guthormones in gastrointestinal disease · of the hormones themselves through the effects of...

J. clin. Path., 33, Suppl. (Ass. Clin. Path.), 8, 76-84

Gut hormones in gastrointestinal disease

H. S. BESTERMAN

From the Department of Medicine, Royal Postgraduate Medical School, Du Cane Road, London W12 OHS

Considerable advances have been made in the under-standing of the physiology of gut hormones. Thus,knowledge of the mechanisms of release and of theactions of many of the hormones is rapidly expand-ing. The known clinical importance of gut hormonesis at present confined only to the excess productionof gastrin, VIP, and pancreatic glucagon by endo-crine tumours. The role of these three and the othergut hormones in disease states affecting the pancreas

and gut has been studied little. Investigation of thepatterns of gut hormone release in alimentarydisease may provide new insight into the patho-physiology of these disorders. Not only may guthormones be implicated as primary agents in thepathological processes, but also secondary changesin gut hormone release may be related to compensa-tory and adaptive mechanisms. Further insight mayalso be gained into the normal physiological rolesof the hormones themselves through the effects ofdiminished or augmented release found in gutdiseases. We have, therefore, studied the gut hormoneprofile after a normal meal in several well definedgastrointestinal diseases, with features summarisedin Table 1.The distribution of the known gut hormones has

been elucidated by the combined techniques ofquantitative immunocytochemistry and radio-immunoassay of extracted tissues (Bloom et al.,1975; Bryant and Bloom, 1979). The hormones havecharacteristic locations which are summarised inTable 2.

Diseases affect the alimentary tract in manydifferent ways, some of them affecting only certainportions of the gut.

It is to be expected that the release ofgut hormonesfrom areas damaged by the disease would be abnor-mal. The release of other hormones from areas ofbowel uninvolved in disease, however, might alsoshow secondary changes.The plasma levels of most gut hormones rise

substantially after food. Thus the stimulus tohormone release used in studying the variousdisease states was a 'physiological' test breakfast.This consisted of two medium-sized boiled eggs,10 g butter, 60 g bread as toast, 35 g marmalade, and

Disease or Area mavimally Clinical andpathological state affected pathologicalfeatures

Coeliac disease Duodenum, jejunum Flat mucosa, proximalmalabsorption,increased enterocyteturnover, increasedileal absorption

Acute tropical sprue Entire small intestine Flat mucosa, mal-absorption, delayedtransit time

Pancreatic Exocrine pancreas Reduced enzymeinsufficiency secretion, malabsorp-

tionMorbid obesity - CHO intolerance,

increased insulinrelease

Morbid obesity and Most of small Weight loss, improvedjejunoileal bypass intestine out of CHO tolerance,

continuity villous hypertrophyCrohn's disease Terminal ileum Inflammation of

whole gut wall,diarrhoea

Ulcerative colitis Colon Mucosal inflammation,diarrhoea

Infective diarrhoea Ileum, colon Transient severediarrhoea

Gut resection Ileum, colon Shortened bowel,villous hypertrophy

Table 1 Characteristics of diseases studied

Hormone Principal location

Gastrin AntrumGIP (Glucose-dependent insulin-releasing polypeptide) Duodenum, jejunumMotilin Duodenum, jejunumSecretin DuodenumPancreatic polypeptide PancreasNeurotensin IleumEnteroglucagon Ileum, colon

Table 2 Principal distribution ofgut hormones measured

150 ml of unsweetened orange juice (containing atotal of 18 g protein, 22 g fat, 66 g carbohydrate, and530 kilocalories).

Coeliac disease

This disease of unknown aetiology is characterisedby a flat mucosa involving predominantly the duo-denum and jejunum. Although rarely it may extendto affect a short segment of proximal ileum, the distal

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small intestine and colon are not involved (Rubinet al., 1960; Booth et al., 1962). Similarly, thestomach and pancreas escape direct involvement bythe pathological process. Although there is loss ofvilli in the proximal small intestine resulting in a flatmucosa, there is in fact hyperplasia of the entero-blasts (Booth, 1970) and a greatly increased rate ofenterocyte production from the base of the crypts(Wright et al., 1973). Since there is a great reductionin the effective mucosal absorptive surface area in theupper small intestine, reduced absorption of ingestedfood occurs, so that the intestinal contents descendfurther down the gut than normal. There is also acompensatory increased absorption of several sub-stances in the ileum beyond the diseased part(Schedl et al., 1968; MacKinnon et al., 1975; Silket al., 1975). These adaptive mechanisms might wellbe mediated via gut hormones. Despite the absenceof direct involvement of the pancreas, there isassociated impairment of pancreatic exocrine andendocrine function in that a considerable reductionoccurs in the secretion of pancreatic bicarbonateand enzymes after perfusion of the duodenum withacid or amino-acids (Worning etal., 1967; Wormsley,1970; Colombato et al., 1977). Administration ofexogenous secretin and cholecystokinin, however, isfollowed by a normal pancreatic secretory response.This suggests that there is a failure of release of therelevant gut hormones from the upper small intestine.In addition an increased incidence of diabetesmellitus is reported to occur in coeliac disease(Walsh et al., 1978).

GUT HORMONE PROFILE (FIG. 1)Patients with untreated coeliac disease have arelative failure of release of both GIP and secretin,two hormones -localised to the area of maximalmucosal damage in coeliac disease (Besterman et al.,1978d). A failure of cholecystokinin release has alsobeen reported (DiMagno et al., 1972; Low-Beeret al., 1975), which would fit with the observeddiminished pancreatic endocrine and exocrineresponse to intraduodenal stimuli.

In our studies, the release of gastrin and pancreaticpolypeptide, whose tissues of origin are unaffected,was entirely normal. Plasma motilin levels wereslightly increased above normal, following a tendencyfor this peptide to be raised in steatorrhoeal con-ditions. Plasma enteroglucagon levels, in contrast,were greatly raised. Not only were basal levelssignificantly increased, but a massive rise was seenafter the test breakfast. These abnormalities werereversed on successful treatment with a gluten-freediet. Enteroglucagon has been suggested to have atrophic action on mucosal growth (Jacobs et al.,1976) and an action slowing intestinal transit (Bloom,

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Fig. 1 Postprandial gut hormone profile in coeliacdisease (integrated 3 hour response expressed as % ofnormal).

1972). Both of these actions would be appropriate tocoeliac disease, and may contribute to the increasedrate of enterocyte turnover, the increased ilealabsorption, and also to the clinical impression thatmany of these patients have slow transit times.Neurotensin is another predominantly ileal hormone.In contrast to enteroglucagon, the release of thishormone was only mildly increased compared tonormal.

Tropical malabsorption (acute tropical sprue)

Tropical malabsorption (TM) is characterisedclinically by the sudden onset of diarrhoea in apreviously healthy subject while travelling in atropical country. The diarrhoea progresses to overtmalabsorption with steatorrhoea, weight loss, folatedeficiency, and anaemia. The pathophysiology of thecondition is poorly understood. These patients havea flat mucosa, usually to a milder degree than thatfound in coeliac disease, but involving the entire smallintestine rather than just the duodenum and jejunum(Morson and Dawson, 1972; Mathan, 1973). It isof interest that they have a significantly delayedsmall intestinal transit (Cook, 1978). As in coeliacdisease, they are also reported to have a relative

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failure of pancreatic exocrine function after a Lundhtest meal1 (Balagopal et al., 1975).

GUT HORMONE PROFILE (FIG. 2)Eight patients with severe TM were studied (Bester-man et al., 1979a). There was a significant diminu-tion of both GIP and insulin release associated witha delayed and impaired rise in blood glucose. Incontrast, however, plasma motilin levels weregreatly raised. Basal plasma enteroglucagon con-centrations were also much higher than in normals,with only a small further rise after the test breakfast.This pattern differs from that seen in coeliac disease,possibly reflecting the different pathophysiologicalprocesses and the greater area of gut involved intropical malabsorption. Gastrin, neurotensin, andpancreatic polypeptide responses were all similar tonormal.

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Fig. 2 Postprandial gut hormone profile in acutetropical sprue (integrated 3 hour response expressed as

% ofnormal).

Crohn's disease

This disease is characterised by inflammation of thegut wall often affecting segments of bowel withapparently normal areas in between. The distal ileumis the area most often affected, but the rectum,colon, and jejunum may also be involved.'A mixture of casein hydrolysate and vegetable oil.

H. S. Besterman

GUT HORMONE PROFILE (FIG. 3)Fourteen patients with Crohn's disease were studied(Besterman et al., 1978c). After the test breakfastthe release of the upper small intestinal hormone GIPwas increased, in contrast to the poor rise found incoeliac disease and acute tropical sprue. Motilin,however, showed the greatest response, thoughthere was also an augmented pancreatic polypeptideresponse. Fasting plasma enteroglucagon levels inthese patients and the postprandial response wereboth greater than normal, but of a lower order ofmagnitude than in coeliac disease.

Fig. 3 Postprandial gut hormone profile in Crohn'sdisease (integrated 3 hour response expressed ao. %ofnormal).

Ulcerative colitis

This inflammatory bowel disease affects the mucosaand submucosa of the colon. Thus, the principalhormone-containing areas are all normal.

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GUT HORMONE PROFILE (FIG. 4)In 24 patients with ulcerative colitis the response ofGIP after the test breakfast was entirely normal(Besterman et al., 1978c). Basal plasma motilinlevels were significantly raised. There was an aug-mented gastrin response which might be secondaryto hypochlorhydria (acid studies were not performed)or possibly due to loss of some colonic gastricinhibitory substance secondary to the pathologicaldamage. Both enteroglucagon and pancreaticpolypeptide, as in Crohn's disease, showed amoderately raised response.

Fig. 4 Postprandial gut hormone profile in ulcerativecolitis (integrated 3 hour response expressed as %ofnormal).

Infective diarrhoea

Twelve patients, previously in good health, requiredurgent admission to an isolation hospital for severediarrhoea which required intravenous fluid andelectrolyte treatment. Pathogens were isolated inonly four patients, the rest presumably had eitherbacterial or viral pathogens which were not identi-fiable in the routine laboratory. They all subse-quently made uneventful recoveries.

GUT HORMONE PROFILE (FIG. 5)The test breakfast was eaten at an early time duringrecovery. The responses of pancreatic polypeptide

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and GIP were normal (Besterman et al., 1979b). Incontrast, augmented responses of gastrin, motilin,and enteroglucagon were found. These may relateto compensatory mechanisms occurring in the gutto the diarrhoea. As the diarrhoea abated basalmotilin levels fell in parallel.

Fig. 5 Postprantdial gut hormone profile in infectivediarrhoea (integrated 3 hour response expressed as %ofnormal).

Pancreatic insufficiency

Gross steatorrhoea and malabsorption may occuras a result of chronic pancreatitis causing extensivegland destruction and thus considerable reductionin pancreatic enzyme output. The intestinal mucosain these cases is normal. Gut hormone releasein sixteen patients with chronic pancreatitisand proved pancreatic exocrine insufficiency werestudied (Besterman et al., 1978a). The commonestaetiological factor was excess alcohol intake butsome patients had biliary disease and in a few nopredisposing cause could be identified. The patientshad either grossly impaired or absent responses toinjected secretagogues or to a Lundh test meal. Allhad subsequently improved on being treated with

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H. S. Besterman

pancreatic enzyme supplements. All patients hadeither pancreatic calcification or other abnormalitydiscovered at laparotomy, or endoscopic retrogradecanulation of the pancreatic duct (ERCP), and manywere diabetic.

GUT HORMONE PROFILE (FIG. 6)In these patients the GIP response was entirelynormal in contrast to the diminished release incoeliac disese and acute tropical sprue, in both ofwhich the malabsorption is secondary to mucosaldamage. The gastrin response was diminished butboth the motilin and enteroglucagon responses wereincreased. The increased enteroglucagon releasewas, however, much less than that found in associa-tion with atrophic small intestinal mucosa. Thiscould suggest that the grossly raised levels in coeliacdisease and acute tropical sprue are not merelysecondary to the steatorrhoea (fat is a potentstimulant of enteroglucagon release) as this is muchgreater in the patients with pancreatic insufficiency.The most striking finding in patients with pan-

creatic insufficiency was the gross failure ofpancreaticpolypeptide release following the test breakfast(Adrian et al., 1979). This probably reflects theextensive damage to pancreatic tissue as the pan-creatic poplypeptide cells are scattered throughoutthe pancreatic parenchyma.

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Fig. 6 Postprandial gut hormone profile in pancreaticinsufficiency (integrated 3 hour response expressed as %of normal).

Intestinal resection

The subsequent effects of surgical removal of alength of intestine depend on the site and on thelength of gut resected. The loss of absorptive areamay give rise to severe malabsorption, even whenonly a short length of distal ileum has been resected(for example failure of vitamin B12 and bile saltabsorption). After small intestinal resection there isvillous hypertrophy of the mucosa of the remainder(Porus, 1965; Dowling and Gleeson, 1973). Thiscompensatory mechanism is probably stimulated bya humoral agent, enteroglucagon being a possibility.We have studied patients who have undergone

varying degrees of gut resection for a number ofdifferent pathological states (Besterman et al.,1978b). The commonest indication for surgery wasCrohn's disease when most patients had between oneand two metres of terminal ileum resected. Partialresection of the ascending or transverse colon orboth was carried out for Crohn's disease or ulcerativecolitis. Neoplasia, trauma, and post-radiationfibrosis were less common reasons.

GUT HORMONE PROFILE (FIG. 7)There was no significant difference between theeffects of partial ileal and partial colonic resectionin the responses of gastrin, pancreatic polypeptide,GIP, and neurotensin. The post-breakfast releaseof both gastrin and pancreatic polypeptide wasgreater than normal in both groups of patients.Raised gastrin levels after intestinal resection havebeen reported by others (Straus et al., 1974) and thismay be relevant to the gastric acid hypersecretionwhich occurs in these patients (Frederick et al.,1965; Osborne et al., 1966). The GIP and neuro-tensin responses, in contrast, were similar to normal.There was, however, a striking difference in theresponses of motilin and enteroglucagon between thetwo groups of patients. The patients with partialresection of the colon had only mildly raised motilinresponses and even a somewhat decreased entero-glucagon release. Those with partial resection of theileum had a greatly augmented motilin response andalso a substantially increased release of entero-glucagon.

Despite the pathological heterogeneity of thesegroups and variations in the time between operationand the study, clear patterns of gut hormoneresponse are found. These changes, varying with thedifferent types of intestinal resection, may wellreflect important compensatory mechanisms.

Morbid obesity and the effect of jejunoileal bypass

The control of appetite and the regulation of bodyweight are very poorly understood. An interaction

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hypertrophy of the remaining small intestine (Fenyoet al., 1976; Iversen et al., 1976; Dudrick et al., 1977).The role of gut hormones in the control of satietyand their involvement in these metabolic complica-tions is not known.

GUT HORMONE PROFILE (FIG. 8)In 19 patients with morbid obesity (225 ± 7% idealweight) no abnormality of gut hormone release wasfound to match the exaggerated blood glucose andinsulin responses to the test breakfast (Bestermanet al., 1978e). Thus, deficiency of none of the guthormones measured in the present 'profile' seemsresponsible for the failure of satiety mechanisms.There is a relatively drastic alteration of functionalgut anatomy after jejunoileal bypass. This is reflectedby several alterations in the pattern of gut hormonerelease in 21 patients studied between two and twelvemonths after bypass (181 ± 8% ideal weight). The

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Fig. 7 Postprandial gut hormone profile after gutresection (integrated 3 hour response expressed as %ofnormal).

between the gut and the hypothalamus is likely, withthe sensation of satiety possibly being mediated by agut hormone. Gross obesity is accompanied bymetabolic disturbances, sometimes profound, whichgive rise to increased morbidity and mortality.Glucose intolerance and raised insulin levels maygive rise later to frank diabetes mellitus. Morbidobesity may be literally life-threatening and oneform of treatment which has been widely used is theoperation of jejunoileal bypass. Seven inches ofproximaljejunum are anastomosed to seven inches ofdistal ileum, with the remaining small intestine leftout of contact with food as a blind loop. Patientsinvariably lose weight after this procedure, but rarelydo they return to ideal body weight. The weight lossis thought not to be the result of malabsorptionsecondary to the vast reduction in mucosal surfacearea, but to a self-imposed decrease in the amount ofingested food. Eating any great amount of food isusually associated with diarrhoea and abdominalpain from distension.The operation of jejunoileal bypass of itself may

give rise to metabolic complications. One adaptivefeature which is observed in these patients is villous

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Fig. 8 Gut hormone profile after jejunoileal bypass formorbid obesity (integrated 3 hour response expressed as% ofnormal).

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82 H. S. Besterinan

gastrin response was moderately increased, fittingwith the known gastric hypersecretion occurring inthese patients. The GIP response was greatly reduced,and insulin release was also much less than normal,being greatly reduced compared with the increasedrelease in obesity. HPP and motilin responses werenormal. There was an eightfold increase in neuro-tensin and a massive sixteenfold increase in entero-glucagon after the test meal compared to normal.The augmented neurotensin response may be relevantto the altered carbohydrate metabolism. Theexaggerated enteroglucagon levels may well be afactor in the villous hypertrophy. Both of thesehormones may also have an effect on gut motility.

Irritable bowel syndrome (IBS)

This common diagnosis is made by exclusion ofdemonstrable organic disease and is usually regardedas a 'functional' disorder. Abnormalities of intestinalmotility have been described (Misiewicz, 1974) andabnormal gut hormone release has been postulatedas an aetiological factor (Harvey, 1977).

GUT HORMONE PROFILEA total of 42 patients with IBS were studied. Nine-teen had abdominal pain and frequency of bowelaction, 11 had pain and constipation, and 12 hadpain but normal bowel function. All had beenthoroughly investigated and no organic diseasefound. In contrast to all other disease groupsstudied, these patients had entirely normal responsesof all the gut hormones measured.

Conclusions

The study of differential gut hormone release invarious diseases affecting different segments of thegut has shown many abnormalities. In general afailure of hormone release has been found when thehormone under study is located in the area ofmaximal disease activity. Thus a diminished GIPresponse is found in coeliac disease and a greatlyreduced release of human pancreatic polypeptide isseen in pancreatic insufficiency. Increased hormonalrelease may be secondary to the altered function ofthe gut. Thus ingested food will reach the ileum andconstitute an increased stimulus when there is mal-absorption in the jejunum, or if the anatomy hasbeen altered to eliminate much of the proximal smallgut. These phenomena might be thought to explainthe very great release of enteroglucagon found incoeliac disease, in acute tropical sprue, after ilealresection, and after jejunoileal bypass operation.However, in considering malabsorption alone as anexplanation of the findings in coeliac disease and

tropical sprue, the absence of such augmentedresponses in pancreatic insufficiency, when thedegree of steatorrhoea was much greater, must beremembered. In the gut resection group, highlysignificant rises of enteroglucagon occurred in manypatients who had undergone removal of only a smalllength of ileum. In addition, in all the groups ofpatients with very large enteroglucagon responses,significantly raised basal levels were found. Theseproperties, shared by very different diseases, have anumber of factors in common. Each disease grouphas a reduction in the effective mucosal absorptivesurface area in the small intestine. A number ofcompensatory mechanisms are observed. Forinstance, in coeliac disease increased absorption inthe ileum beyond the diseased portion and anincreased enterocyte turnover occurs; in tropicalsprue there is delayed transit; in both gut resectionand jejunoileal bypass villous hypertrophy is seen.Observations on a patient with excessive secretion ofenteroglucagon by an endocrine tumour (Bloom,1972) suggest that delayed intestinal transit andvillous hypertrophy might well be actions of thishormone.The study of gut hormones in disease states thus

identifies many situations where there is an abnor-mality of hormone release. Abnormal gut hormonerelease may help in the further understanding of thepathophysiology of several gut diseases which haveremained enigmas for many years. Hypo- and hyper-secretion of the individual gut hormone and correla-tion with the altered gut function may also provideimportant new insight into the normal physiologyof the hormone. Lastly, it is not inconceivable thata simplified gut hormone profile, based perhaps onjust three blood samples taken by a clinic nurse, mayin the future provide an additional investigationaltool towards the diagnosis of gastrointestinal disease.

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Gut hormones in gastrointestinal disease 83

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