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).
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
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. Table 190.1
Main causes of chronic diarrhea according to the age of onset
030 days
136 months
318 years
Abetalipoproteinemia
Acrodermatitis enteropathica
Autoimmune enteropathy
Celiac disease
Autoimmune enteropathy
Celiac disease
Eosinophilic gastroenteritis
Glucosegalactose malabsorption
G. lambilia
Congenital lymphangectasia
Sucrase-isomaltase deficiency
Infectious gastroenteritis
Infectious gastroenteritis
Hirschsprungs enterocolitis
Postinfectious enteropathy
Lactose intolerance
ShwachmanDiamond Syndrome
Laxative abuse
Postinfectious enteritis
Postinfectious enteropathy
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.
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
>125
<50
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Chronic Diarrhea
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
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.
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Chronic Diarrhea
Chronic Diarrhea
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
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Chronic Diarrhea
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
190
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
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
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Chronic Diarrhea
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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