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Pathogenesis of acute diarrhea in children

Pathogenesis of acute diarrhea in children
Authors:
Jay R Thiagarajah, MD, PhD
Martin G Martin, MD, MPP

Section Editor:
B UK Li, MD
Deputy Editor:
Alison G Hoppin, MD

Literature review current through: Dec 2022. | This topic last updated: Feb 22, 2021.

INTRODUCTION — Diarrheal diseases have been a major health problem

throughout human history. Prior to the advent of modern medicine, severe diarrhea was
often fatal and disease outbreaks spread quickly, affecting large populations. Today, despite
the success of interventions such as oral and intravenous rehydration therapy, diarrheal
diseases remain a substantial cause of mortality and morbidity worldwide, particularly in
children and older adults. In 2016, it was estimated that worldwide, 446,000 children aged
<5 years and 694,000 adults aged >70 years died from diarrheal diseases [1]. The underlying
causes of diarrhea in children are numerous and vary by age and geographical location,
among other factors.

Regardless of etiology, the evaluation and management of an infant or child with diarrhea
require an understanding of the physiology of fluid and electrolyte transport in the

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gastrointestinal tract. This topic focuses on the pathophysiology of fluid absorption and
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secretion in diarrhea and a classification of diarrhea relevant to diagnostic evaluations.

Detailed reviews of the diagnostic approach and management of diarrhea in children are
found in the following topics:

●(See "Diagnostic approach to diarrhea in children in resource-rich countries".)

●(See "Approach to the child with acute diarrhea in resource-limited countries".)

●(See "Persistent diarrhea in children in resource-limited countries".)

●(See "Overview of the causes of chronic diarrhea in children in resource-rich settings".)

DEFINITIONS
Diarrhea — The presence of diarrhea can be defined in a number of ways, either
related to volume and/or consistency of stool or frequency of bowel movements.

●For practical use in the clinical setting, diarrhea is typically defined by stool frequency and
consistency. A common definition is the passage of three or more loose or liquid stools per
day, or more frequent passage than is normal for the individual [2]. In infants and children,
it can be difficult to establish the presence of diarrhea based on stool frequency or
consistency as the normal range for these parameters can vary greatly by age and diet. As
an example, some healthy breastfed infants pass eight or more loose stools daily.

●A more objective definition of diarrhea relies on measured stool weight or volume. In

hospital settings where the volume of stools can be measured, diarrhea is defined as stool
volume of more than 20 grams/kg/day in infants and toddlers (<10 kg) or more than 200
grams/day in older children or teenagers [3].

Acute versus chronic diarrhea — Diarrhea is generally considered

acute if it lasts less than two weeks and chronic if it lasts more than two weeks. However,
there remains a lack of clear consensus on the use of symptom-based and/or duration-
based definitions of diarrhea [4].

FLUID MOVEMENT IN THE

GASTROINTESTINAL TRACT
Normal fluid absorption and secretion — Large quantities of
fluid are transported bidirectionally across epithelial barriers in the gastrointestinal tract for

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secretion of saliva, gastric juice, bile, and pancreatic fluid and for fluid absorption in the
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intestine. The quantity of fluid transported in the intestine is second only to the kidney,
where approximately 180 L of fluid per day are filtered by the glomerulus and processed by
various nephron segments.

In healthy adults, several liters of fluid are absorbed and secreted by the different segments
of the intestine each day (figure 1). The salivary glands produce approximately 1.5 L of fluid
per day, the stomach secretes 2.5 L of gastric juice, the liver produces 0.5 L of bile, and the
pancreas produces 1.5 L of enzyme- and bicarbonate-rich fluid. To balance this, the small
intestine absorbs 6.5 L of fluid and the colon additionally absorbs 1.3 L of fluid against
significant osmotic gradients.

The small intestine performs most of the fluid absorption (83 percent) in the
gastrointestinal tract. Therefore, diseases that affect the small intestine often result in
clinically significant diarrhea. Although the colon absorbs a much smaller volume of fluid
than the small intestine, it is critical for the generation of formed feces. The intestinal
contents enter the colon with a water content of approximately 90 percent and leave the
colon as feces, with a water content of 65 to 75 percent. Therefore, significant alteration of
colonic function alone can also lead to clinical diarrhea.

Molecular mechanisms — Movement of fluid between the intestinal lumen

and blood is driven by the active transport of ions (mainly Na+, Cl–, HCO3–, and K+) and
nutrients (mainly glucose). Fluid absorption or secretion involves the coordinated activity of
membrane transporters located on the apical (lumen-facing) and basolateral (circulation-
facing) epithelial membranes. The intestinal epithelium is structurally configured into long,
finger-like (in three-dimensional pathologic sections) or leaf-like projections (in two
dimensions; villi) and glandular tube-like structures (crypts). The stem cells at the base of
the crypt provide various differentiated epithelial cell types, including the more numerous
enterocytes that ascend and populate the villus structure. In the small bowel, each villus is
supported by as many as 10 distinct crypts. In the colon, the crypts are considerably longer
than in the small bowel and produce epithelium that covers a flat luminal surface devoid of
villi. Functionally, both ion and fluid absorption and secretion occur in enterocytes located in
both villi and crypts, although, in the small intestine, secretory processes predominate in
crypts and absorptive processes in villi (figure 2).

Intestinal fluid absorption is driven by the active transport of Na+ across the epithelium,
with parallel Cl– or HCO3– absorption ((figure 2), panels A and C). The electrochemical driving
force for this process is provided by the basolateral Na+/K+-ATPase that exports intracellular
Na+. In the small intestine, fluid absorption is facilitated by the Na+/H+ exchanger 3 (NHE3,
also known as SLC9A3), Na+/glucose cotransporter 1 (SGLT1 [SLC5A1]), and Cl–/HCO3–
exchangers (DRA [SLC26A3] and PAT1 [SLC26A6]). Electroneutral fluid absorption is carried

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out by the coordinated activity of NHE3 with Cl–/HCO3– exchangers (PAT1 for HCO3–
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absorption in the jejunum and DRA for Cl– absorption in the ileum and colon). Substrate-
specific transporters such as SLC5A1 facilitate cotransport of Na+ across the apical
membrane together with D-glucose (or D-galactose), with the electro-neutral glucose
transporter SLC2A2 facilitating glucose exit across the basolateral membrane. In the colon,
in addition to electroneutral Na+ transport by Na+/H+ exchange (proximal colon), absorption
is facilitated by the epithelial Na+ channel (eNaC) and short-chain fatty acid transporters
(sodium-coupled monocarboxylate transporter, or SMCT [SLC5A8]) [5,6].

Intestinal fluid secretion is driven by transepithelial Cl– secretion through basolateral and
apical Cl– channels and transporters ((figure 2), panels B and D). Cl– is transported into the
cell at the basolateral membrane by a Na+/K+/Cl- symporter (NKCC1, also known as
SLC12A2), which is driven by the Na+ concentration gradient produced by the Na+/ K+-
ATPase. K+ channels (KCNQ1/KNE3 and KCNN4) provide the electrochemical driving force for
apical Cl– exit across Cl– channels, which are primarily the cyclic-nucleotide-activated cystic
fibrosis transmembrane conductance regulator (CFTR) and Ca2+-activated Cl– channels
(CaCCs). Enteric nerves and cell surface receptors such as the calcium-sensing receptor
(CaSR) are thought to modulate intracellular signaling pathways and hence electrolyte
absorption and secretion [7-9].

Pathophysiology of fluid transport in diarrheal

disease
Overview — Water movement in the intestine occurs by osmosis across the
semipermeable barrier formed by the lining epithelial cells, similar to other fluid-
transporting surfaces in the body. Diarrhea occurs when excessive amounts of fluid remain
within the lumen of the intestine (figure 3). This can occur because of increased secretion
into the intestinal lumen or reduced absorption of water from the lumen to the body. In
either case, there is an increased concentration of osmotically active particles (nutrients
and/or electrolytes) within the lumen of the intestine, resulting in a net increase in the water
content of the intestinal contents. Increased concentrations of osmotically active particles
within the lumen occur through three primary mechanisms:

●Loss of nutrient absorption or the presence of nonabsorbable solutes in the intestinal

lumen ((figure 3), panel B). Examples include the loss of nutrient absorption seen in celiac
disease or in inflammation, and diarrhea caused by laxatives such as polyethylene glycol
3350 (PEG 3350). This mechanism underlies diet-induced (previously classified as osmotic)
diarrhea, which improves with fasting. (See 'Diet-induced (osmotic)' below.)

●Increased secretion or reduced absorption of electrolytes (Na+, Cl-, K+, HCO3-) across
the epithelium ((figure 3), panel C). Examples include diarrhea secondary to infection with
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Vibrio cholerae, which causes excessive secretion of chloride and loss of electroneutral
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sodium absorption. This mechanism underlies electrolyte transport-related (previously
classified as secretory) diarrhea, which fails to improve with fasting. (See 'Mechanisms of
altered fluid transport in diarrheal diseases' below and 'Electrolyte transport-related
(secretory)' below.)

●Rapid intestinal transit resulting in reduced time for fluid absorption ((figure 3), panel D).
Examples include a variety of conditions that cause hypermotility of the intestine, including
the functional diarrhea seen in infants and toddlers (sometimes termed "toddler's
diarrhea"). (See 'Motility-related' below and "Overview of the causes of chronic diarrhea in
children in resource-rich settings", section on 'Functional diarrhea in young children'.)

Many of the underlying etiologies of diarrhea in children cause diarrhea through a

combination of these primary mechanisms. For example, in inflammatory bowel disease,
inflammation causes a loss of absorptive surface area and capacity, causing loss of nutrient
transport as well as increasing active Cl- secretion and intestinal motility.

Mechanisms of altered fluid transport in diarrheal

diseases — Alterations in fluid transport between the intestinal lumen and the body
underlie many of the causes of diarrheal illness.

Several common diarrheal conditions are characterized by loss of nutrient-driven electrolyte

transport. As an example, patients with lactase deficiency are unable to hydrolyze lactose
into glucose and galactose. This leads to loss of fluid absorption driven by the Na+/glucose
co-transporter (SGLT1) and increased osmolality in the intestinal lumen. Lactase deficiency
can be either acquired (eg, due to mucosal injury from enteric injury from infection or celiac
disease), congenital (loss-of-function mutation in the lactase gene), or genetically driven,
age-dependent acquired deficiency (hypolactasia). (See "Lactose intolerance and
malabsorption: Clinical manifestations, diagnosis, and management", section on 'Primary
lactose malabsorption'.)

Certain enterotoxigenic pathogens cause diarrhea by stimulating fluid secretion. As

examples, V. cholerae and enterotoxigenic Escherichia coli release bacterial enterotoxins
(cholera toxin, heat-stable enterotoxin), which alter the intracellular levels of second
messenger molecules such as cAMP, cGMP, and Ca2+ (figure 4) [10]. These signal to the key
channels that drive fluid absorption and secretion. Cholera toxin induces elevations in cAMP,
leading to activation of the chloride channel CFTR and inhibition of Na+ exchanger NHE3,
resulting in a massive secretory diarrhea. Bacteria can also increase various humoral
agonists, neurotransmitters, or neuropeptide receptors such as 5-hydroxytryptamine,
vasoactive intestinal peptides and the galanin receptor type 1, also activating Cl– secretion
and inhibiting Na+ absorption. Similarly, diarrhea caused by viruses is partly due to the

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action of viral enterotoxins such as rotavirus NSP4, resulting in intracellular Ca2+ elevation,
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inhibition of Na+ absorption, and increased Cl- secretion (figure 4) [11]. (See "Clinical
manifestations and diagnosis of rotavirus infection", section on 'Pathogenesis and
histopathology'.)

Other bacteria cause diarrhea through an inflammatory mechanism. Invasive bacteria such
as Salmonella and Shigella cause a tissue inflammatory response involving recruitment of
immune cells and release of cytokines, resulting in intracellular Ca2+ signaling.
Enteropathogenic and invasive bacteria also result in alterations in channel protein
expression, with consequent impaired Na+ and Cl– absorption. (See "Cholera: Microbiology
and pathogenesis" and "Pathogenic Escherichia coli associated with diarrhea", section on
'Enterotoxigenic E. coli' and "Shigella infection: Epidemiology, microbiology, and
pathogenesis".)

Role of the colon — Because the bulk of daily fluid absorption is carried out in the
small intestine, any disease that significantly affects the small intestine (eg, celiac disease,
short bowel syndrome, enteric infections) can result in clinically significant diarrhea.
However, fluid absorption in the colon can often compensate for moderate loss of small
intestinal absorptive function.

Although the colon absorbs a much smaller volume of fluid than the small intestine, it is
critical for the generation of formed (dehydrated) feces [12]. Therefore, any condition that
alters colonic fluid transport or increases colonic motility tends to result in abnormally
watery stool and therefore diarrhea.

The colonic microbiome also plays an important role in driving fluid absorption in the colon.
Colonic bacteria participate in the fermentation of dietary carbohydrates unabsorbed by the
small intestine to produce short-chain fatty acids such as acetate, propionate, and butyrate.
These are rapidly absorbed in the colon, enhancing absorption of Na+ and water, and
secretion of HCO3-. Disruption of short-chain fatty acid production may therefore play a role
in antibiotic-associated diarrhea. Conversely, stabilization of the colonic microbiome
through the administration of probiotics can reduce diarrhea associated with antibiotic use.
Alterations to commensal bacteria in the colon after antibiotic administration allows
opportunistic pathogens such as Clostridioides difficile to displace the normal flora and can
result in toxin-mediated inflammation and diarrhea. (See "Diagnostic approach to diarrhea
in children in resource-rich countries", section on 'Antibiotic-associated diarrhea'.)

The presence of excessive bile acids in the colon as occurs in ileal resection or disease (eg,
Crohn disease) leads to activation of colonic Cl- secretion resulting in bile-acid diarrhea (see
"Chronic complications of short bowel syndrome in children", section on 'Chronic diarrhea').
A bile acid-enriched state is thought to occur in a subset of patients with diarrhea-
predominant irritable bowel syndrome, inducing fluid secretion as well as reducing the
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transit time through the colon, resulting in incomplete fecal dehydration and diarrhea. (See
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"Treatment of irritable bowel syndrome in adults", section on 'Bile acid sequestrants'.)

DIARRHEA CLASSIFICATION
Terminology — Previous classifications have divided diarrhea into osmotic,
secretory, inflammatory, and motility-related categories, but these terms can be misleading
for the following reasons:

●Osmotic diarrhea – The term "osmotic diarrhea" is traditionally used to refer to diarrhea
resulting from unabsorbed solutes or nutrients (figure 3), but this use is misleading since all
diarrhea involves osmotic forces. We prefer to use the more precise term "diet-induced
diarrhea" (or "substrate-induced diarrhea").

●Secretory diarrhea – The term "secretory diarrhea" is also problematic because it has
different definitions that are often used interchangeably. Some authors use the term to
refer to diarrhea caused by active ion secretion into the intestine; this definition is
problematic because it does not include watery diarrhea caused by defects in intestinal
sodium absorption (eg, due to some causes of congenital sodium diarrhea and in viral
infections). Others use the term to describe diarrhea with a low stool osmotic gap (see
"Approach to the adult with chronic diarrhea in resource-abundant settings", section on
'Characterizing the diarrhea type'). This definition is also problematic because a low stool
osmotic gap generally results from a combination of anion-driven fluid secretion and loss of
Na+-driven fluid absorption. Referring to this type of diarrhea as only "secretory" is
therefore somewhat misleading. Because of these definitional issues, we prefer to use the
more precise term "electrolyte transport-related diarrhea" rather than "secretory diarrhea."

●Mixed diarrhea – Lastly, diarrhea that is obviously neither "secretory" or "osmotic" or has
an intermediate stool osmotic gap has been referred to as "mixed." Although intermediate
values for the stool osmotic gap occur frequently, these often reflect the dietary intake at
the time of testing. From a diagnostic standpoint, this category is rarely helpful.

Despite the above caveats, the terms "osmotic" and "secretory" diarrhea are widely used
clinically and historically, and for the purposes of this topic review, we will refer to both the
existing terms and our newer terminology.

Diet-induced (osmotic) — Diet-induced diarrhea occurs when osmotically

active substances are present in the intestinal lumen, resulting in water retention. This can
occur because of loss of absorption of a dietary solute, such as lactose, or administration of
a nonabsorbable solute such as polyethylene glycol 3350 (PEG 3350). Because this form of
diarrhea is driven by osmotically active ingested nutrients (eg, carbohydrates) or exogenous

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substances (eg, osmotic laxative), the diarrhea will abate during fasting. Thus, a trial of
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fasting (>12 hours) is a useful diagnostic test. This is ideally done in a hospital to carefully
monitor both stool output and hydration status but can also be inferred from the history if
the diarrhea abates during either deliberate or inadvertent fasting.

Primary lactose intolerance or PEG 3350 ingestion are examples of diarrheas with a purely
osmotic mechanism. A diet-induced mechanism can also contribute to diarrhea from a
variety of other causes. For example, enteric infections and inflammatory conditions such as
Salmonella and inflammatory bowel disease can cause damage to intestinal epithelial cells
and loss of absorptive surface area, leading to impaired nutrient absorption and diet-
induced diarrhea. (See 'Inflammation-related' below and "Approach to chronic diarrhea in
children >6 months in resource-rich countries", section on 'Warning signs'.)

Electrolyte transport-related (secretory) — This type of

diarrhea occurs as a result of alterations in ion transport mechanisms in epithelial cells. The
distinguishing clinical characteristic is that this type of diarrhea will persist unabated during
fasting because it is independent of ingested osmotically active nutrients. Several types of
diarrheal diseases fall into this category:

●Enterotoxigenic bacteria – The classic example of electrolyte transport-related diarrhea

(although rarely encountered in resource-rich nations) is infection with the pathogen V.
cholerae, in which the enterotoxin, cholera toxin, causes massive (liters) fluid secretion of Cl-
and water. Other examples of bacterial enterotoxins include the enterotoxins produced by
Clostridia perfringens and C. difficile, and the heat-stable enterotoxin of E. coli. (See
"Cholera: Microbiology and pathogenesis" and "Causes of acute infectious diarrhea and
other foodborne illnesses in resource-rich settings", section on 'Clostridium perfringens'
and "Clostridioides difficile infection in adults: Epidemiology, microbiology, and
pathophysiology", section on 'Pathophysiology' and "Pathogenic Escherichia coli associated
with diarrhea", section on 'Enterotoxigenic E. coli'.)

●Enterotoxigenic viruses – Viral enterotoxins also may cause secretory diarrhea. As an

example, rotavirus produces a viral enterotoxin, the nonstructural glycoprotein (NSP4).
NSP4 causes Ca2+-dependent transepithelial Cl- secretion from the crypt cells, resulting in
secretory diarrhea. (See "Clinical manifestations and diagnosis of rotavirus infection" and
"Acute viral gastroenteritis in children in resource-rich countries: Clinical features and
diagnosis", section on 'Pathogenesis'.)

●Other secretory diarrheas – Noninfectious causes of secretory diarrhea include:

•Diarrheas mediated by gastrointestinal peptides (such as vasoactive intestinal peptide and

gastrin) (see "VIPoma: Clinical manifestations, diagnosis, and management" and "Zollinger-
Ellison syndrome (gastrinoma): Clinical manifestations and diagnosis")
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•Certain physiologic substances, such as bile acids, and certain medications (magnesium
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sulfate, lubiprostone, linaclotide) (see "Approach to the adult with chronic diarrhea in
resource-abundant settings", section on 'Post-cholecystectomy diarrhea' and "Chronic
complications of short bowel syndrome in children", section on 'Chronic diarrhea')

•Congenital defects (eg, congenital chloride diarrhea) (see "Approach to chronic diarrhea in
neonates and young infants (<6 months)", section on 'Evaluation for suspected congenital
diarrheas and enteropathies')

Motility-related — Changes in gastrointestinal motility can significantly influence

fluid absorption, particularly in the colon. Hypomotility, or the severe impairment of
intestinal peristalsis, results in stasis with subsequent bacterial overgrowth and secondary
bile acid deconjugation, bile acid malabsorption, and activation of colonic secretion. In
contrast, hypermotility, which probably contributes to the pathogenesis of functional
diarrhea in infants and toddlers (along with excessive carbohydrate intake), can lead to
diarrhea secondary to inadequate time for colonic absorption. Hypermotility also
contributes to some cases of diarrhea predominant in irritable bowel syndrome. (See
"Overview of the causes of chronic diarrhea in children in resource-rich settings", section on
'Diarrhea-predominant irritable bowel syndrome'.)

Inflammation-related — Intestinal inflammation leads to diarrhea through

multiple mechanisms. The diarrhea can have a diet-induced component because the
inflammatory process causes destruction or impairment of epithelial cells, resulting in loss
of surface area and transports, resulting in impaired nutrient absorption and increased
osmotic load in the intestinal lumen (see 'Diet-induced (osmotic)' above). Inflammation can
also cause electrolyte transport-related diarrhea by inducing active Cl- secretion and a loss
of Na+ absorption (see 'Electrolyte transport-related (secretory)' above). In addition, the
inflammatory process also can lead to the breakdown in intestinal barrier function, resulting
in exudation of mucus, protein, and blood into the gut lumen (eg protein-losing
enteropathy).

The most common cause of inflammatory diarrhea is infection. A number of relatively

common enteric pathogens (eg, Salmonella, Campylobacter, C. difficile) cause primarily
inflammatory responses, resulting in either watery or often bloody diarrhea (dysentery) (see
"Diagnostic approach to diarrhea in children in resource-rich countries", section on 'Causes'
and "Approach to the child with acute diarrhea in resource-limited countries", section on
'Infectious gastroenteritis'). Intestinal inflammation can also be caused by chronic diseases,
such as inflammatory bowel disease and celiac disease. (See "Clinical presentation and
diagnosis of inflammatory bowel disease in children" and "Epidemiology, pathogenesis, and
clinical manifestations of celiac disease in children".)

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RELEVANCE FOR DRUG TREATMENT — A

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number
interventions are available to treat diarrhea by altering the underlying pathophysiologic
processes. These include oral rehydration solutions (ORS) and several classes of drugs;
other candidate drugs are in development. Each of these treatments targets a different
pathophysiologic cause of diarrhea, as outlined below:

Oral rehydration solution — ORS is an orally ingested solution that

stimulates intestinal Na+ absorption by Na+/glucose cotransporter 1 (SGLT1 [SLC5A1]) and
Na+-coupled amino acid transporters. The World Health Organization (WHO)-recommended
ORS is hypo-osmolar (245 mOsm/L), with optimized glucose-to-Na+ ratios to increase water
absorption. ORS is a highly effective treatment that relies on the fact that SGLT1 transport is
preserved in electrolyte transport-related (secretory) diarrheas such as those caused by
bacterial enterotoxins. Beverages commercially marketed for hydration during exercise
("sports" beverages) have much higher concentrations of glucose and higher osmolarity,
which reduces fluid absorption; these are less effective for oral rehydration. Alternative ORS
solutions including rice starch or amino acids have also been shown to be effective in
maintaining hydration during diarrhea [13]. (See "Oral rehydration therapy".)

Antimotility agents — Drugs that inhibit intestinal motility have been used

extensively to treat diarrhea. The putative mechanism of action for antimotility drugs is
increased Na+ and fluid absorption as a result of slow intestinal transit. Loperamide and
diphenoxylate and atropine are mu-opioid receptor agonists that are widely used for mild,
nonspecific diarrhea. They are not recommended in bacterial diarrheas, primarily owing to
the risk of paralytic ileus, and diphenoxylate also has substantial central opioid effects.

Antisecretory agents — Inhibiting intestinal fluid secretion is another

mechanism by which some agents reduce diarrhea. Historically, bismuth subsalicylate was
shown to have antidiarrheal efficacy, although it is now rarely used. Racecadotril, an
enkephalinase inhibitor, or its active metabolite thiorphan, is used in Europe and South
America as an antidiarrheal agent, with varying reports of efficacy; it is not approved by the
US Food and Drug Administration (FDA) in the United States. It acts via inhibition of the
breakdown of endogenous enkephalins that exert antisecretory effects through enkephalin-
stimulated activation of epithelial mu-opioid receptors [14]. A natural-product antisecretory
agent, crofelemer, has been approved for use in HIV-related diarrhea based on a clinical
trial showing efficacy in improving chronic diarrhea in patients with HIV [15]. Crofelemer is a
heterogeneous proanthocyanidin oligomer extracted from the bark latex of the South
American tree Croton lechleri. Crofelemer acts by inhibiting Cl– channels in the apical
membrane. (See "Evaluation of the patient with HIV and diarrhea", section on 'Empiric
therapy'.)

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Investigational drugs — A number of investigational or moreYour

recently
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approved drugs target several of the pathophysiologic pathways described above:

●The bile acid analog obeticholic acid has shown efficacy in bile-acid diarrhea (see
'Electrolyte transport-related (secretory)' above and "Overview of the management of
primary biliary cholangitis", section on 'Subsequent therapy')

●The opioid receptor agonist eluxadoline is approved for diarrhea-predominant irritable

bowel syndrome (see "Treatment of irritable bowel syndrome in adults", section on
'Antidiarrheal agents' and 'Motility-related' above)

●Drugs directly targeting ion channels, such as absorbable inhibitors of the chloride
channel CFTR (BPO-27), are under clinical development [8]

SUMMARY
●For practical use in a clinical setting, diarrhea is defined as the passage of three or more
loose or liquid stools per day, or more frequent passage than is normal for the individual.
(See 'Definitions' above.)

●The normal movement of fluid between the intestinal lumen and blood is driven by the
active transport of ions (mainly Na+, Cl–, HCO3–, and K+) and nutrients (mainly glucose)
(figure 2). Fluid absorption is driven by the active transport of Na+ across the epithelium
with parallel Cl– or HCO3– absorption. Fluid secretion is driven by transepithelial Cl– secretion
through basolateral and apical Cl– channels and transporters. (See 'Molecular mechanisms'
above.)

●Diarrhea occurs when there is excessive fluid maintained within the lumen of the intestine.
This occurs due to either loss of nutrient absorption or the presence of nonabsorbable
solutes in the intestinal lumen, increased secretion or reduced absorption of electrolytes,
rapid intestinal transit, or a combination of these factors (figure 3). (See 'Pathophysiology of
fluid transport in diarrheal disease' above.)

●The causes of diarrhea can be categorized as diet-induced (osmotic), electrolyte transport-

related (secretory), motility-related, or inflammation-related, but multiple mechanisms often
are involved.

•Diet-induced (osmotic) diarrhea occurs when there is loss of absorption of a normally

absorbed dietary solute, such as lactose, or ingestion of a nonabsorbable solute such as
polyethylene glycol 3350 (PEG 3350), resulting in water retention within the intestinal
lumen. (See 'Diet-induced (osmotic)' above.)

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•Electrolyte transport-related (secretory) diarrheas occur as a result of alterations in ion

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transport mechanisms in epithelial cells. This can be caused by an infectious process (eg,
cholera, rotavirus, and some forms of Escherichia coli), secretion of gastrointestinal
peptides (eg, vasoactive intestinal peptide and gastrin), or by the stimulatory effect of bile
acids and laxatives. Some rare inherited disorders of intestinal transport, such as congenital
chloride diarrhea, also may cause secretory diarrhea. (See 'Electrolyte transport-related
(secretory)' above.)

•Disorders associated with reduced intestinal motility can cause diarrhea indirectly by
causing intestinal stasis and bacterial overgrowth, which leads to bile acid malabsorption.
Disorders with increased intestinal motility can cause diarrhea by reducing intestinal transit
time and absorption. Examples of increased motility include functional diarrhea in young
children (sometimes termed "toddler's diarrhea") and some cases of diarrhea-predominant
irritable bowel syndrome. (See 'Motility-related' above.)

•Inflammatory processes can cause destruction of epithelial cells and/or loss or dysfunction
of electrolyte transporters, leading to diarrhea through both osmotic and secretory
mechanisms, as well as exudation of mucus, proteins, and blood into the intestinal lumen.
This can be caused by infectious processes (eg, Shigella), inflammatory bowel disease, or
immune-mediated processes (eg, celiac disease). (See 'Inflammation-related' above.)

●A number of drugs or other interventions are available to treat diarrhea by altering the
underlying pathophysiologic processes. These include oral rehydration solutions (ORS) and
a variety of drugs. (See 'Relevance for drug treatment' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges

Mark A Gilger, MD, who contributed to an earlier version of this topic review.
1. GBD 2016 Diarrhoeal Disease Collaborators. Estimates of the global, regional, and
national morbidity, mortality, and aetiologies of diarrhoea in 195 countries: a
systematic analysis for the Global Burden of Disease Study 2016. Lancet Infect Dis 2018;
18:1211.
2. World Health Organization. Diarrhoeal disease. 2017. Available at:
http://www.who.int/mediacentre/factsheets/fs330/en/ (Accessed on July 29, 2019).
3. Vanderhoof JA. Chronic diarrhea. Pediatr Rev 1998; 19:418.
4. Johnston BC, Shamseer L, da Costa BR, et al. Measurement issues in trials of pediatric
acute diarrheal diseases: a systematic review. Pediatrics 2010; 126:e222.
5. Yeo CJ, Barry K, Gontarek JD, Donowitz M. Na+/H+ exchange mediates meal-stimulated
ileal absorption. Surgery 1994; 116:388.
6. Krishnan S, Ramakrishna BS, Binder HJ. Stimulation of sodium chloride absorption from
secreting rat colon by short-chain fatty acids. Dig Dis Sci 1999; 44:1924.

https://pro.uptodatefree.ir/show/5860 12/14
3/19/23, 10:20 AM Pathogenesis of acute diarrhea in children - Uptodate Free

7. Barrett KE, Keely SJ. Chloride secretion by the intestinal epithelium: molecular basis and
Your activity: 5 p.v.
regulatory aspects. Annu Rev Physiol 2000; 62:535.
8. Thiagarajah JR, Donowitz M, Verkman AS. Secretory diarrhoea: mechanisms and
emerging therapies. Nat Rev Gastroenterol Hepatol 2015; 12:446.
9. Chattopadhyay N, Cheng I, Rogers K, et al. Identification and localization of extracellular
Ca(2+)-sensing receptor in rat intestine. Am J Physiol 1998; 274:G122.
10. Berkes J, Viswanathan VK, Savkovic SD, Hecht G. Intestinal epithelial responses to
enteric pathogens: effects on the tight junction barrier, ion transport, and
inflammation. Gut 2003; 52:439.
11. Morris AP, Scott JK, Ball JM, et al. NSP4 elicits age-dependent diarrhea and
Ca(2+)mediated I(-) influx into intestinal crypts of CF mice. Am J Physiol 1999; 277:G431.
12. Naftalin RJ. The dehydrating function of the descending colon in relationship to crypt
function. Physiol Res 1994; 43:65.
13. Binder HJ, Brown I, Ramakrishna BS, Young GP. Oral rehydration therapy in the second
decade of the twenty-first century. Curr Gastroenterol Rep 2014; 16:376.
14. Salazar-Lindo E, Santisteban-Ponce J, Chea-Woo E, Gutierrez M. Racecadotril in the
treatment of acute watery diarrhea in children. N Engl J Med 2000; 343:463.
15. Macarthur RD, Hawkins TN, Brown SJ, et al. Efficacy and safety of crofelemer for
noninfectious diarrhea in HIV-seropositive individuals (ADVENT trial): a randomized,
double-blind, placebo-controlled, two-stage study. HIV Clin Trials 2013; 14:261.
Topic 5860 Version 18.0

References

1 : Estimates of the global, regional, and national morbidity, mortality, and aetiologies of
diarrhoea in 195 countries: a systematic analysis for the Global Burden of Disease Study 2016.

2 : Estimates of the global, regional, and national morbidity, mortality, and aetiologies of
diarrhoea in 195 countries: a systematic analysis for the Global Burden of Disease Study 2016.

3 : Chronic diarrhea.

4 : Measurement issues in trials of pediatric acute diarrheal diseases: a systematic review.

5 : Na+/H+ exchange mediates meal-stimulated ileal absorption.

6 : Stimulation of sodium chloride absorption from secreting rat colon by short-chain fatty
acids.

https://pro.uptodatefree.ir/show/5860 13/14
3/19/23, 10:20 AM Pathogenesis of acute diarrhea in children - Uptodate Free

Your
7 : Chloride secretion by the intestinal epithelium: molecular basis and regulatory activity: 5 p.v.
aspects.

8 : Secretory diarrhoea: mechanisms and emerging therapies.

9 : Identification and localization of extracellular Ca(2+)-sensing receptor in rat intestine.

10 : Intestinal epithelial responses to enteric pathogens: effects on the tight junction barrier, ion
transport, and inflammation.

11 : NSP4 elicits age-dependent diarrhea and Ca(2+)mediated I(-) influx into intestinal crypts of
CF mice.

12 : The dehydrating function of the descending colon in relationship to crypt function.

13 : Oral rehydration therapy in the second decade of the twenty-first century.

14 : Racecadotril in the treatment of acute watery diarrhea in children.

15 : Efficacy and safety of crofelemer for noninfectious diarrhea in HIV-seropositive individuals

(ADVENT trial): a randomized, double-blind, placebo-controlled, two-stage study.

https://pro.uptodatefree.ir/show/5860 14/14