Biomedical subjects
Publications and source records attributed to J Calam.
A 27-year old female received about 1 kg of salt in about 600 ml of water as an emetic after a self-poisoning attempt. Vomiting did not occur and massive necrosis of gastric, duodenal, and jejunal mucosa resulted in a severe and prolonged illness which required 31 weeks of continuous hospital care and 31 laparotomies over a period of 16 months. The dangers of salt emesis are emphasized.
The amount and type of cholecystokinin (CCK) in duodenal extracts and plasma of celiac patients and normal subjects was studied by radioimmunoassay and gel filtration. In both groups there were similar patterns of molecular forms in extracts of duodenal biopsies, but concentrations in celiac disease were significantly depressed. In boiling water extracts of duodenal mucosa from both groups a factor with the properties of the COOH-terminal octapeptide of cholecystokinin predominated, but there were also significant amounts of a larger molecular weight form. In acid extracts of mucosa a factor with the properties of the 33 or 39 residue form was identified in amounts that were approximately 25% those of CCK8; there were also similar amounts of an acid-soluble form that had an apparent molecular weight higher than CCK39. Plasma immunoreactive cholecystokinin was studied after concentration by immunoaffinity adsorption and fractionation by gel filtration. In normal subjects fasting CCK-like immunoreactivity was less than 0.8 pmol/liter, and after a light breakfast increased to 2.0 +/- 0.7 (range 1.0 to 4.8) pmol/liter; CCK8-like activity accounted for all the increased immunoreactivity. In five of six celiac patients the concentrations of both fasting and postprandial CCK-like immunoreactivity in plasma were undetectable (less than 0.8 pmol/liter). We conclude that diminished production and release of CCK could account for the impaired pancreatic and gall bladder responses to intraluminal stimuli in celiac disease.
Antral G-cell hyperfunction is a rare cause of hypergastrinemia, hyperchlorhydria, and duodenal ulcer disease. We found evidence for a familial basis for this disorder. The probands were two young men with aggressive duodenal ulcer who had basal and postprandial hypergastrinemia, hyperpepsinogenemia I, and basal and pentagastrin-stimulated hyperchlorhydria. All characteristics returned to normal after antrectomy and vagotomy. Antral gastrin concentrations and quantitative G-cell counts were normal, indicating hyperfunction of G-cells rather than hyperplasia. Four of 10 first-degree relatives of the two patients shared with them the combination of postprandial hypergastrinemia and hyperpepsinogenemia I. The aggregation of these abnormalities in tow families, each identified by a proband with hypergastrinemic, hyperpepsinogenemic l duodenal ulcer, suggests that antral G-cell hyperfunction may have a genetic basis.
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A 72-year-old female gave a history of chronic gastrointestinal blood loss necessitating transfusion with over 90 units of blood despite continuous oral iron therapy over a period of 24 years. Gastroscopic appearances were very similar to those recently described by Lewis and by Wheeler in patients with submucosal angiomatous lesions and chronic gastrointestinal blood loss. Striking erythematous streaks radiated from the pylorus and were confined to the antrum. In our case complete achlorhydria to pentagastrin was associated with low serum and antral gastrin concentrations. The introduction of oral prednisolone was followed by a marked fall in the rate of gastrointestinal blood loss, removing the need for transfusion during the following year. Complete achlorhydria persisted and endoscopic appearances remained unchanged, but there was a marked rise in antral and serum gastrin concentrations. The possible modes of action of prednisolone in this case are discussed. The patient remains well in November 1979. The dose of prednisolone was reduced to 10 mg on alternate days in May 1979. Iron supplements have been continued but no transfusion has been required since the start of steroid therapy. The hemoglobin has gradually risen to 14.9 g/dl.
We have studied the relationships between the main molecular forms of gastrin (G17 and G34) in the serum, antral and duodenal mucosa of duodenal (DU) and gastric (GU) ulcer patients. Fasting serum G17 was similar in both DU and GU (about 6 pmol/l) and in both groups increased about three-fold with feeding. In contrast, basal serum G34 was significantly higher in GU (29 pmol/l) than in DU (12 pmol/l) and the peak post prandial increase over basal of G34 was also higher in GU (57 pmol/l) compared with DU (10 pmol/l). In sharp contrast, in the same groups of DU and GU patients mean total antral gastrin concentrations were similar (about 12 nmol/g), and in both groups 95% of antral gastrin was G17, most of the remainder being G34. In both groups total duodenal gastrin concentrations were about 20% those in antral mucosa and about 70% of duodenal gastrin was attributable to G34. The higher serum G34 in GU could therefore be explained by increased secretion of duodenal gastrin, but further work is needed to examine whether there might also be preferential secretion of antral G34 in GU, or a difference in the metabolism (or volume of distribution) of gastrin variants in GU and DU.
In normal, duodenal ulcer, and gastric ulcer subjects the two main forms of gastrin, G17 and G34, were estimated by radioimmunoassay in fasting serum and after feeding. Two antisera were used: one showing high specificity for G17, the other specific for the common COOH-terminus of G17 and G34 and so allowing estimation of G34 by difference. Basal G17 was similar in gastric ulcer, duodenal ulcer, and normal subjects and the increases of G17 after feeding were also similar in these groups. In contrast, basal G34 was similar in normal and duodenal ulcer subjects but raised in gastric ulcer subjects. After a meal the G34 concentration in both gastric and duodenal ulcer patients was significantly higher than normal. It is concluded that the higher post-prandial gastrin responses in peptic ulcer that have been previously described are due largely to increased G34.
The records of the patients over 65 years undergoing jejunal biopsy in two Liverpool gastroenterology units were obtained. Biopsy failed in four of the 52 cases, diagnostic yield was 12% and only appeared to be of value in confirming the diagnosis of gluten-sensitive enteropathy (adult coeliac disease).
Details of jejunal biopsies using the Watson small intestinal biopsy capsule done from 1966 through 1976 at three centers in Liverpool were obtained. The only complications were jejunal perforation which occurred in 2 patients over 65 years of age, 1 of whom died. This increased risk in elderly does not appear to have been previously recognized and both cases are reported. Diagnostic yield in the age group over 65 is discussed. Stricter criteria in selection of these patients for biopsy are suggested. A period of in-patient observation after biopsy in those over the age of 65 may decrease the risks of perforation. In addition, the use of a pediatric capsule, ideally with controlled suction, may lessen the risk further. The use of duodenal biopsy via an endoscope may prove to be a useful additional technique in elderly patients.
VIP containing nerves are present in the kidney and plasma VIP levels are elevated in cardiac failure and severe liver disease. We studied the effects of intravenous VIP; 6 pmol kg-1 min-1 on 6 normal subjects and 3 patients with liver disease. In normal subjects VIP produced flushing and significant rises in heart rate and pulse pressure but the clearance rates of paraaminohippurate and creatinine did not change significantly. Urine flow fell to about 1/3 and the rate of excretion of electrolytes (except phosphate) fell to about a half of control values. Plasma renin activity rose about 3-fold and there were significant rises in haematocrit and the plasma concentrations of solids, calcium and phosphate. The patients with liver disease responded similarly. Elevated plasma VIP could contribute to salt and water retention in disease states.
We report two adult patients in whom portal and mesenteric vein thrombosis was a serious complication of diabetes. The contribution of a hypercoagulable state is considered and the importance of careful glycaemic control in patients with previous thrombotic episodes is emphasized.
Elemental diets have been used extensively in the routine management of patients with Crohn's disease during the past 2 years in this unit. We report our experience in 6 patients in whom perianal fistulae were present. Fistulae improved in 4 patients during elemental feeding; complete healing of fistulae occurred in one of them. No benefit was apparent in 2 patients, but in one the fecal stream had previously been diverted by transverse colostomy, and in the other fecal stasis was marked. The clinical significance of the observations and the difficulties of assessing diet therapy in this condition are discussed.
Helicobacter pylori plays major causative roles in peptic ulcer disease and gastric cancer. Elevated acid secretion in patients with duodenal ulcers (DUs) contributes to duodenal injury, and diminished acid secretion in patients with gastric cancer allows carcinogen-producing bacteria to colonize the stomach. Eradication of H. pylori normalizes acid secretion both in hyper-secreting DU patients and hypo-secreting relatives of gastric cancer patients. Therefore, we and others have asked how H. pylori causes these disparate changes in acid secretion. H. pylori gastritis more or less restricted to the gastric antrum in DU patients is associated with increased acid secretion. This is probably because gastritis increases release of the antral acid-stimulating hormone gastrin and diminished mucosal expression of the inhibitory peptide somatostatin. Bacterial products and inflammatory cytokines including TNFalpha may cause these changes in endocrine function. Gastritis involving the gastric corpus tends to diminish acid secretion, probably because bacterial products and cytokines including IL-1 inhibit parietal cells. Pharmacological inhibition of acid secretion increases corpus gastritis in H. pylori-infected subjects, so it is envisaged that gastric hypo-secretion of any cause might become self-perpetuating. H. pylori-associated mucosal atrophy will also contribute to acid hypo-secretion and is more likely in when the diet is high in salt or lacking in antioxidant vitamins. Data on gastric acid secretion in patients with esophagitis are limited but suggest that acid secretion is normal or slightly diminished. Nevertheless, H. pylori infection may be relevant to the management of esophagitis because: (i) H. pylori infection increases the pH-elevating effect of acid inhibiting drugs; (ii) proton pump inhibitors may increase the tendency of H. pylori to cause atrophic gastritis; and (iii) successful eradication of H. pylori is reported to increase the likelihood of esophagitis developing in patients who had DU disease. Points (ii) and (iii) remain controversial and more work is clearly required to elucidate the relationship between H. pylori, acid secretion, gastric mucosa atrophy and esophagitis.
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The authors review recent progresses made in the understanding of the disturbed gastrin homeostasis in Helicobacter pylori infection and in pernicious anaemia. Regulation of gastrin release in a complex mechanism involving inhibition by a low gastric pH and several peptides including somatostatin, and stimulation by different factors, mainly alimentary peptides and amino-acids. The hypergastrinaemia observed in patients with Helicobacter pylori infection occurs despite a normal intraluminal pH. This may be through alkalinisation of the gastric mucus layer due to the production of ammonia by the bacterial urease or through local release of inflammatory mediators. In pernicious anaemia a factor present in the antacid gastric juice could explain the important hypergastrinaemia observed. The gastrin releasing activity of the gastric juice itself was demonstrated by a decrease of the patients' plasma gastrin concentration during a neutral gastric lavage and by a rise of the gastrin levels in rats whose stomachs were perfused with gastric juice from pernicious anaemia patients. A better understanding of the relation between gastric pH and gastrin release is important not only for these pathological states but also for treatments which suppress acid secretion.
There are (at least) two types of receptor for cholecystokinin (CCK)/gastrin peptides. Highly potent specific antagonists are available for both types. The CCKA-receptor mediates classical CCK-like effects on the gut. Antagonists given to man inhibit pancreatic enzyme secretion and generally shorten gastrointestinal transit times. Potential clinical indications include anorexia, gastro-paresis, pseudo-paresis, pseudo-obstruction, severe constipation and chronic pancreatitis. However gallbladder contraction is markedly inhibited and this led to gallstone formation in baboons. This will obviously have to be avoided if CCKA antagonists are to be used in man. CCKB-receptors mediate the effects of gastrin on the gut and the effects of CCK in the brain. They inhibit gastrin-stimulated acid secretion. If used in acid-peptic disease they might inhibit the trophic effects of gastrin on enterochromaffin cells. CCKB-antagonists can also inhibit the growth of some gastrin-dependent tumours, including certain human colonic cancer cell lines which produce gastrin. CCKB-antagonists have a potent anxiolytic-like effect in animals, and this effect might become their main clinical application.
Helicobacter pylori affects gastric acid secretion via several mechanisms. One of these is by changing gastric regulatory physiology. The infection elevates plasma gastrin levels and decreases gastric mucosal expression of the inhibitory peptide somatostatin. These changes may be due to products of H. pylori itself or inflammatory cytokines released in H. pylori infection: acid secretion is inhibited less by a low intra-gastric pH, infusions of cholecystokinin and gastric distention in infected persons. Eradication of H. pylori rapidly decreases basal acid secretion and gastrin-releasing, peptide-stimulated acid secretion. There are now reports that maximally-stimulated acid secretion, a measure of the parietal cell mass, falls significantly six and 12 months after eradication of H. pylori from duodenal ulcer patients. This might be due to withdrawal of the trophic effect of gastrin. However H. pylori can also decrease gastric acid secretion, both through the mechanisms described in Dr. Cave's paper and by causing gastric mucosal atrophy with loss of parietal cells. The net effect on acid presumably depends on which mechanism predominates. The processes involved may be crucial determinants of clinical outcome. For example, infection with little atrophy and high acid secretion is associated with duodenal ulcers, while infection with atrophy and low acid secretion increases the risk of gastric cancer of the intestinal-type.