Loose

consistency correlates directly with quantity of stool water. This is one area where
the patients description may be difficult to interpret. Verbal descriptors such as
"solid" and "liquid" appear to have reproducible meaning while the meaning of
"loose" and "semiformed" are variable [Mertz, 1995]. Some directed questions
may help the patient describe their current stool appearance.
Diarrhea Questionnaire
A. Stool Form Assessment
1.) Have you been having diarrhea in the past 7 days?
Yes
No
2.) In the past 7 days have your stools typically been:
Well-formed
Semi-formed (very soft but retains some form)
Loose ( no form, breaks apart)
Liquid (mushy like applesauce or watery)
3.) How often have your bowel movements looked like each of the following pictures
in the past 7 days?
All of the time
Most of the time
Some of the time
None of the time

[A pictorial representation may be very helpful.]

Nonspecific antidiarrheal therapy may reduce the looseness of the stool without

causing measurable decreases in stool water [Wenzl, 1995]. The risk of


dehydration may not change in the patient using nonspecific antidiarrheal therapy
even though the stool may appear more formed. In a very general sense, it is
useful to know if the bowel movements are small or large in volume. The severity
of diarrhea strongly correlates with the presence of fecal incontinence and
nocturnal bowel movements. Fecal incontinence in the setting of acute diarrhea
is extremely common. Patients may hesitate to volunteer this as a symptom
unless they are asked specifically.
The pattern of the diarrhea and the relationship to meals or medication times
may be helpful. A history of intermittent diarrhea with some completely normal
stools may suggest lactose intolerance or some other dietary or medication
intolerance. Patients should always be asked about the presence of blood or
mucus. Tenesmus, the sensation of a recurrent sometimes painful and often
ineffectual need to defecate may indicate the presence of proctitis. Associated
symptoms of nausea, vomiting, abdominal pain, fever, chills, anorexia, and loss
of weight should be elicited.
The setting in which the diarrhea began is crucial to the history in adults with
acute diarrhea. The health care provider should ask patients about recent travel,
exposure to untreated water, recent antibiotics, and contacts with day-care age
children, nursing home residents or other individuals with diarrhea. Dietary
history should include recent ingestion of raw or poorly cooked foods (eggs,
meat, shellfish, fruits and vegetables) or foods that may have been improperly
handled or stored (restaurants, buffets or picnics). Patients should be asked
specifically about ingestion of dairy products and sugarless food or candy
containing sorbitol or xylitol. The use of public swimming pools and contact with
domestic or farm animals may also be important. Patients should be asked about
any changes in diet, alcohol or medications (prescribed, over-the-counter,
complimentary, herbal or botanical) which were initiated before the onset of
diarrhea. A number of new medications including recent diet medications that
hamper fat absorption may cause diarrhea in addition to a large number of
medications that have been in use for many years. (Table 9) Sexual history may
be relevant particularly if there has been oral-genital or oral-anal contact. Past
medical history should focus on any prior history of diarrheal illness, significant
underlying medical problems (e.g. AIDS, diabetes, cirrhosis, sickle cell disease,
cancer, endocrine or autoimmune disease), prior radiotherapy and immunological
status. It is very important to ask about any risk factors for AIDS since diarrhea
may be the initial presenting manifestation of HIV infection. Questions about past
surgical history should specifically include cholecystectomy, intestinal resection
and surgery for peptic ulcer disease. A very complete list of medications is crucial
including all prescription, ophthalmologic, nonprescription and herbal
medications.
3.5.2 Physical Examination

The initial physical examination in the adult with acute diarrhea should focus
primarily on the assessment for any signs of significant dehydration.
Hypotension, resting tachycardia and orthostatic changes should be sought by
measuring heart rate and blood pressure in both the supine and standing
positions after 3 minutes have elapsed to allow for equilibration. Changes of 20
points or more in the pulse or blood pressure indicate significant volume
depletion. Other indications of dehydration include dry mucus membranes, poor
skin turgor and if severe, changes in mental status. Physical examination should
also include a careful abdominal and rectal examination to look for signs of
obstipation, obstruction, peritonitis, or anorectal disease.
3.5.3 Laboratory Evaluation
An otherwise healthy adult with mild acute diarrhea of less than 3 days duration
without any obvious cause may be treated symptomatically. Individuals with
significant underlying medical disease or moderate to severe diarrheal illness of
greater than 48 hours should undergo further diagnostic evaluation. This group
would include individuals with bloody diarrhea, significant dehydration, fever or
abdominal pain. Further evaluation is also indicated for individuals with recent
travel, antibiotic use, day-care exposure or nursing home workers, food handlers,
and those present during a community outbreak or following exposure to high
risk foods.
3.5.3.1 Stool Examination
The initial evaluation of the stool in the setting of acute diarrhea may include
visual examination for evidence of gross blood, testing for occult blood, and
microscopic examination of the stool for red and white blood cells. Visual
indicators of gastrointestinal hemorrhage include bright red blood, maroon or
black tarry stools. Dark stools, which are not black and tarry, do not indicate
bleeding. Though hematochezia is nonspecific, one study done in Bangladesh
demonstrated visible blood was found significantly more often in those infected
with Shigella or Entamoeba histolytica than with other pathogens [Stoll, 1983]. In
the United States, E. coli O157:H7 is the most commonly isolated organism from
stool specimens that are visibly bloody.
Testing of the stool for occult blood is problematic. A study of US citizens
studying in Mexico and presenting with acute diarrhea demonstrated the finding
of a negative fecal occult blood test was a reliable indicator of the lack of invasive
bacterial infection [McNeely, 1996]. The percentage of false positive exams,
however is likely increased in the setting of anal trauma associated with acute
diarrhea and there is insufficient positive predictive value. Newer tests for fecal
occult blood using latex agglutination of fecal hemoglobin may improve the
specificity but are currently too complicated and expensive for general use
[Beltinger, 1997].

Direct examination of the stool for fecal leukocytes has been used for decades
as an indicator of intestinal inflammation [Harris, 1972]. The methodology is
simple enough that someone with microscopy skills and a very basic laboratory
can perform the test reliably. Use of a fresh stool sample in a cup rather than one
obtained with a rectal swab is recommended. An aliquot of fresh stool on the tip
of a wooden stick is mixed on a glass slide with normal saline until it is barely
transparent. A drop of methylene blue or Grams stain may facilitate identification
of fecal leukocytes. The finding of >10 fecal leukocytes per high power field is
considered positive. One US study retrospectively examined the utility of fecal
leukocytes as an indicator of a positive stool culture. The sensitivity and
specificity were 40% and 78%, respectively. The positive predictive value was
only 20%. Several other studies have also shown fecal leukocytes are a very
poor predictor of enteric infection. Fecal leukocytes are also present in
noninfectious inflammatory disorders of the colon including inflammatory bowel
disease, ischemia and radiation proctitis.
The measurement of fecal lactoferrin by latex agglutination has been proposed
as a more sensitive test for the detection of fecal leukocytes [Guerrant, 1992].
Stool Hemoccult, fecal leukocyte and fecal lactoferrin all have poor positive
predictive value.
Routine stool culture for enteric pathogens should identify Salmonella, Shigella,
Campylobacter, E coli O157:H7, and Yersinia. Some labs have added
Aeromonas and Plesiomonas.
Clinical predictors of a positive culture include diarrhea of greater than 24 hours
duration, fever, and either blood in the stool or abdominal pain with vomiting
[Koplan, 1980]. A multicenter review of nearly 60,000 stools submitted for culture
revealed an overall positivity rate of 6.4%. Multiple specimens are frequently
submitted from the same patient, however, 96.9% of positives were found on the
first specimen and 99.0% after the second [Valenstein, 1996]. No more than 2
specimens are necessary to exclude an enteric infection.
Stool cultures are frequently sent to evaluate hospitalized patients who develop
diarrhea. At least 5 retrospective and 1 prospective study have evaluated the
likelihood of a positive stool culture in relationship to the number of days in the
hospital [Siegel, 1990], [Rohner, 1997], [Yannelli, 1988]. While the overall
positivity rate was approximately 6%, the yield of stool culture in those
developing diarrhea after the 3rd hospital day was only 0-1% in all studies
[Valenstein, 1996], [Rohner, 1997]. Similarly, specimens submitted for ova and
parasites (O&P) had an overall yield of 2.5%. This decreased to 0.7%, if
submitted from patients hospitalized for more than 4 days [Valenstein, 1996].
Guidelines have been proposed to limit the use of stool cultures to patients in the
hospital <3 days unless they are immunocompromised. Outcome studies using
this type of guideline have reduced the number of specimens submitted by 37%
[Chitkara, 1996].

The examination for ova and parasites (O&P) is recommended for individuals
with persistent diarrhea who are at risk because of foreign travel, high-risk sex,
immunocomprimised status, exposure to unfiltered water, day care aged children
or a community outbreak [DuPont, 1997]. The evaluation is time consuming and
the yield may vary considerably with the available level of expertise. Typically 3
specimens are collected on successive days. In those patients in whom a
parasite was ultimately identified by stool examination, 97.6% of specimens were
positive after 2 specimens were examined. The yield increased to 99.8% after
three specimens were examined. Stool examination for ova and parasites
identifies an organism in only 2.5% of specimens submitted. Specimens from
immunocompetent persons are seldom positive if submitted after the fourth
hospital day [Valenstein, 1996], [Mohr, 1992].
In contrast, testing for Clostridium difficile toxin in appropriate patients has a
high frequency of positivity in both outpatients and inpatients regardless of length
of stay [Barbut, 1996]. C. difficile toxin was detected more frequently from
inpatients than any other bacterial pathogen even though it was requested on
only 50% of the specimens submitted for culture [Valenstein, 1996]. Testing for C.
difficile toxin is appropriate in individuals who are receiving or have received
antibiotics within the previous 2 months.
The evaluation of an adult with watery non-bloody diarrhea and exposure to day
care aged children or unfiltered water should focus on giardiasis. The sensitivity
of the microscopic examination for Giardia lamblia, however, is only 50-70%. In
lieu of stool for O&P, one should submit a single stool specimen for Giardia
specific antigen. This commercially available ELISA has sensitivity and
specificity of 96% and 100%, respectively [Rosoff, 1989].
Routine stool studies for outpatients with mild to moderate diarrhea may not be
necessary and can in the aggregate greatly add to the cost of medical care.
(Table 10) Stool culture for enteric pathogens is indicated if the patient has any
of the alarm signals outlined in (Table 11).
3.5.4 Endoscopy
Endoscopy is generally unnecessary in the evaluation of adults with acute
diarrhea. Flexible sigmoidoscopy may be recommended in the evaluation of
patients with persistent diarrhea and one of the following:
o
o
o
o

Blood in the stool


Lack of response to antimicrobial therapy
Lack of specific diagnosis after routine evaluation
AIDS

The endoscopic and histologic appearance of infectious colitis

is generally not specific but biopsies may be helpful, particularly in distinguishing


acute from chronic colitis.

Upper endoscopy with biopsies may be helpful in selected patients with


persistent watery nonbloody diarrhea and negative routine evaluations [DuPont,
1997].
3.6 Treatment
Excellent treatment guidelines have been published recently by the American
College of Gastroenterology and the British Society for the Study of Infection
[Farthing, 1996], [DuPont, 1997]. The initial approach to the treatment of acute
diarrhea is predicated upon a careful evaluation of the patient. Attention must be
paid to the patients age, underlying medical condition, severity of current illness,
and degree of volume depletion. The determination of volume status is critical in
those who are elderly or debilitated. The clinical indications for medical
evaluation in adults with acute diarrhea are summarized in (Table 11).
3.6.1 Oral rehydration

Most adults presenting with acute diarrhea will have only mild sodium and water
depletion and will respond appropriately to oral hydration. Clear liquids such as
dilute fruit juice, carbonated beverages, and sports drinks may suffice for mild
self-limited diarrhea. These drinks however, should not be recommended for
patients with moderate to severe diarrhea because they have an inappropriate
ratio of sodium to carbohydrate [Avery, 1990]. The physiological principle
explaining the coupled transport of sodium and glucose underlies most current
recommendations. The ideal solution would contain sodium 60-90 mEq/L,
potassium 20mEq/L, citrate 30mEq/L and glucose 20g/L. Rehydration formulas
which incorporate these principles include the WHO-UNICEF oral rehydration
salt packets and commercially available products including Infalyte , Lytren,
Pedialyte and Resol. The constituents of several often utilized formulations are
presented in (Table 12). Homemade solutions may be used effectively if clean
water is available and care is taken to avoid errors in mixing (Table 13).
Continued intake of food is now considered an important part of oral therapy for
diarrhea and should not be discouraged [Avery, 1990]. Boiled starches and
cereals (potatoes, noodles, rice, wheat, and oats), crackers and bananas are
ideal. Milk is often avoided, however the development of clinically important
lactose intolerance in the setting of acute diarrhea is rare [DuPont, 1997].
3.6.2 Antidiarrheal Therapy
Nonspecific antidiarrheals are very commonly used in mild to moderate acute
diarrhea. These may include bismuth subsalicylate, diphenoxylate HCl with
atropine sulfate (Lomotil), loperamide (Imodium), attapulgite (KaoPectate) and
cholestyramine (Questran). Anticholinergics are generally ineffective and are not
recommended because of side effects.
Bismuth subsalicylate (Pepto-Bismol) may have both anti-secretory and antimicrobial activity. Salicylate absorption can occur but short term use in adults
appears to be safe [Gorbach, 1990]. In 1977 DuPont et al. published a
randomized double blind placebo controlled study of bismuth subsalicylate
suspension in the treatment of acute diarrhea in US students who had recently
arrived in Mexico [DuPont, 1977]. Bismuth subsalicylate suspension was
associated with a significant decrease in the number of unformed stools and
subjective complaints of diarrhea, nausea and abdominal cramps. There was no
significant difference in water content or total weight of the stools between the
two groups. A subsequent study of healthy volunteers who ingested
enterotoxigenic E. coli (ETEC) demonstrated bismuth subsalicylate tablets taken
four time a day caused a significant reduction in the incidence of acute diarrhea
[Graham, 1983].

ETEC was rarely recovered in the stools of subjects given bismuth subsalicylate.
A second study on US students in Mexico demonstrated bismuth subsalicylate (2
tabs four times a day in doses identical to Pepto-Bismol ) given within 48hours of
arrival was associated with a significant reduction in the incidence of travelers
diarrhea [DuPont, 1987]. This regimen accounted for a protection rate of 65%.
Side effects reported included only darkening of the tongue and stool. There was
no statistically significant increase in the development of tinnitis. Bismuth
subsalicylate may also be effective in reducing symptoms in patients with viral
gastroenteritis [Steinhoff, 1980].
Loperamide is a modified opiate that does not significantly penetrate the central
nervous system. It is available over-the-counter and exerts its antidiarrheal effect
by reducing intestinal motility. It has no demonstrated antisecretory activity.
Loperamide (Imodium A-D) has been compared to bismuth subsalicylate (Pepto
Bismol) and attapulgite (Kaopectate) in two open labeled field trials for the
treatment of acute watery nonbloody diarrhea. Loperamide was more effective
and worked faster than bismuth subsalicylate. 75% of patients achieved relief
from symptoms of diarrhea within only one day of therapy [Johnson, 1986],
[DuPont, 1990].
Diphenoxylate-HCl with atropine (Lomotil) is another opiate-like antimotility
agent. Although data is limited, diphenoxylate-HCl with atropine may be
contraindicated in patients with bloody diarrhea. In one study, diphenoxylate-HCl
with atropine prolonged fever and illness in patients with bloody diarrhea due to
Shigella [DuPont, 1973]. A subsequent study did not confirm this finding however
[Murphy, 1993].
Attapulgite (Kaopectate) is a naturally occurring purified hydrated aluminum
magnesium silicate which is not absorbed systemically. It was tested in a double
blind placebo controlled study of adults with mild to moderate acute diarrhea not
due to bacteria or protozoa. Attapulgite (600mg) two tabs after each bowel
movement for a maximum of 72 hours was associated with a significant reduction
in the frequency of diarrhea [Zaid, 1996]. Stool volume was not evaluated. These

adsorbents may add form to the stool without affecting overall fluid losses and
should therefore be used only in patients with mild diarrhea.
Cholestyramine is a nonabsorbable resin used as a cholesterol lowering agent
with the side effect of constipation. Limited studies have demonstrated
cholestyramine is effective as a nonspecific treatment for acute diarrhea [McCloy,
1971]. A specific role may exist for treatment of relapsing pseudomembranous
colitis secondary to Clostridium difficile.
3.6.3 Antibiotic Therapy
Empiric antibiotic therapy may be indicated in selected adults with acute
diarrhea. Pending culture results, empiric antibiotic therapy may be considered in
patients with fever >38.5 C (101 F), dysentery or bloody diarrhea (excluding
amebiasis), and moderate to severe travelers diarrhea. The rationale for empiric
antibiotic therapy in moderate to severe travelers diarrhea, is that most of these
patients harbor a bacterial pathogen. Few studies have evaluated the benefit of
empiric antimicrobial therapy for acute diarrhea in adults who are not recent
travelers. One such study evaluated 202 patients treated with either
ciprofloxacin, trimethoprim/sulfamethoxazole or placebo for 5 days in a
randomized double blind fashion [Goodman, 1990]. Ciprofloxacin, but not
trimethoprim/sulfamethoxazole shortened the duration of illness and had a higher
cure rate than placebo. 82% of patients who received ciprofloxacin had improved
or were cured by the third day. Despite a lack of strong scientific evidence,
empiric antibiotic therapy is also commonly used for patients over age 60 with
moderate to severe diarrhea or those with significant underlying medical
conditions [Ericsson, 1987], [Wistrom, 1992].
When indicated, the drug of choice for antimicrobial therapy of diarrhea of
unknown cause is a quinolone such as norfloxacin 400mg, ciprofloxacin 500mg
or ofloxacin 300mg bid for 3-5 days [Farthing, 1996], [DuPont, 1997].
Unfortunately, as feared, reports of quinolone resistance have begun to appear.
The decision to use antimicrobial therapy, after stool studies reveal a causative
agent, will depend on whether or not symptoms have persisted. The benefits of
antibiotics are most well demonstrated for Shigella, C. difficile and Giardiasis.
The drugs of choice for specific antimicrobial agents are listed in (Table 14).
4.0 Chronic Diarrhea
4.1 Introduction
Chronic diarrhea implies an increased frequency of passing looser stools for
more than a month.
Healthy, young Americans eating controlled diets containing 20g of dietary fiber

have stool weights of about 100 g daily [Saunders, 1988]. The stools are 70%
water by weight, but the water entrapped in fibrous residue or in bacteria
comprises 30-75% of the wet weight of stools [Stephen, 1980].
Healthy humans can have heavier stools if their diet contains food stuffs which
enhance fecal bacteria, or contribute to fecal fiber. Vegetarians may have stool
weights normally in excess of 200g. On the other hand, patients may have
abnormally loose stools whose daily weight is less than 200g. The consistency of
stools is determined by the water content and by the ability of fecal insoluble
solids to bind the fecal water [Wenzl, 1995].
The punch-line: a decreased consistency of feces should be the major
characteristic in the definition of diarrhea rather than an arbitrarily defined
excessive daily fecal weight (exceeding 200g per day, for example), or increased
frequency of defecation.
Diarrhea is said to be chronic after one month because most infectious causes of
acute diarrhea resolve within this period of time [Donowitz, 1995], except in
patients who are immunosuppressed.
We present an approach to the differential diagnosis of chronic diarrhea based
on groups of diseases, although pathophysiologic mechanisms can overlap
considerably. However, clinicians should be able to use this scheme to develop a
hypothesis and to test the hypothesis in a logical manner.
4.2 The Diarrhea History
Physicians begin to generate hypotheses as soon as a patient is greeted, and as
the presenting complaint is heard. The ensuing questioning will depend on the
initial hypotheses. The essence of this disease-oriented approach to chronic
diarrhea is the emphasis on eliminating expeditiously diseases causing
hematochezia and diseases with malabsorption, so that the difficult group of
predominantly watery diarrheas can be considered without distraction.
4.2.1 Immunocompetence
It is essential to establish that the patient with chronic diarrhea is
immunocompetent. Otherwise, an infectious etiology for the diarrhea would be of
paramount concern. Questions about blood transfusions, intravenous drug use,
occupational or recreational exposure to HIV, and immunosuppressive medical
therapy must be asked.
4.2.2 Onset
An abrupt onset may connect the symptom of chronic diarrhea to the cause such
as cyclospora (mountaineering in Nepal) or as lactose intolerance (following viral

enteritis).
4.2.3 Frequency of Defecation
4.2.3.1 Diarrhea After Meals
Diarrhea after meals suggests a heightened gastro-colic reflex. Patients with
irritable (idiopathic) bowel syndrome often voice this complaint.
4.2.3.2 Awakening from Sleep
Diarrhea which awakens a patient from sleep is an alarm signal for organic
disease. Diarrhea rarely awakens the patient with functional (idiopathic) bowel
disease.
4.2.3.3 Daily Diarrhea
Daily diarrhea suggests organic disease. Patients with irritable (idiopathic) bowel
syndrome often have good days interspersed with bad ones.
4.2.4 Volume of Diarrhea
4.2.4.1 Teaspoons or Tablespoons?
Is the patient passing teaspoons or tablespoons (small volume) of stools?
Affirmation suggests anorectal dysfunction (incontinence), or proctitis (especially
if tenesmus or hematochezia is present).
4.2.4.2 Cupfuls?
Is the patient passing cupfuls of stool (large volume)? Patients who pass more
than 1 L of stool daily have small bowel mucosal disease, or a combination of
small and large bowel mucosal disease, or a hypersecretory state; these
inferences are based on the absorptive capacity of the normal colon [Debongnie,
1978].
4.2.5 Relationship to Eating
4.2.5.1 Worsened by Eating?
Is the diarrhea worsened by eating, and, if so, is the diarrhea worsened by eating
fatty foods? An affirmation suggests steatorrhea.
4.2.5.2 Lessened by Fasting?
Is the diarrhea lessened by fasting? An affirmation suggests malabsorption, but

patients with irritable (idiopathic) bowel syndrome often give a positive response.
4.2.5.3 Unaffected by Fasting?
Is the diarrhea unaffected by fasting? A positive response suggests an exudative
enteropathy (inflammatory bowel disease), or a hypersecretory state.
4.2.6 Fecal Characteristics
4.2.6.1 Blood in Stools?
Has the patient seen blood in stools? (Inflammatory bowel disease)
4.2.6.2 Stool Consistency?
What is the consistency of the stools? The patient should be challenged to
describe the stools as semi-formed, or as mushy (like applesauce), or as loose
(like thin soup). A formal diarrhea questionnaire is offered by Mertz et al [Mertz,
1995]. Steatorrheic stools are sometimes mushy rather than loose [Bo-Linn,
1984], [Hofmann, 1985].
4.2.6.3 Color and Odor?
The color and the odor of stools are only informative if these characteristics have
changed dramatically.
4.2.6.4 Excessive Flatus?
Floating stools and excessive flatus suggest carbohydrate malabsorption. Stools
float because of their content of gas, not of fat [Levitt, 1972].
4.2.6.5 Oily Droplets?
Oily droplets in the toilet water indicate steatorrhea, and especially malabsorption
of dietary triglyceride.
4.2.6.6 Recognizable Food Stuffs?
Has the patient recognized food stuffs in the stool, and of additional importance,
is there an estimate of elapsed time between ingestion and expulsion? This head
of meal transit time can be very helpful. A HOMTT less than 12 hours has been
associated with experimentally induced diarrhea [Read, 1980]. Food stuffs such
as corn kernels, or whole beets, which color the stools red, can be used as
markers.
4.2.7 Previous Abdominal Surgery or Irradiation

4.2.7.1 Intestinal Resection


Gastric resection used to be a major condition associated with malabsorption.
Nowadays, intestinal resection is much more common. It is important to obtain
past records; the amount of right colon resected can exceed in importance the
amount of ileum resected in the pathogenesis of the post-operative diarrhea
[Cummings, 1973].
4.2.8 History of Medication Use
Virtually any medicine can impair the 99% efficiency of normal salt and water
absorption. Major culprits include antibiotics, antiarrhythmics, antimetabolites,
and alcohol (Table 9).
4.2.9 Characteristics of the Patient
4.2.9.1 Does the Patient Appear Well?
If the patient appears well, has a normal screening physical exam, and has no
alarm signals, irritable (idiopathic) bowel syndrome can be pursued further.
4.2.9.2 Family History
A family history of inflammatory bowel disease, celiac sprue, or cancer can
strengthen suspicions about the etiology of chronic diarrhea.
4.2.9.3 Risk factors for immunosuppression?
4.2.10 The Diarrhea Diary
A patient can be instructed to keep a diary for a week or more which lists the
times of defecation, some fecal characteristics, relationship to meals, etc (Table
15). Such a questionnaire could be sent to a patient prior to the office visit.
4.3 Simple Stool Studies
These simple tests are used to accept or reject initial hypotheses about the
cause(s) of chronic diarrhea. Surprisingly, collecting a stool specimen is often a
neglected essential in the investigation of the patient.
4.3.1 Head of Meal Transit Time
Head of a meal transit time (HOMTT) can be assessed by asking a patient to
measure the time elapsed between swallowing half a cup of corn kernels, or
eating four whole canned beets. A HOMTT averaged 22 hours (median, 20
hours; range 9-45 hours) in 24 presumably healthy medical students who

observed a red discoloration of their stools after eating four whole canned beets
with a meal [Saunders, Unpublished Observations]. The clinician is interested
only in abnormally rapid transit times in the work-up of diarrhea. Diarrhea can be
induced experimentally when the HOMTT becomes less than 12 hours [Read,
1980]. Furthermore, steatorrhea (up to 14 g of fat per day) can be induced in
normal subjects by osmotic laxatives [Fine, 1992] which would be expected to
hasten transit of chyme through the small intestine. So having an idea of
intestinal transit time contributes to understanding the etiology of diarrhea, and
the interpretation of measurements of fecal fat.
4.3.2 The Sudan Test for Fecal Fat
This test can be performed on a spot specimen, or on a timed collection of stool.
A representative sample of stool is placed on a glass slide, and it is acidified with
glacial acetic acid to protonate long-chain fatty acids so that they are converted
from insoluble salts to fatty crystals. After adding an ethanolic solution of Sudan
III and applying a cover slip, the slide is gently heated to melt the fatty acids into
oily droplets [Drummery, 1961]. Up to 100 tiny (<4 microns) droplets may be seen
in normal stool at a magnification of 400x. If the number and size of the orange
fatty droplets is increased, a second fecal slurry in water should be prepared.
This specimen is not acidified; it is examined directly after adding the Sudan III
[Drummery, 1961].
The Sudan Test is very sensitive for the detection of fatty acid (Part One of the
test) and of triglyceride (Part Two of the test) [Khouri, 1989]. Therefore, if Part
Two (and Part One) of the Sudan Test is positive, the clinician should suspect
maldigestion of dietary triglyceride (pancreatic insufficiency, small bowel
resection). A negative Part Two of the Sudan Test does not exclude pancreatic
insufficiency. Mineral oil, and the unabsorbable fat substitute, sucrose polyester
(Olestra ) could cause false positive Sudan Tests (Parts One and Two).
The bottom line: If a patient is ingesting fat (> 80 g per day), the Sudan Test is
excellent for proving clinical suspicion of fat malabsorption [Drummery, 1961],
and it has the added advantage of being able to suggest maldigestion of dietary
triglyceride.

4.3.3 The pH of Fecal Water


The pH of fecal water can be estimated with color-fast indicator strips (for
example, ColorpHast, EM Science, 480 Democrat Road, Gibbstown, NJ 08027)
which can be dipped into a fresh specimen of liquid stool and washed briefly
under tap water. Fecal pH of <5.5 is diagnostic of carbohydrate malabsorption
[Eherer, 1992], because it is caused by the fecal excretion of excessive amounts
of short-chain fatty acids from colonic fermentation of carbohydrate.
4.3.4 Fat Balance
This test should be designed to obtain a timed collection of feces while the
digestive and absorptive functions of the small intestine are being challenged,
that is, when the etiological hypothesis is predominantly fatty diarrhea.
A critical factor in a meaningful result from a fat balance is knowing the patients
fat intake. Consider if the patient has a coefficient of fat absorption of 80%
(normal, 95%) and yet is eating only 40 g of fat a day: a potential additional
excretion of 8 g of fat in 24 hours can be underwhelming. The patient should
have dietary counseling to ensure that > 80 g of fat are ingested daily during the
test. A Big Mac with large fries is nearly 50 g of fat. Some patients think that a
prescription of two Big Macs plus fries per day is inspired; other patients plead
cruel and unusual punishment.
A fat balance can be combined with the HOMTT test, and with collections of stool
samples for searching for parasites (Table 16). Patients are instructed in how to
place feces in precalibrated vials containing a fixative-preservative which allows
storage without obscuring subsequent microscopic search for eggs, cysts, and
trophozoites (Ecofix, Meridian Diagnostics Inc., Cincinatti, Ohio 45244). Another
portion of stool can be placed in a plastic jar so that giardia antigen can be
sought by immunoassay. One adequate fecal specimen is sufficient for the
detection of Giardia antigen. Three stools should be examined if E. histolytica
trophozoites are being sought.
The weight of a 24 hour stool can be helpful. Patients with irritable (idiopathic)
bowel syndrome rarely have daily stool weights over 500 g; low stool weights
may indicate that a patients true trouble is fecal incontinence. On the other hand,
patients with hormonally-driven, hypersecretory diarrhea often have daily stool
weights over 1000 g.
If the fecal fat has been quantified, and the weight of the 24 hour stool is known,
a concentration of more than 8 g of fat per 100 g of stool suggests pancreatic
insufficiency [Bo-Linn, 1984], although, as a test, fecal fat concentration is neither
very sensitive or specific [Hofmann, 1985].

4.3.5 Measuring Fecal Electrolytes


Fecal water has about the same osmolality as plasma, 290 mosmols / kg. K + is
the predominant cation, and short-chain fatty acids the predominant anion (~
120mm) in normal fecal water. Fermentation continues in stored stools;
consequently fecal osmolality rises as short chain fatty acids (SCFA) continue to
be generated. Therefore it is essential to use a freshly passed specimen of stool,
and to obtain the supernatant solution as quickly as possible if fecal osmolality is
to be measured. Alternatively, a fecal osmolality of 290 mosmol / kg can be
assumed [Eherer, 1992]. The osmotic gap is estimated by subtracting the sum of
the concentrations of K+ plus Na+ (multiplied by a factor of 2 to allow for the
accompanying anions) from 290. In experimentally induced hypersecretory
diarrhea, the osmotic gap shrinks to less than 50 mosmols / kg [Eherer, 1992] as
the electrolyte composition of the watery stools comes to resemble that of
plasma. On the other hand, osmotic gaps are widened when unmeasured solutes
such as lactose, or as Mg++ are present in fecal water.
One perquisite of measuring the osmolality of fecal water is that factitial diarrhea
can be discovered if the fecal osmolality is less than 290 mosmols / kg; water or
dilute urine must have been added to the fecal specimen [Eherer, 1992], [Phillips,
1995].
4.3.6 Diarrheal Response to Fasting
Patients with hormonally-driven, hypersecretory diarrhea usually have daily stool
volumes of over 700 ml [Donowitz, 1995] so they may need to be hospitalized for
correction of hypovolemia and hypokalemia. Typically, hypersecretory diarrhea
continues unabatedly even if the patient is fasting. The hospitalized patient can
be "fed" intravenously during a controlled fast. A modified fast can be
accomplished in selected out-patients by proscribing food for 24 hours while
prescribing sufficient Na+ and water to prevent hypovolemia should the diarrhea
continue. Drinks such as Gatorade contain insufficient Na+. Solutions such as
Pedialyte (Na+, 45 meg / L; K+, 20 meg / L; glucose, 25 g / L) can be drunk in
quantities sufficient to keep urinary output above one L per day while the patient
keeps a diarrhea diary.
4.4 Types of Diarrhea
4.4.1 Sugary Diarrhea
New experimental data, and clinical experience allows definition of this common
cause of chronic diarrhea.
4.4.1.1 Patient Profiles

A non-caucasian patient is advised to drink two glasses of whole milk a day to


provide needed calcium for strong bones.
A patient chews six packs of sugarless gum a day in order to satisfy her sweet
tooth without gaining weight.
A patients diarrhea begins with the ripening of the cherries and her indulgence of
1-2 lbs of cherries a day.
All of these patients complained of excessive flatus, of a feeling of abdominal
bloating, and of passing 3-4 mushy stools a day which floated in the toilet water.
Their diarrhea resolved when the offending sugars (lactose; sorbitol; fruit sugars
such as fructose, mannitol, sorbitol, raffinose, etc.) were eliminated. They had no
alarm signals of other illness.
4.4.1.2 Pathophysiology
Colonic bacteria ferment poorly absorbed osmotically active carbohydrate into
absorbable gases (hydrogen, carbon dioxide, methane), and short-chain fatty
acids. Diarrhea results when the fermentative capacity of colonic bacteria for
soluble carbohydrate and the absorptive capacity of colonocytes for SCFA are
overwhelmed [Saunders, 1981], [Rao, 1988], [Hammer, 1989].
Excessive flatus is a consequence of colonic fermentation. Even small amounts
of carbohydrate such as 5 g of lactulose daily are flatogenic [Levitt, 1996].
Fermentation gases contribute the most to the volume of normal flatus [Tomlin,
1991].
Malabsorption of carbohydrate may contribute importantly to the volume of
diarrhea in patients with combined small and large bowel resections [Hammer,
1990]. Many medicinal elixirs contain sorbitol which is often the cause of diarrhea
in tube-fed patients [Edes, 1990].
4.4.1.3 Diagnosis
Malabsorption of carbohydrate should be suspected when diarrhea is
accompanied by excessive flatus.
Finding a pH of < 5.5 in the fecal water of a freshly-passed stool would be
corroborative evidence. Removal of the offending sugar should eliminate the
diarrhea.
A tolerance test with 50 g of lactose, glucose-galactose is rarely necessary.
Twenty-five g of glucose plus 25 g of galactose might be used as a control. The
lactase-deficient individual will have abdominal cramps, flatulence, and diarrhea
after the lactose challenge, but not after the component monosaccharides.

4.4.2 Predominantly Fatty Diarrhea


Steatorrhea should be suspected from questioning the patient, be proven by
simple stool studies, and then the precise etiologic defect in the absorptive
process should be defined.
4.4.2.1 Profile of a Patient
A 60 year old housewife presented with diarrhea of three months duration. She
was passing 2-3 mushy stools per day whose frequency and volume were
worsened by eating, especially foods rich in fat. Diarrhea awakened her from
sleep; she had lost 10 pounds in weight despite even though she forced herself
to eat extra quantities of food. Physical exam revealed only a wan lady with no
abdominal scars.
Investigations elsewhere included normal hematocrit, thyroid screen, stool ova
and parasites. Upper endoscopy and colonoscopy with biopsies were normal.
Courses of loperamide and metronidazole were unhelpful.
That this lady was malabsorbing should have been suspected from the history of
weight loss with, presumably, an adequate dietary intake (hyperthyroidism, and
diabetes were excluded), and the worsening of her diarrhea with fatty foods.
Even though she was able to eat only one hamburger and fries each day, she
presented us with 700 g of mushy stools. The Sudan Stain was positive, and,
significantly, Part Two of the stain revealed triglyceride droplets. An abdominal
CT scan was performed because she did not have risk factors for pancreatic
disease such as alcoholism, or familial predisposition. The final diagnosis was
cancer blocking her main pancreatic duct.

4.4.2.2 Pathophysiology
Steatorrhea should be an initial clinical suspicion. When steatorrhea is proven,
the definitive cause can be discovered by remembering the way stations along

the route of fat digestion and absorption.


4.4.2.2.1 Stomach
After pyloroplasty and vagotomy, the stomach empties abnormally rapidly
[Carvajal, 1994]. Intestinal transit may be hastened so that fat absorption is less
efficient.
4.4.2.2.2 Small Bowel Lumen
Long-chain fatty acids in the duodenum elicit an outpouring of pancreatic
bicarbonate and enzymes, and of bile. The intraluminal pH is crucial; in patients
with excessive gastric acid secretion (as in Zollinger-Ellison syndrome),
pancreatic enzymes are denatured, bile salts are precipitated, and absorptive
cells are injured so that steatorrhea results [Shimoda, 1968].
Bile salts, by forming mixed micelles, improve the efficiency of LCFA absorption.
This efficiency is impaired when the concentration of luminal bile salts falls
[Porter, 1971]. as in ileal resection, or in cholestasis.
Deficiency of pancreatic enzymes will impair hydrolysis of triglycerides which
have no solubility in luminal water even in the presence of bile salts. Some
hydrolysis of triglyceride occurs in the stomach with gastric lipase [Aoubala,
1993], so that patients with severe pancreatic insufficiency do absorb 30-70% of
their dietary LCFA [Shimoda, 1974].
4.4.2.2.3 Small Bowel Mucosa
Mucosal surface may be lost by resection or by disease such as Crohns
disease.
Absorptive cells may be injured by antigens such as gluten in celiac sprue, or by
abnormal bile salts and bacterial enzymes in small intestinal stasis with bacterial
overgrowth [Ament, 1972].
Duodenal and jejunal mucosa is abnormal when the lamina propria is infiltrated
with macrophages which may be laden with Tropheryma whippelii, or with
Mycobacterium avium intracellulare.
4.4.2.2.4 Small Intestinal Transit Time
It is difficult to delineate the contribution of hastened motility to the pathogenesis
of steatorrhea. We know that experimentally-induced diarrhea can cause mild
steatorrhea [Fine, 1992] so it is reasonable to assume that hastened transit will
further impair digestion and absorption whose efficiencies are already decreased
by an underlying disease.

4.4.2.2.5 Summary
In small intestinal diseases, it is not only the excessive amounts of fat which
contribute to the weight of the stools. Malabsorbed LCFA [Ammon, 1973], and
bile salts [McJunkin, 1981], if solubilized in fecal water, can block absorption of
salt and water by colonocytes.
4.4.2.3 Diagnosis
The importance of gastric, or of intestinal resection to the etiology of steatorrhea
is evidenced by surgical scars. The clinical challenge is to distinguish between
small bowel luminal defects and mucosal diseases.
4.4.2.3.1 Pancreatic Insufficiency
Pancreatic insufficiency is the chief cause of small bowel luminal defects if the
intestinal tract is intact; a history of cystic fibrosis or of recurrent attacks of
abdominal pain associated with ethanolic excesses would be pertinent. Proving
pancreatic insufficiency is more difficult. A plain abdominal film might reveal
pancreatic calcification, but the absence of calcification is unhelpful; not all
patients with calcifications have steatorrhea [Lankisch, 1986].
In our patient, triglyceride in her stool incriminated the pancreas, and the CT
scan revealed an abnormal head of the pancreas. Fecal triglyceride, however, is
an insensitive test for pancreatic insufficiency [Khouri, 1989]. The Secretin Test
involves placing a tube in the proximal duodenum to aspirate pancreatic juice
after an intravenous injection of secretin intravenously; gastric contents must be
prevented from entering the duodenum. Recent modifications [Heij, 1986] of the
Secretin Test (continuous infusion of secretion and CCK-octapeptide) make the
test even more laborious but they allow a sensitivity of 83% and a specificity of
89% for detecting exocrine pancreatic insufficiency.
The Bentiromide Test has a sensitivity of about 80% in severe chronic
pancreatitis when compared to the Secretin Test [Niederau, 1985]. Bentiromide is
benzoyl-tyrosyl-para-amino-benzoic acid which, after ingestion, is hydrolyzed by
pancreatic chymotrypsin; the released p-amino benzoic acid is absorbed, and
excreted in urine where it can be measured. False positive tests have been
reported in renal insufficiency, and in small intestinal disease [Niederau, 1985].
Pancreatic insufficiency is not reliably detected by the bentiromide test until
pancreatic chymotrypsin is less than 5% of normal.
Measuring fecal chymotrypsin has been used as an indirect test of pancreatic
insufficiency especially in cystic fibrosis [Niederau, 1985]. Like the Bentiromide
Test, it is insensitive in mild to moderate disease.
A therapeutic trial of gastric acid inhibition with supplements of pancreatic

enzymes makes good sense although it has not been rigorously tested. The
patient keeps a diarrhea diary while eating a constant diet, and omitting antidiarrheal medicines. After a baseline period of 3 days, a proton-pump inhibitor
(for example, omeprazole 20 mg twice daily) is added for another 3 days. Then
for a final 3 days, pancreatic enzymes (for example, Cotazyme capsules of 8000
lipase units) 4 capsules with meals and 2 capsules with snacks are added to the
PPI. An advantage of this trial is that a definite improvement in the PPI period
directs the clinician to consider Zollinger-Ellison syndrome.
4.4.2.3.2 Mucosal Diseases
Among mucosal diseases, celiac sprue would be suggested by a childhood
history of diarrhea, presence of diabetes, of iron-deficiency anemia that fails to
respond to oral iron, and oral ulcers.
If our patient did not have the clue of triglyceride in her stools, she might have
been screened for celiac sprue by searching for IgA endomysial antibodies. The
sensitivity and specificty of this immunofluoresent test approaches 100% in
specialized laboratories, but there are concerns about the reliability of
commercial assays [Grodzinsky, 1994]. Definitive diagnosis of celiac sprue
depends on small bowel biopsy, and a clinical response to a gluten-free diet.
A trial of a gluten-free diet has no place in the investigation of patients with
suspected celiac sprue unless the endomysial antibody test is postitive, or the
small bowel biopsy is compatible with the diagnosis. Some patients with
gastrointestinal symptoms such as flatulence and abdominal distension due to
functional (idiopathic) bowel disease can feel better when glutenous (cereals and
the attendent poorly absorbed carbohydrates) are avoided.
4.4.3 Bloody Diarrhea
Exudative diarrhea is usually obvious because of bloody stools. Sometimes,
however, Crohns disease is overlooked as a cause of chronic diarrhea if the
stools are not grossly bloody.
4.4.3.1 Profile of a Patient
For the past year an eighteen year old college student had episodes of diarrhea
(3-4 mushy to watery stools daily) which lasted 1-4 weeks. He was thought to be
lactose-deficient, and, indeed, 50 g of a lactose drink provoked abdominal
cramps, flatus, and diarrhea. The diarrhea was improved, but not eliminated by
avoiding lactose. The discovery of occult blood (Hemoccult ) in his stools led to
flexible sigmoidoscopy. The rectosigmoid mucosa was macroscopically normal,
but biopsy specimens contained granuloma typical of Crohns disease. The
patient continues to have occasional episodes of diarrhea which are helped by
loperamide.

4.4.3.2 Pathophysiology
Inflammation can cause disruption of the mucosal surface so that blood or
plasma leaks into the lumen and increases the volume of the fecal stream.
Anemia, and hypoalbuminemia can result. Inflammatory cytokines, and hastened
colonic transit impair colonic absorption of salt and water.
Malabsorption could also be a factor in the diarrhea of Crohns disease.
Involvement of ileal mucosa might impair the absorption of bile salts so that the
concentration of bile salts in fecal water becomes sufficient to block absorption of
Na+ and water by colonocytes [Hofmann, 1972]. If hepatic synthesis of bile acids
can compensate for a minor disruption of the enterohepatic circulation, the
diarrhea can be mainly watery, rather than fatty [Hofmann, 1972].
4.4.3.3 Diagnosis
Chronic bloody diarrhea would prompt investigation of idiopathic inflamatory
bowel disease, or of parasitic disease (E. histolytica, Schistosomiasis). Less
obvious is the patient who has chronic inflammation of the colonic mucosa
without gross blood. A family history of idiopathic inflammatory bowel disease can
be helpful, as well as a past history of hematochezia. Crampy abdominal pain,
and right lower quadrant tenderness or mass suggest Crohns disease.
A history of recent therapy with an antibiotic might incriminate C. difficile and its
exotoxins which should be sought in the patients stool.
The presence of fecal occult blood (or excessive leukocytes), unexplained by C.
difficle or ameba, necessitates at least a flexible sigmoidoscopy with mucosal
biopsy in a young patient, and a colonoscopy in the older patient. The
colonoscopist should try to obtain biopsies of the terminal ileum which can be
informative even if the colon is normal [Geboes, 1998].
4.4.4 Predominantly Watery Diarrhea
4.4.4.1 Diarrhea Due to Endocrinopathies
This group deserves pride of place, not because of its prevalence, but because
thyroid disease, and adrenal disease are eminently treatable.
4.4.4.1.1 Thyroid Disease
Hyperthyroidism is associated with chronic diarrhea with, and without
steatorrhea, and with a hypersecretory state [Donowitz, 1995].
4.4.4.1.2 Hypoadrenocorticalism

Gastrointestinal symptoms may be overshadowed by profound fatigue,


hypotension, and hyperpigmention. The clinical chemistry laboratory reports
peripheral blood eosinophilia, and hyponatremia with hyperkalemia.
4.4.4.1.3 Diabetes mellitus
Typically, diarrhea begins after 8 years of diabetes; peripheral neuropathy is
usually present. Diarrhea is often nocturnal.
4.4.4.1.3.1 Profile of a Patient
A 36 year old manager was referred for an opinion about a diarrheal syndrome of
7 months duration. Defecation usually occurred urgently during supper; formed
stools would be followed progressively by increasingly liquid motions. About half
the time, he was awakened during the night. Glucosuria was discovered 7
months ago, and his diabetes was being treated with glyburide (Micronase ).
A 24 hour stool specimen weighed 760 g, and it contained 5 g of fat. Beets
colored his stools within 6 hours. He began to complain of impotence, and testing
of his autonomic nervous system revealed an abnormal RR interval.
Hemochromatosis was dismissed by a normal hepatic iron index. We assumed
that his diabetes had been subclinical for many years.
4.4.4.1.3.2 Pathophysiology
Clinicians, puzzling over the cause of diarrhea in diabetes mellitus must consider
malabsorption (celiac sprue, pancreatic insufficiency), and watery diarrhea due to
impaired adrenergic function in the myenteric plexus associated with autonomic
(and, usually, peripheral) neuropathy. Our patients diarrhea responded to
loperamide which would improve salt and water absorption by slowing intestinal
transit.
4.4.4.2 The Irritable (Idiopathic) Bowel Syndrome
The Irritable (idiopthic) Bowel Syndrome is a subset of the functional bowel
disorders; it is associated with disturbed defecation, and with symptoms of
abdominal pain and bloating.
4.4.4.2.1 Patient Profile
A 45 year old engineer had 20 years of intermittent diarrhea which was worse
when he had to travel to administrative meetings. Diarrhea may lessen to one
stool a day when he was on vacation. He was dissatisfied with medical
reassurances that his troubles were "due to stress." General physical exams
were normal as were routine laboratory screenings (hemogram, chemistry

battery); negative fecal occult blood and fat.


A diarrhea diary, kept meticulously over one month, revealed that about half the
days were notable for obstipation. Colonoscopy was performed finally because
our patient wanted to insure that "nothing was missed"; it was normal. His bowel
function is now also normal since he relocated to a less stressful job.
4.4.4.2.2 Pathophysiology
Whilst there is general agreement that the physiology of defecation is disturbed
in patients with irritable (idiopathic) bowel syndrome (IBS), how one can have
diarrhea alternating with constipation remains puzzling. Some evidence suggests
that patients with IBS have exaggerated intestinal motility responses when they
are challenged by environmental, or psychological stimuli [Drossman, 1994].
Whole gut transit time is faster in IBS patients with diarrhea [Cann, 1983] The
transit of radiolabelled pellets through the ascending, and transverse colons is
accelerated in IBS patients with diarrhea, and the faster the transit, the higher is
the fecal weight [Vassallo, 1992].
Patients with IBS may have exaggerated intestinal responses to sugars such as
fructose, lactose, and to the more complex carbohydrates in fruits and legumes
[Camilleri, 1992].
4.4.4.2.3 Diagnosis
The recommended approach to patients with suspected IBS involves a tentative
diagnosis based on the history, judicious testing to exclude organic disease, and
careful follow-up to insure that the patients symptoms are improving.
IBS should be suspected when symptom criteria [Camilleri, 1992], [Manning,
1978] are present (Table 17). Many patients with IBS remember symptoms
beginning in their early teens, and the intermittency of their intestinal complaints.
Anxiety, or depression are frequent accompaniments.
A complete examination should include physical exam, hemogram, and stool for
occult blood, ova and parasites. A collection of stool for 24 hours (Table 16)
should be weighed (usually <500 g in IBS), and should be searched for fat
(Sudan Stain), and for ova and parasites.
Our patient had diarrhea for many years without exhibiting any alarm signals. His
diarrhea diary over one month was remarkable for meticulous detail, the
intermittency of his diarrhea (he had as many good days as bad ones), the
association of his diarrhea with travel, and the realization that he was never
awakened from sleep by diarrhea. Loperamide was helpful during his episodes of
diarrhea, which was greatly improved when he changed to a less stressful job.

4.4.4.3 Diarrhea Due to Medications


All patients presenting with chronic (or acute) diarrhea must be questioned
thoroughly about their use of medicines. It is sometimes amazing that
medication-induced diarrhea can become chronic without the association being
suspected by the patient or the clinician.
4.4.4.3.1 Profile of a Patient
A 34 year old executive was referred for flexible sigmoidoscopy to pursue a
diagnosis for a diarrheal syndrome which had not resolved or been explained for
3 weeks. This healthy-appearing woman said that she was passing about a
cupful of mushy stools three times a day; she was awakened from sleep once or
twice by the need to defecate. During the pre-procedure chat, we uncovered that
an anti-inflammatory drug (Clinoril ) had been prescribed three weeks ago
because she sprained her ankle playing badminton. Stopping the Clinoril was
associated with her return to normal bowel function within 45 hours.
4.4.4.3.2 Pathophysiology
The extent of the association between medications and diarrhea is emphasized
by the Physicians Desk Reference Drug Interactions and Side Effects Index,
which lists over 600 medications that can cause diarrhea (Table 9). Mechanisms
are diverse and often poorly understood, but they often involve osmotically active
agents (such as Mg++, citrate, sulfate); drugs which interfere with salt and water
absorption; agents which alter intestinal motility; and drugs which stimulate
intestinal secretion (phenolphthalein as in Ex-Lax ; dioctyl sodium sulfosuccinate
as in Colace; bisacodyl as in Dulcolax).
Ethanol can block salt and water absorption in the human small intestine
[Mekhjian, 1977].
Patients treated with prolonged courses of antibiotics risk developing diarrhea
because the antibiotic perturbs the colonic microflora:
4.4.4.3.3 Antibiotic Use
4.4.4.3.3.1 C. difficile
C. difficile can colonize the colon, and its exotoxins can cause mucosal
inflammation. In the absence of mucosal ulceration, the diarrhea is watery. C.
difficile toxins are usually present in the stools. Diarrhea usually subsides when
the offending antibiotic is withheld [Mitty, 1994], but may require treatment with
oral metronidazole, or vancomycin.
4.4.4.3.3.2 Suppression of Fermentation

Colonic bacteria which ferment carbohydrate are suppressed [Clausen, 1991] so


that osmotically active carbohydrate obligates salt and water in the colonic
lumen. The wetter stools usually become normal when the antibiotic is
discontinued.
4.4.4.3.3.3 Diagnosis
Usually the diagnosis of medication-induced diarrhea is suggested by the history,
and it is proven by withdrawing the offending substance.
Uncommonly (except at tertiary care hospitals), a patient may be abusing
laxatives, a puzzle whose solution may require careful sleuthing, and analyses of
stool, and of urine.
4.4.4.4 Infectious Causes
These invaders can often be suspected from the history, and their presence can
be confirmed by examination of the stools.
4.4.4.4.1 Common Pathogens
4.4.4.4.1.1 Giardia
Contact with children in day-care; intimate sexual contact; drinking pristine water
in the countryside; foreign travel [Shandera, 1990] should prompt a search for
Giardia lamblia in the stools by immunodetection of the Giardia antigen in fresh,
or in formalin-preserved stools [Thompson, 1993].
4.4.4.4.1.2 C. difficile
Use of antibiotics currently, or in the recent past, should prompt a search for the
exotoxins of C. difficile in a fresh stool specimen. Colonic dilatation with bloody
diarrhea is more specific for the diagnosis of overgrowth of this organism.
4.4.4.4.1.3 E. histolytica
Foreign travel, or a history of oral-anal intimacies can incriminate E. histotytica
whose trophozoites can be found in fresh smears of rectal mucus, or in
preserved specimens of freshly-passed stool. IgM antibodies to E. histolytica can
be sought in the patients serum.
4.4.4.4.2 History of Less Common Agents
Less common agents can also be suspected from the patients history:

4.4.4.4.2.1 A. hydrophilia and Cyclospora


Drinking untreated water (Aeromonas hydrophilia, [Holmberg, 1986]), or
contaminated water and fruit (Cyclospora cayetanensis [Huang, 1995]), and
travel to Nepal (Cyclospora [Hoge, 1993]) have been associated with outbreaks.
4.4.4.4.2.2 Spore-Forming Protozoa
Cryptosporidium parvum, Isospora belli, Cyclospora cayetanensis,
Enterocytozoon bieneusi, and Septata intestinalis are intestinal spore-forming
protozoa that invade intestinal mucosal cells. Cellular injury and inflammatory
cytokines impair salt and water absoprtion, and, probably, enhance secretion.
Immunodeficient patients are predisposed to prolonged infection with these
protozoa. In immunocompetent individuals, diarrhea with Cyclospora can persist
after acute infection [Goodgame, 1996].
4.4.4.4.2.3 Diagnosis
Examination of the stools is the most important diagnostic test. The laboratory
should be asked specifically to screen for spores or oocysts; multiple samples
increases the diagnostic yield [Goodgame, 1996].
4.4.4.5 Subtle Inflammation
The rubric, microscopic colitis, probably includes other descriptions (lymphocytic
colitis, collagenous colitis) of macroscopically normal colonic mucosa whose
biopsies are abnormal.
4.4.4.5.1 Profile of a Patient
A 69 year old lady presented with a history of diarrhea of 3 years duration. Stools
were negative for fat and for parasites. Colonoscopy was said to be within normal
limits. Many therapeutical trials had been performed; supplemental pancreatic
enzymes were thought to lessen the diarrhea.
She was studied according to the protocol outlined in (Table 16). Beets colored
her stools within 4 hours. The 24 hour specimen weighed 440 g; it looked like
brown, mucoid pudding which tested negative for occult blood (by Hemoccult ),
and for fat (by Sudan Stain). Colonoscopy was repeated because colonic
disease seemed the most likely cause of her diarrhea. Eleven biopsies were
taken throughout the length of a macroscopically normal colon. A spotty mucosal
inflammation was discovered (mainly with eosinophils in the lamina propria and
with lymphocytes in the surface epithelium); marked thickening of the
subepithelial collagen plate was found in many areas. Based on the diagnosis of
microscopic colitis, an anti-inflammatory agent (5-amino salicyclic acid) was
prescribed; her diarrhea gradually resolved.

4.4.4.5.2 Pathophysiology
The cause of microscopic colitis is unknown. Speculations include impending
inflamatory bowel disease (ulcerative colitis, or Crohns colitis), or the sequel of
an infectious colitis. It seems certain that the abnormal mucosa is a factor in the
pathogenesis of diarrhea, because colons of patients with microscopic colitis
malabsorb salt and water infused under steady state conditions [Bo-Linn, 1985].
4.4.4.5.3 Diagnosis
Microscopic colitis should be considered in patients when malabsorption and
medication-induced diarrhea have been excluded. Irritable (idiopathic) bowel
syndrome would not be expected to present de novo in the middle-aged, or
elderly. Colonoscopy with biopsy is probably more informative than flexible
sigmoidoscopy because the right colonic mucosa can be more involved than that
in the left colon [Janda, 1991]. Multiple (>12) mucosal biopsies should be
obtained. Perhaps Subtle Colitis is a better rubric than Microscopic Colitis,
because all colitides have microscopic abnormalities.

4.4.4.6 Hypersecretory (Hormonally-Induced) Diarrhea


This category of predominantly watery diarrhea is uncommon, and physicians
often order searches for vasoactive intestinal polypeptide (VIP), without first
ascertaining if the diarrhea is voluminous (it usually exceeds 1000 ml a day), if
the diarrhea improves with fasting (it should not), or if the osmotic gap in a fresh
fecal supernate is less than 50 mosmols / kg. Laxative abuse is much more
commonly encountered than VIPomas [Read, 1980].
A history of facial flushing may direct a search for carcinoid tumor, or for
pheochromocytoma.
4.5 Diarrhea of Unknown Cause

For this phrase to have any credence, it must be carefully defined, much as is
Fever of Unknown Origin in Infectious Disease. By definition, then, patients with
DUO have an increased frequency of passing stools of decreased consistency
for more than 2 months. Thorough investigation of the groups of diseases
outlined in Sections 4.4 is unrewarded. In particular, there is no evidence for
immunosuppression. Finally, the patients diarrhea is difficult to control with
customary non-specific measures. A virtue of an appellation of DUO is that there
are a small group of diseases that can be revisited so that selected study can
establish a diagnosis [Schiller, 1991].
4.5.1 Fecal Incontinence
Incontinence is probably paramount if an elderly, parous lady admits to
involuntary passage of small amounts of stool. Corroborative evidence might be
obtained in a direct physical exam. An anal "wink" (cutaneo-anal reflex) indicates
that neural pathways are intact. Visual and digital exam can assess the tissue
mass of the pudenal body, and the strength of the external anal sphincter. A
descent of the pelvic floor of more than 1 - 2 inches during straining (in the left
lateral position) denotes muscle weakness. The toilet test (whereby the patient
strains on a toilet while the pelvic floor is viewed with a hand mirror) can highlight
abnormal descent of the pelvic floor, hemorrhoids, and rectal prolapse. A 24 hour
stool might weigh 100 - 200 g. Such a patient should be referred to a specialized
clinic for electrophysiological and manometric tests; biofeedback training can
help many patients.
4.5.2 Overlooked Malabsorption
A fat balance may give a spuriously high coefficient of absorption because the
stool collection was incomplete, or because the patient was eating insufficient
amounts of fat. Furthermore, the underlying disease may have progressed since
the initial testing so that steatorrhea is now readily detectable.
Repeating the inquiry outlined in (Table 16) involves no risk or major financial
penalty.
4.5.2.1 Profile of a Patient
A 47 year old lawyers diarrhea began one year ago at a time when his daughter
contracted diarrhea in a daycare center. He did not respond to two courses of
metronidazole based on a suspicion of giardiasis. Random stool specimens were
said to be negative for blood, fat, and leukocytes. Sigmoidoscopy with biopsy
was unremarkable. The familys pediatrician suggested a diet of bananas,
applesauce, and rice on which the diarrhea seemed to improve.
Six months after his initial work-up, he consented to the protocol in (Table 16).

The 24 hour stool weighed 1070 g, containing 21 g of fat. The Sudan Stain
revealed sudanophilic droplets after acidification only.
The hypothesis of celiac sprue was unsupported by the duodenal mucosal
biopsies which contained normal villi; however, patchy areas of inflammation and
mucosal erosions were seen. Additionally, a lesser curve gastric ulcer was
encountered by the endoscopist. The suspicion of Zollinger-Ellison symdrome
was supported by a serum gastrin of 860 pg / ml (normal 46 142 pg / ml), and
a dramatic improvement in his diarrhea with a proton pump inhibitor. Subsequent
CT-directed biopsy of a hepatic mass revealed neuroendocrine tumor.
4.5.3 Induced and Factitious Diarrheas
As emphasized in 4.4.4.3, many medications can cause diarrhea. Laxative abuse
can be especially vexatious; it should be suspected in patients who seem overly
concerned about maintaining a thin body. Phenolphthalein can be readily
detected by alkalinizing fecal supernate, or urine with a drop of 1 N NaOH. The
clinical chemistry laboratory can search for bisacodyl, Mg ++, sulfate, phosphate,
and anthraquinones.
4.5.3.1 Profile of a Patient
A 40 year old licensed practical nurse was referred with a diarrheal syndrome of
3 years duration. Multitudinous investigations had been unrewarded, and her
diarrhea continued even when she fasted. Therapy with prednisone 20 mg a day
ameliorated her diarrhea, but she was now confined to a wheelchair because of
osteopenic fractures.
While fasting, and on intravenous feeding, her 24 hour stool weight was 770 g.
The supernate of this liquid stool had an osmolality of 316 mosmols / kg; [Na +],
31 meq / L; [K+], 53 meq / L. The osmotic gap of 148 was found to consist of Mg +
+
. Bottles of milk of magnesia were uncovered in her dresser drawer and in her
suitcase; she said that she was using milk of magnesia to regulate her bowels.
4.5.3.2 Profile of a Patient
A 36 year old roofer complained of diarrhea since a laparotomy for abdominal
pain 4 years previously. A Meckels diverticulum and a small carcinoid were
resected. Extensive work-ups were unrewarded; 24 hour stools of 300 - 400 g
contained no excess fat, blood, or leukocytes. Because he was applying for
disability (as a roofer with diarrhea!) he was admitted to hospital for a 48 hour
fast. He said that beets passed through his gut within 10 minutes. A random stool
specimen had a [Na+] of 28 meg / L, [K+] of 41 meg / L, and an osmolality of 168
mosmols / kg.
Our patient had factitious diarrhea. A whole gut transit time of 10 minutes might

be compatible with an oro-anal fistula, but a fecal osmolality of 168 mosmols / kg


can be achieved only by watering the stool specimen!
4.5.4 Malabsorption of Bile Salts
This penultimate category of DUO contains some inconsistencies. Malabsorption
of bile salts can occur in a wide variety of intestinal troubles such as postvagotomy, post-cholecystectomy, post-abdominal irradiation, diabetes, and
chronic idiopathic diarrhea [Schiller, 1991]. However, not all of these patients are
improved when cholestyramine, an anion-binding (bile salt binding) exchange
resin is ingested therapeutically. This inconsistency can be explained by our
ignorance of the concentration of bile salts in fecal water which must be high
enough to block salt and water absorption by colonocytes. In other words, bile
acid malabsorption as measured with radiolabeled bile salts does not predict the
response to cholestyramine.
If a therapeutic trial of cholestyramine is undertaken, sufficient resin must be
ingested (for example, cholestyramine as colestipol is supplied in packets of 5
g; 2 packets with each of three meals, and at bedtime). The dosage of this
unpalatable therapy should be reduced promptly to the lowest effective amount.
A confounding factor of a therapeutic trial with cholestyramine is that the resin
non-specifically may improve the consistency of the stools just as psyllium does
[Wenzl, 1995].
4.5.5 Occult Infections and Inflammations
The boundaries encompassed by chronic idiopathic diarrhea will shrink as
knowledge grows for "all experience is an arch where through gleams that
untraveled world, whose margins fade for ever and forever when (we)
move" [Tennyson, Poems, 1842]. At present, the clinician must pursue an
epidemiological history, and an alliance with the gatroenterologist and mucosal
histopathologist.
The sudden onset of diarrhea which becomes chronic suggests an infectious
etiology because this syndrome occurs in foreign travelers, and in local folk who
ingest untreated water, or raw milk. Brainerd diarrhea [Osterholm, 1986] is a
rubric which is used to embrace such an illness persisting for many months
without an infectious or non-infectious etiology being found. A relationship
between acute and chronic disease can be found by colonoscopy and
histopathology: focal areas of inflammation are present in a patchy manner
mainly in the right colon. In the one patient studied, these abnormalities were still
present two years later [Janda, 1991]. We can speculate that an unknown
infectious agent altered the balance between the mucosal immune system, the
intestinal neuroendocrine system, and the inflammatory cascade.
The punch line: after a careful review and sagacious repetition of simple stool

studies, the gastroenterologist and histopathologist should combine forces to


study systematically the proximal small mucosa, and especially, the entire colonic
mucosa. Distal ileal biopsies should be obtained for good measure. If the
mucosal biopsies are normal, distraught patients with DUO may be assured that
their chronic diarrhea will eventually resolve [Afzalpurkar, 1992].
5.0 When a Gastroenterologist Should Be Consulted
5.1 Bloody Diarrhea For More Than Two Weeks Stool Culture is Negative
5.2

The patient is immunosuppressed and has the following attributes:

Three fresh stool samples have been examined for common bacterial, and
parasitic pathogens, and for unusual pathogens.
The patients diarrhea is poorly controlled by loperamide (4 mg every 6
hours), and there are alarm signals (see Glossary). Flexible
sigmoidoscopy to 40 cm and four mucosal biopsies (two from the sigmoid,
and two from the rectum) are helpful.

5.3

The patient is immunocompetent, and has one of the following hypotheses


for chronic diarrhea:

The patient has malabsorption as suggested by history, and as proven by


modified fat balance (Table 16), and a positive Sudan stain.
The suspicion of pancreatic disease is supported by a lessening of
diarrhea with supplemental pancreatic enzymes, but there is no history of
alcoholism, and abdominal CT scan is unrevealing. The patient may need
endscopic investigation of the pancreas.
The suspicion of mucosal disease is supported by iron-deficiency anemia,
low serum folate, and a positive endomysial antibody serum test . The
diagnosis of celiac sprue must be confirmed by proximal small bowel
biopsy, and then, a response to a gluten-free diet.
The patient who has had ileal resection (presumably for Crohns disease)
should be followed by the subspecialist who can substantiate the
diagnosis and gauge the extent of the inflammatory disease by endoscopy
and biopsy.

The patient gives a past history of hematochezia, and there is a family


history of idiopathic inflammatory bowel disease. A flexible sigmoidoscopy
may be normal, or abnormal. Such a patient should be referred to a
gastroenterologist whose responsibilities include defining the type and the
extent of the inflammation, screening for neoplastic progression, and
selecting and updating therapeutic options.

A patient with typical features of irritable (idiopathic) bowel syndrome may


require colonoscopy (for reassurance, and for cancer screening) and
mucosal biopsies (for subtle inflammation), or require consultation
because the patients diarrhea is refractory to therapy.
A patient has diarrhea of unknown origin after thorough study. The
gastroenterologist must review all available evidence before obtaining
systematically mucosal biopsies from the terminal ileum and large
intestine if small bowel and pancreatic disease has been excluded.

Overview
Definition
Diarrhea is characterized by unformed, watery stools (200 to 250
g/day) and increased bowel movement frequency, often
accompanied by fever, chills, malaise. The symptom of an
underlying condition or conditions, diarrhea is considered to be
acute at onset, and chronic after two to three weeks. Although
diarrhea is a common condition and usually self-limiting (two to
three days), complications can be serious, even fatal, in infants
and elderly patients, consequently it is important to attempt to
determine the cause(s).
Diarrhea has four primary classifications.

Osmotic: reduced solute absorption


Secretory: increased electrolyte and water secretion
Exudative: loss of fluid and protein from intestinal mucosa

Motility disorder: intestinal transit alterations

Etiology
Common causes include viral, bacterial, and parasitic infection
(often spread person-to-person), inflammation, drugs, and
psychogenic causes. In particular:

RELATED INFORMATION

Conditions with
Similar Symptoms

View Conditions

Drug Monographs
Antidiarrheal Drugs
Cholestyramine Resin

Herb Monographs
Barberry
Goldenseal
Licorice
Marshmallow
Slippery Elm

Supplement
Monographs
Brewer's Yeast
Glutamine
Lactobacillus Acidophilus
Quercetin
Vitamin A (Retinol)
Vitamin C (Ascorbic Acid)

Acute:

Infection (primary)
Inflammatory bowel disease (primary)
Iatrogenic causes

Learn More About


Acupuncture
Homeopathy
Nutrition

Poisoning

Chronic:

Malabsorption (notably lactose intolerance)


Inflammatory bowel disease
Colitis
Irritable bowel syndrome
Food allergies
Giardia
Chronic constipation
AIDS and other immune disorders

Chronic subdivisions (multiple types of diarrhea may be present):


Osmotic diarrhea:

Malabsorption
Low sugar absorption (lactose intolerance)
Antacids

Secretory diarrhea:

Bacterial infections (e.g., cholera)


Collagenous colitis
Crohn's disease
Celiac sprue
Laxative abuse (common with chronic diarrhea)
Tumors
Hyperthyroidism

Exudative diarrhea:

Bacterial infections (e.g., Shigella, Salmonella)


Ulcerative colitis
Inflammatory bowel disease

Motility disorder diarrhea:

Irritable bowel syndrome


Scleroderma
Diabetes
Surgical procedures

Western Herbalism

Laxatives

Hyperthyroidism

Risk Factors

Dairy products, some fruits and legumes


Sugar substitutes (hexitols, sorbitol, mannitol)
Hospitalization/surgery (iatrogenic)
Foreign travel
Hiking, camping, fishing trips
Exposure to infected persons
Medications (e.g., antibiotics, antacids, diuretics,

antihypertensives, anti-inflammatories, and cardiovascular


medications)
Stress

Recent antibiotic therapy

Signs and Symptoms

Loose stools, with or without blood and mucus


Frequent need to defecate
Abdominal pain, cramping
Fever, chills, malaise

Weight loss

Differential Diagnosis

Crohn's disease
Colitis, ulcerative colitis
Whipple's disease
Inflammatory bowel disease
Irritable bowel syndrome
Reiter's syndrome
Zollinger-Ellison syndrome
Over-the-counter medications
Various rare intestinal tumors (ganglioneuroblastoma,

mucinous cystadenoma, and intestinal lipoblastoma)


Congenital microvillous atrophy

Congenital chloride diarrhea

Magnesium or vitamin C supplementation

Diagnosis
Physical Examination
For most patients, diarrhea is relatively benign and self-limiting. A
few patients, however, have an underlying illness that should be
diagnosed and treatedin particular, patients with diarrhea that
has persisted for longer than three days or with blood in the feces
(suggesting exudative diarrhea). Determining the mechanism
(osmotic, secretory, exudative, or motility) helps direct treatment.
Because patients will not be capable of reporting stool weight/day,
patient history plays a major role in diagnosing diarrhea.

Confirm that the condition is diarrhea, not fecal

incontinence.
Determine the volume type of diarrhea.
Determine if diarrhea is acute (generally related to

infection) or chronic.
Note signs and symptoms.
Ask patient about risk factors, lactose intolerance,

antibiotics use, sexual orientation, and surgery.


Explore the effect of diet. (Osmotic diarrhea generally
ends when fasting. Secretory diarrhea generally does not
end when fasting. Lactase deficiency generally is an
accurate diagnosis if symptoms improve with the
elimination of milk and dairy products).

Assess:

Hydration
Abdominal tenderness
Bowel sounds

Rectum (carcinoma, fecal impactions)

Laboratory Tests

Stool sample

CBC
Serum electrolytes
BUN
d-xylose
Pancreatic function

Urinalysis

Pathology/Pathophysiology
Blood:

Leukocytosis
Pathogens
Anemia
Biochemical deficiencies

Endoscopy:

Mucosal abnormalities
Bleeding
Ulcers

Stool:

Blood (generally exudative diarrhea)


Weight/volume
Fecal fat
Electrolytes
Osmolality

Parasites

Imaging

Small-bowel radiography

Barium enema

Other Diagnostic Procedures

In addition to patient history and physical assessment, endoscopy,


laboratory tests (including stool analysis), and rectal biopsy
(occasionally) can help determine the causeand thus the
treatmentof diarrhea.

Treatment Options
Treatment Strategy
Because diarrhea is a symptom, treatment should be dictated by
the cause (or causes). For acute, uncomplicated diarrhea, it may
be sufficient to reassure patients that the diarrhea is benign and
will resolve in a couple of days and simply treat the symptoms.
For some chronic diarrhea, dietary change can be sufficient
without additional evaluation.
Serious acute bloody diarrhea and chronic diarrhea will require
evaluation and treatment of underlying cause(s). Hospitalization
should be considered with dehydration; in any case, replacement
of fluids (clear fluids without caffeine and rehydration fluids) and
electrolytesparticularly with very young and very old patientsis
critical.

Drug Therapies
Because some medications prescribed for diarrhea can delay
resolution of certain infectious diarrhea conditions (as well as
other contraindications), diarrhea should be diagnosed before
drug therapy is undertaken. Common drug therapies (many OTC)
include the following.

Opioid derivatives: diphenoxylate-atropine (Lomotil) and

loperamide (Imodium). May have CNS effect.


Adsorbents: bismuth salts (Pepto-Bismol), kolin, and

pectin (Kaopectate), aluminum hydroxide (Amphojel),


cholestyramine (Questran)
Bulk-forming medications: psyllium (Metamucil, Konsyl)

Specific guidelines include:

Bismuth salts for traveler's diarrhea

Cholestyramine for bile-acid-induced diarrhea

Complementary and Alternative Therapies


Severe diarrhea can be life-threatening, and it is imperative that
the underlying etiology be assessed before initiating any treatment
other than fluid replacement. Nutrition suggestions should be
followed for all types of diarrhea.

Nutrition

Avoid coffee, chocolate, dairy products, strong spices, and

solid foods. Introduce clear soup, crackers and white


bread, rice, potatoes, applesauce, and bananas as
diarrhea begins to resolve. Sips of black tea may help
settle the stomach when nausea is present.
To restore and maintain fluid and electrolyte balance,

consider rice and/or barley water, fresh vegetable juices


(especially carrot and celery), miso broth, or other clear
broths. Rice and barley water are made using 1 cup of
grain to 1 quart of boiling water. Let steep for 20 minutes.
Strain and drink throughout the day.
Lactobacillus species taken as powder or in capsules

helps to normalize bowel flora and may help resolve


diarrhea. Take as directed, or one dose with each meal.
Saccharomyces bolardii and brewer's yeast are specific
for treating antibiotic-induced diarrhea that has caused
Clostridium difficile overgrowth.
Vitamin C (250 to 500 mg bid) and vitamin A (10,000 to
20,000 IU/day) support immune function. High doses of
vitamin C may cause diarrhea. High doses of vitamin A
should not be taken long-term without physician
supervision.

Glutamine (3,000 mg tid) is helpful to treat diarrhea that is


caused by mucosal irritation rather than infection, such as
chemotherapy-induced diarrhea.

Herbs

Herbs are generally a safe way to strengthen and tone the body's
systems. As with any therapy, it is important to ascertain a
diagnosis before pursuing treatment. Herbs may be used as dried
extracts (capsules, powders, teas), glycerites (glycerine extracts),
or tinctures (alcohol extracts). Unless otherwise indicated, teas
should be made with 1 tsp. herb per cup of hot water. Steep
covered 5 to 10 minutes for leaf or flowers, and 10 to 20 minutes
for roots. Drink 2 to 4 cups/day. Tinctures may be used singly or in
combination as noted.
Do not initiate antidiarrheal therapy if the diarrhea is secondary to
an infectious agent. Herbs can be used as anti-inflammatories,
antimicrobials, or antidiarrheals. Choose one or two from each
category as needed. They are best used as teas unless otherwise
noted.
Anti-inflammatory herbs:

Quercetin (250 to 500 mg bid to qid)


Chamomile (Matricaria recutita) is a soothing

antispasmodic.
Marshmallow root (Althea officinalis) is best prepared as
cold-water tea. Soak 2 tbsp. root in one quart of water
overnight. Strain and drink throughout the day.

Antimicrobial herbs:

Barberry (Berberis vulgaris), 250 to 500 mg tid


Goldenseal (Hydrastis canadensis), 250 to 500 mg tid
Licorice root (Glycyrrhiza glabra) (contraindicated in
hypertension)

Antidiarrheal herbs:

Blackberry leaf (Rubus fruticosus) or raspberry leaf

(Rubus idaeus)use 1 heaping tsp./cup. Drink 1/2 cup


per hour.
Carob powderuse 4 tsp. per 4 oz. of water or mix in
applesauce. Take 1/2 to 1 tsp. every 30 to 60 minutes.

Slippery elm powder (Ulmus fulva) or marshmallow root


powderuse 1 oz. powder to 1 quart of water. Make a
paste with the powder and a small amount of water.

Gradually add in the rest of the water and then simmer


down to one pint. Take 1 tsp. every 30 to 60 minutes.

Homeopathy

In the practice of homeopathy, illness is viewed as a composite of


the physical, mental, and emotional responses of the patient;
therefore, an experienced homeopath will assess the individual's
constitution to select the appropriate remedy and potency.
Treatment recommendations for diarrhea are based primarily on
professional knowledge and clinical experience. However, in a
recent randomized, double-blind, placebo-controlled study that
compared two groups of children with acute diarrhea,
homeopathic treatment shortened the duration of diarrhea
compared to controls (P < 0.023). One hundred twenty-six
Nepalese children with diarrhea (defined as > 3 stools in the 24hours prior to the study) were randomly assigned to individualized
homeopathic treatment or to placebo control; none of the children
had received medication prior to the start of the trial. Treatment or
placebo was administered for 5 days. These results demonstrate
the potential benefit of individualized homeopathy for the
treatment of childhood diarrhea, and duplicate the findings of
another study conducted by the same authors in Nicaragua
(Jacobs et al 2000).
The following homeopathic remedies were administered for the
symptoms indicated:

Arsenicum albumfor malodorous diarrhea from food

poisoning or traveler's diarrhea accompanied by burning


sensation in the abdomen and around the anus; the
person generally feels exhausted yet restless; symptoms
are aggravated by cold and temporarily relieved with
warmth; vomiting may be present. Arsenicum may be
considered for prophylactic use when traveling (Jonas and
Jacobs 1996; Ullman 1992; Ullman 1995).
Chamomilla for greenish, frothy stool with the odor of

rotten eggs; used primarily for children, especially those


who are irritable, argumentative, and inconsolable;
commonly recommended for colicky or teething infants
(Ullman 1992; Ullman 1995)
Calcarea carbonica for the child who fears being in the
dark or alone and has perfuse diaphoresis while sleeping;

stools have a sour odor


Podophyllum for explosive, gushing, painless diarrhea

that becomes worse after eating or drinking; exhaustion


often follows bowel movements and the patient may
experience painful cramps in lower extremities. Often
used in infants for diarrhea experienced from teething
(Jonas and Jacobs 1996; Ullman 1992; Ullman 1995)
Sulphur for the child who presents with irritability and
weeping, and who may have a red ring around the anus
and diarrhea with the odor of rotten eggs.

Additional agents that may be considered clinically by a


homeopath include:

Mercurius for foul-smelling diarrhea that may have

streaks of blood accompanied by a sensation of


incomplete emptying; appropriate patients tend to feel
exhausted following bowel movements, experience
fluctuations in body temperatures, suffer from diaphoresis,
and have a thirst for cold fluids (Ullman 1992; Ullman
1995)
Pulsatilla for diarrhea after overconsuming fruit or rich,
greasy food; stools will be greenish in infants and of
changing consistencies in older children (Ullman 1992)

Veratrum album for profuse, watery diarrhea


accompanied by stomach cramps, bloated abdomen,
vomiting, exhaustion, and chills; the diarrhea is
aggravated by fruit, and the patient craves cold liquids
(Ullman 1992; Ullman 1995)

Acupuncture

Although there are published reports from China indicating that


childhood diarrhea is treated with acupuncture (Lin et al. 1993; Su
1992), the study designs and reporting methods do not provide
enough information to make a judgment about the effect of
acupuncture for diarrhea or any condition manifesting this
symptom. In general, childhood diarrhea is not frequently treated
by acupuncturists in the United States. However, acupuncture may
be used when conventional treatment has failed and, in this case,
a basic acupuncture evaluation would be undertaken in order to
make a Traditional Chinese Medicine diagnosis. Acupuncture is

also used an adjunctive therapy for treating diarrhea in adults.


A clinical evaluation would likely include consideration of food
choices and examining both the nutritional value and the
"energetic" qualities of food that might affect digestion and
elimination. In classical Traditional Chinese Medicine diagnosis,
diarrhea may indicate a problem with the spleen; acupuncture
treatments will therefore often focus on strengthening this
meridian. Moxibustion is frequently used in the treatment of
diarrhea because its effect is thought to reach deeper into the
body than needling alone. The treatment strategy for adults and
children would be similar, with perhaps stronger stimulation and
more intensive treatment for adults.

Patient Monitoring
Dehydrated patients and infant and elderly patients with serious
signs and symptoms should be monitored carefully. Patients with
acute diarrhea should report conditions that do not resolve in three
to five days. Follow up with chronic patients as required.

Other Considerations
Prevention
Avoid risk factors as possible.

Complications/Sequelae

Dehydration
Syncope, arrhythmias (from loss of electrolytes)

Anemia

Prognosis

Acute: generally resolves in two to three days

Chronic, idiopathic diarrhea: generally self-limiting,


although it may continue indefinitely

Pregnancy
Dehydration can cause preterm labor. Gastrointestinal spasm may
have reflexive action on uterine muscle and induce contractions.
Goldenseal (Hydrastis canadensis) and barberry (Berberis
vulgaris) should be avoided in pregnancy as they may stimulate
contractions. High doses of vitamin A may be teratogenic and
should be avoided.

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