Aluminium hydroxide and colon cancer.
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Biomedical subjects
Publications and source records attributed to M R Lewin.
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The effects of aspirin on gastric acid and sodium have been studied in a perfused rat stomach preparation. In the pentagastrin-stimulated stomach, as intraluminal aspirin concentration increased, there was a significant fall in acid output together with a significant decrease in the loss of sodium from the gastric lumen. It was concluded that these observations were due to a back-diffusion effect resulting from disruption of the gastric mucosal barrier rather than parietal cell inhibition
Serum gastrin has been studied in dogs with and without surgically produced duodenal reflux. Fasting levels and the gastrin response to a standard meal have been assayed using a radioimmunoassay technique. Duodenal reflux caused no significant change in fasting serum gastrin immuno-reactivity but led to a markedly elevated and prolonged gastrin response to a standard meal.
Blood concentrations of cimetidine were measured and the therapeutic effect of the drug assessed patients undergoing maintenance haemodialysis. Thirteen patients were given a single oral 200-mg dose of cimetidine a mean of 2.7 hours before the start of dialysis. Dialysing for 6--12-6 m2 hours led to a mean fall of 71% in blood cimetidine concentration during haemodialysis. Nine patients with various upper gastrointestinal lesions diagnosed endoscopically were treated for up to six weeks with a reduced cimetidine dose of 200 mg 12-hourly; two patients received two courses of treatment. Repeat endoscopy after treatment disclosed satisfactory healing, and the drug did not accumulate. This lower dose regimen is recommended for patients receiving dialysis who develop upper gastrointestinal lesions for which a histamine H2-receptor antagonist is indicated.
Gastric function and histology were investigated in 24 patients with untreated chronic renal failure. At endoscopy nine patients had oesophagitis, 12 patients were considered to have gastritis, and the duodenum appeared inflamed in 20 patients. Endoscopic biopsies were taken at standard sites in the stomach and duodenum; gastritis was found in all patients, and 17 patients had duodenitis. Stimulated acid secretion was impaired in seven out of 20 patients and acid hypersecretion was found in a further two patients. Pepsin output correlated well with acid output in these patients. Fasting serum gastrin levels were elevated in 12 of the 19 patients tested. Patients with atrophic gastritis had low acid outputs and hypergastrinaemia, and when extensive gastritis was present, the patients tended to have more severe renal failure and hyposecretion of acid. Three patients were studied again after regular haemodialysis or renal transplantation and were found to show marked endoscopic and histological improvement.
The effects of unconjugated bile acids on colonic mucus production have been studied in the dog. Isolated segments of both ascending and descending colon were simultaneously perfused with either chenodeoxycholic, deoxycholic or cholic acid and the mucus production estimated from the total hexose output. Each bile acid produced a significant increase in mucus output in both the right and left colonic segments. There were no differences between the right and left colon in terms of mucus output for any of the bile acids studied. Deoxycholic had a greater effect than chenodeoxycholic which had a greater effect than cholic acid in colonic mucus production. Further, these effects on mucus secretion were completely reversible. In diarrhoea associated with disease or resection of the ileum, the effect of bile acids on mucus secretion may be as important as their effects on the inhibition of water and electrolyte absorption.
The ability of dietary fibre to prevent colon cancer was tested in rats injected with 1,2-dimethylhydrazine (D.M.H.), a substance which induces cancer of the colon. 60 rats were fed the same formula solid diet but allocated three different amounts of dietary fibre--20 were given 4.8% w/w crude fibre, 20 were given 20% w/w bran, and 20 received no fibre. Half of the animals in each fibre group received a course of subcutaneous D.M.H. and half were given subcutaneous saline. After a year's observation, there was no significant difference in the incidence of, or mortality from, colonic carcinoma between the D.M.H.-treated groups.
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At operation for haematemesis in bilharzial hepatic fibrosis, the gallbladder was always found to be diseased but devoid of stones. This led to a study of gallbladder bile composition in a group of bilharzial patients and comparison with a group of cholelithiasis patients. When values for biliary lipid composition were plotted on triangular coordinates, both groups fell well outside the line of maximum cholesterol solubility. The bilharzia group had significantly more cholesterol and less phospholipid than the gallstone group. The absence of stones in patients with bilharzial hepatic fibrosis was possibly due to their early demise and the suggestion is that, in this condition, it is the disease of the gallbladder itself which renders the bile lithogenic.
Inactivation of gastrin was studied (a) in vitro by incubation with a high-speed supernatant fraction of rat small bowel mucosa and (b) in vivo by perfusing gastrin through the small bowel vascular bed in anaesthetized dogs. In both types of experiment there was a highly significant loss in the bioactivity of gastrin, but no significant change in its immunoreactivity. This showed that gastrin was inactivated by a subtle chemical change which rendered the molecule biologically inactive, yet left its immunoreactivity unimpaired.
Using an in vitro system, the effect of gastrin on the colonic handling of water and electrolytes has been investigated. Gastrin converted the normal mucosal absorption of water and sodium into a net secretion. The colonic response to gastrin was done-related with respect to sodium, and the effects were greater when it was added to the serosal side. The potassium handling of the isolated colonic mucosa was not altered by gastrin. At a concentration of 800pg/ml, gastrin signficantly reduced the normal movement of sodium from mucosa to serosa (absorption) but significantly increased serosal to mucosal movement (secretion). This alteration in the bidirectional flux of ions under the influence of gastrin may be clinically important and could account in partt for the diarrhoea associated with the Zollinger-Ellison syndrome.
Gallbladder bile obtained at operation from five patients with no symptoms of biliary disease was undersaturated with cholesterol in every case. However, gallbladder bile from patients with stones composed of 97-100% crystalline cholesterol was on average just saturated with cholesterol when the gallbladder was functioning and undersaturated when it was not. Regardless of gallbladder function, the patients with stones had on average significantly more cholesterol in their bile than in the control group, but the differences between the mean composition of bile from functioning and non-functioning gallbladders were not significant. Common duct bile from patients with non-functioning and functioning gallbladders was on average supersaturated with cholesterol, but there was significantly more bile salt and significantly less cholesterol in the bile from patients with non-functioning gallbladders. Only in the case of patients with functioning gallbladders did the mean composition of the common duct and gallbladder biles differ significantly. The former contained significantly more cholesterol and less bile salt than the latter. It is suggested that patients with non-functioning gallbladders may be 'autocholecystectomised' with the duct bile reverting to a more 'normal' composition.
One hundred and fifty patients suspected of having Zollinger-Ellison syndrome were investigated. High plasma gastrin levels were found in 23 and in 16 a diagnosis of Zollinger-Ellison syndrome was confirmed. Measurement of the basal and maximal acid outputs showed that these simpler investigations have considerable value as screening tests for the selection of those patients in whom gastrin studies are indicated.
Some patients with the Zollinger-Ellison syndrome appear to have hypergastrinaemia and hyperplasia of the antral G cells but no tumour. This subgroup has been classified as Zollinger-Ellison syndrome type 1. We have treated such a patient by vagotomy and antrectomy, the fasting plasma gastrin and acid secretion subsequently returning to normal.A 17-year-old male had a four-year history of duodenal ulcer. Gastric secretion tests showed acid hypersecretion. Fasting plasma gastrin was 8350 pg/ml (normal 50-170 pg/ml). At laparotomy duodenal ulceration was confirmed but no pancreatic or other tumours were found. Truncal vagotomy and antrectomy was performed with distal pancreatectomy. Immunofluorescent staining showed hyperplasia of G cells in the resected antrum but a normal pancreas and duodenum. Six months after operation he was symptom free and acid secretion was reduced by 92%. The fasting plasma gastrin at two months was <50 pg/ml. These findings suggest that type 1 Zollinger-Ellison syndrome may be a clinical entity.
Sixteen patients underwent proximal gastric vagotomy (highly selective vagotomy) for chronic duodenal ulceration. All were subjected to preoperative and postoperative acid secretion studies. A reduction in the secretory response to pentagastrin and abolition of the response to meat extract occurred postoperatively. Plasma gastrin levels in response to meat extract were studied by radioimmunoassay. Basal plasma gastrin levels were unaffected by vagotomy and it was found that the plasma gastrin response to meat extract was not impaired after operation if the postoperative insulin test was positive. Only if the insulin test was negative was the amount of gastrin released by meat extract reduced.
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