OCCASIONAL REVIEW

Pathophysiology ofdiarrhoeaL A Whyte

H R Jenkins

AbstractThe 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 22:10 443

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

� 2012 Published by Elsevier Ltd.

Osmotic diarrhoea Secretory diarrhoea

Excess osmotically active

particles in the gut lumen

Bowel mucosa secretes

excess water into the lumen

Stops when the child

is fasted

Continues when the child is fasted

Underlying causes

C Osmotic laxatives

C Excessive solutes within

the lumen

C Inflammation within

the mucosa

C Motility disorders

Underlying causes

C Cholera toxin

C Other infective causes

C Specific electrolyte transport

defects (e.g. congenital

chloride-losing diarrhoea)

or structural abnormalities

(e.g. microvillous atrophy)

OCCASIONAL REVIEW

of sodium absorption is by the glucoseesodium transporter

1 (SGT1), which promotes the active absorption of sodium, allied

to the absorption of glucose, with water moving down the elec-

trochemical gradient that is created as jejunal contents are

broken down. A second mechanism is via an active, linked

sodiumehydrogen exchanger. The active sodium/glucose and

sodium/hydrogen pumps cause sodium to be absorbed into the

cells (enterocytes) lining the gut with the sodium that has moved

into the cells then actively pumped from epithelial cells into the

circulation via the sodium/potassium ATPase located in the

basolateral membrane (Figure 1).

The movement of sodium provides energy for the active

transport of amino acids, glucose and galactose across the

membrane. Di and tripeptide amino acid transport over the brush

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

net secretors of electrolytes and water. In these crypts there is

also a luminal bidirectional sodium/chloride channel which is

opened when there are higher levels of cyclic AMP and calcium

ions. When these channels are open there is a net movement of

sodium, chloride and water into the lumen. Consequently, if

there is a slight change in the flow across this channel then

secretion dramatically increases. Cholera toxin and Escherichia

coli cause an increase in the levels of cAMP, so driving chloride

flow across the brush border into the lumen, and hence the net

movement of water with it. This results in watery, secretory

diarrhoea.

The reabsorption of ions such as chloride and bicarbonate in

general is linked to the reabsorption of sodium with an additional

chloride/bicarbonate exchange pump present in both the ileum

and colon.

Lumen Serosa

Na Na

ATPase)

KGlucose

H2O

Na

H

Figure 1 Diagrammatic representation of enterocyte electrolyte and water

movement in the small intestine.

PAEDIATRICS AND CHILD HEALTH 22:10 444

The colon is also important for the adequate reabsorption of

fluid and whilst the majority of water and electrolyte absorption

takes place in the small intestine, it is often the adequacy of

colonic function that determines whether or not the patient

experiences diarrhoea. The maximal absorptive capacity of the

adult large bowel is 2e3 litre/day and, if the amount of fluid

secreted from the small bowel exceeds this, then diarrhoea

results.

Pathophysiology of diarrhoea

Diarrhoea is the result of a disruption in the delicate balance

between the absorptive and secretory processes within the

bowel. In general, diarrhoea can be considered to be either

osmotic or secretory.

Osmotic diarrhoea

When excessive numbers of osmotically active particles are

present in the lumen, more fluid passively moves into the bowel

lumen down the osmotic gradient which may exceed the

absorptive capacity of the gut and hence diarrhoea occurs.

Osmotic diarrhoea therefore will stop when the child is not fed.

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

laxatives such as lactulose

� Malabsorption of specific solutes e.g. disaccharide defi-

ciency, glucoseegalactose malabsorption

� Damage to the absorptive area of the mucosa resulting in

less fluid absorption e.g. acute gastroenteritis, cow’s milk

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

consequently a higher concentration of solutes within the

lumen.

� 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 22:10 445

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.

� 2012 Published by Elsevier Ltd.

Secretory Osmotic

Osmotic gap <50 mOsm/kg >135 mOsm/kg

Chloride concentration >40 meq/litre <35 meq/litre

pH >6.0 <5.5

Sodium concentration >70 meq/litre <70 meq/litre

Test Normal values Implications/possible

diagnosis

Alpha 1 antitrypsin

levels

<0.9 mg/g Protein-losing

enteropathy

Steatocrit <2.5% (in older

than 2 years)

Fat malabsoprtion

Faecal elastase >200 micrograms/g Pancreas function

Faecal calprotectin <50 micrograms/g Inflammation of the gut

Faecal reducing

substances

Absent Carbohydrate

malabsorption

OCCASIONAL REVIEW

Cryptosporidium parvum e cryptosporidiosis. This proto-

zoan organism can cause chronic diarrhoea. Diagnosis is made

by specific antigen testing and although usually self-limiting may

be treated with nitazoxanide for 3 days.

Viruses e in immunosuppressed children viruses such as

cytomegalovirus can cause chronic diarrhoea and must be

considered in the differential diagnoses.

Non-infective causes:

Secondary to damage to the mucosa e in coeliac disease or

inflammatory bowel disease, inflammatory mediators act locally

within the intestinal mucosa to stimulate secretion and inhibit

reabsorption of electrolytes. They also act on enteric neurones, to

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

is autoimmune enteropathy where anti-enterocyte antibodies

(IgG) damage the bowel mucosa.

Specific and rare electrolyte transport defects

Carbohydrate malabsorption: primary (very rare) or

secondary lactose intolerance, sucroseeisomaltase deficiency,

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

a differential diagnosis in chronic diarrhoea.

Congenital chloride losing diarrhoea in which the chloride/

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

contents of the intestinal lumen are therefore of a higher osmolality,

resulting in osmotic diarrhoea. The liver disease, cholestasis may

cause reduced bile salts and insufficient fat malabsorption, thereby

causing diarrhoea secondary to highly osmolar luminal contents.

Disorders of intestinal motility e these disorders may cause

rapid transport through the gut resulting in less overall absorp-

tion of electrolytes and water.

IBS variant of childhood e “chronic non-specific diarrhoea of

childhood” or irritable bowel variant of childhood is a useful

term for what used to be called toddler diarrhoea. This diagnosis

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

PAEDIATRICS AND CHILD HEALTH 22:10 446

� Nutritional status including height and weight and skin

fold thickness.

Suggested initial Investigations

� Full blood count

� C-reactive protein

� Erythrocyte sedimentation rate

� Coeliac disease screen e anti-tissue transglutaminase

antibody and total serum IgA

� Stool culture (including clostridium difficile and giardia).

Further specific investigations e secondary care

� Stool assessment

� Stool electrolytes:

� Other stool assessments:

� Imaging

� Barium meal and follow through/MRI enterography

� Endoscopy and biopsy.

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

� 2012 Published by Elsevier Ltd.

Practice points

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

secretory functions of the gastrointestinal tract

C The causes of diarrhoea can be either osmotic or secretory

C Children can and do die from severe diarrhoea and therefore

fluid and electrolyte balance must always be carefully

assessed

C Oral fluid resuscitation with oral rehydration solution is usually

effective in the management of acute diarrhoea

OCCASIONAL REVIEW

chronic diarrhoea a careful history and specific investigation and

management in secondary or tertiary care are necessary. A

FURTHER READING

Deepak P, Ehrenpreis E. Diarrhoea. Dis Mon 2011; 57: 490e510.

Kleinman RE, Sanderson IR, Goulet OG, Sherman PM, Mieli-Vergani G,

Shneider BL. Paediatric gastrointestinal diseases. 5th Edn. Hamilton:

BD Decker Inc, 2008.

Online learning in gastroenterology OLGa. http://olga.uegf.org/portal/

index.php.

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 � 2012 Published by Elsevier Ltd.