Current Paediatrics (2001) 11, 291d295^ 2001 Harcourt Publishers Ltddoi:10.1054/cupe.2001.0188, available online at http://www.idealibrary.com on

Understanding diarrhoeaW. M. Bisset

Consultant Paediatric Gastroenterologist, Royal Aberdeen Children’s Hospital, Cornhill Road, Aberdeen, AB25 2ZG, UK

KEYWORDSdiarrhoea,paediatric,coeliac disease,food hypersensitivity,short gut syndrome

Summary Diarrhoeal diseases are among the most common causes of childhoodmortality and morbidity throughout the world. In health, the gut is in a dynamic state withthe secretion of intestinal juices being balanced by the absorptive capacity of the intestine.When this equilibrium is disturbed by increased secretion or reduced absorption,diarrhoea will occur.

The absorption of sugars and amino acids by the small intestine is facilitated byco-transport with sodium, with water following passively. Most secretory processes aredependent on the active transport of chloride into the lumen of the gut. In infectiousdiarrhoea, secretion may be stimulated by enterotoxins or by inflammation of the gut.Mucosal damage secondary to allergic processes, coeliac disease or surgical resection willreduce absorption.

Armed with an understanding of the pathophysiology of diarrhoea, the clinician is ina better position to diagnose and treat children with such problems.^ 2001 Harcourt Publishers Ltd

PRACTICE POINTS

f Water is absorbed passively by the intestine andfollows the osmotic gradient created by the activetransport of electrolytes and solute

f Oral rehydration solution promotes increased in-testinal absorption; they have no effect on secretion

f Osmotic diarrhoea ceases when the patient has nooral intake, but secretory diarrhoea continues

f The true incidence of coeliac disease of one in 300is 10 times higher than previously thought (mosteffected individuals have no symptoms)

f One in 20 infants may have a dietary proteinintolerance, and cows milk protein is the mostfrequent cause

f After surgical resection, the remaining smallintestine grows in length and electrolyte absorptionincreases

INTRODUCTION

Millions of children die each year as a consequence ofdehydration secondary to diarrhoeal illnesses. In deve-loping countries, infective diarrhoea is one of the major

E-mail: michael.bisset@arh.grampian.scot.nhs.uk

causes of childhood mortality, while in wealthiercountries, although few children die as a result ofdiarrhoeal illness, it remains a very significant cause ofinfant morbidity. The aim of this review is to describe thenormal physiology of the gastrointestinal tract andhighlight how derangement of these processes can leadto the development of diarrhoea.

Definition

Stool consistency or colour can vary greatly, but the totalstool volume is probably the best indicator of whethernormal intestinal function is deranged. The normalstool output in an infant is between 5 and 10 g/kg/dayand diarrhoea is said to occur when this upper limitis exceeded or the total daily output is more than200 g.

NORMAL INTESTINAL FUNCTION

Digestion

The main function of the small intestine is to allow thenormal digestion and absorption of nutrients. Luminaldigestion is facilitated by the presence of bile salts whichsolubilize lipids, and by pancreatic enzymes which are

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responsible for the digestion of lipids, protein and carbo-hydrate. Lipids are broken down to free fatty acids,proteins to amino acids, di and tripeptides, and carbohy-drates to monosaccharides, disaccharide and limit dex-trins. Most nutrients have been absorbed by the timeluminal contents reach the ileum, although bile salts andvitamin B12 are both absorbed exclusively from the ileum.

Fluid and electrolyte transport

It is important to realize that the intestine does notactively transport water and that its movement is alwayssecondary to the active transport of some other soluteor electrolyte across the intestinal epithelium. Theseactive processes are powered by the sodium potassiumATPase pump which ensures that the inside ofenterocytes have a low sodium concentration anda negative charge. The electrical and osmotic gradientcreated by this pump drives most intestinal transportprocesses (Fig. 1).

Figure 1 A schematic view of an absorptive villus enterocyte(A) and a secretory crypt enterocyte (B). The mucosalabsorption (A) of glucose and amino acids is primarily throughco-transport with sodium. Mucosal secretion (B) is driven bythe movement of chloride. The sodium/potassium ATPasepump ensures that the inside of the enterocytes have a lowsodium concentration and a negative charge relative to thelumen. This electrochemical gradient drives the movement ofsodium into absorptive cells, and chloride out of secretorycells. Water moves down the osmotic gradient passively.

Following a meal, sodium absorption is coupled to thetransport of monosaccharides and amino acids. Speci-fic membrane proteins co-transport sodium with eitherglucose or galactose, while a family of proteins isresponsible for the transport of neutral, aromatic, imino,dibasic and acidic amino acids with sodium. The sodiumand glucose in oral rehydration solutions work throughthe above mechanism to potentiate water absorption bythe small intestine. In glucose-galactose malabsorption,the sodium glucose/galactose transport protein isdefective leading to the development of a chronicosmotic diarrhoea from the time of the first feed.

Ileal and colonic sodium absorption is predominantlyvia sodium channels which are under the regulatoryinfluence of glucocorticoid and mineralocorticoids. In thecolon, the junction between enterocytes is much lessleaky than in the small intestine, allowing sodium to beabsorbed even when luminal concentrations are low.This facilitates the conservation of electrolytes, and theformation of a low volume stool. The absorption ofsodium in the colon is stimulated by the presenceof short-chain fatty acids (the break down products ofundigested carbohydrate). Antibiotic therapy is likely todisrupt short-chained fatty acid production witha resultant reduction in colonic absorption and thedevelopment of diarrhoea. In the terminal ileum andcolon, sodium absorption is also coupled with hydrogenand chloride absorption with bicarbonate. Failure of thelatter later mechanism results in the development ofcongenital chloride losing diarrhoea.

Intestinal fluid secretion is driven primarily by theactive secretion of chloride. Chloride is transported intothe enterocytes coupled with sodium, down the sodiumgradient created by the sodium potassium ATPase on thebasal lateral membrane. Increases in cyclic AMP, cyclicGMP and ionic calcium result in the opening of chloridechannels on the luminal enterocyte membrane, withresultant movement of chloride, down its electro-chemical gradient, into the lumen followed by thesecretion of water. This chloride channel is defective incystic fibrosis

MECHANISMS OF DIARRHOEA

In an infant, about 280 ml/kg of digestive juices pour intothe small intestine each day; more than double that foundin an adult. Much of this volume is re-absorbed in thesmall intestine, but approximately 20% passes into thecolon. Further absorption of fluid and electrolyte bythe colon results in relatively small volumes of stoolbeing passed, and in both children and adults, less than2% of all water and electrolytes entering the small intes-tine is passed as stool.

An increase in stool volume leading to diarrhoea canoccur if:

UNDERSTANDING DIARRHOEA 293

f the amount of fluid passing into the colon from thesmall intestine is increased

f the absorptive capacity of the colon is reducedf the colon is actively secreting fluid.

In older children and adults, increased small intestinalsecretion may not necessarily lead to the development ofdiarrhoea if the colon has enough reserve capacity tocope with the added volume load. In young infants,however, where a relatively larger volume of fluid ispassed into the colon, this reserve capacity is alreadytaken up and therefore any pathological process is likelyto more readily result in the development of diarrhoea.Where solute is inadequately absorbed, this willinevitably have an osmotic effect, drawing extra fluidinto the lumen of the gut with resulting diarrhoea.A characteristic feature of so-called osmotic diarrhoea isthat it ceases completely when the oral intake is stopped.This is in contrast to patients with active secretorydiarrhoea where the secretion continues irrespective ofthe oral intake.1

CAUSES OF DIARRHOEA

Acute infective diarrhoea

By far the most common cause of acute diarrhoea isenteropathogenic infection. The pathogenesis of entericinfection, with the exception of a few organs such asStaphylococcus aureus and Bacillus cereus where toxiningestion produces symptoms, is dependant on the en-teric pathogens entering and colonizing some part of theintestine.2 The first stage of this process is theattachment of the infective agent to the lining of the gut.Once bound to the cells, diarrhoea may be inducedeither by the release of enterotoxins which stimulateintestinal secretion or, alternatively, the infective agentmight disrupt the structure of the enterocytes eitherwith or without invasion. Infective agents may alsoinduce a local inflammatory response which can lead to

Table 1 Common causes of malabsorption in childhood

Intraluminal

Pancreatic: Cystic fibrosis

Hepatics: Hepatocellular failureCholestasis

Infective: Bacterial overgrowth

Anatomical: Ileal resection

further secretion and bleeding into the gut. Infectionswith some intestinal helminths may also induce an IgE-mediated intestinal anaphylactic reaction.

Enteric pathogens induce diarrhoea by increasing se-cretion, decreasing intestinal absorption throughmucosal damage, or a combination of the two.

Increased intestinal secretion

Cholera is the classic example of a secretory diarrhoea.The cholera toxin stimulates an increase in cAMP levelswithin the enterocytes which leads to massive secretionof chloride and water. The presence of many infectiveagents initiates a local inflammatory response, and therelease of substances such as 5HT and VIP will furtherstimulate secretion. In cryptosporidia infection, mucosalprostaglandin levels are thought to be a major factor inthe secretory process.

Decreased intestinal absorption

Where the enteric pathogens damage the brush bordermembrane of the cells or disrupt the villous structure,nutrient absorption will be compromised, resulting ina large osmotic load that will in itself lead to increaseddiarrhoea. The most common cause of diarrhoea intemperate countries in young children is rotavirusinfection. This virus invades the enterocytes and disruptsthe micro villus structures, leading to cell death and thedevelopment of villus atrophy.3 Intestinal motility isincreased with many enteric infections, leading tosymptoms of pain and marked intestinal hurry whichfurther compromises the ability of the colon to salvagethe increased fluid load within the gut.

Malabsorption

Malabsorption may result if either the early luminal orlater mucosal stages of digestion are disrupted (Table 1).

Mucosal

Enteropathies: Post gastroenteritisFood allergicCoeliac disease

Inflammatory: Crohn’s disease

Anatomical: Short gut syndrome

Drugs: Chemotherapeutic agentsCongenital: Transport defects e rare

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This will be further compromised by rapid intestinaltransit or loss of absorptive surface due to surgicalresection.

Cystic fibrosis, a genetic defect of the chloride trans-porter found in duct and mucosal membranes, is themost common hereditory cause of luminalmalabsorption in developed countries. The productionof inspissated secretions in the pancreas leads topancreatic insufficiency and, in the small intestine, tomeconium ileus. Luminal digestion will also becompromised if there is a failure of bile salt secretion inchronic liver disease or premature deconjugation of bilesalts due to bacterial overgrowth.

Failure of mucosal digestion can occur where brushborder enzyme activity is reduced. This most commonlyoccurs after enteric infections when lactase activity maybe temporarily reduced, but less commonly, genetic de-fects of these enzymes may result in conditions such assucrose-isomaltose deficiency. Structural damage to thesmall intestinal mucosa will compromise both digestionand absorption. Damage to the villi occurs in someinfective diarrhoeas, in food allergic disease or may resultfrom specific sensitization to the dietary protein found ingluten, resulting in coeliac disease. The end result irre-spective of the primary cause is malabsorption withdevelopment of an osmotic diarrhoea.

Coeliac disease

Coeliac disease requires the combination of a geneticpredisposition and the presence of gluten in the diet.Contact of gluten with the small intestine of a susceptibleindividual leads to a marked inflammatory infiltrate withinthe lamina propria, with the development of a crypthyperplastic subtotal villus atrophy. In the most severeform, this leads to profound malabsorption with severediarrhoea.4,5 Over 95% of individuals with coeliac diseasehave raised circulating antibodies to gliadin, reticulin orendomysium, making it possible to screen for thiscondition. This has led to the realization that the majorityof individuals with coeliac disease probably have few ifany symptoms and the suggested incidence of thiscondition has increased 10-fold in recent years toa present level of one in 300. This lack of symptoms isa reflection of the lower dietary gluten load on youngchildren, and the increasing functional reserve of theintestine in the older child that compensates for theproximal enteropathy. Coeliac disease is much morecommon in children with Down syndrome and diabeteswith an incidence of about one in 20.

Food allergy

In developed countries, the incidence of food allergy isincreasing and it has been suggested that up to one in 20

children under the age of 3 years may have some form ofallergy to dietary food protein. When a child ingestsa dietary antigen to which he or she is sensitized, this maylead either to a local reaction such as abdominal pain,diarrhoea or vomiting, or more distant reactions such asurticaria or wheeze.6 Where the allergic reaction isacute, dietary antigen stimulates sensitized mast cellswith the release of inflammatory mediators, causingintestinal secretion and diarrhoea. Some children,however, have more delayed reactions with tissuedamage which in the small intestine causes villusdestruction and symptoms of malabsorption, withdamage to the colon leading to a colitis with symptoms ofblood and diarrhoea. These delayed symptoms maydevelop days after the ingestion of the offending protein.

By far the most common dietary protein that causesallergy is cows milk protein, followed by soya, egg andwheat. Treatment is with antigen avoidance under closedietary supervision. In the majority of children, theproblem is self-limiting and improves spontaneously inthe second or third year of life.

Surgical causes

Resection of intestine may be required in babies withnecrotizing enterocolitis, in infants with malrotation or inolder children with Crohn’s disease. Small resectionshave very little if any effect on the child but resection oflarger lengths of small intestine is compensated by ad-aptation of the remaining segment with villushypertrophy and gut lengthening. It is known that theileum adapts better than the jejunum and that where theileo-caecal valve has been resected, adaptation may besignificantly compromised. The major stimulus to thisadaptation is the presence of food within the lumen ofthe gut. The adaptive process after massive smallintestinal resections will take many months.7,8

In a child with a terminal ileostomy, the absorption ofnutrients is not adversely affected, but because the ab-sorption surface area of the colon is lost, loss of waterand electrolytes is greatly increased. Stimulation of ilealsodium pumps by increased mineralocorticoid levelsleads in time to a reduction in losses, but such childrenremain vulnerable to the effects of gastroenteritis andchronic sodium depletion may lead to poor growth.

Intractable diarrhoeal processes

Most infective diarrhoeas in well-nourished individualsare self limiting. In malnourished children, however, re-peated infection will lead to further malnutrition, whichin turn will compromise healing and repair of entericmucosa.9,10 Repeated infections are also likely to lead tobacterial overgrowth of the small intestine, withresultant bile salt deconjugation and fermentation of

UNDERSTANDING DIARRHOEA 295

carbohydrates. Damage to the enteric mucosa will alsofacilitate the passage of antigen across the mucosa, whichin turn may lead to sensitization to dietary proteins.Unless these processes can be interrupted by theinstitution of adequate nutrition and the prevention offurther infections, the child is likely to enter a downwardspiral resulting ultimately in death.

EVALUATION OF THE PATIENTWITH DIARRHOEA

As in most areas of paediatrics, a good history will giveclues to the underlying cause of diarrhoea and the exam-ination will ascertain if the child is dehydrated or mal-nourished. With an acute onset of symptoms, and otherfamily members similarly affected, an infective problem ismost likely. Symptoms related to the ingestion of specificdietary proteins or diarrhoea developing in a bottle-fedbaby in the first few months of life raises the possibility ofan allergic aetiology. Where symptoms of diarrhoea arepresent from birth, one of the rarer congenital causesmight also be considered. Serial measurements of heightand weight will give valuable information about growth,and will help differentiate the well child with chronicloose stools due to a benign condition, such as toddlerdiarrhoea, from the patient with coeliac disease or cysticfibrosis who might be failing to thrive.

Investigations and treatment

Investigations depend on the likely differential diagnosisfor the patient. Where the problem is likely to be

infective, stool culture, microscopy or immunofluores-cence is most appropriate. Treatment is supportive andaimed at preventing dehydration and further infection.Allergic disease can be diagnosed by the process ofwithdrawal and challenge, and if coeliac disease issuspected, measurement of circulating antibodies andultimately a jejunal biopsy is required. Treatment in boththese conditions is with dietary exclusion.

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