Lecture X

Diarrhea

Diarrhea is the passage of unusually loose or watery

stools, typically at least three times in a 24-hour
period, and should be considered in a child who is
passing stools more frequently than usual with a
consistency looser than what is considered normal
for that individual. Diarrhea is classified broadly by
the duration of symptoms. Acute diarrhea is usually
a self-limited illness that lasts for 2 weeks or less.
Chronic diarrhea persists for more than 2 weeks.
The etiologies of acute and chronic diarrhea differ
by age . Diarrhea is further classified by
pathophysiology, which typically involves one or
more of the following mechanisms:
(1) osmotic diarrhea, characterized by an increased
intraluminal osmotic load leading to passive
diffusion of fluid into the gastrointestinal lumen;
(2) secretory diarrhea, characterized by increased
active secretion of fluid into the gastrointestinal
lumen beyond the capacity to be reabsorbed; and
(3) altered gastrointestinal tract motility.
Osmotic diarrhea may be related to the
malabsorption of carbohydrate, fat, or protein or to
the presence of nonabsorbable substances in the
gastrointestinal lumen. The characteristics of the
stool may provide information that allows for the
identification of the malabsorbed substance,
particularly for isolated carbohydrate and fat
malabsorption. Secretory diarrhea is characterized
by an excess of crypt cell fluid and electrolyte
secretion that exceeds the absorptive capabilities of
the villi and is classified by the presence or absence
of normal villi. Inflammatory diarrhea of both
infectious and noninfectious etiologies usually
involves both osmotic and secretory components.
Finally, surgical bowel resection may decrease the
surface area available for the resorption of both
fluid and solutes, leading to both secretory and
osmotic diarrhea.
ACUTE DIARRHEA: History - Acute diarrhea in
children is most often infectious, although it may be
secondary to noninfectious inflammatory processes,
toxins, or medications. The etiology of acute
diarrhea is suggested by both the history and
characteristics of the stool. Fever or blood in the
stool suggests an infectious cause. Watery diarrhea
is typical of viral gastroenteritis, as well as some
bacterial and parasitic infections. Dysentery,
characterized by severe diarrhea and the presence
of blood and mucus in the stool, suggests bacterial
colitis. Vomiting and diarrhea developing within
hours of food ingestion suggests exposure to
preformed toxins in the food, rather than the
acquisition of an enteric pathogen from the food,
which is characterized by a predominantly diarrheal
illness developing within days of exposure. A recent
history of travel suggests traveler’s diarrhea, more
than 80% of which is caused by bacterial species
that are endemic to the area of travel, to which the
patient has not been previously exposed. Recent
travel may also suggest parasitic or helminthic
infection. Exposure to health care settings suggests
nosocomial diarrhea. Patients with a history of
immunodeficiency or malnourishment may be more
likely to have an infection with atypical or
opportunistic organisms or to have a more
protracted and severe course. Hematuria or oliguria
may suggest hemolytic uremic syndrome (HUS) as a
complication of infection with Escherichia coli
0157:H7 or Shigella. Other extraintestinal
manifestations may also provide a clue to the
diagnosis.
Physical Examination: Physical examination should
focus on assessing the level of hydration and the
need for fluid resuscitation. The general
examination may reveal nonenteric infections that
could present with diarrhea, such as otitis media,
pneumonia, or sepsis. Abdominal tenderness or
masses suggest appendicitis, intussusception, or,
less commonly, toxic megacolon. Generalized
toxicity or shock may occur with HUS or with sepsis,
such as from invasive Salmonella or staphylococcal
toxic shock syndrome.
Viral Diarrhea:
Rotavirus Infection:

Rotavirus is the most frequent cause of severe

diarrhea in unvaccinated infants and young
children. The introduction of an effective vaccine
has decreased the incidence, with most infections
occurring in unvaccinated children under 3 years of
age. In countries with a higher baseline
socioeconomic status, it is typically seen in winter
months, with prevalence decreasing substantially in
summer months. Transmission is by the fecal-oral
route and the incubation period ranges from 1 to 3
days. Patients typically present with the acute onset
of fever and vomiting followed 1–2 days later by
watery diarrhea. Symptoms generally persist for 3–
8 days. In moderate to severe cases, dehydration,
electrolyte abnormalities, and acidosis may occur.
In immunocompromised children, persistent
infection and chronic diarrhea can develop, with
persistently positive diagnostic assays. Chronic
infection is to be differentiated from postinfectious
malabsorption seen in some immunocompetent
children, in whom the small intestinal mucosa may
require 3–8 weeks to recover its absorptive ability.
Diagnosis is confirmed by nucleic acid amplification
assays, enzyme immunoassay (EIA),
immunochromatography, or latex agglutination
assay for group A rotavirus antigen detection in the
stool.
Norovirus Infection

Norovirus is a single-stranded RNA virus of the

Calciviridae family and is the leading cause of
epidemic outbreaks of acute gastroenteritis, as well
as the most common cause of foodborne illness and
foodborne disease outbreaks in the United States.
Young children have the highest incidence of
infection. Transmission is via the fecal-oral route or
through contaminated food or water. Norovirus
gastroenteritis typically presents with the abrupt
onset of vomiting accompanied by watery diarrhea,
abdominal cramps, nausea, and vomiting. Systemic
manifestations, including myalgia, fatigue, and
headache, may accompany gastrointestinal
symptoms. Diagnosis is confirmed by nucleic acid
amplification assays that detect viral RNA from the
stool. Norovirus can cause persistent infection in
immunocompromised patients and is difficult to
clear without reconstitution of the immune system.
Bacterial Diarrhea: Most bacterial diarrheal
illnesses are foodborne and affect infants and young
children more frequently than adults. Bacterial
infections of the intestine cause diarrhea via direct
invasion of the intestinal mucosa, followed by
intraepithelial cell multiplication or invasion of the
lamina propria. Cellular invasion may be followed
by the production of cytotoxin, which disrupts cell
function, and/or the production of enterotoxin,
which alters cellular electrolyte and water balance.
Bacterial adherence to the mucosal surface may
result in flattening of the microvilli and disruption of
normal cell functioning. Symptomatic differentiation
from viral causes of diarrhea may be difficult, and
sequelae or extraintestinal manifestations of
infections are varied.
Salmonella Infection:

Nontyphoidal Salmonella organisms are estimated

to cause 1 million annual gastrointestinal infections
in the United States. The attack rate is highest in
infancy; the incidence of symptomatic infections is
lower in patients older than 6 years. Salmonella
infection may cause an asymptomatic intestinal
carrier state that is rare in children, enterocolitis
with diarrhea, or bacteremia without
gastrointestinal manifestations but with subsequent
local infections, such as meningitis or osteomyelitis.
Salmonella infection is usually spread through
contaminated water supplies or food (e.g., meat,
chicken, eggs, raw milk, and fresh produce). Most
infections in the United States are sporadic rather
than epidemic. Although an infected food handler
may contaminate food sources, farm animals or
pets are more often the vector. Cats, turtles, lizards,
snakes, and iguanas may also harbor Salmonella
organisms.
After a 12- to 72-hour incubation period,
gastroenteritis develops and is characterized by the
sudden onset of diarrhea, abdominal cramps and
tenderness, and fever. The diarrhea is watery, with
stools containing polymorphonuclear leukocytes
and, on occasion, blood. The peripheral blood white
blood cell count is usually normal. Symptoms slowly
resolve within 3–5 days, although excretion of the
organism may persist for several weeks. The
organism is readily isolated from culture of the stool
or a rectal swab or may be identified via multiplex
PCR assays that detect multiple bacterial, viral, and
parasitic enteric pathogens.
Shigella Infection

Most Shigella infections in the United States occur

in young children aged 1–4 years, with a peak
seasonal incidence in late summer and early
autumn. It may also be the most common bacterial
cause of diarrhea outbreaks in daycare settings. The
organism is transmitted via the fecaloral route,
most often by the hands. During a 12- to 72-hour
incubation period, patients may develop a
nonspecific prodrome characterized by fever, chills,
nausea, and vomiting. A predominantly
rectosigmoid colitis develops and results in
abdominal cramps and watery diarrhea. In more
severe infections (bacillary dysentery), blood and
mucus are passed in small, very frequent stools.
High fever in young infants may induce febrile
seizures, and some patients may develop HUS.
Bacterial culture of the stool or a rectal swab, or the
use of multiplex PCR assays, allows for
differentiating this organism from other pathogens.
If positive, antibiotic treatment is usually indicated.
Campylobacter Infection

Many animal species, including poultry, farm

animals, and household pets, serve as reservoirs for
Campylobacter jejuni. Transmission occurs through
ingestion of contaminated food, especially
undercooked food, and through person-to-person
spread via the fecal-oral route. The disease is
common in infants and adolescents, and both
daycare and college outbreaks have been reported.
Asymptomatic carriage is uncommon.
Campylobacter infection symptoms may range from
mild diarrhea to frank dysentery. The organism
causes diffuse, invasive enteritis that involves the
ileum and colon. Fever, cramping, abdominal pain,
and bloody diarrhea are characteristic and may
mimic symptoms of acute appendicitis or
inflammatory bowel disease (IBD). Fever and
diarrhea usually resolve after 5–7 days; prolonged
illness or relapse occasionally occurs.
Campylobacter infection is also known to cause
meningitis, abscesses, pancreatitis, and pneumonia.
Guillain-Barré syndrome has been reported after
Campylobacter infection. Identification is via stool
or rectal swab bacterial culture or via multiplex PCR
assay. If positive, antibiotic treatment is indicated.
Yersinia Infection

Infection with either Yersinia enterocolitica or

Yersinia pseudotuberculosis may cause various
clinical syndromes, including gastroenteritis
mesenteric adenitis, pseudoappendicitis, and
postinfectious reactive arthritis. The organism is
present in animals and may be spread to humans by
consumption of undercooked meat (especially
pork), unpasteurized milk, and other contaminated
foods. Person-to-person spread also occurs. Young
children are particularly susceptible to disease, and
the frequency of infections increases during the
summer months. The organisms may be identified
via multiplex PCR assay or may be cultured from
rectal swab or stool specimens, but selective media
are required, and the organism may not be
identified via culture for several weeks. The
microbiology laboratory should be notified if
Yersinia infection is suspected. Neonates,
immunocompromised patients, and patients with
bacteremia or extraintestinal infection should
receive antibacterial therapy; treatment decreases
the duration of fecal excretion and can additionally
be considered in immuunocompetent patients with
moderate to severe symptoms.
Escherichia coli Infection

Although E. coli make up the predominant normal

flora in the colon, some strains are pathogenic.
Diarrhea caused by E. coli can be watery,
inflammatory, or bloody, depending on the strain
involved. These diarrheagenic E. coli strains are
classified into five major groups on the basis of
serogrouping or pathogenic mechanisms: (1)
enteropathogenic E. coli (EPEC), an important cause
of diarrhea in infants; (2) enterotoxigenic E. coli
(ETEC), a cause of diarrhea in infants and a cause of
traveler’s diarrhea; (3) enteroinvasive E. coli, a
cause of watery ETEClike illness or, less commonly,
a dysentery-like illness; (4) enterohemorrhagic E.
coli, a cause of hemorrhagic colitis and HUS; and (5)
enteroaggregative E. coli, a cause of persistent
diarrhea. Enteric infections with E. coli are acquired
via the fecal-oral route. Enterohemorrhagic strains
are the only diarrhea-producing E. coli strains
common in the United States and have been
associated with foodborne epidemic outbreaks
transmitted in some cases by undercooked meat.
EPEC is a well-established cause of infantile
diarrhea, especially in countries with a lower
baseline socioeconomic status. Asymptomatic
carriage is common. At least two separate
mechanisms are responsible for diarrhea:
adherence to intestinal epithelial cells leading to
villous injury and mucosal inflammation, and
production of a toxin similar to that of Shigella
organisms. Chronic infection resulting in failure to
thrive may also occur. ETEC is the major cause of
traveler’s diarrhea; occasional nosocomial
outbreaks have also occurred in hospitalized
infants. At least three different types of E. coli
enterotoxins (heat-labile, heat-stable toxin A, and
heat-stable toxin B) have been identified. Definitive
diagnosis requires enterotoxin identification, and
this method is not widely available.
Enterohemorrhagic E. coli produces a Shiga-like
cytotoxin and causes diarrhea, hemorrhagic colitis,
and, in about 20% of infected persons, hemolytic
uremic syndrome (HUS). Both epidemic and
sporadic cases have been recognized. Infection is
more common in the summer and fall. A particular
serotype, E. coli 0157:H7, has been linked to the
development of HUS in young children. The most
common manifestations of enterohemorrhagic E.
coli infection begin with severe abdominal cramps
and watery diarrhea, followed by grossly bloody
stools and emesis. Fever is uncommon. Fecal
leukocytes are absent or few. Other manifestations
include asymptomatic infection and watery diarrhea
without progression to hemorrhagic colitis. E. coli
0157:H7 is cleared from the stool in 5–12 days. If
HUS develops, symptoms become noticeable in the
week after the onset of diarrhea and consist of
oliguric renal failure, microangiopathic hemolytic
anemia, thrombocytopenia, and diarrhea. There is
no role for antimicrobial therapy in
enterohemorrhagic E. coli disease. Antibiotics
neither shorten the duration of disease nor prevent
progression to HUS; they may predispose to HUS.

Clostridioides difficile
Infection Clostridioides difficile (previously termed
Clostridium difficile) causes acute and chronic
diarrhea in children when the normal colonic flora is
disrupted. Pseudomembranous colitis is the most
severe form of this infection, occurring as a result of
a severe inflammatory response to the C. difficile
toxins. Transmission occurs through person-to-
person contact and through environmental
contamination via the spores formed by C. difficile,
which retain viability for up to 1 week on dry
surfaces. The prevalence of carrier status for C.
difficile in healthy, asymptomatic outpatients is as
high as 50% in healthy infants but is usually less
than 5% in patients over 5 years of age. C. difficile
and its toxin have been identified in the feces of
healthy infants in concentrations similar to those
found in adults with pseudomembranous colitis.
The apparent resistance of infants to C. difficile and
its toxin is related to the developmental absence of
the toxin-binding site in the immature intestine.
Asymptomatic carriage rates in hospitalized
patients may be as high as 20%. Infection is highly
associated with recent antibiotic exposure,
particularly to broad-spectrum antibiotics, which
disrupt the endogenous colonic flora that inhibits
the growth of C. difficile. Other risk factors for C.
difficile diarrhea include IBD, cystic fibrosis, use of
proton pump inhibitors, indwelling enteral feeding
tubes, and immunocompromised status.
C. difficile infection should be considered in patients
in whom diarrhea develops during or within several
weeks of antibiotic therapy. Illness associated with
this organism varies from a mild, self-limited,
nonbloody diarrhea to severe hemorrhagic colitis,
protein-losing enteropathy, toxic megacolon,
colonic or cecal perforation, peritonitis, sepsis,
shock, and death. In rare cases, manifestations of C.
difficile infection include fever or abdominal pain
without diarrhea. The colitis is caused by potent
toxins produced by the organism: toxin A, a lethal
enterotoxin that causes hemorrhage and fluid
secretion in the intestines, and toxin B, a cytotoxin
detectable by its cytopathic effects in tissue culture.
Both toxins play a role in disease pathogenesis,
although toxin B may be more important.
Recommendations for diagnosis of C. difficile
infection are to consider a two-step method to
exclude false-positive testing, particularly in the
setting of asymptomatic carriage in infants and
younger children: nucleic acid amplification testing
to identify microbial toxin genes and an enzyme
immunoassay for toxins in stool. Testing is typically
performed only on patients with diarrhea who are
not concurrently taking laxatives or promotility
agents that could otherwise explain the diarrhea;
testing may be considered for patients without
loose stools if C. difficile–induced ileus or toxic
megacolon is suspected. Sigmoidoscopy or
colonoscopy reveals pseudomembranes in up to
50% of cases, typically in association with more
severe disease. Treatment is dependent on the
severity of the disease and whether the infection is
primary or recurrent. Antibacterials include
metronidazole, oral vancomycin, and, in adults,
fidaxomicin.
Aeromonas Infection

Aeromonas species are gram-negative bacilli that

are found in a variety of freshwater sources and
that are capable of causing a wide array of disease,
including a mild, self-limited diarrheal illness in
children. Occasionally, Aeromonas may cause
dysentery or a protracted diarrheal illness. The
most common manifestation is a watery,
nonbloody, nonmucoid diarrhea seen during the
late spring, summer, and early fall. More severe
infections may resemble ulcerative colitis, with
chronic bloody diarrhea and abdominal pain.
Plesiomonas Infection

Plesiomonas shigelloides is a Vibrio-like organism

found in soil and warmer (>8°C) fresh or brackish
water that is sometimes implicated in childhood
diarrhea. It has been linked to consumption of raw
shellfish or contaminated water, exposure to
reptiles and tropical fish, and travel to endemic
areas. The organism is most frequently found in
subtropical or tropical climates though has a wide
geographic distribution. After an incubation period
of 1–2 days, patients typically develop watery
diarrhea and vomiting, although some may develop
dysentery. Diagnosis is via stool culture. Symptoms
may last up to 2 weeks, although the disease is
typically self-limited in immunocompetent
individuals.
Parasitic Diarrhea
Giardiasis:

Giardia intestinalis is a flagellated protozoan that

can cause diarrhea, malabsorption, abdominal pain,
and weight loss. It spreads through contaminated
food and water, as well as through person-to-
person contact via the fecal-oral route. The latter
mode of transmission is responsible for outbreaks
of diarrhea in daycare centers and residential
facilities. Infection is often asymptomatic.
Symptomatic illness usually develops 1–3 weeks
after exposure and may mimic acute gastroenteritis
with low-grade or no fever, nausea, vomiting, and
watery diarrhea. In some patients, a chronic illness
develops, characterized by intermittent, foul-
smelling diarrhea, abdominal bloating, nausea,
abdominal pain, and weight loss. Up to 40% of
patients may develop secondary lactase deficiency
following infection. Diagnosis is via EIA or direct
fluorescent antibody (DFA) tests, which offer
superior sensitivity and specificity compared to
microscopy. If microscopy is performed, three
separate samples of fresh stool should be examined
for cysts or trophozoites, because excretion of the
organism is only intermittent. Treatment is typically
indicated in the presence of symptoms, to prevent
institutional outbreaks, or to prevent spread to
immunocompromised individuals.

Entamoeba histolytica Infection

 Entamoeba histolytica is acquired in warm climates
via the ingestion of cysts in fecally contaminated
food or water. Infected individuals are often
asymptomatic. Amebic dysentery may occur, but
hepatic abscess and other focal infections are
uncommon. Because cysts are shed in the stool on
an intermittent basis, examination of several fecal
specimens may be required for identification. Stool
antigen detection assays allow for differentiation
between E. histolytica and the more prevalent
though less pathogenic E. dispar, which may also be
detected on microscopy. Treatment is indicated to
prevent the development of extraintestinal
manifestations or spread to other individuals.
Cryptosporidium Infection
This intracellular protozoan causes watery diarrhea
in both immunocompetent and
immunocompromised hosts and is an important
cause of severe diarrhea in individuals infected with
HIV. Cryptosporidium has also been recognized as
an occasional cause of self-limited diarrhea in
travelers, as well as in children in daycare centers
and persons in residential institutions. The
mechanisms by which these organisms cause
diarrhea are unknown. Nucleic acid amplification
assays and EIA tests are available for diagnosis.
Identification via microscopy requires specialized
staining techniques that should be requested if
Cryptosporidium infestation is suspected.
Other Causes of Acute Diarrhea
Parenteral Secondary Diarrhea Acute diarrhea that
accompanies infections outside of the
gastrointestinal tract is termed parenteral diarrhea.
Upper respiratory tract and urinary tract infections
may be associated with increased bowel movement
frequency or stool water. The mechanism is unclear
but may involve alterations in bowel motility,
changes in diet, or the effects of antibiotic
treatment. Medications: Various nonlaxative
prescription and over-the-counter medications may
cause acute diarrhea. The most implicated agents
are antibiotics, acting through mechanisms other
than C. difficile.

Food Poisoning
Staphylococcal food poisoning

results from ingestion of preformed enterotoxin,

produced in contaminated food that has incubated
at or above room temperature for a suitable period.
Staphylococcal food poisoning is suggested by the
sudden onset of vomiting that is followed by
explosive diarrhea, usually within 4–6 hours after
ingestion of the contaminated food. The illness is
self-limited and usually resolves within 12–24
hours. The diagnosis is based on the typical
historical presentation. Treatment is supportive;
antibiotics are not indicated. Bacillus cereus, a
gram-positive sporulating organism found in soil, is
usually associated with contamination of refried
rice or vegetables. Two food poisoning syndromes
can occur. A short incubation period disease (1–6
hours) results from ingestion of preformed toxin
and is characterized by nausea, vomiting, and
diarrhea, similar to staphylococcal food poisoning. A
long incubation period disease (8–16 hours) is
caused by in vivo production of an enterotoxin and
is characterized by abdominal pain, tenesmus, and
profuse watery diarrhea. Vomiting is usually absent.
Both syndromes resolve spontaneously within 24
hours and are managed with supportive care.
Clostridium perfringens food poisoning has been
associated with ingestion of contaminated beef and
poultry. The disease results from the production
and release of an enterotoxin into the lower bowel
8–24hours after ingestion of the vegetative form of
the organism. Onset is sudden, with abdominal pain
and watery diarrhea. Fever and vomiting are
absent. Treatment is supportive.
CHRONIC DIARRHEA: The etiology of chronic
diarrhea is dependent on the age of the patient and
is additionally influenced by socioeconomic factors
and the clinical setting. In countries with a lower
baseline socioeconomic status, chronic diarrhea
may be caused by acute infections, as malnutrition
can prolong the course of infectious enterocolitis.
The most common etiologies of chronic diarrhea in
countries with a higher baseline socioeconomic
status are functional intestinal disorders, nutrient
malabsorption (e.g., cystic fibrosis), celiac disease,
and IBD, but persistent infections of the intestinal
tract may also occur. Neonatal or early-infancy-
onset chronic diarrhea is often due to monogenic
disorders.
History- The history should establish the age of
onset, as well as the frequency and nature of the
stools, including the presence of blood, nighttime
stooling, urgency, weight loss, and any associated
systemic symptoms. History should also ascertain
any recent travel, other sick contacts, or swimming
in freshwater sources. A history of recurrent
infections, use of intravenous drugs, or other signs,
symptoms, or risk factors for immunodeficiency
should be documented. Family history should be
probed for the presence of gastrointestinal
disorders or immunodeficiency.
Physical Examination: Hydration status should be
assessed. Growth parameters should be obtained
and charted on age-matched growth charts. The
physical examination should assess for signs of
malnutrition, vitamin and micronutrient deficiency,
and dermatologic manifestations of systemic
diseases. Jaundice may suggest hemolysis or
hepatic dysfunction. Signs of fat-soluble vitamin
deficiency include bone deformities in vitamin D
deficiency, dry scaly skin and Bitot spots (superficial
buildup of keratin in the conjunctivae) in vitamin A
deficiency, hyporeflexia or gait abnormalities in
vitamin E deficiency, and bruises or bleeding in
vitamin K deficiency. Joint examination may reveal
arthritis associated with IBD. Abdominal
examination may reveal evidence suggestive of
neuroendocrine tumors, and perianal examination
may reveal evidence of IBD (fistula, skin tags).
Diagnostic Evaluation: The clinician should try to
focus the diagnostic evaluation on only those
conditions suggested by the history and physical
examination. Laboratory investigation should begin
with microbiologic studies for bacteria and parasites
in the stool. Acute infection with bacteria, such as
Yersinia, E. coli, and Salmonella, may develop into a
chronic illness and can be detected by routine stool
cultures and multiplex PCR assays. C. difficile testing
should be performed, especially in the presence of
risk factors. Antigen detection and PCR-based
assays for Giardia and Cryptosporidium are more
sensitive and specific than routine microscopy-
based examinations and are indicated if these
infections are suspected. Except in the setting of
neonatal-onset diarrhea and factitious diarrhea,
stool electrolytes and osmolality are of limited use.
The differentiation of osmotic and secretory
diarrhea is typically made by a trial of fasting and
determining if there is improvement in the stool
output: osmotic diarrhea improves or resolves upon
fasting, whereas secretory diarrhea does not. Stool
reducing substances are positive in the setting of
osmotic diarrhea secondary to carbohydrate
malabsorption. In patients with osmotic diarrhea
and negative reducing substances, it is essential to
determine whether steatorrhea is present. If
qualitative assays for fecal fat are negative, a more
precise indication of steatorrhea may be obtained
by quantifying fecal fat and calculating the
coefficient of fat absorption, which requires a 72-
hour collection of stool. Low fecal elastase suggests
pancreatic insufficiency. Elevated levels of stool α1-
antitrypsin (A1AT) are suggestive of protein-losing
enteropathy (PLE). Elevated fecal calprotectin or
fecal lactoferrin are indicative of intestinal
inflammation. The presence of fecal leukocytes or
occult blood may indicate mucosal inflammation as
well, though neither is sufficiently sensitive nor
specific. Blood tests should include a CBC to
evaluate for anemia and thrombocytosis, which
may suggest blood loss and inflammation,
respectively. In the presence of anemia, red blood
cell indices may reveal a microcytosis potentially
indicative of iron deficiency or a macrocytosis
suggestive of vitamin B12 or folate deficiency. A
normocytic anemia may be seen in chronic
inflammatory diseases. White blood cell count and
differential and quantification of immunoglobulins
A, G, and M screen for immune deficiency
disorders. Elevated ESR and CRP indicate
inflammation but are nonspecific. Low albumin
could be indicative of an inflammatory process or
PLE. Elevated antitissue transglutaminase
immunoglobulin A (IgA) antibody is sensitive and
specific for celiac disease, but a low total serum IgA
level may result in a false-negative test. Levels of
the fat-soluble vitamins A, 25-OH vitamin D, vitamin
E, and vitamin K (reflected by prothrombin time)
may be measured if fat malabsorption is suspected.
Disorders of Carbohydrate Malabsorption

The brush border epithelium of the small bowel

contains enzymes necessary for carbohydrate
digestion. These enzymes hydrolyze disaccharides
and oligosaccharides into monosaccharides that are
then absorbed by transporters on the luminal
surface of enterocytes. Carbohydrate
malabsorption is secondary to either deficiency of a
particular enzyme (e.g., congenital sucrase-
isomaltase deficiency) or an abnormality in a
transport protein involved with the absorption of
monosaccharides (e.g., glucose-galactose
malabsorption). The onset of various carbohydrate
malabsorption syndromes can vary based on the
timing of the introduction of particular
carbohydrates. Patients with carbohydrate
malabsorption disorders present with severe watery
diarrhea, which results from osmotic action exerted
by the malabsorbed carbohydrate in the intestinal
lumen. Colonic bacteria ferment the malabsorbed
sugars, which generates a mixture of gases (e.g.,
hydrogen, methane, and carbon dioxide) and short-
chain fatty acids. These gases form the basis of
carbohydrate-specific breath hydrogen testing,
which is often used in diagnosis. The stools become
acidified to a pH of less than 7, which can lead to
diaper dermatitis.

Disaccharidase Deficiency:
Congenital sucrase-isomaltase deficiency (CSID).
CSID is an inherited deficiency of the ability to
hydrolyze sucrose, maltose, and starch. Exposure to
these substances leads to osmotic diarrhea, pain,
bloating, abdominal distension, and, at times,
chronic malnutrition and failure to thrive. The
sucrase-isomaltase gene is located on chromosome
3 (3q25.2-q26.2) and more than 25 pathogenic
variants in the gene have been identified. These
variants result in a variety of defects in the
structure and function of the enzyme, including
isolated deficiencies in sucrase activity or
isomaltase activity. This genetic heterogeneity
results in phenotypic variability ranging from
completely absent to low-residual sucrase activity,
and from completely absent to normal isomaltase
activity. Because sucrase-isomaltase is responsible
for up to 80% of the maltase activity in the brush
border, maltase activity is significantly reduced in
almost all cases. The classic presentation of CSID is
severe watery diarrhea, failure to thrive, irritability,
and diaper dermatitis in a 9- to 18-month-old infant
who has been exposed to sucrose and starch in the
form of fruit juices, fruit purees, and starch-laden
foods such as crackers and cookies. Intrinsic factors
that contribute to the severity of presentation
during infancy include the shorter length of the
colon and a decreased capacity for colonic
reabsorption of fluid and electrolytes, more rapid
small intestinal transit, a high-carbohydrate diet,
and lower levels of amylase prior to 2 years of age.
Some patients with milder sucrase deficiency may
improve with age as their colonic bacteria develop
an increased capacity to ferment residual sucrose
and the intestinal tract develops an increased
capacity for reabsorption. Patients may be
misdiagnosed as having food allergies or irritable
bowel syndrome (IBS) or may remain undiagnosed.
Symptoms may abate with the restriction of
carbohydrate in the diet or with the use of enteral
sucrase enzyme supplements. Diagnosis typically
involves endoscopy for histologic examination of
small bowel morphology and measurement of
disaccharidase levels on biopsy specimens.
Diagnosis requires the following: 1. Normal small
bowel morphology 2. Absent or markedly reduced
sucrase activity 3. Isomaltase activity varying from
absent to full activity 4. Reduced maltase activity 5.
Normal lactase activity, or in the setting of reduced
lactase, a sucrase:lactase ratio of<1.0
Other less invasive methods of diagnosis include
sucrose breath hydrogen quantification and
differential urinary disaccharide assessment;
however, both modalities are associated with high
false-positive and false-negative rates.
Furthermore, differential urinary disaccharide
testing requires a 10-hour urine collection
specimen, which is often impractical in infants and
younger children.
Maltase-glucoamylase deficiency

Maltase-glucoamylase is a brush border hydrolase

that serves as an alternate pathway for starch
digestion that complements sucrase-isomaltase
activity. Congenital maltase-glucoamylase
deficiency is rare, with only several cases described
in the literature. Genetically, maltase-glucoamylase
shares approximately 59% of its sequence with
sucrase-isomaltase, and the enzyme has two
catalytic sites that are identical to those of sucrase-
isomaltase. Symptoms are similar to those seen in
CSID. Diagnosis requires the demonstration of
reduced glucoamylase activity in the setting of
normal small bowel histology and normal
pancreatic amylase activity.
Congenital glucose-galactose malabsorption
(CGGM).

Congenital glucose-galactose malabsorption results

from defective sodiumcoupled transport of glucose
and galactose into enterocytes. It is a rare
autosomal recessive disorder that results from
pathogenic variants in the sodium-glucose
cotransporter gene SGLT1 located on chromosome
22q12.3. CGGM presents as a neonatal-onset
profuse, watery diarrhea that ceases immediately
following the elimination of glucose and galactose
sources from the diet. Symptoms recur if the
patient is fed formula containing either of these
carbohydrates, including polymers such as sucrose
and lactose. The disorder may lead to dehydration
and electrolyte abnormalities, both of which can
become life threatening, and patients may be
hypoglycemic. Stool reducing substances are
positive secondary to the presence of glucose in the
stools. Intestinal morphology is normal. The
diagnosis can be further established by an abnormal
glucose breath hydrogen test and SGLT1
sequencing, although neither is required to confirm
the diagnosis.

Congenital lactase deficiency

A rare autosomal recessive disorder leading to very
low or complete absence of brush border
lactasephlorizin hydrolase activity, congenital
lactase deficiency usually presents with diarrhea
starting soon after the introduction of breast milk or
any lactose-containing formula. Most infants
manifest within the first 10 days of life. Unless the
disorder is recognized and treated quickly, the
condition is life-threatening secondary to
dehydration and electrolyte abnormalities. Small
bowel biopsies reveal normal histology but low or
completely absent lactase concentrations. A
presumptive diagnosis can be made if osmotic
diarrhea in a neonate resolves by introducing
lactose-free formula. Primary lactase deficiency
(lactose intolerance). Approximately 65% of the
world’s population has primary lactase deficiency,
although prevalence varies by ethnicity. While
primary lactase deficiency is nearly universal in
Children with clinical signs of lactose intolerance at
an earlier age than would be typical for their
ethnicity may warrant an evaluation for an
alternate cause. Symptoms typically develop
insidiously over the course of many years, with
most affected individuals experiencing onset of
symptoms in late adolescence or adulthood. Within
30 minutes to 2 hours of ingesting lactose, patients
develop abdominal cramping and distension, foul-
smelling flatulence, nausea, and diarrhea. While the
severity of symptoms is directly correlated with the
quantity of ingested lactose, each individual exhibits
a unique dose threshold beyond which symptoms
develop. Diagnosis is suggested historically. When
lactose intolerance is suspected, a trial of a lactose-
free diet can aid in confirming the diagnosis.
Patients must be sure to eliminate all sources of
lactose, including some that may be hidden.
Generally, a 2-week trial of a strict lactose-free diet
producing resolution of symptoms, followed by a
subsequent reintroduction of dairy foods resulting
in recurrence of symptoms, is diagnostic. In subtler
cases, hydrogen breath testing is the least invasive
and most helpful test to diagnose lactose
malabsorption. Secondary lactase deficiency:
Secondary lactase deficiency develops when an
inflammatory process, such as a viral
gastrointestinal infection, damages the brush
border epithelium and leads to the loss of the
lactasecontaining epithelial cells from the tips of the
villi. The immature epithelial cells that replace these
are often lactase deficient, leading to lactose
malabsorption. Secondary lactase deficiency in
most children with acute gastroenteritis is rarely
clinically significant. Most affected children can
safely continue breast milk or standard lactose-
containing formula without any significant effects,
although infants under 3 months of age may
develop clinically significant symptoms. Giardiasis,
cryptosporidiosis, and other parasites that infect
the proximal small intestine often lead to lactose
malabsorption from direct injury to the epithelial
cells by the parasite. Secondary lactase deficiency
with clinical signs of lactose intolerance can be seen
in celiac disease, Crohn disease, and immune-
related and other enteropathies and should be
considered if children with these diagnoses have
symptoms of lactose intolerance. Diagnostic
evaluation should be directed toward these entities
when secondary lactase deficiency is suspected and
an infectious etiology is not found. Severe
malnutrition can also produce secondary lactose
intolerance via small bowel atrophy. Most infants
and children with malabsorption attributable to
malnutrition are able to continue to tolerate dietary
carbohydrates, including lactose. However, the
World Health Organization recommends avoidance
of lactose in children with persistent postinfectious
diarrhea lasting more than 14 days, if they fail a
dietary trial of milk or yogurt. Treatment of
secondary lactase deficiency and lactose
malabsorption attributable to an underlying
condition generally does not require elimination of
lactose from the diet but, rather, treatment of the
underlying condition.
Trehalase deficiency- Trehalose is an α(1,1)-linked
glucose dimer that is produced by certain bacteria,
fungi, plants, and invertebrates as an energy source
and as a method of surviving freezing temperatures
or lack of water. Potential dietary sources include
mushrooms and processed foods that have
trehalose added to improve frozen shelf life.
Symptoms are similar to lactose intolerance.
Deficiency is rare in most populations though is
estimated to affect up to 8% of the indigenous
population in Greenland.
Functional Diarrhea (Chronic Nonspecific Diarrhea)
Functional diarrhea, previously termed chronic
nonspecific diarrhea or toddler’s diarrhea, typically
affects children between 1 and 3 years of age and is
characterized by the passage of several watery and
unformed stools each day. Stools are typically
relatively well formed in the morning but become
looser as the day progresses. The stools often have
undigested vegetable matter but lack blood, mucus,
or excessive fat. Children with functional diarrhea, if
offered an unrestricted and age-appropriate diet,
gain weight normally. However, in an attempt to
treat the diarrhea, many children are placed on
restrictive diets that may lack dairy, fats, and
occasionally starches; such restrictions lead to
failure to thrive. Rome IV diagnostic criteria specify
that all of the following must be present: 1. Daily
painless, recurrent passage of four or more large,
unformed stools 2. Symptoms lasting more than 4
weeks 3. Onset of symptoms between 6 and 60
months of age 4. No failure to thrive if caloric intake
is adequate
Chronic nonspecific diarrhea is thought to be a
variant of IBS, and a family history of IBS is
common. The pathophysiology may involve
abnormal intestinal motility with decreased mouth-
to-anus transit time. Excessive fruit juice intake may
also contribute to the diarrhea by overwhelming
the carbohydrate absorptive ability of the gut.
Chronic nonspecific diarrhea is a benign and self-
limited condition that usually resolves without
intervention by 3–4 years of age. Parents should be
reassured and encouraged to place the child on a
regular, unrestricted diet to provide adequate
calories. The diarrhea often improves with removal
of prior dietary restrictions and by limiting fruit juice
intake. Some patients may improve with increasing
the fat content of the diet (e.g., switching from low-
fat milk to whole milk), which can slow
gastrointestinal transit time.
Small Intestinal Bacterial Overgrowth

The normal small intestine is colonized with

relatively few bacteria, typically 105 organisms/ mL
are suggestive of small intestinal bacterial
overgrowth, although established cutoff ranges and
specificity are imperfect. Irritable Bowel Syndrome
IBS is characterized by recurrent abdominal pain
and altered bowel habits and typically presents in
adolescence. Symptoms include abnormal stool
frequency (either four or more stools per day or
two or fewer stools per week), abnormal stool form
(either loose and watery or lumpy and hard),
abnormal passage of stool (e.g., straining, urgency,
feeling of incomplete evacuation), the passage of
mucus, and bloating or distension. Diagnosis
requires that patients have a normal physical
examination and growth curve and meet both of
the following criteria at least once per week for at
least 2 months before diagnosis: 1. Abdominal pain
at least 4 days per month associated with one or
more of the following: a. Pain related to defecation
b. Change in the frequency of stool c. Change in the
form or appearance of stool 2. After appropriate
evaluation, the symptoms cannot be fully explained
by another medical condition The etiology and
pathogenesis of IBS are not well understood.
Visceral hypersensitivity has been well documented
in children with IBS. Genetic predisposition, early
stressful events, and ineffective coping mechanisms
are compounding factors. Additional mechanisms
may include infection, inflammation, intestinal
trauma, allergy, and disordered gut motility.
Celiac Disease
[Link]

Celiac disease is an immune-mediated systemic

disorder elicited by exposure to gluten and related
proteins in genetically susceptible individuals.
Clinical presentations vary, although the hallmarks
of celiac disease include enteropathy and the
presence of disease-specific antibodies. Prevalence
is as high as 1% in Western nations, with most
affected individuals presenting in childhood. A
genetic predisposition is suggested by familial
aggregation and the high concordance in
monozygotic twins, which approaches 100%. A
strong association with human leukocyte antigen
(HLA)-DQ2.5, and to a lesser degree HLA-DQ8, has
been identified. A family or personal history of
autoimmune disease and certain genetic conditions
confers a higher risk. The pathogenesis of celiac
disease involves exposure to gliadin, a protein
component of wheat gluten, or structurally related
storage proteins (prolamines) found in rye and
barley. Altered processing by intraluminal enzymes,
changes in intestinal permeability, and activation of
the innate immune response precede the
development of an adaptive immune response that
results in systemic autoimmunity and an
inflammatory enteropathy characterized by villous
atrophy, elongated crypts, and intraepithelial
lymphocytosis. The age of onset is variable, and a
high degree of suspicion is needed. Manifestations
include recurrent abdominal pain, nausea and
vomiting, iron deficiency with or without anemia,
short stature, aphthous stomatitis, chronic fatigue,
arthritis, raised aminotransferase levels, and
reduced bone mineral density (osteopenia). Rare
manifestations include ataxia; dermatitis
herpetiformis, which is a blistering rash with
pathognomonic cutaneous IgA deposits; and celiac
crisis, which is a rare life-threatening syndrome
mostly observed in children that is characterized by
severe diarrhea, hypoproteinemia, and metabolic
and electrolyte imbalances. The classic presentation
of a toddler with chronic diarrhea, abdominal
distension, and failure to thrive is uncommon. Most
patients are identified via serologic screening in the
context of a strong family history or other risk
factors. Serologic tests are the cornerstone of
screening for celiac disease in patients with risk
factors or a suggestive history. Establishing the
diagnosis is dependent on the levels of disease-
specific antibodies detected. Total serum IgA should
be obtained to exclude IgA deficiency. If total serum
IgA is normal and antitissue transglutaminase IgA
antibodies are negative, celiac disease is unlikely.
Patients with positive antitissue transglutaminase
IgA antibodies that are 25 lymphocytes/100
enterocytes), the diagnosis is confirmed. Patients
with positive antitissue transglutaminase IgA
antibodies that are ≥10 times the upper limit of
normal should have antiendomysial IgA antibodies
and HLA testing performed. If the patient is positive
for antiendomysial IgA antibodies and is positive for
HLA-DQ2 or HLA-DQ8 testing the diagnosis is
confirmed; if either or both are negative, the
patient should undergo biopsy. Patients with celiac
disease experience relief in their symptoms when
placed on a strict gluten-free diet. Complications
associated with untreated celiac disease include
osteoporosis, impaired splenic function, neurologic
disorders, infertility or recurrent spontaneous
abortion, ulcerative jejunoileitis, and cancer.
Enteropathy-associated T-cell lymphoma and
adenocarcinoma of the jejunum are rare
complications of celiac disease. Refractory celiac
disease is diagnosed when there are persistent or
recurrent malabsorptive symptoms and signs of
villous atrophy on biopsy despite strict adherence
to a gluten-free diet for more than 12 months.
Refractory celiac disease can be classified as type 1
(characterized by the presence of normal
intraepithelial lymphocytes) or type 2
(characterized by abnormal intraepithelial
lymphocytes; clonal intraepithelial lymphocytes
lacking surface markers CD3, CD8, and T-cell
receptors; or both). Type 2 refractory celiac disease
is associated with a higher risk of ulcerative
jejunoileitis and lymphoma. Inflammatory Bowel
Disease IBD is divided broadly into ulcerative colitis
and Crohn disease, idiopathic systemic chronic
inflammatory diseases whose primary symptoms
are related to relapsing gastrointestinal tract
inflammation. Common signs and symptoms include
diarrhea, abdominal pain, blood in the stools, and
nutritional compromise. Ulcerative colitis consists of
mucosal inflammation restricted to the colon, while
Crohn disease consists of transmural inflammation
that affects all layers of the intestinal wall and may
involve any portion of the gastrointestinal tract
from the mouth to the anus. Ulcerative colitis
involves the colon in a continuous fashion, typically
starting in the rectum and extending proximally to
variable degrees.
Crohn disease
[Link]
is characterized by skip lesions, in which there are
areas of normal-appearing mucosa interspersed
with inflammatory lesions.
Clinical Presentation- Up to 80% of children with
Crohn disease will present with diarrhea. Stool may
contain microscopic blood although may not be
grossly bloody, especially in the absence of
significant left-sided colonic disease. Diarrhea is
more common in colonic disease and may be absent
altogether in cases of isolated small bowel
inflammation. In ulcerative colitis, diarrhea is a
more consistent presenting feature, often insidious
in its development but eventually progressing to
hematochezia.
Nocturnal diarrhea with urgency may be a sign of
left-sided colonic inflammation in both entities.
Gastrointestinal and extraintestinal manifestations
otherwise vary between Crohn disease and
ulcerative colitis. Extraintestinal manifestations are
present in up to 23% of children at diagnosis, with a
higher frequency in those over 6 years of age.
Physical examination should establish nutritional
status and include an assessment of growth
parameters, including the review of previous
growth charts. Pubertal status should also be
recorded. Oral cavity examination should look for
aphthous ulcers that are present in approximately
10% of IBD patients (more commonly in Crohn
disease). An eye examination should look for
episcleritis, painful inflammation of the outer layer
of the sclera, and patients with known IBD should
be followed by an ophthalmologist to assess for
uveitis and keratopathy. A detailed abdominal
examination should document abdominal
distension, mass, tenderness, and hyper- or
hypoactive bowel sounds. Particular attention
should be paid to assessing the perianal region for
any abscesses or fistulas. Skin examination should
look for erythema nodosum, painful raised red
lesions about 1–3 cm in diameter typically found on
the shins; pyoderma gangrenosum, a severe
ulcerating rash; and psoriatic lesions. Two clinical
features suggest a diagnosis of Crohn disease over
ulcerative colitis: the presence of perianal disease
and the presence of stricturing and fistulizing
disease of the bowel. No other systemic or
extraintestinal manifestations reliably suggest one
diagnosis over the other. Diagnosis IBD is a clinical
diagnosis that integrates history and physical
findings with objective data from imaging studies,
laboratory evaluation, and endoscopic findings
including histopathology. As such, every patient
with a history and examination suggestive of IBD
should have stool studies for infectious organisms
and special request should be made for Yersinia
culture if multiplex PCR assays that include Yersinia
testing are not available. Patients presenting with
suggestive symptoms prior to 6 years of age may
require an evaluation for an underlying immune
disregulation disorder as an additional mimic of IBD.
Stool biomarkers such as calprotectin and
lactoferrin should be utilized to exclude
noninflammatory causes before considering
endoscopic procedures. The suggested diagnostic
evaluation of suspected IBD is presented.
[Link]