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Gastrins and Gastrinomas J Postgrad Med J: first published as 10.1136/pgmj.60.709.767 on 1 November 1984. Downloaded from Postgraduate Medical Journal (November 1984) 60, 767-772 Gastrins and gastrinomas J. HANSKY F.R.A.C.P. Reader in Medicine, Monash University, Melbourne 3004, Australia Introduction The gastrins Gastrin was first postulated by Edkins in 1906 as the Gastrin exists in multiple molecular forms that not hormone responsible for gastric acid secretion but it only differ in one or two amino acids in different took a further 65 years of debate before Gregory and species but also occur in different chain lengths Tracey (1961) reported on the properties and struc- within species. It is thought that a large precursor ture of this hormone. With the elucidation of the molecule, Pre-Pro-Gastrin, is synthesized in cells and complete amino acid structure and synthesis of the undergoes post-translational enzymatic cleavage at peptide, immunochemical and immunocytochemical specific arginine or lysine residue to yield first gastrin methods quickly led to measurement of the hormone 34 and then gastrin 17 (Yanahaira, 1980). In addition in blood and other biological fluids, localization, to there being molecules ofdifferent chain length, the physiology and pathophysiology. Although gastro- molecules may have the single tyrosine sulphated or by copyright. intestinal hormones were not amongst Avery Jones' unsulphated. There is little doubt about six molecular primary interests in gastroenterology, the unit's forms of gastrin in mammals-G34 sulphated or expertise in peptic ulcer particularly with reference to unsulphated, G17 sulphated and unsulphated and bleeding led to the author's search for a possible role G 14 sulphated and unsulphated. A form larger than of gastrin in the pathophysiology of ulcer and to G34 has been identified on gel chromatography and general studies of gastrin by radioimmuno assay. named 'Component I' but its structure has not yet This review will describe the advances in the past been elucidated (Rehfeld, Stadil and Vikelsoe, 1974). 20 years in gastrin physiology and pathophysiology There has also been a peak eluting in the void with particular reference to gastrinoma. volume of sephadex columns called 'big big gastrin' but this is probably an artefact. There is also Radioimmunoassay of gastrin controversy whether G4 exists in cells. The most http://pmj.bmj.com/ abundant forms in blood and tissues are G34 and The ability to measure femtomol (10-I'M) amounts G17. G34 accounts for most of the fasting serum of gastrin by radioimmunoassay has led to intensive gastrin and for about half of that released by a study of the release ofthe hormone. Since McGuigan stimulus. The predominant site of extractable gastrin (1968) first developed this assay for gastrin, numer- is the antrum and the form is as G17. Gastrin can ous groups have followed and the assay is now widely also be extracted from the duodenum where about available. The most useful gastrin antibodies are half is G34. Sulphated and unsulphated forms are on September 25, 2021 by guest. Protected those that are directed against the C-terminus, equally distributed. measure all forms equally and do not cross react with other peptides that share the C-terminus such as cholecystokinin or caerulein. Using such antibodies, serum gastrin can be detected in unextracted samples Actions of gastrin and role in physiology at a dilution of 1:10 and usually measures amounts of The full range of biological actions of gastrin 10-50 fmol ml-' in the fasting normal subject. reside in the C terminal tetrapeptide amide. G 17 and Region specific antisera have been generated for the G 14 are equipotent in stimulating gastric acid C and N terminus ofgastrin 17, for unsulphated G 17, secretion whereas G34 has about 1/6 the potency in for G34 and the N terminus of G34. Utilizing these the circulation. When infused exogenously, all three region specific antisera, the characterization of the are equipotent on a molar basis. Table 1 shows the various molecular forms of gastrin in plasma or actions of gastrin on the gastrointestinal tract: of tissues can be made without resort to gel filtration or these, the effect on gastric acid secretion, antral affinity chromatography (Dockray, 1979). motility and gastric and intestinal growth may be Postgrad Med J: first published as 10.1136/pgmj.60.709.767 on 1 November 1984. Downloaded from 768 J. Hansky physiological. The other effects are almost certainly TABLE 3. Inhibition of gastrin release pharmacological. Luminal: Decreasing pH of antral contents Topical prostaglandins Blood borne: Secretin Calcitonin TABLE 1. Actions of gastrin Somatostatin Vasoactive intestinal peptide Glucagon Stimulates: Gastric acid secretion* Gastric enzyme secretion* Antral motility* Contraction of lower oesophageal Intravenous injection of somatostatin and calci- sphincter tonin inhibit gastrin release as do some members of Pancreatic enzyme secretion the 'secretin' family. In particular vasoactive intesti- Liver bile flow nal and secretin lead to a fall in Gastric, intestinal growth* peptide, glucagon Inhibits: Contraction pyloric sphincter circulating gastrin levels. This is of some clinical Contraction sphincter of Oddi importance in that in normal subjects or where gastrin is originating from the antrum (e.g. antral G- *Physiological. cell hyperfunction or retained excluded antrum), secretin injection leads to a fall in gastrin whilst in Zollinger-Ellison syndrome it leads to a paradoxical rise (Korman et al., 1972). The role of these Release of gastrin hormones in the physiology of gastrin release is not The factors which stimulate and inhibit the release known and the effects may be pharmacological of gastrin have been fully elucidated with the advent (Hansky, Soveny and Korman, 1971). of radioimmunoassay in its measurement. The fac- tors which stimulate gastrin release are shown in Pathophysiology of gastrin release Table 2. Small peptides, amino acids and calcium in Ulcer disease. In duodenal ulcer, fasting serum the gastric lumen stimulate gastrin release. Low doses gastrin levels are generally within the normal rangeby copyright. of atropine enhance release of gastrin in response to but food stimulated gastrin levels are greater than in food, an increase also seen after all forms of gastric normal subjects (Hansky and Korman, 1973). This, vagotomy suggesting removal of cholinergic inhibi- together with the finding that parietal cells in tory fibres. Vagal stimulation by insulin hypoglycae- duodenal ulcer disease are more sensitive to gastrin mia and sham feeding result in gastrin release. This (Lam et al., 1980) indicates some role for gastrin in suggests that cholinergic influences on gastrin release the pathophysiology of duodenal ulcer. In gastric are complex and both stimulatory and inhibitory ulcer, basal levels of gastrin are elevated and there is mechanisms operate. Intravenous infusion of cate- a large release of food stimulated gastrin. This is cholamines, calcium and bombesin stimulate gastrin probably consequent on the diminished acidity in the release by mechanisms not fully determined. There is antrum due to concomitant gastritis (Hansky andhttp://pmj.bmj.com/ increasing evidence that gastrin is released into the Korman, 1973). All forms of vagotomy in man lead lumen of the gut as well as into the blood stream. to an increase in fasting serum gastrin and increased release after food stimulation. It is considered that this may be due to both removal ofa vagal inhibitory TABLE 2. Release of gastrin mechanism and an increase in the gastrin cell mass Luminal: Peptides, amino acids ) lumen (Hansen, Larsen and Svendsen, 1979). Calcium 1Gastric lumen Hypergastrinaemia. The causes of an increase in Nervous: Vagal stimulation fasting serum gastrin are shown in Table 4. The on September 25, 2021 by guest. Protected Blood borne: Catecholamines associated with Calcium group hyperacidity, hypergastrinae- Bombesin mia and usually peptic ulceration form the most interesting and probably the commonest group. Gastrinoma will be considered separately and the hypergastrinaemia associated with massive small Table 3 shows the factors which inhibit gastrin bowel resection has been reported only by Straus, release. Decreasing the pH of the contents bathing Berson and Yalow (1974) but not confirmed by the antrum inhibit gastrin-this commences at a pH others. Retained excluded antrum and antral G cell of 3-0 and is maximal at a pH of 1 0 or less. hyperfunction are uncommon but definite entities. Presumably this is part of the normal feedback Retained excluded antrum was first described by control of gastrin release. Topical prostaglandins and Korman et al. in 1972, but only a few patients have local anaesthetics have also been shown to inhibit the been reported. Recently Basso et al. (1981) have release of antral gastrin. assessed bombesin in differentiating between gastrin Postgrad Med J: first published as 10.1136/pgmj.60.709.767 on 1 November 1984. Downloaded from Gastrins and gastrinomas 769 of antral origin and that from other sites. They found sin is not large enough to permit an opinion on its an increase in gastrin after bombesin in five patients value. with the retained antrum syndrome and postulated this as a good differentiating test. Antral G cell Chronic renalfailure hyperfunction (hyperplasia) has been reported spo- radically and consists of hypergastrinaemia, hyper- Studies on the metabolism of gastrin suggest that acidity and peptic ulceration in the absence of the kidneys are a major site of gastrin breakdown definite evidence of a gastrinoma with a major particularly for the G34 form. Hypergastrinaemia distinguishing feature being a grossly exaggerated has been reported in patients with acute renal failure, gastrin release after food. Some reports have indi- after nephrectomy and in chronic renal failure. In a cated an increased number ofG cells in these patients study on a large number of patients, it has been but the feature which distinguishes them from shown that the serum gastrin rises proportionally gastrinoma is that the serum gastrin returns to with the serum creatinine, the higher the creatinine, normal levels following antrectomy (Walsh, 1979).
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