OCCASIONAL REVIEW
Pathophysiology of
diarrhoea
L A Whyte
H R Jenkins
Abstract
The absorption and secretion of water and electrolytes throughout the
gastrointestinal tract is a finely balanced, dynamic process and, when
there is loss of this balance caused either by decreased absorption or
increased secretion, diarrhoea results. Diarrhoea remains a major cause
of morbidity and mortality worldwide, accounting for 3 million deaths
per year in young children, and it is therefore important for those who
care for children to have a clear understanding of the pathophysiology
of diarrhoea. Diarrhoea can be considered to be either osmotic or secre-
tory. Osmotic diarrhoea occurs when excessive osmotically active parti-
cles are present in the lumen, resulting in more fluid passively moving
into the bowel lumen down the osmotic gradient. Secretory diarrhoea
occurs when the bowel mucosa secretes excessive amounts of fluid
into the gut lumen, either due to activation of a pathway by a toxin, or
due to inherent abnormalities in the enterocytes. The management of
acute diarrhoea is based on assessment of fluid balance of the child
and rehydration. Oral rehydration with oral rehydration solution is
extremely effective and has significantly reduced childhood mortality
over the past 40 years. Chronic diarrhoea has a number of infective and
non-infective causes, careful history and specific investigation and
management in secondary or tertiary care is often necessary.
Keywords child; chronic diarrhoea; diarrhoea; infant
Introduction and definition
Diarrhoea (from the Greek word to “flow through”) is defined as
the rapid transit of gastric contents through the bowel. The
frequency of defecation is variable in childhood, but the median
is one bowel movement per day, with The World Health Orga-
nisation describing diarrhoea as three or more loose or watery
stools per day. The absorption and secretion of water and elec-
trolytes in to the gut is a finely balanced, dynamic process and,
when there is loss of this balance, diarrhoea results.
L A Whyte MBChB MRCPCH ST6 Paediatrics (Grid Trainee in Paediatric
Gastroenterology, Hepatology and Nutrition) in the Department of
Paediatric Gastroenterology at the Children’s Centre, University
Hospital of Wales, Cardiff, UK. Conflicts of interest: none.
H R Jenkins MA MD FRCP FRCPCH is Consultant Paediatric Gastroenterolo-
gist in the Department of Paediatric Gastroenterology at the Children’s
Centre, University Hospital of Wales, Cardiff, UK. Conflicts of interest:
none.
PAEDIATRICS AND CHILD HEALTH 22:10
Diarrhoea in childhood remains a major cause of morbidity and
mortality throughout the world and a common cause of death
worldwide in children under the age of 5 years, currently
accounting for over 3 million deaths per year. This problem is
confined not only to the developing world, but is also a significant
cause of morbidity in the developed world, particularly in the first
year of life. If diarrhoea becomes protracted, then severe malnu-
trition may develop and result in prolonged impairment of phys-
ical and intellectual development. This is particularly the case
when there is restriction of growth at a vulnerable period of brain
development. Episodes of acute diarrhoea occur most commonly
in the first year of life, at a time when not only brain development
is incomplete, but also when the wide variety of intestinal trans-
port mechanisms which are concerned with the absorption and
secretion of fluid and electrolytes are poorly developed. Therefore,
clinicians who regularly see children with acute and chronic
episodes of diarrhoea must have a good understanding of the
pathophysiology, and different treatment and management
options, in order to reduce this mortality and morbidity.
Physiology of intestinal absorption and secretion
In the course of the average day the human intestine handles
large quantities of water, electrolytes and nutrients. The majority
of the fluid entering the upper small intestine comes from
endogenous gastrointestinal secretions, with the minority from
oral intake. The data that are available for quantitative handling
of water and electrolytes in the small intestine of infants and
children are very limited, but it probably follows the same
pattern as seen in adults.
The input of fluid to the small intestine in adult humans is as
follows:
 9 litre/day (diet 1.8 litre, endogenous secretions 7.2 litre)
 Input of fluid into the colon: 1.5e2.0 litre/day
 Output of fluid in faeces: 100e200 ml/day.
The intestinal mucosa is a complex epithelium in which
absorption and secretion occur simultaneously with the majority
of water and electrolyte absorption occurring in the small intes-
tine. Current concepts of water and electrolyte transport suggest
that the mucosa of the intestine acts a semipermeable membrane
with pores in the membrane at intercellular junctions. Water
movement is entirely passive, the majority passing para-
cellularly in response to osmotic gradients created by the trans-
cellular absorption of solutes, particularly sodium.
The jejunum is the most permeable area of the small intestine
and consequently there are rapid changes in luminal osmolality
as food is digested and products absorbed. The most important
absorptive mechanisms are those of sodium-coupled co-transport
of organic substrates such as glucose, galactose, amino acids and
tripeptides.
The ileum is less permeable to water, though there is
absorption of the same sodium and organic substrates as in the
jejunum, but also with other specific electrolyte absorptive
mechanisms becoming more significant.
Mechanism of water and solute absorption in the small
intestine
Overall water absorption is dependant on the movement of
electrolytes, especially sodium. The primary mechanism
443 Ó 2012 Published by Elsevier Ltd.
 OCCASIONAL REVIEW

of sodium absorption is by the glucoseesodium transporter The colon is also important for the adequate reabsorption of
1 (SGT1), which promotes the active absorption of sodium, allied fluid and whilst the majority of water and electrolyte absorption
to the absorption of glucose, with water moving down the elec- takes place in the small intestine, it is often the adequacy of
trochemical gradient that is created as jejunal contents are colonic function that determines whether or not the patient
broken down. A second mechanism is via an active, linked experiences diarrhoea. The maximal absorptive capacity of the
sodiumehydrogen exchanger. The active sodium/glucose and adult large bowel is 2e3 litre/day and, if the amount of fluid
sodium/hydrogen pumps cause sodium to be absorbed into the secreted from the small bowel exceeds this, then diarrhoea
cells (enterocytes) lining the gut with the sodium that has moved results.
into the cells then actively pumped from epithelial cells into the
circulation via the sodium/potassium ATPase located in the Pathophysiology of diarrhoea
basolateral membrane (Figure 1).
Diarrhoea is the result of a disruption in the delicate balance
The movement of sodium provides energy for the active
between the absorptive and secretory processes within the
transport of amino acids, glucose and galactose across the
bowel. In general, diarrhoea can be considered to be either
membrane. Di and tripeptide amino acid transport over the brush
osmotic or secretory.
border is coupled with hydrogen ion reabsorption, and so helps
to create the electropotential across the brush border which again
aids the transport of sodium.
The ATPase sodium/potassium pump is located in the
basolateral membrane of the intestinal crypt and villus tip cells.
The epithelial cells at the tips of the villi are active in net
absorption, whereas the cells in Lieberkuhn’s crypts function as Osmotic diarrhoea Secretory diarrhoea
net secretors of electrolytes and water. In these crypts there is
Excess osmotically active Bowel mucosa secretes
also a luminal bidirectional sodium/chloride channel which is
particles in the gut lumen excess water into the lumen
opened when there are higher levels of cyclic AMP and calcium
Stops when the child Continues when the child is fasted
ions. When these channels are open there is a net movement of
is fasted
sodium, chloride and water into the lumen. Consequently, if
Underlying causes Underlying causes
there is a slight change in the flow across this channel then
secretion dramatically increases. Cholera toxin and Escherichia
C Osmotic laxatives C Cholera toxin
coli cause an increase in the levels of cAMP, so driving chloride
C Excessive solutes within C Other infective causes
flow across the brush border into the lumen, and hence the net
the lumen C Specific electrolyte transport
movement of water with it. This results in watery, secretory
C Inflammation within defects (e.g. congenital
diarrhoea.
the mucosa chloride-losing diarrhoea)
The reabsorption of ions such as chloride and bicarbonate in
C Motility disorders or structural abnormalities
general is linked to the reabsorption of sodium with an additional
(e.g. microvillous atrophy)
chloride/bicarbonate exchange pump present in both the ileum
and colon.

Osmotic diarrhoea
Lumen Serosa When excessive numbers of osmotically active particles are
present in the lumen, more fluid passively moves into the bowel
Na Na lumen down the osmotic gradient which may exceed the
ATPase) absorptive capacity of the gut and hence diarrhoea occurs.
Osmotic diarrhoea therefore will stop when the child is not fed.
Glucose K
Excessive numbers of osmotically active particles can be
present for a number of reasons including:
 Ingestion of solutes that cannot be absorbed e.g. osmotic
H2O
laxatives such as lactulose
 Malabsorption of specific solutes e.g. disaccharide defi-
ciency, glucoseegalactose malabsorption
Na  Damage to the absorptive area of the mucosa resulting in
less fluid absorption e.g. acute gastroenteritis, cow’s milk
H protein allergy, coeliac disease and Crohn’s disease
 Motility disorders such as those seen in gastroschisis,
irritable bowel syndrome, and hyperthyroidism which
result in reduced contact with the bowel lumen and
Figure 1 Diagrammatic representation of enterocyte electrolyte and water consequently a higher concentration of solutes within the
movement in the small intestine. lumen.

PAEDIATRICS AND CHILD HEALTH 22:10 444 Ó 2012 Published by Elsevier Ltd.
 OCCASIONAL REVIEW
Secretory diarrhoea
This occurs when the bowel mucosa secretes excessive amounts
of fluid, either due to activation of a specific pathway by a toxin
(such as cholera toxin), or inherent abnormalities in the enter-
ocytes, (e.g. congenital microvillous atrophy). Often absorptive
mechanisms, although present, are overwhelmed, resulting in
diarrhoea. In the case of secretory diarrhoea, this does not stop if
the child’s enteral feeds are withheld.
In some instances both osmotic and secretory diarrhoea can
occur together, in acute or chronic disease, depending on the
underlying cause.
Aetiology and management of acute diarrhoea
Acute diarrhoea can be caused in a number of ways, the com-
monest being infective. In this case diarrhoea may be a beneficial
physiological response to harmful material within the bowel,
thus expelling the harmful bacteria and toxins from the body.
Infective causes e results from either
 damage to the mucosa (e.g. in rotavirus)
 toxins produced by the infective organism itself (e.g. in
cholera).
Causative pathogens include:
Viruses Bacteria Parasites
Rotavirus Campylobacter jejuni Cryptosporidium
Norwalk virus Salmonella Giardia lamblia
Norovirus Escherichia coli
Calicivirus Shigella
Yersinia entercolitica
Clostridium difficile
Management of acute infective diarrhoea
Oral rehydration: the use of specific oral rehydration solution
(ORS) is one of the most significant factors in the reduction in
childhood mortality over the last 40 years. Indeed, since its
introduction the childhood mortality rates from acute infective
diarrhoea in the under 5-year olds have reduced from some 5
million per year to 2e3 million per year.
In 1966 it was discovered that the sodiumeglucose trans-
porter is not necessarily affected by microbes and when sodium
and glucose are present in the lumen the co-transporter will
continue to work, even when the chloride channels continue to
cause secretion. Therefore when a solution is taken containing
both sodium and glucose, in the correct proportions, the
absorption of sodium is increased with a consequent increase in
passive water absorption. This transporter works effectively even
in the presence of inflammation of the gut and is the reason why
ORS is effective in diarrhoeal illness. The ORS does not actually
“stop” the diarrhoea, which often continues, but the absorption
PAEDIATRICS AND CHILD HEALTH 22:10
of water and solutes will exceed the secretion and will ensure the
child remains hydrated until the infective organism is eradicated.
The ORS recommended by the WHO in 2002 contains 75 mmol/
litre sodium, 75 mmol/litre glucose, and has a total osmolarity of
247 mOsm/litre. Of note, other traditional rehydration solutions
such as coca-cola and apple juice have a significantly lower
content of sodium and a very high osmolarity and are thus
inadequate as oral rehydration solutions.
ORS has been shown to be effective in both developing and
developed countries for the rehydration of children. Studies have
shown that less than 5% of children with acute diarrhoea,
regardless of the underlying cause, fail to improve with oral
therapy and IV rehydration, with its consequent risks, is rarely
needed.
Refeeding: breastfed infants should continue to be breastfed
during an episode of acute diarrhoea as it promotes faster
recovery and rehydration. Artificially fed infants may return to
normal feeding after a 6 h period of oral rehydration solution if
they recover well. The long held myth that a lactose-free diet is
necessary after diarrhoea is not evidence-based and the 3% of
children who develop reducing substances in their stools
following diarrhoea will recover within 5 days (NICE guidance
on the management of acute gastroenteritis).
Antibiotics: antibiotics are rarely indicated in acute suspected, or
proven bacterial gastroenteritis and some studies suggest that
symptoms may actually be prolonged, except in immunocom-
promised children when proven bacterial infection is present.
Probiotics: it remains unclear as to the role of probiotics in the
treatment and/or recovery from diarrhoea and currently these
are not routinely recommended.
Non-infective causes
 Inflammatory processes within the bowel cause a reduc-
tion in the absorptive surface of the bowel as the villi are
damaged e.g. coeliac disease, cow’s milk protein allergy,
and surgical conditions such as acute appendicitis and
intussusception
 Drug induced e this may cause increased motility of the
bowel, allowing less time for absorption
 Antibiotics
 Laxatives.
Aetiology and management of chronic diarrhoea
Chronic diarrhoea is defined as diarrhoea that lasts for more than
3 weeks. As with the acute diarrhoea, the pathophysiology of
chronic diarrhoea can be either secretory or osmotic, or indeed
a combination of the two.
Main causes
Infective causes:
Giardia lamblia e giardiasis. This flagellate protozoan causes
acute watery diarrhoea, abdominal pain, intermittent diarrhoea,
abdominal distension, weight loss and chronic diarrhoea. It is
diagnosed on a stool smear, but sensitivity of this test is only 75e
95%, and an empirical trail of metronidazole for 3e5 days may be
a more appropriate option.
445 Ó 2012 Published by Elsevier Ltd.
 OCCASIONAL REVIEW

Cryptosporidium parvum e cryptosporidiosis. This proto-  Nutritional status including height and weight and skin
zoan organism can cause chronic diarrhoea. Diagnosis is made fold thickness.
by specific antigen testing and although usually self-limiting may Suggested initial Investigations
be treated with nitazoxanide for 3 days.  Full blood count
Viruses e in immunosuppressed children viruses such as  C-reactive protein
cytomegalovirus can cause chronic diarrhoea and must be  Erythrocyte sedimentation rate
considered in the differential diagnoses.  Coeliac disease screen e anti-tissue transglutaminase
antibody and total serum IgA
Non-infective causes:  Stool culture (including clostridium difficile and giardia).
Secondary to damage to the mucosa e in coeliac disease or Further specific investigations e secondary care
inflammatory bowel disease, inflammatory mediators act locally  Stool assessment
within the intestinal mucosa to stimulate secretion and inhibit  Stool electrolytes:
reabsorption of electrolytes. They also act on enteric neurones, to  Other stool assessments:
increase motility.
Specific and rare abnormalities of enterocytes or the brush
border membrane e these are rare conditions usually presenting
as congenital or chronic diarrhoea from early infancy. Examples
include, congenital microvillus inclusion disease where there is
a net reduction in the surface area of the bowel and there is
massive excretion of electrolytes in the stools. Another rare cause Secretory Osmotic
is autoimmune enteropathy where anti-enterocyte antibodies
(IgG) damage the bowel mucosa. Osmotic gap <50 mOsm/kg >135 mOsm/kg
Specific and rare electrolyte transport defects Chloride concentration >40 meq/litre <35 meq/litre
Carbohydrate malabsorption: primary (very rare) or pH >6.0 <5.5
secondary lactose intolerance, sucroseeisomaltase deficiency, Sodium concentration >70 meq/litre <70 meq/litre
congenital glucoseegalactose malabsorption cause osmotic
diarrhoea due to the high osmolality of luminal contents.
Excessive fructose intolerance, usually the result of excessive
intake of fruit juices (especially apple juice) is known to cause
osmotic diarrhoea in children and should be considered as  Imaging
a differential diagnosis in chronic diarrhoea.  Barium meal and follow through/MRI enterography
Congenital chloride losing diarrhoea in which the chloride/  Endoscopy and biopsy.
bicarbonate transporter does not function resulting in high luminal
chloride levels and secretion of fluid. In this situation, the Na H
exchangers continue to operate, so hydrogen is secreted in the faces
without bicarbonate to neutralize it, thus resulting in a metabolic
alkalosis.
Pancreatic and biliary disorders e cystic fibrosis may lead to
pancreatic insufficiency and protein and fat malabsorption. The Test Normal values Implications/possible
contents of the intestinal lumen are therefore of a higher osmolality, diagnosis
resulting in osmotic diarrhoea. The liver disease, cholestasis may
cause reduced bile salts and insufficient fat malabsorption, thereby Alpha 1 antitrypsin <0.9 mg/g Protein-losing
causing diarrhoea secondary to highly osmolar luminal contents. levels enteropathy
Disorders of intestinal motility e these disorders may cause Steatocrit <2.5% (in older Fat malabsoprtion
rapid transport through the gut resulting in less overall absorp- than 2 years)
tion of electrolytes and water. Faecal elastase >200 micrograms/g Pancreas function
IBS variant of childhood e “chronic non-specific diarrhoea of Faecal calprotectin <50 micrograms/g Inflammation of the gut
childhood” or irritable bowel variant of childhood is a useful Faecal reducing Absent Carbohydrate
term for what used to be called toddler diarrhoea. This diagnosis substances malabsorption
is one of exclusion, but can be useful as many parents have heard
of it and there is often a positive family history.

Investigation of chronic diarrhoea

The differential diagnosis of chronic diarrhoea is vast and
a careful history and specific investigations will usually result in
a definitive diagnosis and appropriate management strategy.
Examination of the child with acute and chronic diarrhoea
 General assessment including assessment of hydration
status
Summary
Regardless of the cause or type of diarrhoea, dehydration may
ensue rapidly and this must be recognized and treated promptly.
In the majority of cases of acute diarrhoea, oral rehydration with
oral rehydration solution is effective. In those children with

PAEDIATRICS AND CHILD HEALTH 22:10 446 Ó 2012 Published by Elsevier Ltd.
 OCCASIONAL REVIEW

chronic diarrhoea a careful history and specific investigation and

management in secondary or tertiary care are necessary. A Practice points

C Diarrhoea is a result of an imbalance of the absorptive and

FURTHER READING
secretory functions of the gastrointestinal tract
Deepak P, Ehrenpreis E. Diarrhoea. Dis Mon 2011; 57: 490e510.
C The causes of diarrhoea can be either osmotic or secretory
Kleinman RE, Sanderson IR, Goulet OG, Sherman PM, Mieli-Vergani G,
C Children can and do die from severe diarrhoea and therefore
Shneider BL. Paediatric gastrointestinal diseases. 5th Edn. Hamilton:
fluid and electrolyte balance must always be carefully
BD Decker Inc, 2008.
assessed
Online learning in gastroenterology OLGa. http://olga.uegf.org/portal/
C Oral fluid resuscitation with oral rehydration solution is usually
index.php.
effective in the management of acute diarrhoea
Powell CV, Jenkins HR. Toddler diarrhoea: is it a useful diagnostic label?
Arch Dis Child 2012; 97: 84e6.

PAEDIATRICS AND CHILD HEALTH 22:10 447 Ó 2012 Published by Elsevier Ltd.