Gut Hormones in Gastrointestinal Disease

J Clin Pathol: first published as 10.1136/jcp.s1-8.1.76 on 1 January 1978. Downloaded from J. clin. Path., 33, Suppl. (Ass. Clin. Path.), 8, 76-84 Gut hormones in gastrointestinal disease H. S. BESTERMAN From the Department ofMedicine, Royal Postgraduate Medical School, Du Cane Road, London W12 OHS Considerable advances have been made in the under- Disease or Area mavimally Clinical and standing of the physiology of gut hormones. Thus, pathological state affected pathologicalfeatures knowledge of the mechanisms of release and of the Coeliac disease Duodenum, jejunum Flat mucosa, proximal actions of many of the hormones is rapidly expand- malabsorption, increased enterocyte ing. The known clinical importance of gut hormones turnover, increased is at present confined only to the excess production ileal absorption Acute tropical sprue Entire small intestine Flat mucosa, mal- of gastrin, VIP, and pancreatic glucagon by endo- absorption, delayed crine tumours. The role of these three and the other transit time states pancreas Pancreatic Exocrine pancreas Reduced enzyme gut hormones in disease affecting the insufficiency secretion, malabsorp- and gut has been studied little. Investigation of the tion patterns of gut hormone release in alimentary Morbid obesity - CHO intolerance, increased insulin disease may provide new insight into the patho- release physiology of these disorders. Not only may gut Morbid obesity and Most of small Weight loss, improvedcopyright. jejunoileal bypass intestine out of CHO tolerance, hormones be implicated as primary agents in the continuity villous hypertrophy pathological processes, but also secondary changes Crohn's disease Terminal ileum Inflammation of whole gut wall, in gut hormone release may be related to compensa- diarrhoea tory and adaptive mechanisms. Further insight may Ulcerative colitis Colon Mucosal inflammation, also be gained into the normal physiological roles diarrhoea Infective diarrhoea Ileum, colon Transient severe of the hormones themselves through the effects of diarrhoea diminished or augmented release found in gut Gut resection Ileum, colon Shortened bowel, diseases. We have, therefore, studied the gut hormone villous hypertrophy http://jcp.bmj.com/ profile after a normal meal in several well defined Table 1 Characteristics of diseases studied gastrointestinal diseases, with features summarised in Table 1. The distribution of the known gut hormones has Hormone Principal location been elucidated by the combined techniques of quantitative immunocytochemistry and radio- Gastrin Antrum GIP (Glucose-dependent insulin- on September 30, 2021 by guest. Protected immunoassay of extracted tissues (Bloom et al., releasing polypeptide) Duodenum, jejunum 1975; Bryant and Bloom, 1979). The hormones have Motilin Duodenum, jejunum Secretin Duodenum characteristic locations which are summarised in Pancreatic polypeptide Pancreas Table 2. Neurotensin Ileum Ileum, colon Diseases affect the alimentary tract in many Enteroglucagon different ways, some of them affecting only certain Table 2 Principal distribution ofgut hormones measured portions of the gut. It is to be expected that the release ofgut hormones from areas damaged by the disease would be abnor- 150 ml of unsweetened orange juice (containing a mal. The release of other hormones from areas of total of 18 g protein, 22 g fat, 66 g carbohydrate, and bowel uninvolved in disease, however, might also 530 kilocalories). show secondary changes. The plasma levels of most gut hormones rise Coeliac disease substantially after food. Thus the stimulus to hormone release used in studying the various This disease of unknown aetiology is characterised disease states was a 'physiological' test breakfast. by a flat mucosa involving predominantly the duo- This consisted of two medium-sized boiled eggs, denum and jejunum. Although rarely it may extend 10 g butter, 60 g bread as toast, 35 g marmalade, and to affect a short segment of proximal ileum, the distal 76 J Clin Pathol: first published as 10.1136/jcp.s1-8.1.76 on 1 January 1978. Downloaded from Gut hormones in gastrointestinal disease 77 small intestine and colon are not involved (Rubin 1400 et al., 1960; Booth et al., 1962). Similarly, the stomach and pancreas escape direct involvement by the pathological process. Although there is loss of 1200 villi in the proximal small intestine resulting in a flat mucosa, there is in fact hyperplasia of the entero- blasts (Booth, 1970) and a greatly increased rate of 0o0 i enterocyte production from the base of the crypts (Wright et al., 1973). Since there is a great reduction a, 800 F in the effective mucosal absorptive surface area in the '0L- upper small intestine, reduced absorption of ingested U food occurs, so that the intestinal contents descend ai 600 F further down the gut than normal. There is also a 0- compensatory increased absorption of several sub- stances in the ileum beyond the diseased part 40C (Schedl et al., 1968; MacKinnon et al., 1975; Silk et al., 1975). These adaptive mechanisms might well be mediated via gut hormones. Despite the absence 200 of direct involvement of the pancreas, there is Normal associated impairment of pancreatic exocrine and 1~ ~ ~ ~ ~ endocrine function in that a considerable reduction cb cb occurs in the secretion of pancreatic bicarbonate RIR ~~,R and enzymes after perfusion of the duodenum with c acid or amino-acids (Worning etal., 1967; Wormsley, copyright. 1970; Colombato et al., 1977). Administration of exogenous secretin and cholecystokinin, however, is followed by a normal pancreatic secretory Fig. 1 Postprandial gut hormone profile in coeliac response. disease (integrated 3 hour response expressed as % of This suggests that there is a failure of release of the normal). relevant gut hormones from the upper small intestine. In addition an increased incidence of diabetes mellitus is reported to occur in coeliac disease 1972). Both of these actions would be appropriate to http://jcp.bmj.com/ (Walsh et al., 1978). coeliac disease, and may contribute to the increased rate of enterocyte turnover, the increased ileal GUT HORMONE PROFILE (FIG. 1) absorption, and also to the clinical impression that Patients with untreated coeliac disease have a many of these patients have slow transit times. relative failure of release of both GIP and secretin, Neurotensin is another predominantly ileal hormone. two hormones -localised to the area of maximal In contrast to enteroglucagon, the release of this mucosal damage in coeliac disease (Besterman et al., hormone was only mildly increased compared to 1978d). A failure of cholecystokinin release has also normal. on September 30, 2021 by guest. Protected been reported (DiMagno et al., 1972; Low-Beer et al., 1975), which would fit with the observed Tropical malabsorption (acute tropical sprue) diminished pancreatic endocrine and exocrine response to intraduodenal stimuli. Tropical malabsorption (TM) is characterised In our studies, the release ofgastrin and pancreatic clinically by the sudden onset of diarrhoea in a polypeptide, whose tissues of origin are unaffected, previously healthy subject while travelling in a was entirely normal. Plasma motilin levels were tropical country. The diarrhoea progresses to overt slightly increased above normal, following a tendency malabsorption with steatorrhoea, weight loss, folate for this peptide to be raised in steatorrhoeal con- deficiency, and anaemia. The pathophysiology of the ditions. Plasma enteroglucagon levels, in contrast, condition is poorly understood. These patients have were greatly raised. Not only were basal levels a flat mucosa, usually to a milder degree than that significantly increased, but a massive rise was seen found in coeliac disease, but involving the entire small after the test breakfast. These abnormalities were intestine rather than just the duodenum and jejunum reversed on successful treatment with a gluten-free (Morson and Dawson, 1972; Mathan, 1973). It is diet. Enteroglucagon has been suggested to have a of interest that they have a significantly delayed trophic action on mucosal growth (Jacobs et al., small intestinal transit (Cook, 1978). As in coeliac 1976) and an action slowing intestinal transit (Bloom, disease, they are also reported to have a relative J Clin Pathol: first published as 10.1136/jcp.s1-8.1.76 on 1 January 1978. Downloaded from 78 H. S. Besterman failure of pancreatic exocrine function after a Lundh GUT HORMONE PROFILE (FIG. 3) test meal1 (Balagopal et al., 1975). Fourteen patients with Crohn's disease were studied (Besterman et al., 1978c). After the test breakfast GUT HORMONE PROFILE (FIG. 2) the release ofthe upper small intestinal hormone GIP Eight patients with severe TM were studied (Bester- was increased, in contrast to the poor rise found in man et al., 1979a). There was a significant diminu- coeliac disease and acute tropical sprue. Motilin, tion of both GIP and insulin release associated with however, showed the greatest response, though a delayed and impaired rise in blood glucose. In there was also an augmented pancreatic polypeptide contrast, however, plasma motilin levels were response. Fasting plasma enteroglucagon levels in greatly raised. Basal plasma enteroglucagon con- these patients and the postprandial response were centrations were also much higher than in normals, both greater than normal, but of a lower order of with only a small further rise after the test breakfast. magnitude than in coeliac disease. This pattern differs from that seen in coeliac disease, possibly

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