4/21/2020 Pathogenesis of acute diarrhea in children - UpToDate

Authors: Jay R Thiagarajah, MD, PhD, Martin G Martin, MD, MPP

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

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Mar 2020. | This topic last updated: May 10, 2019.

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 gastrointestinal tract.
This topic focuses on the pathophysiology of fluid absorption and 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 "Approach to diarrhea in children in resource-rich countries".)

● (See "Overview of the causes of chronic 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".)

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

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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 secretion of saliva, gastric
juice, bile, and pancreatic fluid and for fluid absorption in the 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
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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 out by the
coordinated activity of NHE3 with Cl–/HCO3– exchangers (PAT1 for HCO3– 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
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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
Vibrio cholerae, which causes excessive secretion of chloride and loss of electroneutral
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 countries", section on 'Functional diarrhea'.)

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: 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-
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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 action of viral enterotoxins such as rotavirus
NSP4, resulting in intracellular Ca2+ elevation, 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 Escherichia
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
(formerly Clostridium) difficile to displace the normal flora and can result in toxin-mediated
inflammation and diarrhea. (See "Approach to diarrhea in children in resource-rich countries",
section on 'Antibiotic-associated diarrhea'.)
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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 'Watery 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 transit time through the colon,
resulting in incomplete fecal dehydration and diarrhea. (See "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-rich 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.

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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 substances (eg, osmotic laxative),
the diarrhea will abate during fasting. Thus, a trial of 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 'Initial diagnostic approach'.)

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 (formerly Clostridium) difficile infection in adults: Epidemiology, microbiology,
and pathophysiology", section on 'Pathophysiology' and "Pathogenic Escherichia coli
associated with diarrhea", section on 'Enterotoxigenic Escherichia 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'.)

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● 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")

• Certain physiologic substances, such as bile acids, and certain medications

(magnesium sulfate, lubiprostone, linaclotide) (see "Chronic complications of short
bowel syndrome in children", section on 'Watery diarrhea' and "Approach to the adult
with chronic diarrhea in resource-rich settings", section on 'Post-cholecystectomy
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 countries", section on 'Functional diarrhea'.)

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 "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

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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".)

RELEVANCE FOR DRUG TREATMENT

A number of interventions are available to treat diarrhea by altering the underlying

pathophysiologic processes. These include oral rehydration solutions (ORS) and several classes
of drugs (table 1); 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
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the apical membrane. (See "Evaluation of the HIV-infected patient with diarrhea", section on
'Empiric therapy'.)

Investigational drugs — A number of investigational or more recently 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 treatment of primary
biliary cholangitis (primary biliary cirrhosis)")

● 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

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 (table 1). (See 'Relevance for drug treatment' above.)

ACKNOWLEDGMENT

The editorial staff at UpToDate would like to acknowledge Mark A Gilger, MD, who contributed to
an earlier version of this topic review.

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

1. GBD 2016 Diarrhoeal Disease Collaborators. Estimates of the global, regional, and
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