Journal of Enam Medical College
Vol 11 No 2 May 2021
120
Review Article
Chronic Diarrhea in Children
Fahmida Begum1, Khan Lamia Nahid2, Md. Wahiduzzaman Mazumder3,
Md. Rukunuzzaman4, ASM Bazlul Karim5
Received: 4 April 2020 Accepted: 18 March 2021
doi: https://doi.org/10.3329/jemc.v11i2.65194
1. Professor, Department of Pediatric Gastroenterology and Nutrition, Bangabandhu Sheikh Mujib Medical University,
Shahbag, Dhaka
2. Assistant Professor, Department of Pediatric Gastroenterology and Nutrition, Bangabandhu Sheikh Mujib Medical
University, Shahbag, Dhaka
3. Associate Professor, Department of Pediatric Gastroenterology and Nutrition, Bangabandhu Sheikh Mujib Medical
University, Shahbag, Dhaka
4. Professor, Department of Pediatric Gastroenterology and Nutrition, Bangabandhu Sheikh Mujib Medical University,
Shahbag, Dhaka
5. Fellow, Pediatric Gastroenterology, Liver Diseases (Australia)
Correspondence Fahmida Begum, Email: fahmidalily@gmail.com
Abstract
Chronic diarrhea (CD) is a common but challenging clinical scenario in pediatric medicine. It
has several hundred disorders in the differential diagnosis and can create a complex situation for
practitioners and families. Some of the disorders cause failure to thrive but some are not. This
article focuses on important aetiologies of CD, their clinical features, diagnostic approach as
well as treatment approaches.
Key words: Chronic diarrhea; Osmotic diarrhea; Secretory diarrhea
J Enam Med Col 2021; 11(2): 120−127
Introduction
Diarrhea is defined as stool volume >10 g/kg per
day in infants and toddlers, and >200 g/day in older
children.1 Chronic diarrhea (CD) is one which lasts
for more than 14 days, is usually noninfectious and
associated with malabsorptive features. Some experts
also refer CD for episodes lasting more than 4 weeks.2
On the other hand persistent diarrhea (PD) is an
episode of diarrhea of presumed infectious etiology,
which starts acutely but lasts for more than 14 days
and excludes recurrent diarrheal disorders such as
tropical sprue, gluten sensitive enteropathy or other
hereditary disorders.3
Epidemiology
According to the World Health Organization,
diarrheal illness is the second leading cause of death
in developing countries in children younger than 5
years of age and is responsible for 1.7 million child
morbidities and 760,000 child mortalities.4 In 2002,
the World Health Organization estimated that 13.2%
of all childhood deaths worldwide were caused
by diarrheal diseases, 50% of which were chronic
diarrheal illnesses.5 Among children aged 1 to 4 years,
persistent diarrhea accounted for more than 25% of
diarrheal deaths in Bangladesh, Ethiopia and Uganda.6
Large-scale studies indicate that the prevalence of
chronic diarrheal illnesses worldwide ranges from 3%
to 20%, and the incidence is ≈ 3.2 episodes per child
year.7
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Pathophysiology
The basic pathophysiology of CD is incomplete
absorption of water from the intestinal lumen. This
occurs either because of a reduced rate of net water
absorption (related to impaired electrolyte absorption
or excessive electrolyte secretion) or because of
osmotic retention of water in the lumen. Reduction
of net water absorption as little as one percent is
sufficient to cause diarrhea.8
The four principal pathophysiologic mechanisms of
CD are osmotic, secretory, dysmotility associated, and
inflammatory. Often, a single disorder may involve
multiple overlapping mechanisms.
Osmotic diarrhea is caused by a failure to absorb a
luminal solute. As a result, there are secretion of fluids
and net water retention across an osmotic gradient.
This may occur from either congenital or acquired
diseases such as lactose malabsorption.9
Secretory diarrhea occurs when there is a net secretion
of electrolyte and fluid from the intestine without
compensatory absorption. Endogenous substances,
often called “secretagogues,” induce fluid and
electrolyte secretion into the lumen even in the absence
of an osmotic gradient. Typically, secretagogues
affect ion transport in the large and small bowel both
by inhibiting sodium and chloride absorption and
by stimulating chloride secretion via cystic fibrosis
(CF) transmembrane regulator activation. Multiple
congenital diarrheal disorders associated with identified
genetic mutations that affect gut epithelial ion transport
are the example of secretory diarrhea.10 Congenital
chloride diarrhea (CCD) is one such disorder. Children
with a pure secretory diarrhea will therefore continue
to experience diarrhea even while fasting.
CD associated with intestinal dysmotility typically
occurs in the setting of intact absorptive abilities.
Intestinal transit time is decreased, the time allowed for
absorption is minimized, and fluid is retained within
the lumen. High-amplitude propagated contractions
cause diarrhea predominant irritable bowel syndrome
(IBS) in older adolescents and changes in small
intestinal motility results chronic nonspecific diarrhea
(CNSD) in toddlers.11
Inflammatory diarrhea may include all of the
pathophysiologic mechanisms. Inflammation that
results injury to the intestine may lead to malabsorption
of dietary macronutrients which, in turn, creates
a luminal osmotic gradient. Moreover, particular
infectious agents may induce secretion of fluid into
the lumen, and blood in the gut may alter intestinal
motility. Diseases such as inflammatory bowel
disease (IBD) and celiac disease are the example of
this inflammatory mechanism.9
Common causes of chronic diarrhea in
children
Causes of chronic diarrhea can also be divided into
following subgroups (Table II).
Table II: Causes of chronic diarrhea
Infective
Due to exogenous substances
Abnormal digestive processes
Nutrient malabsorption
Immune and inflammatory
Structural defects
Defects of electrolytes and metabolite transport
Motility disorders
Neoplastic
Chronic non-specific diarrhea
Table I: Differences between osmotic and secretory diarrhea
Variables Secretory diarrhea Osmotic diarrhea
Volume of stool >200 ml/24 hours <200 mL/24 hours
Response to fasting Diarrhea continues Diarrhea stops
Stool Na >70 mEq/L <70 mEq/L
Reducing substances Negative Positive
Stool pH >6 <5
Stool osmotic gap
{Stool osmolarity – 2 (stool Na+ K )}
< 100 >100
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Infective causes: Infective causes of chronic diarrhea
can be seen in any age and common organisms
implicated includes Salmonella, Yersinia, E.coli,
Campylobacter, Aeromonas, Plesiomonas, Giardia,
Cryptosporidium, viral causes (Rota, Entero,
Norwalk). They have associated fever, abdominal
pain, exposure history, blood/mucus in stool.
Giardia causes both osmotic and secretory diarrhea.
Microscopic examination of a freshly passed stool on
three consecutive days is recommended for detection
of Giardia trophozoites. Antimicrobial therapy for
giardiasis is metronidazole, tinidazole, or nitazoxanide.
Non typhoidal Salmonella organisms typically cause
gastroenteritis with diarrhea, abdominal cramping,
and fever. Salmonella organisms typically are detected
in routine stool culture for up to 5 weeks but may
be excreted in stool for >1 year in 5% of patients.12
Antibiotic therapy for uncomplicated nontyphoidal
serotypes is not indicated as it does not shorten the
disease duration but may prolong the duration of
excretion of bacteria in the stool.13 Antibiotic is
indicated only for children younger than 3 months of
age or those with immunosuppressive diseases.14
Small bowel bacterial overgrowth: There are
overgrowths of aerobic and anaerobic bacteria in
the small bowel such as in short bowel syndrome,
bowel strictures, pseudo-obstruction, malnutrition.
Osmotic diarrhea occurs due to enhanced bile acid
deconjugation and fatty acid hydroxylation by
bacteria. The patients present with abdominal pain
and diarrhea. The diagnosis can be made by breath
hydrogen with lactulose testing. Metronidazole or non
absorbable rifaximin is the treatment of choice.15
Whipple’s disease: Whipple’s disease is caused
by Gram +ve bacteria: Tropheryma whipplei. The
patients have malabsorption, central nervous system,
joints and cardiovascular involvement. It is a rare
condition and carries a poor prognosis.
Tropical sprue: It is a rare condition in children
and coliform organisms are implicated in its etio-
pathogenesis.
Abnormal digestive processes
Cystic fibrosis
Pancreatic insufficiency is common in approximately
90% of patients with CF and this causes diarrhea in
this disorder.16 Loss of exocrine pancreatic function
leads to malabsorption of carbohydrates, fat, and
protein because of dysfunctional amylases, lipases,
and proteases, respectively. Pancreatic exocrine
function can be assessed by fecal elastase, and low
levels indicating possible pancreatic insufficiency.
Pancreatic enzyme replacement therapy may improve
malabsorptive diarrhea in patients with CF.
Nutrient malabsorption
Carbohydrate malabsorption: Intestinal lactase
deficiency causes carbohydrate malabsorption that
can be congenital, adult-onset and secondary lactase
deficiency. Congenital lactase deficiency is a rare
entity. Adult onset is relatively common and ‘normal’
for most humans. Secondary lactase deficiency is
seen after infectious gastroenteritis or injury to small
intestinal mucosa caused by gluten or other sensitizing
substances, Crohn’s disease, and other enteropathies.
Symptoms of lactose intolerance are independent of
the cause. Incompletely digested lactose reaches the
dense colonic microbial population, which ferments
the sugar to hydrogen and other gases, thereby
causing gassy discomfort and flatulence. The no
absorbed lactose serves as an osmotic agent, resulting
in an osmotic diarrhea. Diagnosis can be made by
a successful lactose-free diet trial of 2 weeks or by
hydrogen breath-testing. Minimizing lactose intake
is the treatment of choice, as the symptoms are dose
dependent and so complete removal of dietary lactose
is not necessary.17
Lipid malabsorption: Lipid malabsorption is seen in
diseases like cystic fibrosis, Shwachman- Diamond
syndrome, Pearson syndrome, Johanson-Blizzard
Syndrome, celiac disease, cholestatic liver disease,
beta lipoproteinemia, lymphangectasia and short
bowel syndrome.
Protein malabsorption: Protein malabsorption is
seen in condition like pancreatitis, cystic fibrosis,
trypsinogen deficiency, enterokinase deficiency,
hartnup disease, lymphangectasia, lowes syndrome
and lysinuric protein intolerance.
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Cow’s milk protein allergy (CMPA): Cow’s milk
protein allergy presents in first year of life, but may
present up to two years of age. The child present with
streaks of blood and mucus in stool, in otherwise
healthy infant. It typically occurs in child on top milk,
however 0.5% may present in exclusive breast-fed
infants. Withdrawal of cow’s milk from diet is the
treatment of choice.
Inflammatory bowel disease21
Inflammatory bowel diseases (IBD) can present in
children and adolescents with chronic diarrhea along
with passage of blood or mucus in stools. The child
can have weight loss, anemia, tenesmus, joint pains,
and redness of eyes. In Crohn’s disease, stool may
contain microscopic blood but may not be grossly
bloody. In ulcerative colitis, diarrhea is a more
consistent presenting feature.
Immune and inflammatory
Celiac disease: Celiac disease is an immune-
mediated systemic disease that occurs due to gluten
ingestion in a genetically susceptible individual. With
its prevalence in adults and children approaching 1%
worldwide.18 It is most common cause of chronic
diarrhea and malabsorption in more than 2 years age
group patients.19
The typical presentation of celiac disease in children
is failure to thrive, diarrhea and abdominal distension.
The presence of raised anti-tissue transglutaminase
antibody/anti endomysial antibody make the
suspicion of celiac disease and is confirmed by
histologic findings in the duodenum which is graded
according to Marsh Criteria.20 The management of
celiac disease is lifelong restriction of food containing
gluten in diet which includes wheat, rye, and barley.
Multivitamin and mineral deficiency should also be
managed appropriately.
Patient with suspected IBD
Screen with fecal calprotectin level
Negative Positive
Urgent endoscopy
Negative Positive
Plan other investigation Start treatment for IBD
Fig 1. Workup for suspected inflammatory bowel disease (IBD) in adults20
Treatment includes anti-inflammatory agents like
steroids, 5ASA, Azathioprine etc. Nocturnal diarrhea
with urgency may be a sign of left-sided colonic
inflammation in either Crohn disease or ulcerative
colitis. Diarrhea associated with IBD typically
improves with therapy as mucosal inflammation
resolves.
Autoimmune enteropathies: Autoimmune
enteropathies are rare disorders that may present
as severe diarrhea during infancy or toddlerhood.
The diarrhea may be isolated, or may occur in
association with diabetes mellitus as part of the
IPEX (Immunodysregulation polyendocrinopathy
enteropathy X-linked) syndrome. Diagnosis is made
by documenting antienterocyte, anticolonocyte, or
antigoblet cell antibodies in the blood. Treatment
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is difficult but may be accomplished with
immunosuppressive agents such as corticosteroids,
6-mercaptopurine, tacrolimus, and infliximab.
Immunodeficiency: Patient with chronic diarrhea
should be evaluated for primary or secondary
immunodeficiency such as HIV disease. In this case,
the evaluation should focus on potential infectious
causes of the diarrhea, particularly parasites and
opportunistic infections such as Cryptosporidium,
Isospora, and Cyclospora.20
Structural defects: These include disease like
tufting enteropathy, microvillous inclusion disease,
phenotypic diarrhea, lymphangiectasia, intergrin
deficiency, heparan sulphate deficiency. These are
rare diseases and cause neonatal diarrhea and carries
a poor prognosis.
Defects with effects of electrolytes and metabolite
transport: It includes congenital chloride diarrhea
(CCD) and congenital sodium diarrhea (CSD), these
disorders cause secretory diarrhea and present in 1−2
week of life and carry a poor prognosis.
Chronic Nonspecific Diarrhea of Childhood or
Infancy (CNSD)
CNSD is the most common form of chronic diarrhea in
the first 3 years after birth.21 The typical time of onset
may range from 1 to 3 years of age and can last from
infancy until age 5 years. It presents with varied stool
frequency and consistency without blood or mucus
and stool contain undigested food particles. There
is no failure to thrive. Potential pathophysiologic
mechanisms for CNSD include increased intestinal
motility and osmotic effects of intraluminal solutes
(e.g. carbohydrates).12
Reassurance is the cornerstone of therapy for CNSD.
Treatment includes decreased fruit juices (fructose)
and reassurance along with liberalization of fat to
encourage normal caloric intake and to slow intestinal
transit time is also important.22
Motility disorders
Irritable Bowel Syndrome (IBS)
According to Rome IV Diagnostic Criteria Irritable
Bowel Syndrome must include all of the followings:
1. Abdominal pain at least 4 days per month associated
with one or more of the followings: a. Related to
defecation; b. A change in frequency of stool; c. A
change in form (appearance) of stool; 2. In children
with constipation, the pain does not resolve with
resolution of the constipation (children in whom
the pain resolves have functional constipation, not
irritable bowel syndrome). 3. After appropriate
evaluation, the symptoms cannot be fully explained
by another medical condition.23
Criteria fulfilled for at least 2 months before diagnosis
treatment is often challenging. Antispasmodic agents,
tricyclic antidepressants, and selective serotonin-
reuptake inhibitors may improve symptoms. Some
probiotics have been useful in adult and pediatric IBS,
but results are not consistent.24
Among the causes of CD some are associated with
failure to thrive and some are not (Table III).
Table III: Causes of chronic diarrhea
Without failure to thrive With failure to thrive
CNSD IDI (Intractable Diarrhea of Infancy)
Infectious colitis Allergic enteropathy
Lactose malabsorption IBD
Small bowel bacterial overgrowth Celiac disease
IBS Immunodeficiency state (various diseases)
Congenital secretory diarrhea (Chronic chloride and
chronic sodium diarrhea)
Tufting enteropathy
Microvillous inclusion disease
Autoimmune enteropathy
CF
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Evaluation of CD
History and physical examination
For diagnosis of different causes of CD detailed
history and examination is a must. Characteristics of
the stool as well as feeding history are very important
in assessing the cause and severity of the illness.
There are differences in pattern of stool in small
and large bowel diarrhea. So, it is important to
differentiate small bowel diarrhea from large bowel
type of diarrhea. Small bowel diarrhea differs from
large bowel diarrhea with its large volume, foul-
smelling stools with undigested food particles
and often it is associated with features of lactose
intolerance like explosive diarrhea and bloating.
On the other hand, large bowel type of diarrhea has
blood, mucus, tenesmus, urgency and high frequency.
In toddler’s diarrhea children often have loose stools
with undigested food particles. Frequent loose
watery stools may indicate carbohydrate intolerance
and pasty or loose foul-smelling stools indicate fat
malabsorption. It is also necessary to take history of
extraintestinal symptoms like presence or absence of
weight loss, rash, fatigue, vomiting, joint aches, or oral
ulcers. A detailed history of source of drinking water,
family history, complementary feeding and whether
onset of diarrhea after introduction of specific foods
like seen in celiac disease and cow’s milk protein
allergy should be evaluated. There may be history
of repeated infections in cystic fibrosis or immune
deficiency syndromes.
In physical examination one should have to look for
anthropometry assessment and status of dehydration.
Clubbing may be seen in celiac disease and IBD.
Extraintestinal manifestations of IBD like joint pain,
swelling and erythema may also be found. There
also may be signs of various nutrient and vitamin
deficiencies like zinc, vitamin D,Vitamin A, Vitamin
K and B complex. Distended abdomen may be seen
in malabsorption syndromes or small bowel bacterial
overgrowth. Rectal examination is also important as
it may reveal perianal disease in IBD and perianal
excoriation in carbohydrate malabsorption.
Laboratory evaluation: A detailed history
and examination is needed so that unnecessary
investigations are better avoided. Initial
investigations include a complete hemogram to
evaluate anemia, total counts and platelets. Stool
routine and culture with urine routine should
be done in all cases of chronic diarrhea. Stool
may contain RBC, WBC and mucus indicating a
mucosal inflammation in large bowel and analysis
of the stool for electrolyte content and osmolarity
may be helpful in distinguishing an osmotic from
a secretory diarrhea. Serum electrolytes with renal
function test should also be done. Serology for celiac
disease, tTG with total IgA should be done in cases
of small bowel diarrhea. Upper GI endoscopy and
when required colonoscopy with mucosal biopsy
are required in many diseases like celiac disease,
IBD, eosinophilic enteropathy, microvillous inclusion
disease, tufting enteropathy, giardiasis, Intestinal
lymphangiectasia. In special cases, fecal fat estimation,
fecal elastase, H2 breath test, hormonal assays may be
required.
Treatment
It depends on primary cause of chronic diarrhea; it
may vary from just reassurance in cases of chronic
nonspecific diarrhea to bowel transplant in structural
enteropathies. In addition to specific disease-oriented
therapy the patients should be given vitamin and mineral
supplement. Disease like Cow’s milk protein
allergy, celiac disease, and giardiasis are easily
treatable. Celiac disease management includes
a lifelong strict adherence to gluten free diet
and nutritional counseling. For CMPA, the ideal
management it extensively hydrolyzed formula,
unfortunately they are not still available
in India and are to be imported
thereby increasing their cost.
Conclusion
Chronic diarrhea is important cause of morbidity
in developing countries. Timely evaluation and
management are of paramount importance to prevent
complications. The patient should be referred to a
tertiary care center in time for appropriate diagnosis
and treatment.
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