Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01350 (gastrin)
 9,683 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 42-yr-old woman presented with multiple carcinoid tumors in her stomach and a markedly elevated serum gastrin level. Total gastrectomy was performed, and 22 small carcinoid tumors were found in the gastric fundus and body. A high serum gastrin level was revealed in the gastric drainage veins; still more gastrin was detected in the carcinoid tumors by the immunohistochemical method, and many secretory granules were found in the tumor cells with an electron microscope. The fundic gland showed marked atrophy, and there was some conglobation of endocrine cells (ECL cells). This case suggests a hypothetic sequence of anacidity due to atrophic gastritis----hypergastrinemia----proliferation of ECL cells----multiple carcinoids. A search of the Japanese literature revealed that 26 cases of multiple carcinoid tumors in the stomach have been reported so far, and most of them support this hypothesis.
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PMID:Multiple carcinoid tumors of the stomach with hypergastrinemia. 159 Mar 18

Achlorhydria has been discussed as a possibly dangerous consequence of therapeutic inhibition of gastric acid secretion since the introduction of H2-receptor antagonists. The risk of long-term hypergastrinaemia has only been considered for about 5 years. The reason for this was the demonstration that gastric carcinoids (ECLomas) observed after life-long treatment of rats with the proton pump inhibitor omeprazole could also be produced in rats by other methods leading to long-lasting profound hypergastrinaemia. Such methods were the 80% resection of the oxyntic mucosa or feeding of ranitidine (2000 mg/day) for 2 years. The endocrine tumours corresponded to the gastric carcinoids found in patients with long-lasting hypergastrinaemia due to pernicious anaemia or with a gastrinoma as part of the MEN I syndrome. Neither in animals nor in man could other endocrine tumours or adenocarcinomas of the gastrointestinal tract be related to hypergastrinaemia. Epidemiologic data do not support gastrin dependence of adenocarcinoma of the stomach or the colon. Experimental findings of gastrin effects on tumour growth in vivo and in vitro have been contradictory and may be explained by the presence of gastrin receptors on tumour cells and the role of gastrin as an autocrine growth factor in some of these tumours. Since acid blockade by proton pump inhibitors or H2-receptor blockers dose-dependently increase serum gastrin levels, patients with ranitidine-resistant peptic ulceration receiving long-term treatment with high-dose omeprazole have been followed up with serial gastric biopsy specimens for up to 5 years. Complete healing, moderate hypergastrinaemia, and a slight hyperplasia but no dysplasia of the ECL cells in the oxyntic mucosa have been observed, which seemed to be correlated to chronic gastritis progressing over the years. Despite these negative findings excessive hypergastrinaemia by overdosage of potent drugs for inhibition of gastric secretion should be avoided and monitoring of plasma gastrin levels is recommended in case of long-term treatment.
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PMID:Is hypergastrinaemia dangerous to man? 167 24

After proton pump inhibitors (omeprazole) became available, discussions about safety aspects of (particularly long-term) inhibition of gastric acid secretion have been renewed. In contrast to animals, hypergastrinaemia does not seem to be a relevant problem in man: marginal increases of serum gastrin during proton pump inhibition may induce proliferation of gastric endocrine ("enterochromaffin-like"; ECL-) cells in some cases which are without clinical importance, the risk for development of gastric carcinoids seems negligible if existent at all. Other aspects of acid inhibition (e.g. protein malabsorption, diminished iron and cobalamin absorption, bacterial overgrowth of the stomach, risk of gastric cancer) do also not appear to be of clinical relevance. However, data from larger numbers of patients on long-term therapy with proton pump inhibitors should be available until such treatment can be generally recommended.
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PMID:[Reduction of gastric acid secretion: pathophysiologic and clinically relevant sequelae]. 168 86

Expression of the alpha-subunit of glycoprotein hormones is an acquired feature of the endocrine cells of the oxyntic mucosa in patients with sustained serum levels of gastrin, and may be related to the hyperplasia-carcinoid sequence occurring in these patients. In the present study we have investigated the intragastric cellular localization and the circulating levels of alpha-subunit in a patient with Zollinger-Ellison syndrome. In this patient we have found that: 1) Endocrine cells accounted for 2.29% +/- 1.44% of the total oxyntic mucosal volume (normal value: 0.9% +/- 0.4%), with the ECL cells representing 63.22% +/- 10.9% of the total endocrine cell volume (normal value: 29.8 +/- 8.8%). 2) Cells immunoreactive for the alpha-subunit were found to correspond ultrastructurally to a subpopulation of enterochromaffin-like cells, indistinguishable from similar cells devoid of significant immuno-electron microscopic labeling. 3) Immunoreactive cells included a portion of oxyntic endocrine cells with punctate granules, a feature previously observed only in carcinoid tumors of the oxyntic mucosa. 4) In consecutive sections of freeze-dried vapor-fixed biopsies a fraction of alpha-subunit storing cells was found to co-express histamine. 5) The serum alpha-subunit levels were abnormally elevated and paralleled those of gastrin in a secretin-stimulation test. Analysis of similar curves in two other patients with Zollinger-Ellison syndrome, and five patients with hypergastrinemic atrophic gastritis, all presenting alpha-subunit containing oxyntic endocrine cells, showed significant alpha-subunit elevations only in the patients with ulcerogenic syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Glycoprotein hormone alpha subunit in endocrine cells of human oxyntic mucosa. Studies on its relation to neuroendocrine tumors. 169 Jan 69

Receptors for the main neural (acetylcholine), hormonal (gastrin) and paracrine (histamine) secretory stimulants and the signal transduction pathways to which these receptors are coupled have been identified on the parietal cell. The stimulatory effect of histamine is mediated via an increase in adenylate cyclase activity, whereas the effect of acetylcholine and gastrin are mediated via an increase in cytosolic levels of calcium. Strong synergism between histamine and either gastrin or acetylcholine may reflect postreceptor interaction between the distinct pathways. Acetylcholine and gastrin are also capable of releasing histamine from the gastric mucosa, probably from ECL cells. The inhibitory effects of somatostatin and prostaglandin E on acid secretion are mediated by receptors coupled via guanine nucleotide binding proteins to inhibition of adenylate cyclase activity. All the pathways converge on and modulate the activity of the luminal enzyme, H+K(+)-ATPase, ultimately responsible for acid secretion. The intramural neural and paracrine pathways involved in the regulation of gastrin secretion in the antrum and acid secretion in the fundus have also been identified. Of prime importance is the somatostatin cell, which exerts a paracrine restraint on gastrin secretion and acid secretion. Elimination of this restraint or disinhibition is one of the mechanisms by which the stimulatory influence of cholinergic neurons is exerted on gastrin and parietal cells. Gastrin secretion is regulated by a cholinergic neuron that causes inhibition of somatostatin secretion and thus stimulation of gastrin secretion (disinhibition) and a noncholinergic neuron that causes direct stimulation of gastrin secretion by releasing the neurotransmitter, bombesin (or gastrin-releasing peptide). Acid secretion is regulated by a cholinergic neuron that causes direct stimulation of the parietal cell and indirect stimulation by decreasing somatostatin secretion, thus eliminating its inhibitory effect on the parietal cell (disinhibition). In addition, a regulatory feedback mechanism exists whereby intraluminal acidification stimulates somatostatin secretion, which in turn attenuates acid secretion. Gastric acid secretion may also be regulated by one or more intestinal inhibitory hormones, the most likely candidates being secretin, intestinal somatostatin, and neurotensin. Enterogastrone activity probably reflects the combined effect of all these hormones. Precise information on receptors and signal transduction mechanisms as well as on intramural neural and paracrine regulatory pathways has led to the development of new drugs capable of inhibiting acid secretion. These include antagonists that interact with stimulatory receptors (histamine H2-receptor antagonists, muscarinic receptor antagonists, and gastrin receptor antagonists), agonists that interact with inhibitory receptors (somatostatin and prostaglandin E analogues), and irreversible inhibitors of the luminal enzyme, H+K(+)-ATPase.
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PMID:Control of acid secretion. 169 38

During the last few years the endocrine stomach has come into focus much due to the side-effects produced by powerful acid blockers. A sustained and marked inhibition of acid secretion in the rat results in hypergastrinemia, with gastrin cell hyperplasia, and a consequent hyperplasia of the ECL cells. This response of the ECL cells was predictable in view of previous observations that sustained hypergastrinemia causes ECL cell hyperplasia. While the gastrin cell hyperplasia levels off at about twice the normal cell density a few weeks after start of treatment, the ECL cells continue to proliferate for months to reach a five-fold higher density than normally. Evidence is accumulating that ECL cells proliferate through self replication. After life-long inhibition of acid production (high doses of ranitidine or omeprazole) or after extirpation of 75% of the acid-producing part of the stomach, ECL cell carcinoids develop. Endocrine cells in the gut often contain more than one putative messenger. Thus, gastrin cells in many species store GABA and peptide YY; in e.g. cat and man they store in addition a xenopsin-like peptide. Neuromedin U and pituitary adenylate cyclase activating peptide (PACAP) have recently been demonstrated in gut nerves. Their role in gut physiology remains to be identified.
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PMID:The neuroendocrine system of the gut--an update. 185 99

The management of maintenance therapy in peptic disease (oesophagus, stomach, duodenum) with antisecretory drugs should keep in consideration the aspect of developing hypergastrinemia: gastrin exerts a throphic effect on gastric ECL and parietal cells. After a long term maintenance therapy (3-5) years) with ranitidine 150mg/die in a group of 55 patients affected by duodenal ulcer, 20% of them developed hypergastrinemia and gastric hypersecretion (evaluated after one week of drug withdrawal). The same 20% of the subjects showed increased relapse rates with respect to those who did develop the same gastrin/gastric acid increase.
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PMID:Gastrin pathophysiology: antisecretory drugs. 198 15

The administration of the currently available H2-blockers (at a dosage that induces only partial inhibition of the intragastric acidity) is effective in nearly all peptic ulcer patients in the short and long- term treatment. The benefits of more profound gastric acid inhibition (as achieved with omeprazole) in the short-term treatment of acid peptic diseases has been demonstrated in clinical studies. However, gastric acid has an important physiological role and the potential consequences of profound inhibition of gastric acid include intragastric bacterial colonization and hypergastrinaemia. Bacterial overgrowth of the stomach renders the gut more susceptible to enteric infection and another possible sequela of intragastric bacteria is the formation of N-nitroso compounds with carcinogenic potency. Hypergastrinaemia has a trofic effect on the gastric mucosa and gastric endocrine cells and, in animal, ECL cell hyperplasia and carcinoid formation has been observed as a result of high serum gastrin levels. So far, these potential risks have precluded the long-term administration of omeprazole.
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PMID:Inhibition of gastric acid secretion: advantages and risks in short and long-term treatment. 198 19

Studies in the rat have shown that partial gastric corpectomy, in which about 75% of the acid-producing oxyntic mucosa was removed, leads to markedly reduced acid secretion and a feedback increase in the plasma gastrin levels. Ten weeks after operation, the gastric enterochromaffin (ECL)-like cell density in the remaining part of the oxyntic mucosa had increased significantly. In the present study, the effects on the gastric ECL cells of lifelong persistent hypergastrinemia induced by partial (75%) corpectomy have been investigated. Seventy-five partially corpectomized rats and 40 control rats were investigated for plasma gastrin and oxyntic mucosal changes in a 124-week study. The partially corpectomized rats showed increased plasma gastrin levels after the operation; the mean increase compared with the controls was almost 10-fold during the entire study. The remaining oxyntic mucosa of the partially corpectomized rats differed from that of control rats in two respects, showing first general hypertrophy and second a marked hyperplasia of argyrophil ECL cells. The degree and incidence of these changes increased towards the end of the study, i.e., in the aging rats. An age-related increase in ECL-cell density occurred spontaneously also in the control rats but to a lesser extent than in the partially corpectomized group. ECL-cell carcinoids were found in the oxyntic mucosa of 26 of the 75 partially corpectomized rats. The first carcinoid was found 78 weeks after the beginning of the study. Six rats with carcinoids (23%) were found before week 104 (2 years) and the remainder, 20 (77%), were discovered later. No carcinoid tumor was found in the control rats. It is concluded that lifelong hypergastrinemia induced by partial corpectomy leads to the development of ECL-cell carcinoids in the oxyntic mucosa of some rats towards the end of their life span. This observation strongly supports the hypothesis that the gastric ECL-cell carcinoids found in rats treated with antisecretory drugs are caused by long-standing hypergastrinemia developing secondary to inhibition of gastric acid secretion.
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PMID:Partial gastric corpectomy results in hypergastrinemia and development of gastric enterochromaffinlike-cell carcinoids in the rat. 198 29

Certain substances when given orally to rats have effects on the neuroendocrine cells of the fundic stomach. Such compounds also have effects on acid or its secretion, which is to a greater or lesser extent suppressed, with a consequent rise in serum gastrin, followed by an increase in the number of histamine-secreting ECL cells. These changes are seen with the histamine H2 receptor antagonists loxtidine, SKF 93479, ICI 162,846 and ranitidine; with the hypolipidaemic agents clofibrate, ciprofibrate and benzofibrate; with sodium bicarbonate and pentagastrin; and with omeprazole, a potent inhibitor of the parietal cell proton pump mechanism. Changes in the pH of the rat stomach stimulate the neuroendocrine G cells of the pylorus to secrete gastrin, which acts on the ECL cells of the fundus causing the production of histamine, which in turn stimulates the parietal cell. This sequence leads to an excess of circulating gastrin, which is detectable within 5 days. Subsequently increases in the number of ECL cells occur, the hyperplasia being related to hypergastrinaemia and the degree of acid suppression. The hyperplastic response is rapid, being so obvious with loxtidine at 39 days that there is good reason to suppose it could well be detected earlier. Using omeprazole, hyperplasia was found at 28 days after oral doses of 140 mg/kg/day. In order to get an equivalent degree of acid suppression with ranitidine it was necessary to deliver 420 mg/kg/day by subcutaneous infusion using an osmotic minipump, when hyperplasia occurred. Interestingly, only omeprazole produced a hyperplastic response of G cells. Such results reflect the covalent binding of omeprazole to the proton pump as opposed to the competitive binding of ranitidine to the histamine H2 receptor site. In addition to ECL cell hyperplasia there is ample evidence from lifetime studies in rats and mice that neoplasia may result. Neuroendocrine carcinomas (carcinoids) of the rat fundic stomach have been observed with loxtidine, omeprazole, SKF 93479 and ICI 162,846. They are seen late in the 2-year rat studies and are most unlikely to have arisen purely as an extension of the hyperplastic response. It is possible that the prolonged disturbance of gastric homoestasis resulting from achlorhydria result in the production of a carcinogen or carcinogens, in which event it is not too surprising, in view of the neuroendocrine hyperplasia, that the tumours seen are neuroendocrine carcinomas.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Neuroendocrine cell hyperplasia and neuroendocrine carcinoma of the rodent fundic stomach. 204 87


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