Overview of The Causes of Chronic Diarrhea in Children in Resource-Rich Settings - Uptodate Free

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Overview of the causes of chronic diarrhea

in children in resource-rich settings
Overview of the causes of chronic diarrhea in children in resource-rich settings
Authors:
Martin G Martin, MD, MPP
Jay R Thiagarajah, MD, PhD

Section Editor:
B UK Li, MD
Deputy Editor:
Alison G Hoppin, MD
Literature review current through: Dec 2022. | This topic last updated: Sep 19, 2022.
INTRODUCTION — While diarrhea is among the most common ailments

affecting children, chronic diarrhea is relatively unusual in resource-rich countries. It may be
the manifestation of a broad group of disorders, ranging from an intolerance to a specific
food (or food component) to an indication of a much broader multisystem condition.
This review will outline causes of chronic diarrhea in children that first present beyond early
infancy (ie, after six months of age), organized by general pathophysiologic categories. A
clinical approach to evaluating children with chronic diarrhea is presented separately:
https://pro.uptodatefree.ir/show/5877 1/19
●(See "Approach to chronic diarrhea in children >6 months in resource-rich countries".)

●(See "Approach to chronic diarrhea in neonates and young infants (<6 months)".)
DEFINITIONS
●Diarrhea – Objective definitions of diarrhea are based on stool weight or volume.
However, because assessment of daily stool weights/volumes is difficult in the outpatient
clinic setting, changes in the frequency and consistency of stool compared with baseline can
also be used as a convenient gauge of diarrhea. Thus, one or both of the following
measures can be used:
•Stool weight – Daily stool weight greater than 250 g in children that weigh more than 10 kg
is considered diarrhea. In young children (<10 kg), stool in excess of 20 g/kg/day is
abnormal.
•Stool consistency – The Bristol stool chart is a useful tool to define stool consistencies [1,2].
Diarrheal stools typically correspond to types 6 and 7 on the Bristol stool chart [3] (or its
slightly modified versions for children [4] or infants [5]). Low-volume loose stools are not a
significant predictor of underlying disease in the absence of other symptoms such as
weight loss, dehydration, or significant changes in biochemical/nutritional indicators.
●Chronic diarrhea – Chronic diarrhea is generally defined as diarrhea lasting greater than
four weeks [6]. This timeline is selected to distinguish between the acute diarrheal episode,
which tends to be self-limited, and more prolonged diarrheal disease that warrants further
evaluation and possibly intervention.
●Persistent diarrhea – The term persistent diarrhea is sometimes defined as diarrhea

lasting longer than two weeks, but sometimes this term is used interchangeably with
chronic diarrhea.
EPIDEMIOLOGY — Globally, the prevalence of diarrhea in children varies

widely. Large-scale studies report that 3 to 20 percent of children under five years old have
at least one episode per year, with an incidence of approximately 2.7 episodes per child-
year in children younger than five years [7]. In resource-poor environments, chronic
diarrhea is common and associated with significant mortality and morbidity.
In resource-rich countries such as the United States, the prevalence of acute diarrhea is
high, with 15 to 20 episodes per child-year in young children. However, the incidence of
chronic diarrhea is substantially lower (less than 0.2 episodes per child-year) and is rarely
severe, with less than 1 percent of episodes resulting in hospitalization [8,9].
CATEGORIZATION OF DIARRHEA — For clinical

purposes,
it is helpful to categorize chronic diarrhea by its proximate cause and other clinical
characteristics, as outlined in the table (table 1):
●Physiologic (lactase nonpersistence)
●Infection-related
●Drug-induced
●Functional
●Immune-mediated
●Fat malabsorption
●Neuroendocrine disorders and tumors
●Congenital anomalies with bowel obstruction
●Other mechanisms
Other schemes classify diarrheas by the physiologic mechanism, ie, diet-induced (osmotic),
electrolyte transport-related (secretory), motility-related, or inflammation-related. This
framework is also important at certain steps in the evaluation process. These mechanisms
are discussed in a separate topic review. (See "Pathogenesis of acute diarrhea in children",
section on 'Diarrhea classification'.)
PHYSIOLOGIC
Lactase nonpersistence — Lactase nonpersistence (also called acquired
lactose intolerance or hypolactasia) is a genetically determined phenotype that is
particularly common in children of African, Hispanic, and Asian descent, typically developing
in early to mid-childhood. Typical symptoms are abdominal pain, flatulence, nausea,
bloating, and diarrhea after ingestion of milk or milk-containing products. Management is
tailored to the symptoms and consists of dietary lactose restriction and/or taking a lactase
enzyme preparation with lactose-containing foods. Children who avoid dairy products
should be monitored and supplemented as needed to ensure adequate intake of calcium
and vitamin D. (See "Lactose intolerance and malabsorption: Clinical manifestations,
diagnosis, and management".)
INFECTION-RELATED CAUSES — Diarrhea caused

by bacterial
or viral infections are often associated with constitutional symptoms of nausea, vomiting,
fever, and, occasionally, dysentery. Most episodes of infectious diarrhea in an
immunocompetent host resolve within two weeks since they either resolve spontaneously
or are treatable with targeted antimicrobial therapies. (See "Diagnostic approach to
diarrhea in children in resource-rich countries", section on 'Common conditions'.)
Persistence of symptoms beyond two to four weeks may be related to underlying mucosal
damage (postinfectious malabsorptive diarrhea including secondary lactose intolerance). If
the infectious agent persists or recurs, an underlying primary or secondary
immunodeficiency should be considered (table 1).
Postinfectious malabsorptive diarrhea — Postinfectious

malabsorptive diarrhea is characterized by mucosal dysfunction that persists beyond four
weeks after an acute enteric infection. This pattern is sometimes called postinfectious
irritable bowel syndrome (IBS). In some cases, this is associated with residual mucosal
inflammation and altered mucosal permeability and motility, which can cause diarrhea or
upper gastrointestinal symptoms such as vomiting and dyspepsia [10,11]. As an example,
one study in children who were followed for at least six months after acute bacterial
gastroenteritis found a significantly higher risk (36 versus 11 percent of controls; relative
risk 3.2) of developing abdominal pain that met criteria for IBS (87 percent) or dyspepsia (24
percent) [12].
More commonly, postinfectious diarrhea is caused by transient loss of lactase and other
abnormalities that cause macro- and micronutrient malabsorption. This condition may
persist for weeks or months after the infection resolves, particularly in malnourished
children [12,13]. Lactose intolerance is the most common manifestation, but symptoms may
include intolerance to a broad range of foods, and diarrheal symptoms may last for months.
Persistent or recurrent infection

With immunodeficiency — If the infectious agent persists or recurs, an
underlying primary or secondary immunodeficiency should be considered. These disorders
are characterized by persistence of infection beyond the infectious period that would be
expected in a normal host and/or unexplained recurrences of infectious diarrhea. These
recurrent and prolonged infections are often caused by parasitic or viral agents and lead to
severe and prolonged symptoms in a lymphopenic host.
Specific pathogens that tend to be involved in these cases include:
●Parasites – Cryptosporidium, Isospora, Cyclospora, and Giardia lamblia.

●Viruses – Rotavirus (with or without history of receiving the vaccine (see "Clinical
manifestations and diagnosis of rotavirus infection")), norovirus, astrovirus, adenovirus, and
cytomegalovirus. These viruses tend to cause prolonged or non-self-resolving diarrhea in an
immunocompromised host, in contrast with the self-resolving episodes in an
immunocompetent host.
●Bacteria – Clostridioides difficile, Salmonella, Campylobacter, and Escherichia coli.
T cell defects are associated with recurrent or persistent viral or parasitic infection, while B
cell disorders are more often associated with bacterial infections. Important causes of
primary and secondary immunodeficiency to consider include:
●Primary immunodeficiency
•Cellular and humoral
-Severe combined immunodeficiency
-Regulatory T cell (Treg) dysfunction, including IPEX (immune dysregulation,

polyendocrinopathy, enteropathy, X-linked) and other disorders
-Wiskott-Aldrich syndrome
(See "Severe combined immunodeficiency (SCID): An overview" and "IPEX: Immune

dysregulation, polyendocrinopathy, enteropathy, X-linked" and "Wiskott-Aldrich syndrome".)
•Humoral
-Selective immunoglobulin A (IgA) deficiency
-Common variable immunodeficiency
(See "Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis" and
"Common variable immunodeficiency in children".)
●Secondary immunodeficiency
•Organ transplant recipients (due to immunosuppressants)
•Malnutrition
(See "Malnutrition in children in resource-limited countries: Clinical assessment" and

"Persistent diarrhea in children in resource-limited countries".)
Without immunodeficiency — Many children with recurrent gastrointestinal

infections have no identifiable immunodeficiency. These children are typically asymptomatic
between bouts of infections, whereas those with immunodeficiency are more likely to have
persistent symptoms.
In an immunocompetent host, risk factors for recurrent or chronic infection include:
●Infection with C. difficile, which is notoriously difficult to eradicate. Similarly, children

infected with Salmonella typhi frequently become carriers.
●Underlying inflammatory bowel disease (IBD), which predisposes the patient to recurrent
infections such as cytomegalovirus and C. difficile.
(See "Clostridioides difficile infection in children: Clinical features and diagnosis" and
"Clostridioides difficile infection in children: Treatment and outcome" and "Enteric (typhoid
and paratyphoid) fever: Epidemiology, clinical manifestations, and diagnosis".)
DRUG-INDUCED CAUSES — Drug-induced diarrhea is relatively

common and may be caused by a wide variety of drugs (table 2). Mechanisms may involve
alteration of intestinal fluid, electrolyte and nutrient transport, or direct mucosal damage
[14].
Antibiotic-associated — Antibacterial agents are particularly common causes

of drug-induced diarrhea [15]. The risk of diarrhea depends on the type of antibiotic; it is
particularly common with broad-spectrum antibiotics that are poorly absorbed, such as
amoxicillin-clavulanate.
●Watery diarrhea following antibiotic use is generally benign, self-limiting, and requires no
intervention. It usually results from the drug-induced microbial and metabolomic dysbiosis
that eventually resolves [16]. Probiotics may help to prevent or shorten the course of
antibiotic-associated diarrhea, based on limited information [17-20].
●Bloody diarrhea (indicating colitis) associated with antibiotic use is infrequent but
problematic. It is caused by loss of normal bowel flora and subsequent C. difficile infection.
Very rarely, this can progress to a fulminant colitis with multisystem failure [21]. (See
"Clostridioides difficile infection in children: Clinical features and diagnosis" and
"Clostridioides difficile infection in children: Treatment and outcome".)
Non-antibiotic-associated — Diarrhea associated with nonantimicrobial

drug therapies is common [22].
●Drugs that do not injure the mucosa – For these drugs, diarrhea tends to start shortly
after the drug is started and is often mild.
•Laxatives (either prescribed or surreptitiously used) may result in an osmotic diarrhea in a

dose-dependent manner.
•Promotility agents such as metoclopramide, macrolides, and erythromycin shorten transit

time and impair nutrient assimilation, leading to diarrhea.
•Certain antidepressants (selective serotonin reuptake inhibitors) and anticholinergic agents

reduce gastrointestinal motility, which may predispose to diarrhea due to bacterial
overgrowth or by altering the microbiome [23]. The time course of onset may vary.
•Drugs that impair assimilation of nutrients, such as orlistat (a pancreatic lipase inhibitor),
acarbose, and miglitol (an alpha-glucosidase inhibitor), frequently result in diarrhea.
•Certain antineoplastic agents (eg, tyrosine kinase inhibitors) can result in severe diarrhea
without significant mucosal injury [24].
●Drugs that injure the mucosa – Drugs that are associated with significant alterations of
the mucosa may take longer for clinical symptoms to appear.
•Antineoplastic drugs such as fluorouracil and others are commonly associated with
diarrhea that results from minor mucosal injury.
•The purine synthesis inhibitor mycophenolic acid is commonly used in renal transplant
patients. It frequently causes diarrhea, associated with leukopenia and with villous atrophy
and apoptosis in the crypt.
•Other drugs, such as the angiotensin II receptor blocker olmesartan, are associated with a
sprue-like enteropathy that results in chronic diarrhea that can be severe [25]. (See "Major
side effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor
blockers", section on 'ARBs'.)
•Microscopic colitis is a chronic inflammatory colitis that is seen almost exclusively in adults
but has been reported in children. Risk factors include chronic use of nonsteroidal
antiinflammatory drugs and proton pump inhibitors, among other drugs. (See "Microscopic
(lymphocytic and collagenous) colitis: Clinical manifestations, diagnosis, and management",
section on 'Medications'.)
•Numerous immunotherapies are specifically associated with an immune-related adverse

effect that includes diarrhea. For instance, ipilimumab (CTLA-4) and anti-PD-1 antibodies
may result in a clinical course resembling both celiac disease and inflammatory bowel
disease (IBD) [26].
FUNCTIONAL DIARRHEAL DISORDERS

Functional diarrhea in young children — Functional diarrhea

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young children (sometimes known as "toddler's diarrhea") refers to chronic diarrhea or
loose stools in an otherwise healthy young child with no underlying disease. This disorder
can present as early as six months of age and is characterized by four or more large,
painless stools per day, progressing in consistency from semi-solid in the morning to loose
as the day progresses. Stools can contain undigested food and be watery. Intercurrent
illness and stressors (excitement) may be triggers for exacerbations that last more than four
weeks. The symptoms usually resolve by four to five years of age.
This disorder is thought to be common, with survey studies indicating prevalence among
young children between 0.9 and 6.4 percent [27,28]. However, in many cases, the stools are
simply loose and do not meet the formal definition of diarrhea in terms of volume,
frequency, or severity (ie, no predisposition to dehydration or weight loss), so the true
prevalence of diarrhea caused by this mechanism may be lower.
In some children, the symptoms appear to be associated with the excessive use of fructose-
or sorbitol-based juices or diets high in sugar or other carbohydrates. In these cases, the
severity of the diarrhea is dose-dependent and improves with restricting the intake of
carbohydrate-rich food or beverages. However, in other cases, the diarrhea or loose stools
continue regardless of dietary restriction. If the toddler is growing well and is otherwise
healthy, no diagnostic testing or elimination diet is recommended. The parent/caregiver(s)
can be reassured that the symptoms will likely have a benign course and eventually resolve
by age five.
Diarrhea-predominant irritable bowel

syndrome — Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder
characterized by recurrent abdominal pain and a change of stool form or frequency. It is
more common in adolescents compared with younger age groups. The estimated
prevalence of IBS is between 1 and 3 percent among children in the United States [29]. As
with other functional disorders, the diagnosis is based on symptoms and excluding other
disorders. (See "Functional abdominal pain in children and adolescents: Management in
primary care" and "Clinical manifestations and diagnosis of irritable bowel syndrome in
adults".)
A subset of IBS is associated with mild diarrhea, known as diarrhea-predominant IBS or IBS-
D. IBS-D can be seen at most ages, but it is more prevalent in adolescent females and
generally is associated with low-volume loose stools, abdominal pain, urgency, and
sensation of incomplete evacuation.
IMMUNE-MEDIATED CAUSES — ImmunologicYourmechanisms
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are responsible for several causes of chronic diarrhea, including some common disorders
(table 1):
Common causes
●Celiac disease – Celiac disease is relatively common and may present at any age with
failure to thrive, diarrhea, or, occasionally, with constipation. Many cases are now detected
by testing asymptomatic children who have risk factors for celiac disease (eg, children who
have type 1 diabetes or first-degree relatives with celiac disease). Celiac disease is a gluten-
sensitive enteropathy that leads to an immune-mediated enteropathy that reduces the
nutrient-absorptive capacity of the small bowel. A lifelong strict elimination of dietary gluten
is required and is effective in the majority of cases. (See "Epidemiology, pathogenesis, and
clinical manifestations of celiac disease in children" and "Diagnosis of celiac disease in
children" and "Management of celiac disease in children".)
●Inflammatory bowel disease (IBD) – IBD (ulcerative colitis or Crohn disease) typically
presents with a prolonged history of diarrhea, generally associated with mucous and,
occasionally, blood. While the peak incidence of IBD is during adolescence or mid-
adulthood, it can occur at any age. When IBD begins in infancy, it tends to have more
protracted course that is less responsive to medical therapy and is more likely to result from
a genetic basis. (See "Clinical presentation and diagnosis of inflammatory bowel disease in
children".)
●Food protein-induced allergic proctocolitis – Food protein-induced allergic proctocolitis,

sometimes known as food-protein intolerance, is a common cause of diarrhea or loose
stools in infants. It usually resolves before one year of age but can rarely extend to toddlers
and school-aged children. The most common food triggers are cow's milk, egg, or soy in the
diet. (See "Food protein-induced allergic proctocolitis of infancy".)
Uncommon causes
●Food protein-induced enterocolitis – Food protein-induced enterocolitis is a non-IgE-
mediated food hypersensitivity syndrome that presents during infancy and typically
resolves by three years of age. It is characterized by acute onset of profuse, repetitive
vomiting with or without diarrhea following exposure to the offending food antigen. This
leads to dehydration and lethargy. Chronic symptoms may include watery diarrhea with
intermittent vomiting, leading to weight loss, failure to thrive, dehydration, and metabolic
derangements ’ [30]. The diagnosis of food protein-induced enterocolitis is based upon the
history, constellation of typical clinical symptoms with clinical improvement following
elimination of the suspected causal protein, exclusion of other etiologies, and, if necessary,
results of an oral food challenge. (See "Food protein-induced enterocolitis syndrome

(FPIES)".)
●Eosinophilic gastroenteritis – Eosinophilic gastroenteritis is a relatively rare disorder

whose pathogenesis is poorly understood, but most children have elevated serum IgE
levels. These patients have a propensity for protein-losing enteropathy and significant
asthma and eczema. While a definitive dietary allergen is not usually identified, many
patients respond to an elimination diet or elemental diet but frequently require steroid
management. (See "Eosinophilic gastrointestinal diseases".)
●Microscopic colitis – This disorder occurs primarily in adults and presents with watery,
nonbloody diarrhea. Risk factors include chronic use of nonsteroidal antiinflammatory
drugs and proton pump inhibitors (see 'Non-antibiotic-associated' above). It is characterized
by grossly normal-appearing colonic mucosa, with histologic evidence of either a
lymphocytic or collagenous colitis [31]. (See "Microscopic (lymphocytic and collagenous)
colitis: Clinical manifestations, diagnosis, and management".)
●Polyglandular autoimmune syndrome – This is an autosomal recessive disorder that

results in the clinical triad of mucocutaneous candidiasis, hypoparathyroidism, and adrenal
failure. Type 1 tends to present during childhood and is rare. Affected patients can also
develop either episodic or persistent generalized malabsorptive diarrhea with loss of
enteroendocrine cells and poor weight gain [32]. Severe malabsorptive diarrhea may be the
first clinical manifestation of this disorder. (See "Causes of primary adrenal insufficiency in
children", section on 'Autoimmune disease'.)
●Cutaneous and systemic forms of mastocytosis – The majority of patients with this
disorder have cutaneous lesions, and many have lymphadenopathy, splenomegaly,
gastrointestinal ulcers, and hepatitis. Diarrhea is a common manifestation in either
cutaneous or systemic mastocytosis, mediated by histamine release. This may be triggered
by certain medicines (eg nonsteroidal antiinflammatory drugs and some antibiotics),
infections, or spicy foods. (See "Mastocytosis (cutaneous and systemic) in children:
Epidemiology, clinical manifestations, evaluation, and diagnosis".)
FAT MALABSORPTION — Fat malabsorption may be caused by

several different mechanisms (table 1):
Pancreatic exocrine insufficiency — Deficiency of pancreatic lipase

leads to maldigestion of fat due to lack of micellization in the bowel lumen. Cystic fibrosis is
the most common cause of pancreatic exocrine insufficiency. Other causes include
Shwachman-Diamond syndrome (MIM #260400; associated with bone marrow failure and
skeletal abnormalities), some cases of advanced chronic pancreatitis, and four rare
disorders (Pearson syndrome [MIM #557000], Johanson-Blizzard syndrome [MIM #243800],

pancreatic lipase deficiency [MIM #614338], and colipase deficiency [also MIM #614338]).
(See "Cystic fibrosis: Assessment and management of pancreatic insufficiency" and
"Shwachman-Diamond syndrome".)
Bile acid insufficiency — Deficiency of bile acids in the intestinal lumen also

leads to maldigestion of fat. This may be seen in patients with bile acid malabsorption due
to resection or inflammation of the terminal ileum, which depletes the bile acid pool. Crohn
disease is a common cause of terminal ileal disease. Bile acid insufficiency also may be
caused by bile salt deconjugation, which is one of several mechanisms that can cause
diarrhea in patients with small intestine bacterial overgrowth. (See 'Small intestinal bacterial
overgrowth' below.)
Mucosal malabsorption — Extensive mucosal disease or resection of the

small bowel can lead to fat malabsorption; this may occur in patients with short bowel
syndrome or severe and diffuse small intestinal Crohn disease. (See "Pathophysiology of
short bowel syndrome" and "Chronic complications of short bowel syndrome in children",
section on 'Nutritional complications'.)
NEUROENDOCRINE TUMORS AND RELATED

DISORDERS — Neuroendocrine tumors are rare causes of chronic diarrhea in
children (table 1). When they do occur, they usually are associated with one of the following
disorders:
●Neurofibromatosis – Neurofibromatosis is relatively common and is suspected in children

with multiple café-au-lait macules and neurofibromas. A small subset develop tumors that
can result in secretory diarrhea, including gastrointestinal stromal tumors, carcinoid
tumors, pheochromocytoma, gastrinomas, or somatostatinomas. (See "Neurofibromatosis
type 1 (NF1): Pathogenesis, clinical features, and diagnosis", section on 'Gastrointestinal
stromal tumors'.)
●Neuroblastomas and ganglioneuroblastoma – Relatively well-differentiated forms of

neuroblastomas may be associated with severe secretory diarrhea that is frequently
associated with elevated levels of vasoactive intestinal polypeptide. (See "Clinical
presentation, diagnosis, and staging evaluation of neuroblastoma".)
●Multiple endocrine neoplasia type 2b – This is an exceedingly rare autosomal dominant

disorder characterized by ganglioneuromas, medullary thyroid cancer, and
pheochromocytoma. The ganglioneuromas are associated with severe secretory diarrhea
and flushing. (See "Clinical manifestations and diagnosis of multiple endocrine neoplasia
type 2".)
CONGENITAL CONDITIONS ASSOCIATED

WITH BOWEL OBSTRUCTION — Partial bowel obstruction
may present with chronic or intermittent diarrhea. The underlying mechanism probably
includes dysmotility with small intestine bacterial overgrowth, which in turn causes mucosal
injury and malabsorption and/or deconjugation of bile acids with maldigestion. (See 'Small
intestinal bacterial overgrowth' below and 'Other' below.)
Congenital conditions that predispose to this complication include (table 1):
Chronic intestinal pseudo-obstruction — Chronic intestinal

pseudo-obstruction is a rare disorder that presents during early infancy with severe
constipation, abdominal distention, and dilated bowels, with intolerance to luminal feeds
that usually requires parenteral nutrition. This disorder can be classified as myogenic (MIM
#155310) or neurogenic (MIM #243180) with specific characteristics. Both forms are
associated with severe, recurrent bouts of small bowel bacterial overgrowth that may be
associated with episodic worsening of abdominal distension and diarrhea. (See "Chronic
intestinal pseudo-obstruction: Etiology, clinical manifestations, and diagnosis".)
Hirschsprung disease — Hirschsprung disease is relatively common and

results from failure of neural crest cell migration that leads to an absence of enteric
ganglion from the rectum extending proximally. The resulting aganglionic segment of the
colon fails to relax, causing a functional obstruction. Hirschsprung disease may lead to an
associated enterocolitis with fever, abdominal distention, explosive diarrhea, and vomiting
that can progress to toxic megacolon. Hirschsprung-associated enterocolitis can occur even
after surgery for Hirschsprung disease and in children >6 months old. (See "Congenital
aganglionic megacolon (Hirschsprung disease)" and "Emergency complications of
Hirschsprung disease", section on 'Enterocolitis'.)
Intestinal malrotation with intermittent

volvulus — Intestinal malrotation is a relatively common anatomical abnormality. In
some cases, it leads to volvulus that usually presents early in life with sudden-onset emesis,
rectal bleeding, and circulatory shock. An intermittent form of volvulus has also been
described, which presents with episodic emesis and malabsorptive diarrhea.
OTHER MECHANISMS — Other causes of chronic diarrhea include

(table 1):
Small intestinal bacterial overgrowth — Small intestinal bacterial

overgrowth (SIBO) is a condition in which the small bowel is colonized by excessive aerobic
and anaerobic microbes that are normally present in the colon. This can cause diarrhea by
direct mucosal injury, production of enterotoxins, and/or maldigestion because of bile salt
deconjugation. Typical symptoms include bloating, flatulence, abdominal discomfort, or
watery diarrhea. The incidence of SIBO increases with age. Several disorders predispose to
SIBO by altering mucosal defenses. (See "Small intestinal bacterial overgrowth: Clinical
manifestations and diagnosis".)
Congenital diarrheas and enteropathies — Chronic diarrhea

that presents in early infancy (<6 months) has a unique set of causes, as outlined in the
table (table 3). These include congenital diarrheas and enteropathies, which are primarily
inherited defects of epithelial function and typically present in the neonatal period. (See
"Approach to chronic diarrhea in neonates and young infants (<6 months)".)
Other
●Bile acid malabsorption – Bile acids secreted into the intestinal lumen are normally
reabsorbed in the terminal ileum. In patients with ileal disease or resection, or those with
genetic defects in bile acid transport (eg, MIM #613291), the malabsorbed bile acids enter
the colon, where they can cause a secretory diarrhea (this is sometimes called cholerheic
diarrhea). Treatment with cholestyramine prevents this process by sequestering bile acids.
However, cholestyramine must be used judiciously since some patients may also have bile
acid deficiency; in these patients, cholestyramine may bind the remaining bile salts
necessary for fat and fat-soluble vitamin absorption, thereby creating additional unwanted
nutritional complications.
Bile acid malabsorption diarrhea occasionally occurs after cholecystectomy. (See "Approach
to the adult with chronic diarrhea in resource-abundant settings", section on 'Post-
cholecystectomy diarrhea'.)
●Protein-losing enteropathies – Protein-losing enteropathy is classically seen in the

setting of severe mucosal inflammation and permeability, which may occur in erosive
gastrointestinal diseases (inflammatory bowel disease [IBD] or C. difficile infection) or
nonerosive disease (celiac disease or eosinophilic gastroenteritis) (table 4). Occasionally, it
may be caused by impaired lymphatic drainage or after the Fontan procedure for congenital
heart disease. (See "Management of complications in patients with Fontan circulation",
section on 'Protein-losing enteropathy'.)
While chronic diarrhea is common in these conditions, significant protein-losing

enteropathy may be present even in the absence of diarrhea. Other common features
include peripheral edema, hypoalbuminemia, hypogammaglobulinemia, and, sometimes,

lymphopenia. (See "Protein-losing gastroenteropathy".)
●Factitious diarrhea – Factitious diarrhea may be due to a self-induced true increase in

stool volume (eg, from surreptitious laxative abuse) or the creation of an apparent increase
in stool volume by the addition of various substances (eg, urine, water) to the stool with the
intention of misleading the health professional. Diagnosing factitious diarrhea is often
difficult and requires alertness to this possibility and exclusion of other diseases and may be
aided by specific testing (eg, stool osmolality or a laxative screen). (See "Factitious diarrhea:
Clinical manifestations, diagnosis, and management".)
In children, factitious diarrhea may be contrived by the caregiver in a form of medical child
abuse. (See "Medical child abuse (Munchausen syndrome by proxy)".)
●Vasculitis – Vasculitides including polyarteritis nodosa or Behçet syndrome may be

associated with chronic diarrhea. These disorders usually can be identified by their
constitutional symptoms or signs, skin lesions, laboratory evidence of inflammation, and
bloody diarrhea. (See "Vasculitis in children: Evaluation overview".)
SOCIETY GUIDELINE LINKS — Links to society and government-

sponsored guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Chronic diarrhea".)
SUMMARY
●Definitions – Chronic diarrhea can be defined as daily stool weight of greater than 250 g
in children that weigh more than 10 kg and greater than 20 g/kg/day in children that weigh
less than 10 kg for longer than four weeks. In the outpatient clinical setting, changes in the
frequency and consistency of stool compared with baseline can also be used as a
convenient gauge of diarrhea. The Bristol stool chart is a reliable tool to define stool
consistencies; diarrheal stools typically correspond to Bristol types 6 and 7. (See 'Definitions'
above.)
●Causes of chronic diarrhea in children – For clinical purposes, it is helpful to categorize

chronic diarrhea by triggers and other clinical characteristics (table 1).
•Common causes – Relatively common causes of chronic diarrhea in children include:
-Physiologic lactase nonpersistence (see 'Lactase nonpersistence' above)
-Gastrointestinal infections (especially postinfectious processes) (see 'Infection-related

causes' above)
-Drug-induced diarrhea, eg, due to certain antibiotics, laxatives, and antineoplastic

medications (table 2) (see 'Drug-induced causes' above)
-Functional disorders such as toddler's diarrhea and diarrhea-predominant irritable bowel

syndrome (IBS-D) (see 'Functional diarrheal disorders' above)
-Immune-mediated causes such as celiac disease and inflammatory bowel disease (IBD) (see
'Immune-mediated causes' above)
•Less common causes – Less common mechanisms for chronic diarrhea include other
immune-mediated disorders, pancreatic exocrine insufficiency, and partial bowel
obstruction due to chronic intestinal pseudo-obstruction or other congenital conditions.
(See 'Fat malabsorption' above and 'Congenital conditions associated with bowel
obstruction' above.)
•Causes in young infants – Chronic diarrhea that presents in early infancy (<6 months) has
a unique set of causes, which include anatomic defects and heritable disorders of immune
regulation, macronutrient digestion, mucosal barrier function, and transport (table 3); these
disorders are discussed in a separate topic review. (See "Approach to chronic diarrhea in
neonates and young infants (<6 months)".)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges

Richard Kellermayer, MD, PhD, and Robert Shulman, MD, who contributed to an earlier
version of this topic review.
1. Mearin F, Lacy BE, Chang L, et al. Bowel Disorders. Gastroenterology 2016.
2. Chumpitazi BP, Self MM, Czyzewski DI, et al. Bristol Stool Form Scale reliability and
agreement decreases when determining Rome III stool form designations.
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Topic 5877 Version 40.0
References
1 : Bowel Disorders.
2 : Bristol Stool Form Scale reliability and agreement decreases when determining Rome III
stool form designations.
3 : Are the definitions for chronic diarrhoea adequate? Evaluation of two different definitions in
patients with chronic diarrhoea.
4 : Reliability and validity of a modified Bristol Stool Form Scale for children.
5 : The Modified Bristol Stool Form Scale: A Reliable and Valid Tool to Score Stool Consistency
in Dutch (Non)Toilet-trained Toddlers.
6 : Chronic Diarrhea: Diagnosis and Management.
7 : Global burden of childhood pneumonia and diarrhoea. Your activity: 17 p.v.
8 : Diarrhea- and rotavirus-associated hospitalizations among children less than 5 years of

age: United States, 1997 and 2000.
9 : Characteristics of persistent diarrhea in a community-based cohort of young US children.
10 : Chronic gastrointestinal consequences of acute infectious diarrhea: evolving concepts in

epidemiology and pathogenesis.
11 : Postinfectious irritable bowel syndrome.
12 : Post-infectious functional gastrointestinal disorders in children.
13 : Lactose avoidance for young children with acute diarrhoea.
14 : Drug-induced diarrhoea.
15 : Clinical practice. Antibiotic-associated diarrhea.
16 : Post-Antibiotic Gut Mucosal Microbiome Reconstitution Is Impaired by Probiotics and

Improved by Autologous FMT.
17 : Probiotics for the prevention and treatment of antibiotic-associated diarrhea: a systematic

review and meta-analysis.
18 : Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea in children: a

randomized double-blind placebo-controlled trial.
19 : Probiotics for the prevention of pediatric antibiotic-associated diarrhea.
20 : Multispecies Probiotic for the Prevention of Antibiotic-Associated Diarrhea in Children: A

Randomized Clinical Trial.
21 : Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017
Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare
Epidemiology of America (SHEA).
22 : Spectrum of Drug-induced Chronic Diarrhea.
23 : Extensive impact of non-antibiotic drugs on human gut bacteria. Your activity: 17 p.v.
24 : Intestinal epithelial potassium channels and CFTR chloride channels activated in ErbB
tyrosine kinase inhibitor diarrhea.
25 : Severe spruelike enteropathy associated with olmesartan.
26 : Gastrointestinal and Hepatic Complications of Immune Checkpoint Inhibitors.
27 : Prevalence of functional gastrointestinal disorders in infants and toddlers.
28 : Childhood Functional Gastrointestinal Disorders: Neonate/Toddler.
29 : Functional Disorders: Children and Adolescents.
30 : International consensus guidelines for the diagnosis and management of food protein-
induced enterocolitis syndrome: Executive summary-Workgroup Report of the Adverse
Reactions to Foods Committee, American Academy of Allergy, Asthma&Immunology.
31 : Drug induced lymphocytic colitis.
32 : Autoimmune Polyendocrine Syndromes.

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3/19/23, 10:20 AM Overview of the causes of chronic diarrhea in children in resource-rich settings - Uptodate Free

Your activity: 17 p.v.

Overview of the causes of chronic diarrhea

Jay R Thiagarajah, MD, PhD

INTRODUCTION — While diarrhea is among the most common ailments

●(See "Approach to chronic diarrhea in children >6 months in resource-rich countries".)

●Persistent diarrhea – The term persistent diarrhea is sometimes defined as diarrhea

EPIDEMIOLOGY — Globally, the prevalence of diarrhea in children varies

CATEGORIZATION OF DIARRHEA — For clinical

●Physiologic (lactase nonpersistence)

●Neuroendocrine disorders and tumors

●Congenital anomalies with bowel obstruction

INFECTION-RELATED CAUSES — Diarrhea caused

Postinfectious malabsorptive diarrhea — Postinfectious

Persistent or recurrent infection

Specific pathogens that tend to be involved in these cases include:

●Parasites – Cryptosporidium, Isospora, Cyclospora, and Giardia lamblia.

●Bacteria – Clostridioides difficile, Salmonella, Campylobacter, and Escherichia coli.

•Cellular and humoral

-Severe combined immunodeficiency

-Regulatory T cell (Treg) dysfunction, including IPEX (immune dysregulation,

(See "Severe combined immunodeficiency (SCID): An overview" and "IPEX: Immune

-Selective immunoglobulin A (IgA) deficiency

-Common variable immunodeficiency

•Organ transplant recipients (due to immunosuppressants)

(See "Malnutrition in children in resource-limited countries: Clinical assessment" and

Without immunodeficiency — Many children with recurrent gastrointestinal

In an immunocompetent host, risk factors for recurrent or chronic infection include:

●Infection with C. difficile, which is notoriously difficult to eradicate. Similarly, children

DRUG-INDUCED CAUSES — Drug-induced diarrhea is relatively

Antibiotic-associated — Antibacterial agents are particularly common causes

Non-antibiotic-associated — Diarrhea associated with nonantimicrobial

•Laxatives (either prescribed or surreptitiously used) may result in an osmotic diarrhea in a

•Promotility agents such as metoclopramide, macrolides, and erythromycin shorten transit

•Certain antidepressants (selective serotonin reuptake inhibitors) and anticholinergic agents

•Numerous immunotherapies are specifically associated with an immune-related adverse

FUNCTIONAL DIARRHEAL DISORDERS

Functional diarrhea in young children — Functional diarrhea

Diarrhea-predominant irritable bowel

●Food protein-induced allergic proctocolitis – Food protein-induced allergic proctocolitis,

results of an oral food challenge. (See "Food protein-induced enterocolitis syndrome

●Eosinophilic gastroenteritis – Eosinophilic gastroenteritis is a relatively rare disorder

●Polyglandular autoimmune syndrome – This is an autosomal recessive disorder that

FAT MALABSORPTION — Fat malabsorption may be caused by

Pancreatic exocrine insufficiency — Deficiency of pancreatic lipase

disorders (Pearson syndrome [MIM #557000], Johanson-Blizzard syndrome [MIM #243800],

Bile acid insufficiency — Deficiency of bile acids in the intestinal lumen also

Mucosal malabsorption — Extensive mucosal disease or resection of the

NEUROENDOCRINE TUMORS AND RELATED

●Neurofibromatosis – Neurofibromatosis is relatively common and is suspected in children

●Neuroblastomas and ganglioneuroblastoma – Relatively well-differentiated forms of

●Multiple endocrine neoplasia type 2b – This is an exceedingly rare autosomal dominant

CONGENITAL CONDITIONS ASSOCIATED

Congenital conditions that predispose to this complication include (table 1):

Chronic intestinal pseudo-obstruction — Chronic intestinal

Hirschsprung disease — Hirschsprung disease is relatively common and

Intestinal malrotation with intermittent