Progress report Diarrhoea: Mechanisms and treatment

Gut, 1971, 12, 1021-1036

Progress reportDiarrhoea: Mechanisms and treatmentDiarrhoea can usefully be considered as a disturbance in the balance betweenthe mechanisms controlling secretion and absorption of water resulting inan excess loss of water in the faeces. In this economy, the quantity of waterin food and drink is of little importance,' for compulsive water drinkers,who may drink 10 litres of water a day, do not develop diarrhoea.Flow of water across the gut occurs mainly to maintain isotonicity with

the plasma in a rapidly changing chemical environment. Thus intraluminaldigestion increases the osmotic attraction of water into the bowel, whileabsorption or secretion of solute is accompanied by absorption or secretionof water.2'3 In the upper small bowel the absorptive forces are augmentedby active transport of sugars and amino acids coupled with rather a weaksodium pump. In the ileum and colon a powerful sodium pump is capableof transporting sodium isotonically against large electrochemical gradients.4'5'6These transport systems are closely integrated with the transfer of a numberof other substances such as the interchange of chloride for bicarbonate.7'8Although these transfers may not play a direct part in drawing water out ofthe intestinal lumen, the pathways are so interdependent that a severe dis-turbance of any of them may result in diarrhoea.9 The study of the humoral,electrochemical, and structural factors which control these processes has ledto useful advances in the treatment of diarrhoea, although our understandingof the underlying mechanisms remains fragmentary. The well tried remediessuch as chalk and kaolin and the opium alkaloids and their derivatives,which decrease intestinal 'motility', remain very valuable. We have selectedthe following topics for review since they have recently become growingpoints in our understanding of diarrhoea.

Acute Diarrhoea

Over 4 million working days were certified as lost through acute diarrhoeain England and Wales in the year 1966-1967,10 and the rate in the USAappears to be similar." Acute diarrhoea is usually mild and self-limiting, butmay be dangerous in infants. Pathogenic organisms which can be demon-strated in only a minority of cases include enteropathogenic E. coli (as inrecent serious infantile epidemics), non-invasive salmonellae, and Shigellasonnei. A preformed toxin is occasionally responsible.'2 Enteroviruses,especially echoviruses, have been isolated in mild diarrhoea at a rate slightlyhigher than in control subjects, but there is as yet no conclusive proof thatsuch viruses can cause acute diarrhoea.'3' 1415

Antibiotics are not generally indicated for acute diarrhoea in GreatBritain,'21617"1819 since they do not appear to shorten the illness and mayprolong symptomless excretion of pathogens20,2' and encourage the emergenceof resistant strains.22 This resistance can be transferred to previously sus-ceptible enterobacteria.23'24'25,26

In tropical countries, acute diarrhoea is more serious. Cholera, one of1021

T. S. Low-Beer and A. E. Read

the world's major fatal infections, may kill up to 60% of those infected,sometimes within four hours of the onset of symptoms.27

MECHANISMS OF FLUID LOSS IN ACUTE DIARRHOEATwo main mechanisms have been held responsible for acute diarrhoea.28(1) Excessive secretion of water and electrolytes into the intestine stimulatedby bacterial toxins: in these diseases, of which cholera serves as the model,the intestinal mucosa remains intact. (2) Mucosal injury by bacteria resultingin inflammation, exudation of serum and blood, and impaired absorptivefunction as in bacillary dysentery.

Cholera and related diarrhoeasRapid advances in the understanding of intestinal fluid movements have comefrom the study of cholera in man and in animal models using the vibrioendotoxin, a protein with a molecular weight of about 90,000. Cholera ischaracterized by the rapid onset of diarrhoea with 'rice water' stools of lowprotein content. The patient may excrete more than a litre every hour andbecomes dehydrated and acidotic. Despite its high mortality, the disease isself-limiting and effectively treated by the replacement of fluid and electro-lytes.29

Studies in patients with cholera show an imbalance between small intestinalmucosal secretion and absorption, leading to a great excess in the net secretionof water and electrolytes.30 The small intestinal mucosa appears structurallyintact,31 even by electron microscopy.32,33 Colonic function remains normal,but its absorptive capacity is overwhelmed by the sheer volume of fluidpresented to it.34

Perhaps the most significant and at first sight surprising finding is thatabsorption of electrolytes, sugars, and amino acids remains unimpaired33 ornearly so.36 This suggests oversecretion rather than underabsorption as thecause of the diarrhoea, and in turn indicates a therapeutic approach. Sinceactively transported sugars and amino acids increase both the rate of sodiumabsorption and the flow of water out of the intestine," 35,36,37,38,39,40 it shouldbe possible to increase absorption and correct dehydration by the oral orintragastric administration of glucose-electrolyte solutions. This is in factso,37,41,42 and the addition of glycine further increases the efficiency of themixture.40The study of cholera has highlighted the secretory function of the intestinal

mucosa.3 It has shown that secretion can be dissociated from absorption, andrecent work suggests that secretion occurs mainly from the crypts andabsorption through the villous tips.3'u It has led to a search for the intimatecontrol of these functions by mineralocorticoids, prostaglandins, and thecyclic AMP system.4445 Lastly, recent advances in treatment have demon-strated how such experimentally derived information can be applied in prac-tice.

These discoveries have led clinicians to consider the role of various otherenterotoxins, such as those produced by E. coli, Staph. aureus, Shigelladysenteriae, and Clostridiumperfringens in the pathogenesis ofacute diarrhoea.

E. coli diarrhoea can resemble cholera in several respects.46"7 (1) It maypresent with profuse, watery diarrhoea. (2) When it does so, the organismscolonize both small and large intestine without producing any gross mucosaldamage. (3) Studies have shown net fluid secretion into the small bowel, but

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Diarrhoea: Mechanisms and treatment

not the colon, during the acute stages. Cell-free enterotoxin can reproducethe secretory flux in loops of animal bowel.

E. coli enterotoxin may be responsible for severe infantile enteritis48'49and some forms of traveller's and acute tropical diarrhoea.46'47,50 '1 Entero-toxin production has recently been demonstrated in strains of E. coli notpreviously classified as pathogenic by traditional methods of serotypingand biochemical taxonomy.46 50 The enterotoxin of Clostridium perfringenscan also be shown to stimulate small-intestinal fluid secretion under certainconditions and resemble cholera exotoxin in its effect on adenyl cyclaseactivity.5' Unfortunately present methods of demonstrating enterotoxinproduction are not routine procedures, nor does animal pathogenicity provepathogenicity for man. 52

Acute mucosal damageIn shigella dysentery, the large intestinal wall is invaded, becoming hyper-aemic and sometimes ulcerated.53 The stools may contain blood and mucus,and in severe cases have a characteristic pea-soup appearance. Sonneidysentery, the commonest in Great Britain, is usually a mild, short-liveddisease. An enterotoxin has been demonstrated only in the more virulentshigella dysenteriae (shiga).54 A shigella-like dysentery can also be producedby some strains of E. coli which do not elaborate an enterotoxin.51

Small bowel morphology in acute diarrhoea has rarely been studied andlittle is known about the ways in which mucosal damage produces diarrhoea.55However, two recent studies have shown that when the small bowel isdamaged by staphylococcal endotoxin,56 or by Salmonella typhimurium,57there is an outpouring of fluid and electrolytes by the small intestine. In thelast study, rats were infected with a strain isolated from a human infection.In those rats developing diarrhoea, net ileal secretion occurred. This wascorrected by administering glucose-electrolyte solution in only half theanimals, suggesting that, in contrast to cholera, absorptive mechanisms maybe severely disrupted.58

Stagnant Loop Syndrome

Bacterial contamination of the normally almost sterile upper small bowel59may interfere with digestion and absorption of nutrients, leading to diarrhoea,steatorrhoea, and vitamin Bl2 deficiency.60,61 (This subject has recently beenreviewed in this journal.62) The cause of the diarrhoea is not fully understood.It is tempting to ascribe it to bacterial endotoxins, but there is no evidencefor a direct effect of the contaminating organisms on the control of salt andwater exchange. The suggestion by Dawson and Isselbacher in 196063 thatthe steatorrhoea is due largely to degradation of bile salts has been supportedby more recent work.64-71

Metabolism of bile salts in the small bowel occurs only where conditionsfavour the growth of anaerobes, particularly bacteroides.71-76

Bacterial deconjugation of bile salts can have the following consequences.(1) It reduces the concentration of detergent conjugated bile salts at the verysite at which fat absorption normally takes place.70 (2) It increases theconcentration of unconjugated bile salts. Some of these, such as deoxycholate,have been shown to have a toxic effect in vivo on mucosal structure77'78 andfunction,66'67'79'80 especially when the concentration of conjugated bile salts

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is low.8' However, unconjugated bile salts are absorbed much more rapidlythan conjugates from the upper small bowel,82 so that their relative concen-tration may fall towards the ileum. (3) Unconjugated bile salts have beenshown to inhibit salt and water absorption in both the small83 and largebowel.84'85 They, or the bacteria themselves, also appear to interfere withthe normal digestion and absorption of carbohydrates80'81186 and othercomponents of the intestinal contents.79The irritant and osmotic effects of organic acids derived from bacterial

breakdown of carbohydrate and fat in preventing water and salt absorptionremain to be evaluated.87'88 The hydroxy fatty acid ricinoleic acid is thoughtto be responsible for the purgative effect of castor oil. The calcium soaps ofhydroxy fatty acids and the calcium salts of certain bile salts are insoluble,and it has been claimed that feeding calcium bicarbonate relieves the diarrhoeaof small bowel resection.89

It is not yet clear to what extent diarrhoea and malabsorption are due toa reduced concentration of conjugated bile salts, toxicity of their bacterialmetabolites, or a direct effect of bacteria on the mucosa.90Treatment with conjugated bile salts has been shown to reduce steatorrhoea,

but not diarrhoea.70 Steatorrhoea, therefore, seems to depend primarily onan effect of the bacteria on the intraluminal contents. Effective treatmentof the diarrhoea consists in removing the bacteria, either with the appropriateantibiotic or by resecting the stagnant segment.

Humoral Agents in Diarrhoea

Intestinal motility, absorption, and secretion are influenced by hormones andby mediators at the cellular level, such as cyclic AMP. For instance, thyroidhormones increase intestinal motility and transit rate,9' administration ofcholecystokinin increases small bowel motility,92-95 diarrhoea occurs inadrenal failure,96 while mineralocorticoids increase salt and water absorptionfrom the colon.97'98 Indeed aldosterone secretion may be increased by theloss of sodium in diarrhoea. The balance between the biochemical regulatorsis clearly complex, but study of certain endocrine abnormalities has demon-strated their importance in the control of intestinal function.

ZOLLINGER-ELLISON SYNDROMEDiarrhoea is sometimes a prominent feature of this syndrome. While theabnormally high gastrin levels increase the volume of gastric secretions, themost important cause of diarrhoea and steatorrhoea is the increased acidityof the intestinal contents. This leads to defective lipolysis because of irrever-sible inactivation of lipase and precipitation of bile salts.99" .'0' Smallintestinal absorption of water and electrolytes is impaired, and the jejunalmucosa may show defective fatty acid esterification and amino-acid uptake.1021031"04Mucosal structure may be altered to the extent of villous atrophy andgastric metaplasia.99,100,101"105 although this probably contributes littleto the diarrhoea.'0'Non-beta pancreatic islet-cell tumours may also be associated with the

syndrome of watery diarrhoea, hypokalaemia, and usually diminished gastricacid secretion. The role of hormones in this syndrome has been the subjectof much speculation, but resection of the tumour, as in the Zollinger-Ellison

1024


syndrome, cures the diarrhoea.'06-"-5 Intestinal transit times appear to benormal."" Pancreatic hypersecretion and loss of normal water and electrolyteconservation by the small bowel have been produced by the administrationof large doses of either secretin, glucagon, or both,"17 but neither hormonehas been identified unequivocally from the tumour. Whatever the agent,high doses of corticosteroid appear to have a beneficial effect on the diar-rhoea."10 This is also unexplained.

CARCINOID SYNDROMEIn this syndrome the diarrhoea, unlike the other features, seems to be directlydue to serotonin. Serotonin stimulates small bowel motility but has a pre-dominantly relaxant effect on colonic smooth muscle."18 Diarrhoea maytherefore result from an increased intestinal flow rate due to a decrease inthe intraluminal resistance of the colon. The serotonin antagonists, methy-sergide and parachlorophenylalanine, are often successful in relieving'carcinoid' diarrhoea, but their effect is confined mainly to relief of gastro-intestinal symptoms."19"120 Since patients with this syndrome may have hadan ileal tumour resected, cholerrhoeic enteropathy sometimes contributesto the diarrhoea (see below).

In spite of the usefulness of methysergide and parachlorophenylalaninein resistant diarrhoea, the standard antidiarrhoeal drugs are often adequateand safer.

MEDULLARY CARCINOMA OF THE THYROIDThe diarrhoea which occurs in a third of patients with this carcinoma121 hasaroused special interest since the discovery that these tumours sometimessecrete prostaglandins.122 Prostaglandins stimulate smooth muscle andnormally occur within the gut wall. They are released from the gastro-intestinal tract during peristaltic activity,'23 and when type El is fed in largedoses it produces diarrhoea.'24 The diarrhoea in these patients is associatedwith abnormally rapid intestinal transit but malabsorption of glucose,xylose, and fat does not usually occur.'25 Prostaglandins might play a rolein increasing gastrointestinal motility,126 or in influencing small bowelsecretion,44 depending on the type of prostaglandin, but the links in thechain are still incomplete and their precise role in producing the symptomsremains uncertain.

CYCLIC AMPMany hormone actions on a variety of tissues are transmitted through anintermediate messenger, cyclic 3' 5'-AMP. The level of this substance can beaugmented either through increase in activity of adenyl cyclase, whichcatalyses its synthesis from ATP, or by depressing the activity of the phos-phodiesterase which degrades cyclic AMP to 5'-AMP.

Cholera and certain prostaglandins increase adenyl cyclase activity inthe gut wall.44'45 Experimentally, cyclic AMP increases the net secretoryflux of electrolytes and water in a way similar to that which occurs in cholera.Cholera toxin can produce its effect on the gut even when the vibrio is intro-duced into a remote segment connected to the rest of the bowel only by itsblood supply.'27 This all suggests that the toxin acts via some humoral agent,

1025


most probably mediated by this messenger system. Possibly other bacterialenterotoxins will be shown to act through the same system.

Osmotic Diarrhoea and Disaccharidase Deficiency

Absorption of dietary carbohydrate depends on the presence of disaccha-ridases in the intestinal brush border of the absorptive cells at the villoustips.1281129 Deficiency of one or more of these enzymes leads to osmoticattraction of water by the unabsorbed disaccharides in the gut lumen.'30This isotonic sugar solution necessarily has a lower sodium concentrationthan the plasma,'31 and the upper small bowel cannot absorb sodium fromluminal concentration of less than 90 mM.6'36 Water absorption depends onthe absorption of sodium and sugar which are themselves interdependent,5 132Since these are both impaired, it is clear that water will accumulate in theintestine, distending it, causing abdominal bloating and cramps, probablyaccelerating transit rate, and thereby reducing the time for the more powerfulileal sodium pump to act. Perfusion studies on patients with lactase deficiencyand diarrhoea have shown net secretion of fluid and increased transit rate inthe small bowel."1,133 The effect on large bowel function is considered below.

Treatment consists in avoiding the appropriate carbohydrate and thisdepends on the type of disaccharidase deficiency. The commonest type isalactasia,134 which when severe enough to produce diarrhoea, may requirereduction of milk and dairy products. For this reason the distribution ofdried milk to combat malnutrition in the poorer parts of Africa and Asia,where inherited lactase deficiency is common, may result in diarrhoea andabdominal cramps in those past infancy.'35 Malnutrition itself may increaseintolerance to milk.'36

Disease of the intestinal cell such as occurs in coeliac disease,'37"138tropical sprue,'39"140 and temporarily after most acute infective diarrhoealillnesses"4"'142 can result in deficiency of brush border disaccharidases whichmay contribute to the diarrhoea. Of the seven known disaccharidases,lactase 1 activity is the first to disappear,'37 and restriction of dairy produceoccasionally lessens the symptoms.

Inluence of Small Bowel Disease on Colonic Absorption

Clearly the severity of diarrhoea in disorders of the upper gastrointestinaltract depends on the ability of the colon to absorb the water which flowsinto it. Colonic absorption has recently been reviewed in this journal"43 andelsewhere.'" The colon normally absorbs about 0.5 to 15 litres of water in24 hours, leaving only 20-150 ml in the faeces'4" of people taking a 'western'type diet.'4" The capacity of the colon to compensate for failure of smallintestinal absorption depends on the composition and quantity of the ilealeffluent and on how long the faecal stream remains in the colon."43 Withfaecal losses of over 3 litres a day, the colon is scarcely able to alter the com-position of what flows through it.147,148The osmotic effect of unabsorbed solute on the small bowel is often

augmented in the large bowel by bacterial breakdown of the molecule intoseveral smaller fragments which are themselves poorly absorbed. This occursin alactasia which, particularly in children, may lead to an acid diarrhoeadue to bacterial breakdown of lactose to lactic and other organic acids."49

1026


Since the colonic sodium pump is very powerful, net water secretion does notoccur. However, the osmotic attraction of lactose and its metabolitesgreatly impairs absorption'33 and water loss closely parallels the excretionof organic anion.1"0,151

This mechanism is used therapeutically in hepatic encephalopathy, whereacidification of the colonic contents prevents the absorption of ammonia.Since these patients generally have normal jejunal lactase levels, a syntheticketo-analogue of lactose, lactulose,152 is used, for which no mucosal disac-charidase exists. Magnesium sulphate, which is poorly absorbed, is anotherexample of an osmotic purgative in general use.

It has recently been shown that diarrhoea can result from the entry ofincreased amounts of bile salts into the colon.84"153 Bile salts have long beenrecognized as purgatives,154 and still appear in many proprietary laxativemixtures. Endogenous bile salts may have this effect in ileal disease or afterileal resection, when the enterohepatic circulation of bile salts is interrupted.'55It is estimated that normally 15-30 g of bile salts passes through the smallbowel daily as a result of the repeated cycling of a bile salt pool of approxi-mately 2-4 g.156,157,18 Daily faecal loss amounts to only 0,4 to 0.8 g.In the absence of the specific bile salt reabsorptive mechanism which is con-fined to the terminal ileum,159"160 at least 90% of the bile salt pool is lost intothe faeces during the digestion of a single meal'6'. Ileal disease or resectionhas two consequences: there is a dearth of detergent bile salt passing down thesmall bowel resulting in steatorrhoea,162,163 and an excess of unabsorbedbile salt in the colon causing diarrhoea. The first is due to the depletion ofthe bile salt pool, so that the bile salt perfusing the small bowel is onlythat quantity which the liver can synthesize anew from cholesterol, 2-4 gdaily,'" instead of the normal 15-30 g. This is insufficient to produce themixed micelles necessary for normal fat absorption.163,165,166"167 However,this 2-4 g now also passes through the large bowel instead of the normal0*4-0.8 g. Bile salts inhibit salt and water absorption by the colon, especiallywhen they have been deconjugated by colonic bacteria85. Following ilealresection, patients may therefore develop a severe bile salt-induced waterydiarrhoea called 'cholerrhoeic entero.pathy', which is more troublesomethan the steatorrhoea. Feeding bile salts makes the diarrhoea worse, butcholestyramine, an anion-exchange resin which binds bile salts and protectsthe colon from their action, relieves the diarrhoea at the expense of someincrease in steatorrhoea.155"168 It is most effective when less than 100 cm ofterminal ileum has been resected and when steatorrhoea does not exceed20 g daily.'55 The place of lignin, a fibre derived from pinewood, is moreuncertain. Its interest lies in its presence in vegetable fibre and in its abilityto adsorb certain bile salts, and it has been claimed to be of value in treat-ment.'69 However, lignin has recently been shown to be less effective thancholestyramine in cholerrhoeic enteropathy'70 and it has little effect on theenterohepatic circulation of taurocholate.171

Cholestyramine does not improve tropical diarrhoea,172 nor the diarrhoeaof ulcerative colitis,'73 so that bile salt catharsis does not appear to be afactor in these diseases.

Disorders of Gut Motility

A large number of different techniques have thrown light on the electrical

1027


activity of intestinal smooth muscle, on its pharmacology, and on pressurechanges and movement of markers within the lumen.'74-'79 Nevertheless fewstudies have combined these techniques to give a useful overall picture ofhow different types of diarrhoea are related to abnormalities of muscularactivity and its control.174'180

Evidence that altered small intestinal transit by itself causes diarrhoea ismostly indirect.180'18' Steatorrhoea may accompany the increased transitrate in thyrotoxicosis,94 small bowel resection, and osmotic diarrhoea,182"183and this may be evidence that the small intestine's large reserve capacityhas been exceeded. After massive small bowel resection, interposition of areversed segment of bowel can sometimes slow transit sufficiently to diminishthe diarrhoea.184 A similar technique has been used successfully for thepuzzling diarrhoea that may follow vagotomy.185 Faecal loss of water andelectrolytes after massive resections can also be diminished by substitutingmedium-chain triglycerides for most of the dietary fat.'86 These are wellabsorbed, even in the absence of bile salts, by a different route than long-chainfats.'87 This does not, however, fully explain their efficiency in reducingdiarrhoea.

Decreased motility may cause the stagnant loop syndrome, as in systemicsclerosis,'88andin a small proportion ofpatients with diabetic diarrhoea.'89-'92

Faeces normally remain in the colon for from one to several da-ys,'79 butthis is reduced by a high-residue diet.'46"i,93 Most of the saccular colon'smuscular activity is segmental, churning the contents but moving them foronly short distances.'94 Propulsive movements occur infrequently, stimulatedespecially by physical activity.'95 They consist of a series of mass movements,which shift a column of faeces three or four times a day over the length ofabout a third of the colon in the space of a few seconds, preceded by thesudden disappearance of haustral segmentation.'96The commonest cause of chronic diarrhoea is the irritable bowel syndrome,

generally considered a psychosomatic disorder in which the various symptomsresult from disordered motility.'97 Consequently this aspect has been muchstudied.198-203 Diarrhoea is usually associated with reduced segmentalcontraction, thus offering less resistance to forward flow. There is also anabnormality in the emptying of ileal contents into the colon.20' In ulcerativecolitis intraluminal pressures are also low,198'202'204 but the relationshipbetween impetus to the faecal stream and generation of pressure in thelumen is altered by the fluidity of the faeces, and the change in tone whichresults in the characteristic 'hose-pipe' colon.'99

Increased fluidity of the faeces itself seems to accelerate gastrointestinaltransit.'82 In one study it was reduced from 26 hours in controls to 4-6 hoursin patients with osmotic diarrhoea induced by mannitol and 5.6 hours incholerrhoeic enteropathy.183The rationale of standard antidiarrhoeal therapy is post hoc. Morphine

and its derivatives increase rhythmical segmentation of the small intestineand haustral contraction of the colon. In electrophysiological terms, theycap almost every pacemaker potential by spike discharges and a muscularcontraction. In effect they stir the contents and foster absorption but do notempty the gut.205 Kaolin and the hydrophilic colloids may also act to increaseresistance to flow by solidifying the colonic contents. Bed rest decreases theeffect of gravity and also reduces the propulsive movements stimulated byphysical activity.

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Much has been done to try to correlate psychological stress with neuro-muscular activity.199$2W,205-207 While there can be no doubt of the greatclinical importance of central nervous activity, present research techniqueshave not yet given consistent and predictable results.208

Chronic Colonic Disease

The profuse watery diarrhoea of ulcerative colitis is due in part to exudationthrough the damaged colonic mucosa,219 since the faeces contain pus andblood, and in part probably to impairment of colonic water and salt ab-sorption.210-212 However, the role of exudation has been thought to be limited,since bypass of the diseased colon reduces colonic fluid loss considerably.21There have long been suggestions that small intestinal dysfunction mayconstitute part of the extracolonic manifestations of the disease, and con-tribute to the diarrhoea. Indeed Truelove's group, who have shown non-specific histological and histochemical abnormalities in the small intestinalmucosa of some patients with acute total colitis,214 have also shown thatcolonic sodium absorption may be very efficient in this disease.21s It is ofparticular interest, therefore, that a recent perfusion study has showndiminished jejunal absorption and even net secretion of water, sodium, andchloride in ulcerative colitis.215 Patients treated with corticosteroids did notshow this defect. Jejunal absorption was much increased by adding glucoseto the perfusate, raising the possibility that in untreated colitis, as in cholera,jejunal secretion is increased but absorptive capacity is retained. Thus acholera-like syndrome has been added to abnormalities of colonic absorption,intestinal motility, lactase deficiency, and milk allergy216 as explanations ofthe diarrhoea in ulcerative colitis.

Coeliac Disease

Several of the mechanisms which have been described above probablyoperate to produce diarrhoea in coeliac disease. With destruction of thevilli in the upper small bowel, carbohydrate absorption is impaired.217,218This in turn should lead to inefficiency of the sodium pump. Since carbo-hydrate and sodium absorption are together the main stimuli to waterabsorption, this is likely to be impaired. This will be further compoundedby the osmotic attraction of water by unabsorbed solute. Moreover coeliacdisease is associated with hypertrophy of the crypts of Lieberkiihn, whichrecent work suggests are the major source of intestinal fluid.3 43 Perfusionstudies clearly show net jejunal secretion of water and sodium219-221 and,as expected, this is not reversed by adding glucose to the perfusate.221 Inaddition to these mechanisms, the permeability of the jejunum to solutehas been shown to be reduced so that the resistance to sodium passingthrough the mucosal 'pores' is increased.220 All these abnormalities inintestinal function diminish lower in the bowel. The colon reabsorbs morewater than normal, but its capacity is exceeded and diarrhoea results.

Conclusion

Until comparatively recently diarrhoea was considered merely as a symptomof a variety of diseases, and thought of in terms of malabsorption of food-

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1030 T. S. Low-Beer and A. E. Read

stuffs, overactivity of intestinal musculature, and colonic infection. In 1941Florey predicted that an understanding of the important factors in thecontrol of intestinal secretion might clear the fog surrounding many aspectsof the pathology of the intestine,222 and in 1944 Visscher and his colleaguesshowed that intestinal absoiption is the resultant of a massive two-waytraffic of water and electrolytes across the mucosa.223 224 Much more attentionhas recently been paid to alterations in the balance of this traffic, especiallyin the small bowel. In cholera, acute enteritis, the stagnant loop syndrome,cholerrhoeic enteropathy, and brush border enzyme deficiency this has resultedin improvements in treatment. Nevertheless many important problems remain.The relationship of small intestinal bacteria and mucosal damage to alteredfluid exchange seems to have eluded analysis in tropical sprue: patients withsimilar degrees of mucosal damage or bacterial colonization may or maynot have symptoms; treatment with antibiotics may remove symptomswithout improving histological appearances.225'226 Lastly, until a satisfactorymethod is found for investigating the many patients with the irritable bowelsyndrome, treatment will have to remain largely symptomatic.

T. S. LOW-BEERA. E. READ

University of Bristol Department of Medicine,Bristol Royal Infirmary

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Progress report Diarrhoea: Mechanisms and treatment

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