Gastrointestinal
Hormones
Neuroendocrine tumours of the
gastrointestinal system are rare tumours that usually present with manifestations
related to the actions of the peptide that they secrete. Functioning
neuroendocrine tumours include: the pancreatic tumours insulinomas (insulin
secreting), VIPomas (vasoactive intestinal polypeptide), glucagonomas
(glucagon), gastrinomas (gastrin) and somatostatinomas (somatostatin) and the
small bowel tumours carcinoids (5HIAA), gastrinomas (gastrin) and
somatostatinomas (somatostatin). Pancreatic tumours may form part of the MEN 1
syndrome and sometimes secrete a number of other hormones including ACTH
(presenting as Cushing’s syndrome), GHRH (causing acromegaly), and PTHrP
(presenting with hypercalcaemia). Patients with insulinomas present with
hypoglycaemic symptoms; those with gastrinomas have complex peptic ulcer
disease with diarrhoea; VIPomas cause diarrhoea, acid–base disturbances and
glucose intolerance and an erythematous rash; glucagonomas cause a typical
necrolytic skin lesion associated with glucose intolerance, bowel disturbance,
neuropsychiatric problems and venous thrombosis; and somatostatinomas present
with steatorrhoea, gallstones and diabetes. Carcinoid tumours are the most
common of the group, presenting with flushing, diarrhoea, bronchospasm,
arthropathy and cardiac complications. All these tumours are extremely rare and
require specialist management by multidisciplinary teams of endocrinologists,
surgeons, radiologists and oncologists.
Introduction
Gastrointestinal endocrine hormones
are principally peptides. Many peptides are synthesized by GIT cells but their
role as hormones is unclear. The GIT hormones release enzymes necessary for
digestion; they enhance enzyme activity by stimulating the release of bile
acids, which provide an optimal acid pH for many enzymes, and the bile salts;
some alter GIT motility. Possible mediators of acid secretion and duodenal pH
control are shown in Table 43.1.
Biosynthesis, chemistry and release
The GIT hormones are synthesized
in ‘clear’ cells, named because of their selective staining with silver salts,
and are widely diffused throughout the gut, thus giving rise to the DES, or diffuse
endocrine system of the gut. Gut cells have been arbitrarily named, for
example G cells (gastrin-secreting), S cells (secretin-secreting), D cells
(somatostatin-secreting), K cells (gastric inhibitory peptide-secreting) and I
cells (chole-cystokinin-secreting). The GIT hormones are conveniently grouped
according to their structural similarities into two main families – the gastrin
and secretin families (Fig. 43a).
The secretin family of peptides,
namely secretin, glucagon, VIP and gastric inhibitory peptide (GIP) share
sequence homology in many amino acids. Secretin and glucagon have 14 amino
acids in common. The gastrin family is so-called because gastrin and
cholecystokinin (CCK) have identical C-terminal sequences of the first five
amino acids (Fig. 43b).
Gastrin is secreted by the G cells in the gastric antrum
and the duodenum, and exists in the circulation in several forms, the major
ones being G17 and G34, representing the numbers of amino acids in each. G17 is
found in the stomach and G34 mainly in the duodenum, and, in humans, in the
circulation. The main physiological actions of gastrin are to release HCl from
the parietal cells of the stomach (Fig. 43a), and to regulate growth of the
gastric mucosa. The acidic gastric juice produced by gastrin excites pepsinogen
secretion from the chief cells and secretin release from the S cell. Gastrin
release is stimulated mainly by food and to a lesser extent by free fatty
acids, amino acids and peptides, but dietary sugars do not release gastrin. The
hormone is also released following autonomic vagal stimulation. Gastrin
increases motor activity in the GIT, stimulates enzyme secretion from the
pancreas, relaxes the pyloric sphincter and increases lower oesophageal sphincter
pressure. The mechanism of HCL release from the gastric parietal cell is shown
in Fig. 43c. Cholecystokinin (CCK). CCK-secreting cells (I-cells) occur
mainly in the duodenum and the proximal jejunum. CCK has also been described in
neurones innervating the distal intestine. In the GIT, CCK is released in
response to certain amino acids, particularly tryptophan and phenylalanine,
lipids and free fatty acids. CCK contracts the gall bladder and stimulates the
release of pancreatic enzymes. CCK stimulates glucagon release, as does VIP.
CCK enhances the action of secretin in stimulating bicarbonate release from the
pancreas, and it delays gastric emptying. CCK, or a related peptide, may serve
as a satiety hormone.
Secretin. In humans, secretin is found predominantly in the
granular S cells in the villi and crypts of the small intestinal mucosa.
Secretin is released in response to acidification of the contents of the
duodenum, that is the entry of gastric fluids. Secretin is not released above a
pH of 4.5. Its major action is to stimulate bicarbonate secretion from the
pancreas, and it potentiates CCK-invoked release of pancreatic enzymes.
Clearly, there is a negative-feedback relationship between secretin and
bicarbonate which inhibits secretin release.
Vasointestinal peptide (VIP). Human VIP is a strongly basic polypeptide of 28
amino acids, belonging to the secretin family of peptides. VIP is widely
distributed throughout the body, but especially in the GIT, where it occurs
from oesophagus to rectum. VIP-containing neurones are especially concentrated
in the jejunum, ileum, colon, gall bladder wall, the sphincters and the
pancreas. VIP release from cells is known to be modified by other neurones,
which contain opioids or somatostatin as neurotransmitters. An important
function of VIP within the gut may be to promote descending relaxation, as it
is released only during relaxation.
Gastric inhibitory peptide (GIP) is a 42 amino acid poly- peptide of
the secretin family, present in the GIT at highest concentrations in the
duodenum and jejunum. GIP release is stimulated by glucose, amino acids and
free fatty acids, and release may also be modified by other hormones. An
important action of GIP is to enhance insulin secretion under conditions of
hyperglycaemia. Glucose taken orally is more potent in stimulat- ing insulin
release than when taken intravenously, and this may be explained by the
stimulant effect of glucose on GIP release. Gastrin-releasing peptide (GRP)
is a 27 amino acid (porcine) peptide present in the brain and GIT neurones.
GRP, when introduced into rat brain, causes gastrin release from the G cell.
GRP has been localized to nerve cells in the antral mucosa, and has been shown
to produce a release of gastrin.
Enteroglucagon is the name given to a heterogeneous group of
peptides within the gut. These are fragments of the proglucagon molecule, and
include a peptide termed oxyntomodulin, and glicentin and GRP. The highest
concentrations occur in the ileum and colon, and about 60–80% of the activity
is accounted for by glicentin. The peptides are released by food in the gut,
which is not the stimulus for glucagon release.
Ghrelin is a peptide hormone synthesized and released from
the fundus of the stomach. Ghrelin potently stimulates growth hormone release
from the pituitary. It is also orexigenic (promotes feeding behaviour) through
an action in the hypothala- mus (see also Chapter 45) and is therefore part of
the energy balance system.
Motilin is a peptide secreted in the small intestine and
is chemically unrelated to other known GIT hormones. Motilin causes periodic
contractions of the muscles of the upper GIT, and may perform ‘housekeeping’
duties to keep the GIT free of undigested material.
