190 Chronic Diarrhea

Jumana Shammout . Hisham M. Nazer

Diarrhea is a recognized manifestation of a variety of

gastrointestinal diseases. While the majority of diarrheal
episodes last less than 2 weeks and are self-limited,
a smaller proportion of diarrheal illnesses persists for
more than 2 weeks, substantially impacting the quality of
life and the overall health of the individual; not only
because of the inconvenience of persistent diarrhea, but
also because of the risk of malnutrition and even death.

Definition
Diarrhea is defined as frequent passage of loose stools.
Diarrhea occurs when the stool volume exceeds the
normal value of approximately 10 g/kg/day in infants
and toddlers, and 200 g/day in older children and adults.
This is typically manifested as loose or watery stools
occurring at least three times a day. However, since the
absolute limits of normal bowel movements is difficult to
define, with normal bowel movements ranging from three
times/week to three times/day, any deviation from the
childs usual pattern should raise concern (particularly if
passage of blood or mucus, or dehydration occurs),
regardless of the actual number of bowel movements or
their water content.
Diarrheal episodes are classically divided into acute
and chronic based on their duration. The WHO defines
acute diarrhea as less than 14 days in duration and persistent diarrhea episodes as 14 days or longer in duration.
Such a distinction can help in forming a differential diagnosis, and thus impact management, as well as prognosis.
Acute diarrhea lasts no longer than 14 days, is often
infectious in etiology (bacterial, viral, or parasitic infections), and is usually self-limited. Chronic diarrhea refers
to the persistence of loose stools (with or without an
increase in stool frequency) for at least 14 days.
Chronic diarrhea may occur in many conditions,
including a variety of infectious and immunologic states,
as well as several congenital syndromes. Reports have
indicated that between 5% and 18% of all diarrheal episodes are categorized as persistent diarrhea; however the
exact cutoff point between acute and chronic diarrhea and
persistent diarrhea is arbitrary.

Etiology
Many gastrointestinal and systemic diseases present with
diarrhea. In children, the differential diagnosis may be age
specific; however, a number of diseases may occur at any
age (> Table 190.1).
Furthermore, the etiology of chronic diarrhea differs
between developing and developed countries. In developing countries, most cases of persistent diarrhea are caused
by recurrent bouts of enteric infections leading to chronic
enteropathy and diminished digestive and absorptive
capacity. Poor caloric and protein intake, dietary deficiency of micronutrients such as zinc and vitamin A,
and/or immunodeficiency, further contribute to the development of chronic enteropathy and persistent diarrhea.
In developed countries, the causes of chronic diarrhea
in children range from dietary factors (e.g., excessive consumption of juice), to diseases causing maldigestion or
malabsorption (e.g., celiac disease and other food allergies), to enteric infections (particularly in immunocompromised patients).

Prevalence and Morbidity

Persistent diarrhea occurs in up to 35% of the infant
population worldwide. The prevalence is substantially
higher in developing countries compared to developed
countries. Although less than 10% of diarrheal episodes
become persistent, persistent diarrhea accounts for more
than half of diarrheal deaths, and 3050% of deaths overall
among children younger than 5 years of age in the developing world.

Pathophysiology
The intestine is the major site of gastrointestinal fluid
absorption and secretion. It is lined by a single layer of
polarized epithelial cells that are joined together by tight
junctions. These cells maintain concentration gradients
through specialized channels and ion pumps located in
their apical and basolateral membranes, and thus regulate

Abdelaziz Y. Elzouki (ed.), Textbook of Clinical Pediatrics, DOI 10.1007/978-3-642-02202-9_190,

# Springer-Verlag Berlin Heidelberg 2012

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190

Chronic Diarrhea

. Table 190.1
Main causes of chronic diarrhea according to the age of onset
030 days

136 months

318 years

Abetalipoproteinemia

Acrodermatitis enteropathica

Antibiotic-associated C. difficle colitis

Autoimmune enteropathy

Antibiotic-associated C. difficle colitis

Celiac disease

Congenital chloride diarrhea

Autoimmune enteropathy

Congenital sucrase-isomaltase deficiency

Congenital enterokinase deficiency

Celiac disease

Eosinophilic gastroenteritis

Glucosegalactose malabsorption

Chronic infection by G. lambilia

Fruit juices, sorbitol, carbonated beverages

Congenital lactase deficiency

Chronic nonspecific diarrhea

G. lambilia

Congenital lymphangectasia

Sucrase-isomaltase deficiency

Infectious gastroenteritis

Congenital sodium diarrhea

Cystic fibrosisEosinophilic gastroenteritis

Inflammatory bowel disease

Cows milk protein/soy allergy

Infectious gastroenteritis

Irritable bowel syndrome

Hirschsprungs enterocolitis

Postinfectious enteropathy

Lactose intolerance

Microvillus inclusion disease

ShwachmanDiamond Syndrome

Laxative abuse

Postinfectious enteritis

Postinfectious enteropathy

Primary bile acid malabsorption

ion and water fluxes. The epithelial cells located on the villi
are responsible for absorption, while the cells located in
the crypts are responsible for secretion.
Sodium transport occurs across the brush border membrane through several mechanisms including passive diffusion, special sodium channels, and chloride-linked protein
carriers. A sodium gradient is maintained by a Na+,K+,
-ATPase pump located at the basolateral membrane.
In contrast to sodium, chloride may be actively secreted
into the intestinal lumen and acts as a powerful stimulant
for fluid secretion. Chloride secretion may occur in
response to changes in the intracellular gradient or messenger pathways. Water absorption for the most part occurs
freely in the intestine in response to the osmotic gradient
created by Na+ transport from the lumen across the apical
membrane of the enterocytes. Na+ transport across the
enterocytes occur through three major pathways:
1.
2.
3.

Selective Na+ channels

Sodium chloride-coupled pathway
Cotransport of Na+ with glucose, galactose, or amino
acids

Several other factors play a role in altering the volume

of the stools including fluids and electrolytes, dietary
factors, gut flora, and various gastrointestinal hormones.
Intestinal secretion is activated by an increase in intracellular level of cyclic adenosine monophosphate (cAMP),
cyclic guanosine monophosphate (cGMP), and Ca++.
These mediators increase the secretion of Cl
, and consequently sodium and water.

In normal conditions, the secretory process is balanced

by fluid absorption. Diarrhea occurs when there is an
imbalance between those two processes, leading to incomplete absorption of water. This occurs through two basic
pathologic mechanisms: secretory or osmotic.
As stool leaves the colon, the fecal osmolality is equal
to that of the serum (290 mOsm/kg). Under normal
circumstances, the major osmoles in the stool are Na+,
K+, Cl
, and HCO3+. The stool osmolality may be estimated by multiplying the stool (Na+K)2. The osmotic
gap is the difference between the measured osmolality of
the stool electrolytes and the total osmolality of the stool
(which is approximately 290 mOsm/kg).
Stool osmolal gap 290
2  Na K
Normal stool osmotic gap is <50. An increased
osmotic gap indicates the presence of unmeasured substances in the stool (osmotic diarrhea).
Osmotic diarrhea occurs when poorly absorbed
osmotically active solutes are present in the gut lumen.
These solutes provide an osmotic gradient that draws
water into the intestinal lumen. The most common
cause of osmotic diarrhea is carbohydrate malabsorption;
the classic example is lactose intolerance. In this state,
ingested lactose cannot be digested in the small intestine
due to deficiency of lactase enzyme and reach the colon
intact causing an osmotic load that attracts water and
electrolytes into the bowel. The colonic bacteria ferment
the unabsorbed sugar into free fatty acids which is
absorbed by the colon.

Chronic Diarrhea

The essential characteristic of osmotic diarrhea is that

the stool output is proportional to the intake of the
unabsorbable substrate, and the diarrhea disappears with
fasting or cessation of ingestion of the offending substance. The stool osmolality is increased, and the osmolal
gap is >125. In osmotic diarrhea secondary to carbohydrate malabsorption the stool pH is low (due to the
presence of short-chain organic acids produced by bacterial fermentation of the unabsorbed sugar), and the stool
may be positive for reducing substances (reducing sugars
are glucose, lactose, galactose, maltose, and fructose).
Sucrose is not a reducing sugar (> Table 190.2).
Secretory diarrhea occurs secondary to upregulation of
the mechanisms involved in the active secretion of intestinal
fluids, resulting in large fluxes of water and electrolytes into
the small intestine. Intestinal fluid secretion results predominantly from the active secretion of Cl
through the cystic
fibrosis transmembrane regulator (CFTR) channel. Activation of the CFTR may occur secondary to increase in
intracellular cAMP, cGMP, Ca2+, resulting in Cl
secretion
into the intestinal lumen. Na+ and water are secreted with
Cl
, maintaining electrogenicity and osmotic balance.
The most common cause for secretory diarrhea is
infection. Enterotoxins from a host of infectious agents
bind to specific receptors on the enterocytes, a fragment of
the toxin then enters the cell and activates either adenylate
cyclase (resulting in an increase in intracellular cAMP; e.g.,
cholera toxin, heat-labile Escherichia coli toxin, Salmonella, Campylobacter, Sheila toxins); or guanylate cyclase
(resulting in an increase in intracellular cGMP; e.g., heatstable E. coli toxin, Yersinia enterotoxin); or Ca2+ (e.g.,
Clostridium difficile, Cryptosporidium), and stimulate Cl

secretion. Cl
secretion can also be activated by several
endogenous secretagogues, infiltrating inflammatory cells,
and stimulation of the subepithelial neurons that terminate in the basolateral membrane. Secretory diarrhea is
characterized by high-volume, extremely watery stools.
Stool analysis reveals high sodium and chloride content

(>70 meq/L), and a stool osmolal gap less than 50 mOsm/

kg. Fecal pH is normal, and the stool is negative for
reducing substances. Secretory diarrhea continues with
fasting. Congenital defects of chloride transport such as
congenital chloridorrhea also produce secretory diarrhea.
Diarrhea can be further classified according to the
stool characteristics into watery, fatty, or inflammatory.
Watery diarrhea implies a defect primarily in water
absorption, and as discussed earlier, can either be secretory or osmotic. Fatty diarrhea implies a defect in fat
absorption. Inflammatory diarrhea characterized by the
present of mucus and pus in the stools, imply an infectious
or inflammatory etiology.

Causes of Chronic Diarrhea

Infections
Chronic diarrhea may be associated with intestinal or
extraintestinal infections. In developing countries, chronic
diarrhea usually results from recurrent enteric infections,
often with multiple pathogens, leading to destruction of the
intestinal mucosa, with no sufficient time between infections to allow healing. This leads to chronic enteropathy
which causes malabsorption, and can result in malnutrition
if caloric intake is not sufficient. Malnutrition further contributes to the prolongation of diarrheal episodes by
impairing both the immune system and tissue healing.
The most common causes of infectious persistent
diarrhea are bacterial microorganisms (enteroadherent
E. coli, enteropathogenic E. coli, Shigella, Cryptosporidium,
and Cyclospora). Intestinal parasites can also cause persistent diarrhea, while viruses typically cause acute diarrhea,
though prolonged symptoms may occur due to
postinfectious enteritis. Rotavirus, cytomegalovirus,
Torovirus, and astrovirus have been associated with
chronic diarrhea.

. Table 190.2
Osmotic versus secretory diarrhea

Volume of stool

190

Osmotic diarrhea

Secretory diarrhea

Large

Very large

Response to fasting

Diarrhea stops

Diarrhea continues

Reducing substances

Fecal pH

<5

>6

Stool osmolality

Normal to increased

Normal

Stool ion gap

>125

<50

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Chronic Diarrhea

Rotavirus: Rotavirus usually causes severe acute watery

diarrhea in young children, but may also cause chronic
diarrhea in both immunodeficient and immunocompetent hosts.
Yersinia enterocolitica: Y. enterolitica is associated with
diarrhea, mesenteric adenitis, and terminal ileitis mimicking IBD. Symptoms usually resolve in 514 days, but may
persist for several months.
C. difficile: C. difficile is the most common infectious
etiology of antibiotic-associated diarrhea (AAD) accounting for 20% of cases. AAD manifests with variable degrees of
severity, ranging from acute mild watery diarrhea to persistent bloody diarrhea and fulminant hemorrhagic colitis.
The usual presentation of AAD in children is an acute
onset of profuse watery diarrhea, often associated with
blood, which begins during the first 510 days of antibiotic
therapy, but may develop up to 10 weeks after the completion of the antibiotic therapy. The diarrhea is usually associated with abdominal pain, nausea, and vomiting. Lowgrade fever and leukocytosis may occur. In uncomplicated
cases, the symptoms resolve shortly after stopping the antibiotics. Metronidazole may be used in the presence of fever,
colic, leukocytosis, or pseudomembranous colitis. Vancomycin can be used for severe recurrent cases.
Giardia lambilia is the most common cause of intestinal protozoal infection worldwide. The majority of the
infections are asymptomatic. Infection occurs by the
ingestion of the water-borne cysts; as little as 10100
cysts can cause infection. Once the cysts reach the upper
small intestine, they divide into four trophozites, which
colonize the lumen of the duodenum and jejunum. In the
small intestine, the trophozites adhere to the enterocytes,
causing local effacement of the microvilli which can cause
malabsorption. The most common clinical manifestation
is diarrhea. Weight loss, crampy abdominal pain, steatorrhea, malabsorption, and failure to thrive may occur.
The diagnosis can be made by identifying the cysts, or
antigen in stools, or by identifying the protozoa in
a duodenal aspirate or biopsy. Microscopic examination
of a single stool specimen is approximately 70% sensitive.
Sensitivity increases to 85% when three stool specimens
collected on separate days are examined.
Treatment is with metronidazole. Some apparent clinical treatment failures are due to lactose intolerance, which
can persist for weeks after successful treatment.
Entamoeba histolytica: E. histolytica is transmitted primarily through fecaloral route via ingestion of the cysts of
the protozoan. The cysts can be found in fecally contaminated food and water supplies, and on contaminated hands
of food handlers. The cysts remain viable in the environment for weeks to months, and ingestion of a single cyst is

sufficient to cause disease. Excystation occurs in the terminal ileum or colon, forming trophozoites. The trophozoites
can invade and penetrate the colonic mucosa, leading to
tissue destruction and bloody diarrhea (dysentery).
Chronic nondysenteric syndrome of diarrhea, weight loss,
and abdominal pain, which can last for years, can occur.
The trophozoites can also spread hematogenously via the
portal circulation to the liver, lungs, heart, and brain.
The best method to diagnose E. histolytica is by fecal
antigen detection assay, as stool microscopy cannot differentiate between E. histolytica and Entamoeba dispar or
Entamoeba moshkovskii which are more common than
E. histolytica but are nonpathogenic. A minimum of
three specimens (8595% sensitivity), collected on separate days, should be evaluated since shedding of organisms
vary from day to day. Antibody measurements (detect
E. histolytica but not E. dispar) can also be used but they
remain positive for years.
Treatment is by metronidazole orally (children:
3550 mg/kg/day in three divided doses for 710 days,
adults: 500750 mg/kg/day three times daily for 710
days). Following treatment for invasive amebiasis, treatment with a luminal agent (paromomycin, diiodohydroxyquin, diloxanide furoate) may be required to
eliminate intraluminal cysts. Follow-up stool examinations are required.
Asymptomatic carriers should also be treated with
metronidazole because of the risk of developing an invasive disease, and to prevent shedding of the cysts.
Cryptosporidium: It is a protozoan which causes a selflimited watery diarrhea in normal children, but can cause
prolonged diarrhea in immunocompromised patients.
Infection occurs by ingesting the cysts from infected
feces. The trophozoite divides in the jejunal mucosa and
attaches to the intestinal brush border, destroying the
microvilli reducing the intestinal absorptive capacity,
and producing watery diarrhea and malabsorption. Diagnosis is by stool examination, or by intestinal mucosal
biopsy. Patients can be treated with nitazoxanide, or
paromomycin, or azithromycin.
Small bowel bacterial overgrowth (SBBO): SBBO is
defined as proliferation of bacteria in the upper gastrointestinal tract (stomach, duodenum, and jejunum).
In healthy children, the upper small intestinal tract is
relatively sterile due to a number of factors including
gastric acidity, immunologic factors, and secretory and
motility mechanisms. When a disease or therapy interferes
with these protective mechanisms, bacteria can proliferate
and damage the small intestinal mucosa causing carbohydrate and protein malabsorption. Fat malabsorption can
also occur due to bacterial deconjugation of bile acids.

Chronic Diarrhea

Anaerobic bacteria compete for vitamin B12 uptake,

which can result in macrocytic anemia (on the other
hand, folate which can be synthesized by luminal bacteria
is rarely deficient).
Conditions that predispose to bacterial overgrowth
include hypochlorhydria (e.g., acid-secretion blocker
medications), motility disorders (e.g., chronic intestinal
pseudo-obstruction, scleroderma), and anatomic problems (gastrocolic or enterocolic fistulas).
Although empiric treatment with broad spectrum
antibiotics can be tried when the suspicion of SBBO is
high, the gold-standard test for diagnosing SBBO is culture of the jejunal aspirate. Glucose breath hydrogen test
can also be used to diagnose SBBO. Empiric treatment can
be achieved with Rifaximin (8001,200 mg/day). Other
antibiotics that can be used include amoxicillinclavulanate plus metronidazole, metronidazole combined
with a cephalosporin or trimethoprim-sulfamethoxazole,
or oral gentamicin. Antibiotic treatment is given for 710
days, though some patients require prolonged treatment.
Recurrence is common, and retreatment may be needed.
HIV disease: Persistent diarrhea resulting from immunodeficiency, enteric infections, malnutrition, and medications frequently occur in patients with HIV. The infectious
pathogens associated with diarrheal diseases in HIV infection may vary with the degree of immunocompromise in
the host. Patients with CD4 cell counts <100 cells/microL
are at risk for opportunistic infections which are typically
chronic, such as Cryptosporidium, Mycobacterium avium
complex (MAC), CMV, Isospora, or Microsporidium.

Villous Atrophy
Many pathologic conditions may cause damage to the intestinal mucosa leading to maldigestion/malabsorption and
diarrhea. The most common cause is postinfectious enteritis.
Postinfectious enteritis: Postinfectious enteritis is
a relatively common complication of acute viral and bacterial infections. Patient presents with a prolonged course
of loose diarrhea after an infectious illness had resolved.
The etiology is multifactorial and includes acquired lactase deficiency and protein-losing enteropathy that occur
secondary to intestinal mucosal injury.
Mild cases can be diagnosed by history alone, while
severe, very prolonged diarrhea or weight loss may warrant further investigations. Lactase deficiency can be diagnosed by a hydrogen breath test. Other tests for
malabsorption may also be abnormal depending on the
extent of the mucosal injury. A small bowel biopsy may be
indicated in severe cases for definitive diagnosis.

190

Mild cases usually respond to a lactose-free diet.

Patients with severe cases may require elemental formulas.
Protein-induced proctitis/proctocolitis: It is found
almost exclusively in infants. It can occur in both breastfed
infants, and infants receiving standard cows milk or soybased formulas. Infants usually present by 6 months of age
(mean age of presentation is 2 months) with bloodstreaked, mucusy, loose stools. Some infants may have
increased frequency of bowel movements, but frank diarrhea is not typical. Diagnosis is usually made based on the
clinical presentation and the resolution of symptoms
upon withdrawal of the offending allergen from the diet.
Dietary protein-induced enteropathy: It occurs in
infants with hypersensitivity to cows milk protein. Food
antigens implicated in cows milk allergy are casein, whey
proteins, b-lactoglobulin, and a-lactalbumin. It can also
occur secondary to hypersensitivity to other foods, including soy, eggs, rice, poultry, fish or shellfish, as well as
following an episode of gastroenteritis. Ingestion of the
offending protein causes destruction of the small intestinal villi, causing malabsorption. Infants develop diarrhea,
vomiting, failure to thrive, and hypoproteinemia. Intestinal protein and blood loss may occur and stool tests
positive for an acidic pH with reducing substances, fecal
leukocytes, and blood.
Diagnosis is based on the clinical features, response to
allergen elimination, and endoscopy with biopsy.
It is managed by eliminating the causal food from
maternal diet in breastfed infants, and substituting cows
milk or soy-based formulas with an extensively hydrolyzed
cows milk formula. Some infants may be sensitive to the
residual peptides in extensively hydrolyzed cows milk
formulas and require an amino-based formula. The condition generally resolves after 12 years.
Gastrointestinal symptoms may occur along with
respiratory and skin manifestations as well. Detection of
antigen-specific IgE, either by blood tests (radioallergosorbent test [RAST]) or skin tests, supports the clinical
diagnosis. Total IgE determinations and eosinophil counts
do not reliably correlate with immediate hypersensitivity
responses to foods. Skin testing is done with the puncture
or prick method, a drop of food extract placed on the skin.
Food hypersensitivity responses are unusual with
a negative skin test, but positive tests carry only
a 2030% chance of predicting a positive food challenge.
The RAST and the enzyme-linked immunosorbent assay,
(ELISA) are useful for in vitro determination of IgE to
antigens. The RAST is the most commonly used in vitro
test and is useful particularly when skin tests may be
hazardous. Elimination of the offending food is the treatment of choice.

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Chronic Diarrhea

Food protein-induced enterocolitis syndrome (FPIES): It

most often develops in response to dietary cows milk
protein or soy. Typically, it presents in infants less than
9 months old, with a higher incidence between 1 week and
3 months of age. Patients present with chronic vomiting,
diarrhea, malabsorption, or melena. Failure to thrive,
anemia, and hypoproteinemia may develop. FPIES may
also present acutely if cows milk protein was previously
eliminated from the diet and subsequently re-ingested. In
these cases, patients may present with severe vomiting and
diarrhea within 24 h of ingesting the offending allergen,
progressing to profound dehydration, lethargy, and sometimes shock.
Standard skin prick testing and food-specific IgE assays
are not helpful in the diagnosis of cows milk protein allergy,
and the diagnosis is based on the clinical features, response
to allergen elimination, and endoscopy with biopsies.
Symptoms resolve upon elimination of the offending food.
Eosinophilic gastroenteritis is a disorder of unknown
etiology, thought to be related to environmental or dietary
allergens. It is characterized by eosinophilic infiltration of
one or more areas of the gastrointestinal tract, usually the
stomach and the small intestine. The disease can affect
patients at any age, and usually presents with abdominal
pain, nausea, vomiting, and diarrhea.
The clinical features are related to the anatomical
location of the eosinophilic infiltration within the gastrointestinal tract and the layer(s) of the bowel wall involved
mucosa, muscle, and subserosa. Patients with diffuse small
bowel disease may develop malabsorption, protein-losing
enteropathy, and failure to thrive. Patients with eosinophilic infiltration of the muscle layer of the gastrointestinal
tract may present with symptoms of obstruction (e.g.,
nausea, vomiting, abdominal distention), while patients
with subserosal involvement may present with ascites.
Peripheral eosinophilia may be present. Skin prick/patch
tests can help identify the culprit allergen.
Management is by dietary exclusion of offending food
and/or steroids and immunosuppression.
Celiac disease (gluten-sensitive enteropathy): Celiac disease is an immune-mediated inflammation of the small
intestine caused by sensitivity to gluten (found in wheat,
rye, and barley) in genetically susceptible individuals. The
disorder occurs in 0.51% of the general population in most
countries. It may be asymptomatic, or may present with
a variety of gastrointestinal and non-gastrointestinal manifestations, presenting either in childhood or adult life.
Celiac disease often presents during late infancy or early
childhood with chronic diarrhea, with or without malnutrition. Stools are typically bulky, foul smelling, and may be
floating steatorrhea; alternatively, it may be watery, and in

some patients manifested as frequent passage of normal soft

stools. The stools may also be bulky but infrequent, and
some patients even present with constipation. Patients may
also have abdominal distension, anorexia, weight loss, muscle wasting, and hypotonia. Non-gastrointestinal manifestations include irritability, mouth ulcers, dermatitis
herpetiformis, dental enamel hypoplasia, osteopenia/osteoporosis, short stature, fatigue, delayed puberty, irondeficiency anemia resistant to oral iron supplements, hepatitis, arthritis, and infertility.
Celiac disease is associated with IgA deficiency, Type I
diabetes, autoimmune thyroiditis, Down syndrome, Turners syndrome, and Williams syndrome. Screening for
celiac disease is best done using serum tTG IgA. Recently,
saliva tTG IgA has showed promising results as a screening
test for celiac disease. The disease should be confirmed by
intestinal biopsy.
Treatment is by a lifelong adherence to a glutenfree diet.
Microvillous inclusion disease (microvillous atrophy): is
an inherited abnormality of the intestinal mucosal structure characterized by hypoplastic atrophy of the intestinal
villi that can be identified on light microscopic examination of small intestinal biopsies. Further confirmation is
made through electron microscopic examination. Affected
individuals present with severe secretory diarrhea within
days of birth. Patients may pass over 250300 mL/kg/day
of stool containing electrolyte concentrations similar to
those seen in small intestinal fluid. Intestinal transplantation is the only definitive treatment.
Intestinal epithelial dysplasia (Tufting enteropathy): Its
presentation is very much similar to microvillous atrophy.
Enterocyte heparan sulfate deficiency: similar presentation to microvillous atrophy.

Inborn Errors of Electrolyte Transport

Congenital sodium diarrhea: Congenital sodium diarrhea
is an inherited defect in the Na+/H+ exchanger in the
jejunal brush-border membrane, causing high stool Na+
concentration, often more than 100 mmol/L. Patients
present in utero with maternal polyhydrominous. Prenatal
ultrasound shows a distended fetal abdomen with fluidfilled loops of bowel. Abdominal distension at birth may
be marked, and can be misdiagnosed as intestinal obstruction. Profuse watery, secretory diarrhea is present from
birth. Patients develop metabolic acidosis, and have
increased serum aldosterone and renin activity. Normal
colonic salvage of sodium can subsequently mask net
intestinal secretion, and the diarrhea resolves during the

Chronic Diarrhea

first year of life. The prognosis is generally good provided

fluid and electrolyte losses are replaced in the first few
months of life.
Congenital chloride diarrhea: It is the only type of
diarrhea that causes metabolic alkalosis rather than acidosis. Affected babies are clinically indistinguishable from
patients with congenital sodium diarrhea. Abdominal distension at birth may be marked, and can be misdiagnosed
as intestinal obstruction. Stool may be so profuse and
watery that it is mistaken for urine. Stool chloride concentration is greater than the sum of sodium and potassium (>90 mmol/L). The prognosis is good if it was early
diagnosed and properly managed.
Acrodermatitis enteropathica: A recessively inherited
defect in the intestinal absorption of zinc. Zinc deficiency
becomes apparent in the first few months of life,
manifesting by characteristic symmetrical, scaling erythematous skin lesions around the mouth, perianal area,
and elbows. Patients also develop diarrhea, alopecia, and
failure to thrive.
Plasma zinc is low as is alkaline phosphatase activity. If
untreated, the disease is usually fatal. Lifelong treatment
with oral zinc (3045 mg elemental zinc per day) is
curative.

Carbohydrate Intolerance
Carbohydrate intolerance results from the inability to digest
certain carbohydrates due to deficiency of one or more of the
intestinal disaccharidase enzymes. Disaccharidases, located
in the brush border of the small-intestines enterocytes, split
disaccharides into monosaccharides to be absorbed (lactose
is split into glucose and galactose, maltose into glucose and
glucose, sucrose into glucose and fructose). Undigested
disaccharides cause an osmotic load that attracts water and
electrolytes into the bowel, causing watery diarrhea. Colonic
bacteria ferment the carbohydrates in the colon-producing
gases (H2, CO2, and methane), resulting in excessive flatus,
bloating, distention, and abdominal pain.
Disaccharidase deficiencies can be congenital, late-onset
(primary), or secondary. Congenital deficiencies are rare.
Late-onset lactase deficiency (primary adult
hypolactasia): The most common form of carbohydrate
intolerance is late-onset lactase deficiency. Lactase levels
are high in neonates, permitting digestion of milk; however, in most ethnic groups, the levels decrease later on in
life, rendering older children and adults unable to digest
significant amounts of lactose. The decline in lactase activity level is genetically regulated, with the majority of the
worlds population developing low intestinal lactase levels

190

during mid-childhood (approximately at age 5 years).

Lactose that is not absorbed by the small intestine is passed
rapidly into the colon, where it is converted by the bacterial flora to short-chain fatty acids and hydrogen gas. The
short-chain fatty acids are absorbed by the colonic
mucosa, thereby salvaging the malabsorbed lactose for
energy utilization. The production of hydrogen by colonic
bacteria serves as the basis for the lactose breath hydrogen
test used to diagnose lactose maldigestion.
Secondary lactase deficiency: It occurs in conditions
that damage the small-bowel mucosa (e.g., celiac disease,
acute intestinal infections) due to loss of the brush border
lactase enzyme. The deficiency of the lactase enzyme in
this case is transient, and the enzyme activity normalizes
following the recovery from the underlying disease. In
infants, temporary secondary disaccharidase deficiency
may complicate enteric infections resulting in prolongation of diarrhea, which may be severe enough to purge
other nutrients before they can be absorbed. On biopsy,
the intestinal mucosa appears abnormal with varying
degrees of villous atrophy, and lactase enzyme activity is
reduced concomitantly with other disaccharidases.
The diagnosis of carbohydrate intolerance is suggested if
the stool is acidic (pH<6), and positive for reducing sugars.
Diagnosis can also be done by stool sugar chromatography.
Lactose intolerance can be confirmed by H2 breath test.
Management of disaccharidase deficiency consists of
dietary restriction of the carbohydrates that cannot be
absorbed. However, because the degree of lactose malabsorption varies greatly in patients with lactose intolerance,
many patients can ingest up to 12 oz (18 g of lactose) of
milk daily without symptoms. Yogurt is usually tolerated
because it contains an appreciable amount of lactase produced by intrinsic Lactobacilli. Commercially prepared
predigested milk (i.e., pretreated by the addition of lactase) can be used. Lactase drops and pills are also available.
Sucrase-isomaltase deficiency: can be congenital
(CSID), or acquired.
CSID is an autosomal recessive inherited disorder
characterized by the absence of intestinal sucrase, with
varying degrees of isomaltase activity. The exact incidence
of this condition is unknown. A high incidence has been
observed in the Eskimo population of Greenland, where it
has been reported in 10% of the population. Heterozygote
carriers occur in 1 in 50 persons, and have a lower than
normal sucrase activity. Symptoms will not appear until
sucrose is introduced into the childs diet, and the severity
of the symptoms depends on the residual enzyme activity,
the amount of sucrose ingested, the rate of gastric emptying, the colonic bacteria, and the absorptive capacity of the
colon. Infants usually present with severe watery diarrhea

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Chronic Diarrhea

associated with poor weight gain. Older children and

adults may have less severe symptoms of an osmoticfermentative diarrhea following ingestion of disaccharides
and oligosaccharides. They may present with a picture
identical to a diarrhea-predominant irritable bowel syndrome, with flatulence, especially at the end of the day, and
episodic diarrhea associated with large sucrose intake.
The condition may also present with incontinence
and intermittent watery diarrhea, or incontinence and
intermittent abdominal distention in the older child.
Stools are usually acidic and positive for reducing substances. The diagnosis can be confirmed by a sucrose
breath test. An enzyme assay of the small intestinal mucosa
will demonstrate the characteristic sucrase-isomaltase
deficiency in morphologically normal mucosa. Affected
children usually respond to a sucrose free diet within
24 h. Sacrosidase (Sucraid) supplement can be taken
with each meal and snack.
Colonic adaptation to fermentation may result in
spontaneous improvement.

Inflammatory Bowel Diseases Including

Crohns Disease, Ulcerative Colitis, and
Indeterminate Colitis
Diarrhea associated with abdominal cramps, weight loss,
and the presence of blood in the stools raises suspicion for
inflammatory bowel disease. Although the incidence of
inflammatory bowel disease is lower in young children,
well-documented cases of Crohn and ulcerative colitis
have been seen in children between 2 and 4 years of age.
Crohns disease (CD): CD is an idiopathic chronic
inflammatory disease that can affect any part of the gastrointestinal tract, from mouth to anus, with the terminal
ileum being most frequently affected. CD of the gastrointestinal tract is characterized by skipping lesions, with
inflamed areas interspersed with normally appearing
mucosa. The rectum is usually, but not always, spared in
CD. Crohn disease is characterized by transmural inflammation, anywhere in the gastrointestinal tract, with fissures, cobble-stone appearance, and skip areas. The
inflammation can affect all layers of the bowel wall, and
may lead to perforation, abscess, and fistula formation.
Patients frequently present with chronic diarrhea that is
usually not grossly bloody, and abdominal pain that is
frequently located in the right lower quadrant. Growth
retardation is common. Intestinal biopsy may detect
noncaseating granulomas.
Pharmacologic treatment, during an acute exacerbation, includes the use of methylprednisolone at

12 mg/kg/day, tapered slowly over 46 weeks, depending

on response. Sulfasalazine and meselamine are used to
induce remission.
Ulcerative colitis (UC): UC virtually always involves
the rectum, and the inflammation may extend proximally
in a continuous manner to variable lengths of the colon
though a backwash ileitis may occur in the presence of
severe cecal disease. Patients with UC typically present
with bloody diarrhea, associated with abdominal pain
that is relieved by bowel movement.
Autoimmune enteropathy: Presents with severe, persistent, secretory diarrhea caused by circulating antienterocyte and/or anticolonocyte antibodies. The severity
of the enteropathy is highly variable. Some patients
respond to dietary manipulation, but most require immunosuppression, to which not all respond. In these, the
outcome is often fatal.

Pancreatic Diseases
Pancreatic diseases include conditions associated with
a total pancreatic insufficiency, such as cystic fibrosis and
ShwachmanDiamond syndrome, or with selective
enzyme deficiency, such as congenital lipase deficiency.
Cystic fibrosis (CF): CF is the most common cause of
exocrine pancreatic disease in white Caucasian children,
occurring in 1 per 2,500 live births. The disease is caused
by mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene located on the long arm of
chromosome 7. There are over 640 well-recognized mutations, the commonest being F508 mutation. These mutations lead to impaired chloride transport in epithelial
tissues, and inspissation of secretions and obstruction in
the respiratory tract, pancreatic ducts, biliary tree, and
intestines, as well as impaired chloride reabsorption
from sweat duct which result in the characteristic high
sweat chloride. Clinical signs of pancreatic insufficiency
develop when less than 10% of normal pancreatic enzyme
activity is present in the duodenum.
Most patients with CF (8090%) have pancreatic
insufficiency. In pancreatic insufficient patients, CF usually presents before 6 months of age with malnutrition and
failure to thrive. Hypoalbuminemia and edema may also
occur. Patients may also present with chronic diarrhea;
with bulky, loose, foul, oily or watery bowel movements,
and are at risk of fat-soluble vitamins deficiency (vitamins
A, D, E, K).
Diagnosis is by a sweat chloride test (chloride level
equal or more than 60 is diagnostic). Intermediate results
of sweat testing (3059 mmol/L in infants younger than

Chronic Diarrhea

6 months, and 4059 mmol/L for older children), should

be clarified by DNA analysis using a CFTR multimutation
method, and the sweat test should be repeated.
ShwachmanDiamond Syndrome (SDS): SDS is a rare
autosomal recessive disorder characterized by exocrine
pancreatic insufficiency, ineffective hematopoiesis, and
skeletal abnormalities. After cystic fibrosis, SDS is the
second most common cause of pancreatic insufficiency
in childhood. Patients with SDS have exocrine pancreatic
insufficiency as a result of failure of the pancreatic acinar
cells to develop in utero and their replacement with fatty
tissue. Pancreatic endocrine functions generally remain
intact. Patients typically present in early infancy with
malabsorption, steatorrhea, failure to thrive, and deficiencies of fat-soluble vitamins A, D, E, and K. They may have
fatty stools but this tends to improve with age. Recurrent
bacterial infections are common because of a neutropenia/
neutrophil migration defect.
Evaluation may include a CBC (which may reveal neutropenia, anemia, or thrombocytopenia), but since neutropenia may be intermittent, CBC counts may need to be
repeated biweekly over a 3-week period to document neutropenia. Fetal hemoglobin is elevated in approximately
80% of the patients. Neutrophil function studies may reveal
neutrophil migration defect. Low serum pancreatic trypsinogen and low isoamylase levels are helpful markers for
pancreatic insufficiency depending on the age of the patient.
Fecal fat loss varies from 3% to 60%, and tends to decrease
with age, so absence of steatorrhea in a 72-h fecal fat
measurement test does not exclude the diagnosis of SDS.
Pancreatic insufficiency can be diagnosed by the absence or
decrease of pancreatic enzymes after stimulation with intravenous secretin and cholecystokinin.
For unknown reasons, pancreatic lipase secretion
increases with age, often resulting in normal fat absorption. Approximately 50% of patients with SDS become
pancreatically sufficient later in childhood.

Bile Acid Deficiency

Bile acids play an important role in micelle formation and
fat absorption. Deficiency can occur in cirrhosis and
chronic cholestatic liver diseases (e.g., biliary atresia, primary biliary cirrhosis), diseases affecting the terminal
ileum (where bile acid absorption takes place), and following extensive resection of the terminal ileum. Bile acid
can also be deconjugated by bacteria in patients with small
bowel bacterial overgrowth.
Deconjugation of bile acids renders free bile acids amenable for absorption, thus lowering the luminal bile acid

190

available for micelle formation and fat absorption, leading

to steatorrhea. Additionally, free fatty acids may cause damage to the mucosa and further contribute to malabsorption.

Motility Disorders
Functional diarrhea (also known as chronic nonspecific
diarrhea of childhood, or toddlers diarrhea): Toddler diarrhea is the most common cause of chronic diarrhea in
otherwise well children referred to pediatricians in the
developed world. It is a benign disorder characterized by
daily passage of three or more large, unformed stools foulsmelling, mushy stools containing undigested food, with
onset between 6 and 36 months of age. It is characterized by
normal growth unless the child has been placed on
a hypocalorie diet to relieve symptoms. It may result from
dietary factors such as excessive fiber and low fat intake,
ingestion of large amounts of osmotically active carbohydrates such as fruit juice, carbonated beverages, sorbitol.
Children with functional diarrhea usually pass stools
only during waking hours. Early morning stools typically
are large and semi-formed, then stools become progressively
looser as the day progresses. There are periods of relatively
normal stools or even constipation between the bouts of
diarrhea. Virtually all children develop normal bowel patterns by 4 years of age. Apart from restricting fruit juices and
carbonated beverages and increasing dietary fat to 3050%
of total calories, no other intervention is necessary. Response
to the dietary intervention supports the diagnosis.
Fecal impaction and overflow incontinence: Chronic
constipation often presents with the complaint of diarrhea.
This results from seepage of loose stools around a hardened
fecal matter in the rectum. The rectum becomes chronically
dilated, and the child may lose the sensation of rectal
fullness and the need to defecate. Soiling of the childs
underwear occurs, which the parent may perceive as the
loose stool and loss of control of diarrhea.
Irritable bowel syndrome (IBS): The typical presentation of IBS is that of multiple bouts of diarrhea alternating
with constipation, associated with lower abdominal pain
and flatulence. There is no weight loss, and the stool is
negative for blood. Physical examination is normal. Some
patients respond to fiber intake, others to elimination of
suspected offending food. Antispasmodics, loperamide,
and anticholinergics can be given.

Other Causes
Drugs: Many drugs can cause diarrhea. Identification of
drugs as the cause of diarrhea depends on recognition of

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Chronic Diarrhea

the coincidence of the initiation of drug ingestion with the

onset of diarrhea.
Lymphangectasia: Intestinal lymphangectasia is characterized by the formation of dilated lymphatic channels
in the small intestine. These dilated lacteals result in poor
lymphatic drainage which results in increased intestinal
lymphatic pressure and leakage of protein, lymphocyte,
and chylomicron-rich lymph into the intestinal lumen.
Lymphangectasia may be congenital, or it can occur secondary to disorders that interfere with intestinal lymphatic drainage (e.g., constrictive pericarditis, patients
with cavopulmonary anastomosis (Fontan), retroperitoneal tumors that compress the lymphatic drainage).
Patients may present at any age, with diarrhea, vomiting,
growth retardation, peripheral edema, or lymphopenia.
A number of congenital diseases are associated with
lymphangectasia, including autoimmune polyglandular
disease type 1, Noonans syndrome, and aplasia cutis
congenita.
Diagnosis can be established by measuring the fecal
concentration of alpha1-antitrypsin. Alpha1-antitrypsin
is a protease inhibitor that is present in the serum and
not present in diet. Therefore, its presence in the stool
indicates a protein-losing enteropathy. Mucosal biopsies
show dilated lymphatic channels.
Since intestinal lymph flow varies with meal composition, dietary manipulation can provide symptomatic
improvement. A low fat diet can reduce protein loss.
Medium-chain triglycerides (MCT) are transported in
portal blood and do not increase lymph flow, and can be
used in the diet.
Prognosis is good, and spontaneous remission may
occur.
Neuroendocrine tumors: Neuroendocrine tumors
affecting the gastrointestinal tract are rare in children,
and usually cause secretory diarrhea.
Gastrinoma (ZollingerEllison syndrome): Gastrinomas
arise from enteroendocrine cells, located mainly in the
pancreas and the small intestine, and result in unregulated
gastrin secretion which in turn causes hypersecretion of
gastric acid, and consequent peptic ulcers and chronic diarrhea. Diarrhea occurs because of the high volume of the
gastric acid secreted, which exceeds the neutralizing capacity of the pancreatic bicarbonate, resulting in inactivation of
the pancreatic enzymes, and interfering with the emulsification of fat by bile acids. The acid also damages the intestinal mucosa, causing malabsorption.
Less than 5% of patients with ZES present during
adolescence. The disorder may be suspected in patients
with multiple or refractory ulcers, or ulcers located distal
to the duodenum and/or a secretory diarrhea and fat

malabsorption. Fasting serum gastrin levels are usually

elevated five- to tenfold.
VIPomas: Unregulated hypersecretion of vasoactive
intestinal polypeptide (VIP) causes watery diarrhea, hypokalemia, and achlorhydria. VIPomas are very rare in children, but may occur as ganglioneuromas and
ganglioneuroblastomas.

Diagnosis
History and Physical Examination
A detailed history and physical examination can often
provide clues to the diagnosis, and point toward appropriate investigations. Neonatal onset of watery diarrhea
suggests a congenital disorder (e.g., congenital chloride
diarrhea, congenital sodium diarrhea, Tufting enteropathy).
Steatorrhea and recurrent respiratory infections suggest
cystic fibrosis. A history of excessive ingestion of carbonated
drinks or fruit juices with normal growth parameters
suggest chronic nonspecific diarrhea. Stools that become
looser as the day progresses are typical of functional diarrhea. Small-volume fecal incontinence occurs with constipation and fecal impaction. An irritable child with failure to
thrive, abdominal distention, and foul-smelling diarrhea
may have celiac disease.
Diarrhea of abrupt onset suggests an infectious etiology. Diarrhea that develops during or within 68 weeks of
antibiotic therapy suggests antibiotic-associated diarrhea.
Stools that contain blood or pus suggest inflammation,
which can be caused by dietary protein intolerance (common in infants), inflammatory bowel disease, or rarely
chronic enteric infections. Passage of diarrheal stools at
night raises the suspicion of an organic etiology.
A family history can suggest inherited disorders as
celiac disease, cystic fibrosis, and inflammatory bowel
disease. It is important to remember that as important
a positive family history is, a negative family history does
not rule out the possibility of an inherited disorder.
On physical examination, dry, brittle hair may suggest
fat malabsorption. Pale mucous membranes are seen in
anemia, and may suggest blood loss or iron or vitamin B12
malabsorption. Dental hypoplasia may be seen in patients
with celiac disease or ShwachmanDiamond syndrome.
Clubbing of the fingers suggests a chronic disease like
cystic fibrosis or IBD. Muscle wasting may be noted on
the proximal limbs, and suggest malnutrition or chronic
malabsorption. Edema may be noted on extremities, and
suggest protein-losing enteropathy. Bony defects suggest
ShwachmanDiamond syndrome.

Chronic Diarrhea

Abdominal examination may reveal abdominal distension that can be seen in celiac disease and carbohydrate
malabsorption. A tender abdomen may suggest enterocolitis. Signs of severe perianal erythema point toward carbohydrate malabsorption. Rectal examination may reveal
skin tags, fissures, or fistulas that occur in inflammatory
bowel disease. Soiling may be noted on the underwear, and
fecal impaction may be noted on rectal examination,
suggesting overflow incontinence.
Laboratory evaluation: Because the etiology of chronic
diarrhea differs between developed and developing countries, and in situations where limited resources exist in
developing countries, the diagnostic approach varies
according to the situation.
In the developing countries, the predominant cause of
chronic diarrhea is persistent infectious gastroenteritis,
and because the diagnostic resources are often limited,
an algorithmic approach to diagnosis and management
is practical and usually effective.
Infectious diarrhea can be classified based on the appearance of the stools into watery or bloody. Most cases of
persistent watery diarrhea in children in developing countries improve with improving the nutritious status and
reducing the likelihood of reinfection, and require no further
workup or medications. If watery diarrhea persists, stool
microscopy can be performed to detect trophozoites or cysts.
Bloody diarrhea in most cases is caused by Shigella
spp (4567%), or Campylobacter (3537%). If available,
bloody diarrhea should be tested by stool microscopic
examination, and treatment based on local resistance patterns should be started empirically. If no improvement is
seen within 2 days, treatment should be changed to
another agent known to be effective against local strains.
E. histolytica is the most important nonbacterial pathogen in bloody diarrhea, but is responsible for less than
3% of the episodes. Empiric treatment of intestinal parasites is not recommended, except for persistent bloody
diarrhea in a patient who has failed trials of two different
antimicrobials known to be effective against local strains
of Shigella. In this case, the patient can be treated empirically for amebiasis.
Comorbid conditions that may be the underlying
cause of the malnutrition, such as cystic fibrosis, congenital heart disease, HIV disease, and tuberculosis, should
also be looked for and addressed. All children should also
be evaluated (and treated) for associated nonintestinal
infections, including pneumonia, urinary tract infections,
sepsis, and otitis media.
In developed countries, given the high prevalence of
celiac disease and the availability of noninvasive, sensitive,
and specific testing, most if not all children with chronic

190

diarrhea should be screened for celiac disease. Serum

testing for anti-tissue transglutaminase antibodies (tTG)
is recommended. Testing serum immunoglobulin A (IgA)
levels at the same time is suggested to avoid the possibility
of a false-negative result in patients deficient in IgA (IgA
deficiency is 1015 times more common in patients with
celiac disease than in healthy subjects).
Categorizing the stool type into watery, inflammatory,
or fatty can help narrow the diagnostic possibilities.
In patients with watery diarrhea, assessing the effects
of fasting on stool output can help distinguish between
secretory and osmotic diarrhea, as fasting is associated
with decreased stool volume in osmotic but not secretory
diarrhea. Further distinguishing between osmotic and
secretory types of watery diarrhea can be done by measuring fecal electrolytes, pH, reducing substances, and calculating the osmotic gap (> Table 190.2). In children with
secretory diarrhea, an infectious etiology should be
suspected and evaluated.
Pure secretory diarrhea occurs in some congenital
diarrheas, and should be evaluated according to likely
etiologies. Patients suspected of hyperthyroidism should
have TSH measured. Antienterocyte anticolonocyte antibodies should be done in patients suspected of autoimmune enteropathy.
The presence of reducing substances in the stool or low
fecal pH (<6) suggest carbohydrate malabsorption.
Patients suspected of lactose intolerance can undergo
a hydrogen breath test (H2 breath test).
In patients suspected of factitious diarrhea, stools
should be checked for phenolphthalein, magnesium, sulfate, and phosphate to determine whether the diarrhea is
secondary to laxative abuse.
Empiric treatment with broad spectrum antibiotics
can also be done.
In patients with gross or occult blood, fecal leukocytes,
or fecal calprotectin (a protein found in leukocytes), an
inflammatory etiology of the diarrhea should be suspected
and evaluated. A stool examination should be performed
to exclude infection. If this is negative, the patient must be
evaluated for inflammatory bowel disease; a complete
blood count (may depict anemia, or thrombocytosis),
and an increased erythrocyte sedimentation rate and/or
C-reactive protein level, although not specific for IBD,
suggest an inflammatory process. Further evaluation
include small bowel contrast radiographs or CT scan
(which can reveal mucosal thickening, strictures, fistulas)
and upper endoscopy and colonoscopy with biopsies.
In patients with fatty diarrhea, fat malabsorption
should be investigated. Celiac disease should be tested,
and if excluded the patient should be tested for pancreatic

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Chronic Diarrhea

exocrine insufficiency. Cystic fibrosis can be tested by

a sweat test and genetic screening. A secretin test can be
done to evaluate pancreatic insufficiency.
Munchausens syndrome by proxy: Measurement of
stool electrolytes, osmolality, and magnesium content
should be performed in any case of unexplained chronic
diarrhea to evaluate for Munchausens syndrome by proxy.
Low stool electrolytes and osmolality suggests the addition
of water to the stool. If magnesium concentration in the
stool exceeds that in the plasma, it indicates cathartic
administration. Stools should also be tested for phenolphthalein cathartics, emetine, and bisacodyl and its
metabolites. A negative study may have to be repeated
since children may ingest the laxatives intermittently.

Laboratory Evaluation of the Nutritional

Status in Children with Chronic Diarrhea
CBC and red blood cell indices: Identify children with
anemia. A microcytic, hypochromic anemia suggests
iron deficiency which can occur in malabsorptive conditions such as celiac, or chronic blood loss, such as cows
milk allergy or ulcerative colitis. Serum ferritin level
should be checked (may be falsely elevated in inflammatory conditions since ferritin is an acute-phase reactant).
A macrocytic anemia suggests folate, or vitamin B12 deficiency (e.g., Crohns disease of the distal ileum). The levels
of these vitamins can be measured in the blood.
Prealbumin and albumin levels are good indicators of
short- and long-term dietary intake, respectively.
Prealbumin has a short half-life (approximately 2 days);
thus it falls rapidly with poor dietary intake, and rises to
normal values within 10 days of initiation of adequate
nutritional treatment. Therefore, prealbumin can be used
as a marker of acute malnutrition, and as a predictor of
adequate nutritional therapy.
Albumin has a longer half-life (1420 days), reflecting
dietary intake during the preceding 3 weeks, and serves as
a marker of chronic malnutrition (e.g., Crohns), and as an
indicator of the adequacy of long-term dietary intake.
Vitamins: The assessment of specific vitamin deficiencies may be necessary in children with chronic diseases
associated with malabsorption or inflammation. Serum
concentrations of vitamin A, E, and 25-hydroxy vitamin
D can be measured directly. Vitamin K can be assessed by
measuring prothrombin time.
Deficiency of water-soluble vitamins is less common,
and levels should only be measured when clinically
indicated.

Minerals: Zinc and magnesium deficiency may occur

in patients with chronic diarrhea. Bone density studies
may be indicated in children at risk for osteopenia (e.g.,
IBD, celiac disease).
Zinc therapy has proven its efficacy in reducing the
severity and duration and mortality from diarrheal
disease.

Treatment
The most important step in managing a child with chronic
diarrhea is to assess and stabilize the hydration and
nutritional status. Children with severe malnutrition
should be treated in an inpatient setting. Hypokalemia
and hypophosphatemia caused by intracellular ion shifts
may occur during the early refeeding period, and can
cause serious arrhythmias; therefore, serum potassium
and phosphorous concentrations should be carefully
monitored early in the course of nutritional rehabilitation
of severely malnourished children. In most cases, breast
feeding should be continued.
Children with moderate malnutrition, and those
with dehydration, systemic infections, or infants less
than 4 months of age, should be treated in an inpatient
setting if possible. Malnutrition complicates the course of
most cases of persistent diarrhea in developing countries,
and is the primary target for treatment. Dietary
therapy should aim at providing 150 Cal/kg/day. Deficiencies of vitamin A, zinc, folic acid, copper, and selenium
are common in malnourished children, and should be
supplemented. The WHO recommends zinc supplementation for children with diarrhea in developing countries
at a dose of 10 mg/day for infants up to 6 months of
age, and 20 mg/day for older infants and children, for
14 days. The WHO also recommends providing at least
two times the recommended daily allowance (RDA)
for folate, vitamin A, iron, copper, and magnesium, for
2 weeks.
Further treatment depends on the specific etiology of
the chronic diarrhea.

Prognosis
Prognosis in chronic diarrhea depends on the etiology and
the degree of dehydration/malabsorption and associated
comorbidities.

Chronic Diarrhea

Prevention
Control of sanitary conditions decreases the risk of infectious diarrhea. Breastfeeding, especially exclusive
breastfeeding, protects against exposure, furthermore,
breast milk contains lactoferrin, lysozyme, and oligosaccharides against enteropathogens, as well as antibodies
which have a protective effect. In developing countries,
breastfeeding to 2 years of age is recommended by the
World Health Organization (WHO) and other agencies.
Treating cyst carriers can prevent shedding and
spreading of E. histolytica.

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