Joy Ardill

Helicobacter pylori Infection and Abnormalities of Acid Secretion in Patients With Duodenal Ulcer Disease

BACKGROUND & AIMS The mechanism by which Helicobacter pylori predisposes to duodenal ulcers (DUs) remains unclear. The aim of this study was to investigate the effect of the infection on acid secretion. METHODS Acid output was examined basally and in response to gastrin-releasing peptide (GRP) and gastrin in healthy volunteers with and without H. pylori infection and in patients with DUs before and after eradication of the infection. RESULTS Compared with H. pylori-negative healthy volunteers, patients with DUs with H. pylori had the following abnormalities of acid secretion: (1) threefold increase in basal acid output, (2) sixfold increase in acid response to GRP, (3) increased maximal acid response to exogenous gastrin, (4) increased ratio of basal acid output to maximal gastrin-stimulated output, and (5) increased ratio of maximal GRP-stimulated acid output to maximal gastrin-stimulated output. All of these abnormalities resolved fully after H. pylori eradication except for increased maximal acid output to gastrin, which was unchanged. Infected healthy volunteers showed a threefold increase in acid response to GRP that resolved after eradication of H. pylori infection. CONCLUSIONS These disturbances in acid secretion caused by H. pylori infection are consistent with impaired inhibitory control and are likely to be relevant to the mechanism by which the infection predisposes to DU.

Eradicating Helicobacter pylori infection lowers gastrin mediated acid secretion by two thirds in patients with duodenal ulcer.

Helicobacter pylori (H pylori) raises serum gastrin but it is unclear whether this stimulates increased acid secretion. Gastrin mediated acid secretion and plasma gastrin after the intravenous infusion of gastrin releasing peptide was studied in nine H pylori negative and nine H pylori positive healthy volunteers, and in 11 duodenal ulcer patients. Nine of the last group were re-examined one month after eradication of H pylori. The median acid output (mmol/h) to gastrin releasing peptide (40 pmol/kg/h) in the H pylori positive healthy volunteers was 15.1 (range 3.3-38.3), which was three times that of the H pylori negative healthy volunteers (median = 5.5, range 1.0-9.0) (p < 0.02). The median acid output in the duodenal ulcer patients with H pylori was 37 (range 8.5-57), which was > six times that of the H pylori negative healthy volunteers. Eradication of H pylori in the duodenal ulcer patients lowered their acid secretion by a median of 66% (range 30%-80%) (p < 0.01) and to values equivalent to the H pylori positive healthy volunteers. The pepsin output in response to gastrin releasing peptide followed the same pattern as the acid output. The median plasma gastrin concentrations during gastrin releasing peptide were similar in the H pylori positive duodenal ulcer patients (150 ng/l, range 95-400) and H pylori positive healthy volunteers (129 ng/l, range 23-420) and both were appreciably higher than H pylori negative healthy volunteers (60 ng/l, range 28-135) (p < 0.005 for each). Eradication of H pylori lowered the plasma gastrin in the duodenal ulcer patients to values equivalent to the H pylori negative healthy volunteers. These findings show a threefold increase in acid secretion in H pylori positive healthy volunteers that is explained by H pylori induced hypergastrinaemia and a sixfold increase in acid secretion in the duodenal ulcer patients that is explained by the combination of H pylori induced hypergastrinaemia and an exaggerated acid response to stimulation by gastrin. Eradicating H pylori lowers gastrin mediated acid secretion by 66% in duodenal ulcer patients as a result of the resolution of the hypergastrinaemia. Increased gastrin mediated acid secretion seems to be the key factor in the pathophysiology of duodenal ulceration and explains the role of H pylori infection in the disorder.

Rebound hypersecretion after omeprazole and its relation to on-treatment acid suppression and Helicobacter pylori status

BACKGROUND & AIMS There have been conflicting reports regarding acid secretion after treatment with omeprazole. This study examined acid secretion after treatment with omeprazole and its relation to Helicobacter pylori status and on-treatment gastric function. METHODS Twelve H. pylori-negative and 9 H. pylori-positive subjects were examined before, on, and at day 15 after an 8-week course of 40 mg/day omeprazole. On each occasion, plasma gastrin, intragastric pH, and acid output were measured basally and in response to increasing doses of gastrin 17. RESULTS In the H. pylori-negative subjects at day 15 after omeprazole treatment, basal acid output was 82% higher (P < 0.007) and maximal acid output 28% higher (P < 0.003) than before omeprazole. The degree of increase in maximal acid output was related to both on-treatment pH and on-treatment fasting gastrin levels, being 48.0% in subjects with an on-treatment pH of >4 vs. 21. 0% in those with a pH of <4 (P < 0.02) and 49.2% in subjects with an on-treatment gastrin of >25 ng. L-1 vs. 19.8% in those with a fasting gastrin of <25 ng. L-1 (P < 0.006). At day 15 after omeprazole treatment, the H. pylori-positive subjects showed a heterogeneous response with some having increased acid output and others persisting suppression. CONCLUSIONS Rebound acid hypersecretion occurs in H. pylori-negative subjects after omeprazole treatment. Its severity is related to the degree of elevation of pH on treatment. Persisting suppression of acid secretion masks the phenomenon in H. pylori-positive subjects.

Neuroendocrine tumors: A European view

A center in Belfast, Northern Ireland, has established a register for tumors of the gastroenteropancreatic endocrine system. Carcinoid tumors occur most frequently. Of the non-carcinoid tumors, insulinomas, gastrinomas, and unknown types have the highest incidence, with other types being extremely rare. The potentially remediable nature of the tumors is stressed, and frequently a good quality of life can be experienced even in the presence of metastatic disease. The syndromes are probably underdiagnosed as they present with clinical features for which there are more common explanations, and appropriate diagnostic methods are therefore not used. The management of the syndromes is reviewed with particular emphasis on the treatment of patients with inoperable disease. Histamine (H2)-receptor antagonist therapy has made an impact in Zollinger-Ellison syndrome, and streptozotocin and somatostatin analogues can control tumor growth and endocrine syndromes, respectively.

Inhibition of dipeptidyl peptidase IV activity by oral metformin in Type 2 diabetes

Aims  Glucagon‐like peptide‐1 (GLP‐1) and gastric inhibitory polypeptide (GIP) are important insulinotropic hormones that enhance the insulin secretory response to feeding. Their potential for treating Type 2 diabetes is limited by short biological half‐life owing to degradation by dipeptidyl peptidase IV (DPP IV). We investigated the acute effects of metformin on DPP IV activity in Type 2 diabetes to elucidate inhibition of DPP IV as a possible mechanism of action.

Helicobacter pylori infection potentiates the inhibition of gastric acid secretion by omeprazole.

BACKGROUND Omeprazole has a greater intragastric pH elevating effect in Helicobacter pylori positive than negative subjects. Ammonia production byH pylori has been suggested as a probable mechanism. AIMS To assess the effect ofH pylori status on gastric acid secretion during omeprazole treatment, and to examine the possible role of ammonia neutralisation of intragastric acid in increased omeprazole efficacy in infected subjects. METHODS TwentyH pylori positive and 12H pylori negative healthy volunteers were examined before and six to eight weeks after commencing omeprazole 40 mg/day. On both occasions plasma gastrin and acid output were measured basally and in response to increasing doses of gastrin 17 (G-17). Gastric juice ammonium concentrations were also measured. RESULTS Prior to omeprazole, measurements were similar in the H pyloripositive and negative subjects. During omeprazole, median basal intragastric pH was higher in the H pyloripositive (7.95) versus negative (3.75) subjects (p<0.002). During omeprazole basal, submaximal (180 pmol/kg/h G-17), and maximal acid outputs (800 pmol/kg/h G-17) were lower in H pylori positive subjects (0.0, 3.6, 6.0 mmol/h respectively) versus negative subjects (0.3, 14.2, 18.6 mmol/h) (p<0.03 for each). This effect was not explained by neutralisation by ammonia. CONCLUSION The presence ofH pylori infection leads to a more profound suppression of acid secretion during omeprazole treatment. The effect cannot be explained by neutralisation of intragastric acid by bacterial ammonia production and its precise mechanism has to be explained.

The acid response to gastrin distinguishes duodenal ulcer patients from Helicobacter pylori–infected healthy subjects

BACKGROUND & AIMS Helicobacter pylori-induced hypergastrinemia is accompanied by increased acid secretion in patients with duodenal ulcer (DU) but not in infected healthy volunteers. The aim of this study was to investigate the mechanism underlying this difference. METHODS Thirty-four H. pylori-negative and 20 H. pylori-positive healthy volunteers and 15 H. pylori-positive patients with DU were studied. Maximal acid output and sensitivity to gastrin (gastrin concentration required to achieve 50% maximal acid output) were assessed by examining the dose response to gastrin 17. Inhibitory control was tested by comparing the maximal acid response to cholecystokinin octapeptide with that for gastrin 17. RESULTS Sensitivity to gastrin was similar in patients with DU (median, 69.5 ng.L-1; range, 26.2-142) and H. pylori-negative healthy volunteers (median, 82.2 ng.L-1; range, 17.7-410); H. pylori-positive healthy volunteers were less sensitive than either (164.5 ng.L-1; range, 44.8 to > 3360 ng.L-1). Patients with DU had higher maximal acid output (51.2 mmol.h-1; range, 30.8-73.7 mmol.h-1) than either infected healthy volunteers (37.8 mmol.h-1; range, 0.0-65.0 mmol.h-1; P < 0.04) or uninfected healthy volunteers (35.3 mmol.h-1; range, 21.3-67.3 mmol.h-1; P < 0.002). The maximal acid output in both groups of healthy subjects was similar. The proportion of maximal acid output to gastrin 17 achieved by cholecystokinin was similar in patients with DU (36.6%; range, 21.5%-58.2%) and H. pylori-negative healthy volunteers (28.7%; range, 5.9%-85.8%). CONCLUSIONS A combination of decreased sensitivity to gastrin in infected healthy volunteers and increased maximal acid secretory capacity in patients with DU underlies their different acid response to H. pylori-induced hypergastrinemia.

Circulating markers of prognosis and response to treatment in patients with midgut carcinoid tumours

Background and aims: Midgut carcinoid tumours are uncommon tumours with an unpredictable clinical behaviour and few useful prognostic markers. Somatostatin analogues are widely used in treatment but a survival advantage has not been proven. We analysed features associated with poor prognosis and assessed the clinical implications of the biochemical response to therapy. Methods: Clinical and biochemical data were collected for patients with midgut carcinoid tumours attending a tertiary referral neuroendocrine clinic from 1978 to 2000. Using death as the end point, univariate and multivariate survival analyses were performed to identify prognostic indicators. The significance of altering biomarkers with therapy was also studied by including repeated measurements of the most prognostic biochemical parameter in a time dependent covariate survival analysis. Results: We identified 139 patients with sufficient data for our analyses. Factors associated with a poor outcome on univariate analysis included: plasma neurokinin A (NKA), urinary 5-hydroxyindolacetic acid output, age, and ⩾5 liver metastases. Plasma NKA was the strongest and only independent predictor of outcome on multivariate analysis. Patients in whom NKA continued to rise despite somatostatin analogues had a significantly worse survival than those in whom NKA stabilised or fell (one year survival rate 40% v 87%). Time dependent covariate analysis concluded that survival was better predicted by the most recent plasma NKA value rather than by the initial value. Conclusions: Plasma NKA is an accurate marker of prognosis for midgut carcinoid tumours. This is the first paper to support a survival advantage in patients in whom plasma NKA is altered by somatostatin analogues.

A substantial proportion of non-ulcer dyspepsia patients have the same abnormality of acid secretion as duodenal ulcer patients.

Acid secretion in response to gastrin releasing peptide (GRP) is increased six-fold in Helicobacter pylori positive duodenal ulcer (DU) patients and threefold in H pylori positive healthy volunteers, and this fully resolves after eradication of the infection. This study was undertaken to determine whether a proportion of H pylori positive patients with non-ulcer dyspepsia (NUD) have an acid secretion disturbance similar to DU patients. Basal and GRP stimulated gastrin concentrations and acid output were examined in 25 H pylori positive NUD patients and the results compared with those of 25 H pylori positive healthy volunteers, 25 H pylori negative healthy volunteers, and 25 H pylori positive DU patients. Compared with the H pylori negative healthy volunteers, GRP stimulated gastrin was increased approximately three fold in each of the three infected groups. GRP stimulated acid secretion (median, range) was higher in the H pylori positive NUD patients (29.6 mmol/h (5.2-46.5)) (p < 0.005) than in the H pylori positive healthy volunteers (19.0 (1.0-38.3)) (p < 0.001) or H pylori negative healthy volunteers (6.3 (2.8-20.9)) (p < 0.0001). The H pylori positive NUD patients, however, had lower acid output than the DU patients (39.1 (17.9-64)) (p < 0.005). These findings are consistent with approximately 50% of the NUD patients having a similar disturbance of GRP stimulated acid secretion to DU patients.

STIMULATION OF GASTRIN RELEASE BY CATECHOLAMINES

Abstract Plasma-gastrin levels measured by radioimmunoassay were found to be elevated in two patients with phaeochromocytoma. Both the administration of phenoxybenzamine and the later removal of the tumour reduced the fasting plasma-gastrin level to normal. The intravenous infusion of adrenaline in dogs produced a rise in plasma-gastrin level. It is concluded that catecholamines stimulate gastrin release.