Article about hormones and the gastrointestinal tract, which are a group of hormones released from specialized cells in the stomach, pancreas, and small intestine that control various functions of the digestive organs. Gastrin, secretin, cholecystokinin, and vasoactive intestinal polypeptide are the best known of these hormones, but new hormones are still being discovered.

Hormones released from endocrine cells in the stomach, pancreas, and intestine aid digestion by stimulating the release of bile from the gallbladder and enzymes from the pancreas into the duodenum.

Gastrin

Secreted mainly by cells in the stomach in response to eating food (especially protein), gastrin causes the stomach to produce more acid and stimulates contraction of muscle in the wall of part of the stomach, ileum, and colon. This contraction propels food through the digestive tract.

Cholecystokinin

Released by the duodenum in response to fats and acid, cholecystokinin causes the gallbladder to squeeze bile into the duodenum and stimulates the production of pancreatic enzymes, which pass into the duodenum through the pancreatic duct.

Secretin

Secreted by the lining of the duodenum in response to acid entering from the stomach, secretin acts on the pancreas to increase the output of bicarbonate, which neutralizes acid from the stomach. It also increases the release of enzymes from the pancreas.

Hormones and the gastrointestinal tract in detail - technical

Essentials

The gastrointestinal tract is the largest endocrine organ in the body, with its component cells dispersed along its length rather than being clustered in glands. Gut peptides integrate gastrointestinal function by regulating the actions of the epithelium, muscles, and nerves, affect the growth and development of the gut and—as has emerged comparatively recently—they also have a major role in appetite control. There is little evidence that many gut peptides act as hormones in a classical endocrine fashion: many are autocrine, regulating the function of the cell secreting them, or paracrine, influencing the behaviour of neighbouring cells of different types.

Many gut peptides have been described, including the following.

The gastrin–cholecystokinin family—gastrin, which stimulates gastric acid secretion and has a trophic effect on the gastric mucosa, and cholecystokinin, a postprandial satiety signal.

The secretin family—secretin, which stimulates production of watery, alkaline pancreatic juices; glucose-dependent insulinotropic peptide, which stimulates insulin release in response to a mixed meal; vasoactive intestinal peptide (VIP), a stimulator of small-intestinal and colonic enterocyte secretion of water and electrolytes.

Peptide products of preproglucagon—enteroglucagon, which may be important in gut adaptation; glucagon-like peptides 1 and 2 and oxyntomodulin, which induce satiety.

Peptide products of preproghrelin—ghrelin, which is the only hormone known to stimulate food intake; obestatin, whose physiological function is uncertain; and motilin, which accelerates intestinal transit.

Peptide tyrosine tyrosine (PYY), which slows intestinal transit, and neuropeptide Y, which is a potent vasoconstrictor, inhibits intestinal secretion, and depresses colonic motility.

Others—bombesin and the gastrin-releasing peptides; opioids; tachykinins; other gut peptides—neurotensin; somatostatin; chromogranin-derived peptides; and other peptide neurotransmitters.

Gastrointestinal disease may cause abnormalities of these gut peptides, e.g. (1) achlorhydria (from atrophic gastritis or drug-induced) causes elevation of circulating gastrin; (2) malabsorptive conditions are associated with a decrease in the amount of peptides produced in the affected region, and a compensatory elevation of other peptides.

Carcinoid syndrome

Carcinoid tumours are capable of producing serotonin (5-hydroxytryptamine; 5-HT). Carcinoid syndrome occurs in about 10% of patients with carcinoid tumours, usually midgut tumours that have metastasized to the liver. The cardinal feature is the carcinoid flush; other characteristic symptoms are secretory diarrhoea, cramping abdominal pain, nausea, and vomiting; and about 50% of patients have cardiac valve abnormalities. The diagnosis is made on the basis of elevated concentrations of 5-hydroxyindoleacetic acid in a 24-h urine collection, with localization by octreoscan (using radiolabelled octreotide), ultrasonography/CT, or endoscopy. Treatment is with simple antidiarrhoeal agents and octreotide, a long-acting, subcutaneously administered, somatostatin analogue. The 5-year survival rates for carcinoids (depending on location) are 33 to 98%.

Introduction

The discovery of secretin, the first recognized hormone, by Bayliss and Starling in 1902 marked the birth not only of gastrointestinal endocrinology, but of endocrinology itself. This first discovery was followed in 1905 by the identification of gastrin, but the technique of identifying hormones was, thereafter, more successfully applied to the study of secretions from the ductless glands, and gastrointestinal endocrinology languished for the next six decades. The determination of the amino acid structure of gastrin following its extraction from a solid tumour in 1964 marked a renewed interest in the field, and the introduction of techniques for large-scale chemical extraction and purification of hormones resulted in the discovery of further gut peptides. Many of these proved to be neuropeptides and have been identified within the central and peripheral nervous systems.

This section describes gut peptide hormones and neurotransmitters, classifying them by common structure or precursor peptides, and then outlines abnormalities in gastrointestinal disease. The roles of gut peptides in the syndromes associated with gastroenteropancreatic tumours are considered in detail elsewhere, while the carcinoid syndrome is described at the end of this article.

Techniques that have contributed to our understanding of gastrointestinal endocrinology include molecular biology, which has helped identify members of peptide families by molecular cloning techniques and has provided information about peptide processing that, in turn, has shown that different peptides may originate from a single common precursor. Sensitive peptide radioimmunoassay has allowed detection of gut peptides, which often have very low concentrations in plasma and tissues. Furthermore, specific peptide antibodies can be used for immunocytochemistry to demonstrate the cellular localization of peptide-producing cells, and for immunoneutralization studies to elucidate the pathophysiological functions of gut peptides. Peptide localization can be further defined by electron microscopy, which demonstrates specific peptide storage granules, and in situ hybridization, which allows the sites of peptide synthesis to be identified by revealing the cellular distribution of specific mRNA species. A major advance in gastrointestinal endocrinology has been the molecular characterization of hormone receptors by cloning techniques. This has demonstrated different receptors for the same ligand and provides an explanation for the diverse biological actions of many gut peptides in the same tissues.

Gut peptides

Gastrin–cholecystokinin family

Gastrin

Gastrin occurs in various molecular forms, but all the biological activity resides in the four C-terminal amino acids. The major molecular forms contain 17 (G17; 2098 Da), 14 (G14; pentagastrin), and 34 (G34; big gastrin) amino acids. Larger molecular forms have been described but may be artefacts. In humans, gastrin is mainly in the gastric antrum, where G17 predominates, but is also found in the upper small intestine, mainly as G34. These two are the predominant circulating forms. Gastrin is synthesized in G cells where it is stored in large electron-lucent granules.

Gastrin release, following protein ingestion and gastric distension, stimulates gastric acid secretion and has a trophic effect on the gastric mucosa. Infusion of gastrin stimulates gastric motor activity and contraction of the lower oesophageal sphincter, although the physiological significance of this action is unclear.

Cholecystokinin

Cholecystokinin has a C-terminal sequence of five amino acids identical to gastrin, but its specificity is conferred by the adjacent three amino acids, and this octapeptide confers its biological activity. It is found in the gut predominantly in molecular forms with 33, 39, or 58 amino acids, and is produced by the I cells of the duodenal and jejunal mucosa. The octapeptide cholecystokinin is a neurotransmitter in the central and enteric nervous systems.

Cholecystokinin is a postprandial satiety signal. The development of antagonists specific for the two cholecystokinin receptor subtypes (CCK1R/CCK-A, which is cholecystokinin-specific, and CCK2R/CCK-B, which appears to be also the only gastrin receptor) has allowed the important physiological roles of cholecystokinin to be characterized. The CCK-A receptor appears to be involved in stimulation of gallbladder contraction and trophic effects on the duodenum and pancreas. The ability of CCK1R receptor antagonists potently to inhibit meal-stimulated gallbladder contraction may be of therapeutic value in biliary colic.

Secretin family

In addition to secretin itself the secretin family includes glucose-dependent insulinotropic peptide, glucagon, enteroglucagon, vasoactive intestinal peptide (VIP), peptide histidine methionine, and growth hormone (GH) releasing factor. The latter is released from the hypothalamus, mainly as a peptide of 44 amino acids, to stimulate release of GH, but is also found in significant concentrations, mainly in a 40 amino acid form, in the small intestinal mucosa, where its function is unknown.

Secretin

Secretin is a 3056-Da peptide of 27 amino acids, which appears to occur in only one molecular form, the whole molecule being needed for full biological activity. It is produced by S cells sparsely scattered throughout the duodenal and jejunal mucosa. The main stimulus to secretin release is a duodenal pH of less than 4.5, although this occurs rarely. It is probably also secreted late after a meal, but the timing and quantities of this secretion are uncertain. The main physiological role of secretin is stimulating the production of watery, alkaline pancreatic juices in response to acid in the duodenum. It may play an important part in the developing gastrointestinal tract, concentrations of secretin being particularly high in the early postnatal period.

Glucose-dependent insulinotropic peptide

Glucose-dependent insulinotropic peptide is a 5105-Da peptide of 42 amino acids produced by K cells, predominantly in the upper small intestinal mucosa, but also in the gastric antrum and ileum, and is stored in large granules.

At pharmacological doses, glucose-dependent insulinotropic peptide inhibits gastric secretions, hence its original name of gastric inhibitory peptide (GIP). However, its physiological role appears to be as a component of the enteroinsular axis, being released in response to a mixed meal, particularly carbohydrates and long-chain fatty acids, and stimulating insulin release. This incretin effect, also exerted by GLP1 (see later), has been shown to be accompanied by increased levels of cAMP in islet β cells with consequent increased cell mass and resistance to apoptosis.

Vasoactive intestinal peptide (VIP)

VIP is a 3326-Da peptide neurotransmitter of 28 amino acids widely distributed throughout the central and peripheral nervous systems. Its highest concentrations occur in the submucosa of the intestinal tract, where it is found in postganglionic intrinsic nerves. It is a potent stimulator of small-intestinal and colonic enterocyte secretion of water and electrolytes, acting via elevation of cAMP. Other important actions include smooth-muscle relaxation, both in the alimentary tract and in the systemic vasculature; stimulation of insulin release, counteracted by a direct glucagon-like effect of VIP in stimulating hepatic gluconeogenesis and glycogenolysis; stimulation of pancreatic bicarbonate secretion; and relaxation of the gallbladder, pyloric sphincter, and circular muscle of the small intestine with contraction of the longitudinal muscle.

Peptide histidine methionine, a neuropeptide of 27 amino acids with considerable sequence homology to VIP, is derived from the adjacent exon of the prepro-VIP gene. It mimics the actions of VIP, probably acting via the same receptor, but is less potent.

Another peptide with considerable sequence homology to VIP is pituitary adenylate cyclase-activating peptide, which occurs in forms with 27 and 38 amino acids. It has a similar tissue distribution to VIP, sharing the same receptor outside the central nervous system and pituitary gland, and similar actions on

Peptide products of preproglucagon

In the pancreas the major product of the preproglucagon molecule is pancreatic glucagon, but in the intestinal L cells preproglucagon is cleaved into enteroglucagon, a peptide of 69 amino acids containing the entire sequence of pancreatic glucagon, two glucagon-like peptides (GLP-1_7–36 NH₂ and GLP-2), and oxyntomodulin.

Enteroglucagon

Enteroglucagon (sometimes called glicentin) is found in high concentrations in the mucosa of the ileum, colon, and rectum. It is released after a mixed meal, particularly of carbohydrate and long-chain fatty acids. The amount of enteroglucagon secreted is proportional to the amount of unabsorbed food entering the colon, and high enteroglucagon concentrations are found in conditions associated with loss of the small-intestinal absorptive capacity. Thus, it has been postulated that enteroglucagon has a trophic effect on the small intestinal mucosa and may be important in gut adaptation.

Glucagon-like peptide 1

The most common circulating form of glucagon-like peptide 1 is as GLP-1_7–36 NH₂. It is released after a meal and, in humans, is the most potent incretin. It induces satiety, inhibiting secretion of glucagon and potentiating the release of somatostatin.

Glucagon-like peptide 2

This appears to stimulate motility and absorption and has trophic effects on the intestine.

Oxyntomodulin

Enteroglucagon is further cleaved by the L cells to produce oxyntomodulin, a peptide of 37 amino acids which is released into the circulation and is a potent inhibitor of gastric motility and secretion. Like glucagon-like peptide 1, it is released postprandially and appears to induce satiety; chronic administration has been shown to reduce weight. Oxyntomodulin appears to act via the receptor for glucagon-like peptide 1 and reduces food intake with similar potency, despite having a 50-fold lower affinity.

Peptide products of preproghrelin

Ghrelin

Studies on growth hormone (GH) secretagogues led to the identification of a specific G-protein-coupled receptor termed the GH secretagogue receptor (GHSR). Subsequently, the endogenous ligand for this receptor was identified as an acylated peptide of 28 amino acids, called ghrelin, cleaved from a 117 amino acid precursor, preproghrelin. Ghrelin and motilin (see below), along with their precursors and receptors, are structurally related, leading to suggestions that they form a new family of peptides. Ghrelin is a circulating hormone secreted predominantly from the oxyntic mucosa of the stomach but is found in other areas of the gut. Its major action is to stimulate food intake. It is, to date, the only known orexigenic hormone and, as such, it opposes the satiety signal leptin.

Obestatin

The only other product of preproghrelin described so far is the 23 amino acid amidated peptide obestatin. It was reported that its administration, peripherally or centrally, to obese rats suppresses food intake and decreases body weight. However, this suggestion that the two known cleavage products of preproghrelin play antagonistic roles in the control of food intake has not been substantiated by subsequent studies.

Motilin

Motilin, a 2700-Da peptide of 22 amino acids, secreted by small intestinal M cells, was first characterized in 1971. Peaks in motilin secretion coincide with initiation of the duodenal myoelectric complex, and so motilin appears to control the reflex motor activity of the small intestine, keeping the small intestine free of debris. Circulating amounts of motilin rise after a meal or drinking water and it may have a physiological role in accelerating gastric emptying and colonic transit. Macrolide antibiotics, e.g. erythromycin, are motilin receptor agonists, hence their side effects of diarrhoea and abdominal cramps.

Peptide tyrosine tyrosine (PYY) and neuropeptide Y

The pancreatic polypeptide-fold (PP-fold) family includes the gut hormone peptide tyrosine tyrosine, the neurotransmitter neuropeptide Y, and, in the pancreatic islets, pancreatic polypeptide. All are 36 amino acid peptides that require C-terminal amidation for bioactivity and share the PP-fold structural motif. They interact with the Y family of receptors that couple to inhibitory G proteins and are probably derived from a common ancestral gene.

Peptide tyrosine tyrosine

Peptide tyrosine tyrosine (PYY) is a 36 amino acid peptide found in the L cells of the distal gut. It is released into the circulation following a meal, mostly as PYY_3–36, and its levels are reduced during fasting. Its main function appears to be to slow intestinal transit, allowing more time for absorption. Other actions include delaying gastric emptying, decreasing intestinal motility, and inhibiting gastric acid secretion. Clinical trials are testing the efficacy of PYY_3–36 as an antiobesity agent.

Neuropeptide Y

Neuropeptide Y is a 36 amino acid peptide neurotransmitter, which is often colocalized with noradrenaline. It is found in both extrinsic adrenergic nerves to the myenteric plexus and in intrinsic nerves in the myenteric and submucosal plexi, and highest concentrations occur in the upper intestine and distal colon. It is a potent vasoconstrictor, inhibits intestinal secretion, and depresses colonic motility.

Bombesin and the gastrin-releasing peptides

Bombesin is a 1620-Da peptide of 14 amino acids initially isolated from amphibian skin. It was found to be a potent stimulator of gastrin, and hence of gastric acid secretion. Its mammalian counterparts have similar properties and so were named gastrin-releasing peptides. In humans, gastrin-releasing peptide is a 27 amino acid peptide found in the gut in the intrinsic neurons of the myenteric and submucosal plexuses, particularly in the stomach and pancreas. In addition to its effect on gastrin, it stimulates release of motilin and cholecystokinin, and pancreatic enzyme secretion. Gastrin-releasing peptide is mitogenic and has been reported to have trophic effects on the developing gut. It is also a potent chemoattractant of macrophages and lymphocytes and enhances the phagocytic process in macrophages.

Opioids

The opioid peptides leu-enkephalin, met-enkephalin, and dynorphin are widespread throughout the nerves of the myenteric and submucosal plexuses of the gastrointestinal tract. Their principal actions appear to be inhibition of gastrointestinal secretion and increased smooth muscle contractility. In addition, observations of the activity of µ opioid receptors in inflammatory bowel diseases indicate that endogenous opiates may confer a measure of protection against inflammation.

Tachykinins

The existence of substance P, a 1345-Da peptide of 11 amino acids, was demonstrated in 1931 through its ability to cause smooth-muscle contraction and vasodilatation. Several homologous peptides have since been characterized and are collectively known as tachykinins, because of their rapid action. In humans, there are two tachykinin genes; preprotachykinin A (TAC1) encoding substance P and neurokinin-α, and preprotachykinin B (TAC3) encoding neurokinin-β. These three tachykinins are localized to neurons in the myenteric and submucosal plexuses throughout the gastrointestinal tract and their principal effects are smooth-muscle contraction, vasodilatation, and inhibition of intestinal absorption.

Other gut peptides

Neurotensin

Neurotensin is a 1673-Da peptide of 13 amino acids present throughout the central nervous system, and in enteric neurons and N cells of the ileal mucosa. It was originally isolated from bovine hypothalamus. Plasma neurotensin concentrations rise postprandially, particularly after fatty food. At physiological doses, neurotensin inhibits gastric acid secretion and gastric emptying, and stimulates pancreatic exocrine and intestinal secretion.

Somatostatin

Somatostatin was initially isolated from the hypothalamus as a 1640-Da peptide of 14 amino acids that inhibited the release of GH. It is widely distributed throughout the central and peripheral nervous systems and is found in a variety of endocrine tissues. In the gastrointestinal tract, it occurs in 14 and 28 amino acid forms secreted by specialized (D) cells distributed throughout the gut mucosa  and on the inner rim of the pancreatic islets. D cells have all the characteristics of endocrine cells, but also possess axon-like basal elongations along which the peptide can be transported and secreted directly on to local cells. Somatostatin inhibits hormone release, blocks the response of the effector tissue and inhibits a wide range of gastrointestinal functions (Table 15.9.1). Five human somatostatin receptors have been identified and cloned, the type 1 receptor predominating in the gastrointestinal tract. As gastrointestinal and other neuroendocrine tumours often possess high-density somatostatin receptors, scintigraphy with radiolabelled somatostatin analogues has been used for tumour localization (see ‘Carcinoid syndrome’, below).

Chromogranin-derived peptides

These structurally related acidic proteins are present in the secretory granule matrix of neuroendocrine cells and are useful markers of normal and neoplastic neuroendocrine cells. To date, this family of proteins has been shown to consist of three molecules: chromogranin A, the first to be identified and also known as (parathyroid) secretory protein I; chromogranin B, or secretogranin I; and chromogranin C, or secretogranin II. It appears that the chromogranins have dual physiological roles: they may act in the processing of some regulatory peptides and prohormones. Their latter property was suspected when the primary structures of the three proteins were determined. All were found to contain multiple pairs of basic amino acids, forming sites for potential proteolytic cleavage. Chromogranin A gives rise to several peptides, including catestatin, chromostatin, vasostatin, and parastatin. Another derived peptide, pancreastatin, was first characterized as a potent inhibitor of insulin release and later found in mucosal cells throughout the gut, where it is often co-stored with other peptides. It is released by gastrin from enterochromaffin-like cells of the gastric fundus, fitting with its action of enhancing meal-stimulated gastric acid secretion. The chromogranin B molecule yields, among other peptides, GAWK (named from its first four amino acids: glycine, alanine, tryptophan, and lysine), a peptide distributed abundantly throughout the gut in both mucosal endocrine cells and intramural nerves. Chromogranins are proving to be of relevance to clinical medicine as plasma concentrations of chromogranins A and B can be used to determine the presence of a neuroendocrine tumour and as a means to monitor the efficacy of treatment.

Other peptide neurotransmitters

Calcitonin gene-related peptide (CGRP) is a peptide of 37 amino acids produced by alternative splicing of the calcitonin gene transcript. It is a widespread neurotransmitter and in the gut occurs in both extrinsic sensory nerves and intrinsic neurons. It inhibits gastric acid and pancreatic secretion, and causes relaxation of vascular smooth muscle.

Galanin is a peptide neurotransmitter of 29 amino acids isolated from porcine intestine. It is widely distributed in enteric nerve terminals and in nerves supplying the liver and pancreatic islets. Its main actions are inhibition of intestinal smooth-muscle contraction and inhibition of postprandial insulin release.

The potent vasoconstricting peptide endothelin has been demonstrated in the plexuses of the gastrointestinal tract and in mucosal epithelial cells. However, its role in the regulation of gastrointestinal function is unknown.

Gut peptides in gastrointestinal disease

Gastric pathology

The commonest cause of elevated levels of circulating gastrin is achlorhydria, which may result from atrophic gastritis, pernicious anaemia, or uraemia, or from iatrogenic causes such as the use of H₂-receptor antagonists or proton pump inhibitors such as omeprazole, or following vagotomy. The elevation is a consequence of the loss of negative feedback on gastrin secretion by the low stomach pH. If the antrum is mistakenly retained after gastric surgery, this similarly removes the antral G cells from exposure to gastric acid and is associated with high gastrin concentrations. Achlorhydria-related hypergastrinaemia results in hyperplasia of the gastric histamine-producing enterochromaffin-like cells. Long-term increases in gastrin levels are associated with gastric carcinoid tumours that are thought to develop as a result of the direct trophic effect of gastrin on enterochromaffin-like cells. Antisecretory therapy in humans has not been associated with the development of these tumours, but recommended therapeutic doses should not be exceeded and hypergastrinaemia should be avoided in patients on long-term therapy.

Peptic ulcer disease is not usually associated with abnormalities in gut peptide secretion, although a decrease in somatostatin release in patients infected with Helicobacter pylori may influence the paracrine regulation of gastric function.

After gastrectomy or truncal vagotomy, patients may develop the dumping syndrome due to accelerated gastric emptying. In these individuals there is a marked increase in the postprandial rise of VIP, neurotensin, PYY, and enteroglucagon, and a decrease in the release of motilin. VIP and neurotensin may both contribute to the postprandial hypotension associated with dumping, but neurotensin may have a beneficial effect in slowing gastric transit. The long-acting somatostatin analogue octreotide is often a very effective treatment for this condition.

Malabsorption

Malabsorptive conditions are associated with a decrease in the amount of peptides produced in the affected region, and a compensatory elevation of other peptides, particularly those trophic peptides implicated in the bowel’s adaptation to loss of absorptive surface, such as enteroglucagon.

The postprandial peptide response in patients with untreated coeliac disease shows greatly reduced secretion of glucose-dependent insulinotropic peptide and secretin, which originate from the affected region of bowel. In contrast, there is marked elevation of enteroglucagon, neurotensin, and PYY. The decrease in secretin and increase in PYY may be responsible for the reduced pancreatic exocrine and biliary secretion found in this condition. Enteroglucagon stimulates enterocyte turnover in the affected segment, despite the villous atrophy. It may have a trophic effect on the remaining small-intestinal mucosa and delay gut transit time, and neurotensin may help to improve absorption by delaying gastric emptying. In tropical sprue, a postinfective malabsorptive state, a different profile of postprandial peptide release is seen with marked elevation in enteroglucagon and PYY, as in coeliac disease, but also in motilin secretion, while other peptides behave normally. Successful treatment of coeliac disease or tropical sprue returns peptide responses to normal.

The malabsorption associated with pancreatic exocrine insufficiency of any cause leads to an excess of nutriments in the colon, and as a result the concentrations of enteroglucagon, PYY, and neurotensin are raised. The gut adaptation resulting from the effects of these peptides may contribute to the improvement in absorptive function with age in patients with cystic fibrosis.

Intestinal resection

Intestinal resection has profound effects on gut peptide concentrations. A jejunoileal bypass used to be constructed in patients with gross obesity. Peptide concentrations were normal preoperatively, but patients were hyperinsulinaemic and glucose intolerant. After the procedure there was an almost complete absence of the prandial glucose-dependent insulinotropic peptide response and consequently a much reduced first-phase insulin response. The initial beneficial effects of the operation were ultimately negated by massive hypertrophy of the remaining bowel. The appearance of large volumes of undigested nutrients in the distal ileum is associated with a 16-fold increase in enteroglucagon responses and an 8-fold increase in neurotensin secretion, and this may provide an explanation for the hypertrophy. After partial ileal resection, the concentrations of gastrin, enteroglucagon, pancreatic polypeptide, motilin, and PYY are elevated, but after colonic resection only gastrin and pancreatic polypeptide are raised, as there is a decrease in production of the other predominantly colonic peptides.

Diarrhoea

In acute infective diarrhoea, the concentrations of enteroglucagon, PYY, and motilin are increased, probably contributing to the altered gut motility and aiding mucosal repair. Patients with Crohn’s disease have an elevated pancreatic polypeptide, glucose-dependent insulinotropic peptide, motilin, and enteroglucagon, while in ulcerative colitis there is a modest elevation in pancreatic polypeptide, glucose-dependent insulinotropic peptide, motilin, and gastrin, the last in response to the hypochlorhydria associated with the disease. Elevated levels of endothelin have been reported in ulcerative colitis and Crohn’s disease and oral administration of an endothelin receptor antagonist in a model of colitis was found to ameliorate diarrhoea and tissue damage. No demonstrable abnormalities in gut peptides account for disordered motility in the irritable bowel syndrome.

Intestinal tumours

The trophic effects of gut peptides may contribute to proliferation of malignant gut tumours. In particular, colon carcinoma cells have receptors for a number of potentially mitogenic peptides, including gastrin, gastrin-releasing peptides, and VIP.

Neuropathic disease

In conditions associated with destruction of intrinsic enteric nerves there is loss of the neurocrine peptides found in the affected region. Chagas’ disease results from chronic infection with Trypanosoma cruzi and in the gastrointestinal tract can result in mega-oesophagus and megacolon. Concentrations of VIP and substance P and of their nerve fibres are greatly reduced in biopsies from affected segments. Similar changes are seen in the affected bowel from children with Hirschsprung’s disease, which results from an aganglionic colonic segment. In contrast, neuropeptide Y-containing, mostly adrenergic, nerves are not reduced.

Also, patients with the Shy–Drager syndrome, who have chronic autonomic failure with loss of preganglionic extrinsic nerves, have no abnormalities in neurocrine peptides or peptidergic nerve fibres on rectal biopsies. AIDS is frequently accompanied by diarrhoea without evidence of secondary infection, and reduced immunostaining for substance P, VIP, and somatostatin in biopsies suggests a neuropathic process may be responsible. Alterations in neuroactive peptides have been observed in a number of inflammatory diseases. Increased density of VIP innervation has been reported in several gut diseases including reflux oesophagitis, radiation colitis, ulcerative colitis, and Crohn’s disease. CGRP has been shown to mediate the protective effect of sensory nerves in experimental colitis. It was recently reported that upregulation of the galanin-1 receptor is a mechanism for the increased colonic fluid secretion in infectious diarrhoea resulting from various pathogens.

Carcinoid syndrome

Introduction

The term Karzinoide was originally used by Obendorfer in 1907 to describe a carcinoma-like lesion without malignant qualities. It has now come to refer to tumours capable of producing serotonin (5-hydroxytryptamine, 5-HT). However, several different cell types either synthesize or take up 5-HT and so the term carcinoid is applied to a variety of malignant tumours with different biological behaviour grouped by their similar histological appearances. This section focuses primarily on those tumours associated with the classic carcinoid syndrome.

Primary gastrointestinal carcinoid tumours are derived from the embryonic foregut (thyroid, bronchus, stomach, common bile duct, and pancreas), midgut or hindgut. The most common sites for carcinoid tumours are the appendix and rectum, but these tumours, often found incidentally on histological examinations of appendicectomy and rectal biopsy specimens, are almost always benign. Rectal neuroendocrine tumours generally produce glucagon-like peptides and PYY rather than 5-HT and are not usually associated with a clinical syndrome, even when they metastasize.

The carcinoid syndrome occurs in about 10% of patients with carcinoid tumours. It does not develop when the tumour drains through a normal liver, and so midgut tumours have almost always metastasized, usually to the liver, before symptoms develop. The carcinoid syndrome is most commonly due to a metastatic midgut tumour, about 50% of which metastasize to the liver. Primary carcinoid tumours are bronchial in origin in about 10% of cases, and rarely occur in the ovary and testis. Tumours in these sites may be associated with the syndrome in the absence of metastases. The annual incidence of the carcinoid syndrome is about 1 in 500 000.

Clinical manifestations

The cardinal feature of the classic carcinoid syndrome is the flush. The carcinoid flush predominantly involves the head and upper thorax, and is usually associated with tachycardia, hypotension, increased skin temperature and, sometimes, wheezing. Rarely, flushing extends to the trunk and limbs, and may be associated with lacrimation, facial oedema, and great distress. Attacks are paroxysmal and usually unprovoked, although precipitating factors include alcohol or food ingestion, stress, emotion, or exertion. Flushing initially lasts for only a few minutes, but as the disease progresses may become almost continuous, and such patients often develop a chronically reddened and cyanotic facial hue, with widespread telangiectasia, the ‘leonine facies’. This fixed flush is more commonly seen with bronchial carcinoids, which are often metabolically inactive, but when associated with flushing can cause severe attacks lasting for hours or days, occasionally with profound hypotension and even anuria. Gastric carcinoids are often associated with raised, localized, wheal-like areas of flushing, which are usually pruritic and may migrate.

The other characteristic feature of the syndrome is secretory diarrhoea, which may be profuse and accompanied by electrolyte disturbance, cramping abdominal pain, nausea, and vomiting. Rarely these symptoms may result from small-bowel obstruction by a large ileal carcinoid tumour, but the majority of primary tumours are small, usually being less than 1% of total body tumour weight. Hepatic metastases may cause right hypochondrial pain, particularly if the liver capsule is involved or stretched, and acute exacerbations may occur if metastases become ischaemic and undergo autonecrosis. Weight loss and, in the later stages, cachexia are common as a result of poor dietary intake, malabsorption, and increased catabolism. Pellagra with dermatitis of sun-exposed areas may occur, the increased conversion of 5-hydroxytryptophan into 5-HT causing nicotinamide deficiency.

Cardiac valve abnormalities affect about 50% of patients. They occur as a result of endocardial fibrosis, with plaques of smooth muscle in a collagenous stroma deposited on the valves. Lesions are almost always on the right-hand side, left-sided valve damage occurring only in association with bronchial carcinoids, which drain into the left atrium, or atrioseptal defects with right to left shunting. The most common lesions are tricuspid incompetence and pulmonary stenosis, and the usual clinical outcome is oedema and breathlessness due to right ventricular failure, which can be fatal. The other causes of breathlessness in association with the carcinoid syndrome are bronchospasm, which affects a small number of patients, often occurring with flushing attacks, and metastatic involvement of the lung and pleura. Arthritis occurs in a small number of patients, and sclerotic bone metastases may be seen, usually in association with foregut tumours.

Carcinoid tumours, in common with other gastroenteropancreatic tumours, have the potential to produce a variety of peptide products and may be associated with other syndromes, with or without the carcinoid syndrome. The most common of these associated syndromes is Cushing’s, due to an ectopic ACTH-secreting, bronchial or pancreatic carcinoid. Carcinoid tumours may also be a feature of multiple endocrine neoplasia type 1.

Biochemistry

The biologically active metabolite characteristically produced by metastatic carcinoid tumours is 5-HT, synthesized from the amino acid tryptophan. 5-HT probably plays a part in the pathogenesis of some of the symptoms of the carcinoid syndrome, particularly the diarrhoea and bronchoconstriction. It is metabolized to 5-hydroxyindoleacetic acid (5-HIAA), which accounts for 95% of the urinary excretion of 5-HT.

A variety of vasoactive substances may be secreted by carcinoid tumours and have been implicated in the pathogenesis of the flush. Flushing can be provoked by intravenous noradrenaline, which has been shown to activate kallikrein in the tumour, leading to synthesis and release of bradykinin. Other possible mediators of the flush include histamine, the tachykinins substance P and neurokinin A, and prostaglandins, although the flush is rarely affected by inhibitors of prostaglandin synthesis, such as indomethacin. Gastric carcinoids are derived from histamine-producing enterochromaffin-like cells and histamine is possibly the cause of the characteristic wheal-like flush seen with gastric tumours.

Investigations

The diagnosis of carcinoid syndrome is made on the basis of elevated concentrations of 5-HIAA in a 24-h urine collection, and urinary 5-HIAA acts as a marker of disease progression. Various foods, including avocados, bananas, aubergines, pineapples, plums, and walnuts, should be avoided while collecting specimens, to prevent false-positive results. A number of drugs and other substances interfere with the spectrophotometric assay: paracetamol, fluorouracil, methysergide, and caffeine give false-positive results, and ACTH, phenothiazines, methyldopa, monoamine oxidase inhibitors, and tricyclic antidepressants false negatives. The other products of carcinoid tumours are not routinely assayed.

Topographic localization of carcinoid tumours can be done by Octreoscan, CT scan, or endoscopy/ultrasound and is rarely a problem, as most have gross hepatic metastases, visible on CT scan or abdominal ultrasonography, at the time of diagnosis. In those rare cases where the syndrome occurs in the absence of metastases, tumour localization may offer the prospect of cure. These tumours are unlikely to be in the gastrointestinal tract and so chest radiographs and CT scans of the chest and pelvis should be taken. Angiography may be of value in assessing suitability for hepatic embolization. Carcinoid tumours have characteristic histological features being composed of regular polygonal cells arranged in nests. The capacity of 5-HT to reduce silver salts (so-called argentaffinity) led to the development of a classical diagnostic histochemical stain, although immunostaining for 5-HT is also used to identify the tumours.

Treatment

The realistic aim of therapy in patients with the carcinoid syndrome is to relieve the symptoms. Simple treatments such as codeine phosphate, diphenoxylate, and loperamide may help to control the diarrhoea. Many of the symptoms can be controlled with the peripheral 5-HT antagonists: cyproheptadine, a 5-HT type 2 receptor blocker, often helps the diarrhoea; ketanserin may be effective in reducing flushing; and the 5-HT type 3 receptor antagonist ondansetron can alleviate nausea and anorexia. Parachlorphenylalanine, an inhibitor of tryptophan hydroxylase, and chlorpromazine block synthesis of 5-HT, but are rarely used. Histamine may mediate some of the features of the syndrome, especially in patients with gastric carcinoids, and in these cases H₁- and H₂-receptor blockade may be useful. With the exception of simple antidiarrhoeal agents, these treatments have been largely superseded by the long-acting, subcutaneously administered, somatostatin analogue octreotide. This inhibits the release of the mediators of the syndrome by the tumour and antagonizes their peripheral effects.

Octreotide is effective in alleviating symptoms in more than 90% of patients. It is rarely associated with significant side effects: the acidic solution can cause pain at the injection site; gallstones often develop, but are rarely of clinical significance; and a few patients develop steatorrhoea, which can be prevented by giving pancreatic enzyme supplements. Octreotide is now the first-line treatment for most patients and may be life-saving in the carcinoid crisis, when symptoms become severe and continuous. In addition to octreotide, during crises patients usually need close monitoring of fluid and electrolytes, often by measurement of central venous pressure, and appropriate replacement therapy.

Minor injury, including overenthusiastic clinical examination of large carcinoid masses in the liver, may induce a life-threatening state akin to the tumour lysis syndrome characterized by pain, fever, shock, and renal failure compounded by hyperuricaemia and hyperphosphataemia. Allopurinol, and the judicious use of infusions of sodium bicarbonate to make the urine more alkaline, as well as antimicrobials, may reduce the threat of renal failure in this condition. Corticosteroids may improve shock.

The principal disadvantage of octreotide is that patients develop resistance with time, and most become refractory to any form of treatment after about 4 years. Vitamin supplements containing nicotinamide are necessary when patients have pellagra, and these can be given prophylactically. The treatment of cardiac manifestations is the same as for valve disease and cardiac failure of other causes. Patients with painful bony metastases may benefit from palliative radiotherapy.

In patients who fail to respond to octreotide or are intolerant to it, tumour debulking may provide palliative relief. Surgery is rarely indicated, although enucleation of large metastases may give some benefit. Carcinoid tumours rarely respond to any form of chemotherapy. The most effective means of debulking is hepatic embolization, which devascularizes the tumour while the blood supply to the normal liver is maintained by the portal vein. Octreotide should be given in high dose during this intervention, as the necrotic metastases release large quantities of vasoactive mediators that can cause a severe carcinoid crisis with profound hypotension, leading to acute renal failure (see tumour lysis syndrome, above).

Prognosis

Carcinoid tumours behave like other gastroenteropancreatic tumours, with the majority following an indolent course. Estimates given for 5-year survival rates for carcinoids are; appendiceal 98%, gastric (types I/II) 81%, rectal 87%, small intestinal 60%, colonic carcinoids 62%, and gastric type III/IV 33%. Palliation is very worthwhile in these patients, allowing them to lead a normal life until the terminal stages of the disease.

Multiple endocrine neoplasia and nondiabetic pancreatic endocrine disorders are described elsewhere.

Further reading