Official reprint from UpToDate®

www.uptodate.com © 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

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

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

Literature review current through: Jan 2023. | 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 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 "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 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 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
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
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 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 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 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-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 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 '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")

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

(magnesium 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".)

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; 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'.)

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
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.)

• 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. (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.

Use of UpToDate is subject to the Terms of Use.

REFERENCES

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.

7. Barrett KE, Keely SJ. Chloride secretion by the intestinal epithelium: molecular
basis and 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
:
GRAPHICS

Fluid movement in the human gastrointestinal

tract
:
 Schematic diagram of the GI tract showing daily volumes (in liters) of
fluid secretion and absorption.

GI: gastrointestinal.
:
 Modified from: Thiagarajah JR, Verkman AS. Water transport in the gastrointestinal
tract. In: Physiology of the gastrointestinal tract, 5th ed, Johnson LR (Ed), Elsevier Inc,
New York 2012. p. 1757.

Graphic 113253 Version 1.0

:
 Intestinal transport mechanisms
:
 Small intestine:
(A) Fluid absorption in primarily villus epithelial cells showing active transepithelial transport of sodi
via apical membrane transporters (SGLT1, NHE3, and DRA), and the basolateral Na + /K + ATPase with
corresponding passive chloride and water flux.
(B) Fluid secretion in primarily crypt epithelial cells showing active transport of chloride from the
basolateral side via the NKCC and apical chloride channels (CFTR, CaCC) with corresponding passive
sodium and water flux.
Colon:
(C) Fluid absorption in both surface and crypt epithelial cells showing active transepithelial transport
sodium via apical membrane transporters and channels (eNaC, NHE3, and the sodium-driven short-
chain fatty acid transporter [SMCT]).
(D) Fluid secretion in primarily crypt epithelial cells showing active transport of chloride from the
basolateral side via the NKCC and apical chloride channels (CFTR, CaCC) with corresponding passive
sodium and water flux.

SGLT1: sodium-glucose cotransporter 1 (SLC5A1); DRA: downregulated in adenoma chloride/bicarbonate

exchanger (SLC26A3); NHE3: sodium-hydrogen exchanger 3; CFTR: cystic fibrosis transmembrane regulato
CaCC: calcium-activated chloride channels; NKCC: Na + /K + /Cl - symporter 1 (SLC12A2); SMCT: sodium-couple
monocarboxylate transporter (SLC5A8); eNaC: epithelial sodium channel; SCFA: short-chain fatty acids.  

Graphic 113255 Version 4.0

:
 Overview of the mechanisms causing diarrhea

(A) Normal — During normal function, Na + and nutrient absorption drives fluid absorption, with a small b
amount of electrolyte (Cl – )-driven fluid secretion, allowing efficient reabsorption of fluid, leading to minima
loss via feces.
(B) Loss of nutrient absorption, or the presence of nonabsorbable solutes (diet-induced or "osmotic" d
— Loss of nutrient absorption because of damage or loss of the required transporter, or the presence of
nonabsorbable osmoles in the lumen (eg, PEG 3350), prevents fluid absorption and promotes fluid secretio
the intestinal lumen, leading to diarrhea.
(C) Increased secretion or reduced absorption of electrolytes (electrolyte transport-related or "secretor
diarrhea) — Excessive anion-driven fluid secretion and reduced electrolyte-driven fluid absorption, as occu
certain infections such as cholera, leads to accumulation of fluid in the intestinal lumen and diarrhea.
:
 (D) Rapid intestinal transit (motility-related diarrhea) — Increased intestinal motility results in reduced tim
absorb electrolytes and nutrients, leading to excessive unabsorbed substrates in the intestine and reduced
absorption, leading to diarrhea.

PEG 3350: polyethylene glycol 3350.

Graphic 113254 Version 3.0

:
 Pathophysiology of abnormal electrolyte transport in bacterial and viral diarr

(A) Bacterial diarrheas — Some bacteria secrete enterotoxins that increase intracellular cyclic nucleotides
in chloride ion (Cl – ) secretion and inhibition of the NHE3 and sodium ion (Na + ) absorption. Invasive bacter
tissue inflammatory response involving recruitment of immune cells and release of cytokines, resulting in
intracellular calcium ion (Ca 2+ ) signaling.
(B) Viral diarrheas — The rotaviral protein NSP4 causes elevation of cytoplasmic Ca 2+ concentration by bi
integrin-alpha(1)beta(2) and Gal, and/or by activation of enteric nerves. Rotaviral NSP4 also inhibits NHE3 a
SGLT1.

E. coli: Escherichia coli; CFTR: cystic fibrosis transmembrane conductance regulator; DRA: downregulated in
Cl – /HCO 3 exchanger (SLC26A3); NHE3: sodium-hydrogen exchanger 3; CaCC: calcium-activated chloride ch
cholera toxin; STa: heat-stable toxin; eNaC: epithelial Na + channel; EC cells: enterochromaffin cells; cGMP: c
guanine monophosphate; cAMP: cyclic adenosine monophosphate; 5-HT: 5-hydroxytryptamine; VIP: vasoa
intestinal peptide; ENS: enteric nervous system; NKCC: Na + /K + /Cl – symporter; IL-6: interleukin-6; IL-8: inte
TNF: tumor necrosis factor; SGLT1: sodium/glucose cotransporter (SLC5A1); NSP4: nonstructural protein 4;
galanin; GALR1: galanin receptor 1.

Adapted by permission from Macmillan Publishers Ltd: Nature Reviews Gastroenterology & Hepatology. Thiagarajah JR, Donowitz M
AS. Secretory diarrhoea: mechanisms and emerging therapies. Nat Rev Gastroenterol Hepatol 2015; 12:446. Copyright © 2015.
www.nature.com/nrgastro.
:
 Graphic 113256 Version 2.0
:
Contributor Disclosures
Jay R Thiagarajah, MD, PhD Grant/Research/Clinical Trial Support: Napo Pharmaceuticals
[Diarrhea];NIH [NIDDK];TKO Strong Foundation [Microvillus inclusion disease]. All of the relevant
financial relationships listed have been mitigated. Martin G Martin, MD,
MPP Grant/Research/Clinical Trial Support: National Institutes of Health [NIDDK]. All of the relevant
financial relationships listed have been mitigated. B UK Li, MD Consultant/Advisory Boards: GLG
Consulting [Antiemetics]; Takeda [Antiemetics]. All of the relevant financial relationships listed have
been mitigated. Alison G Hoppin, MD No relevant financial relationship(s) with ineligible
companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found,
these are addressed by vetting through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of
all authors and must conform to UpToDate standards of evidence.

Conflict of interest policy

: