Regina Lamberts

Long-term omeprazole therapy in peptic ulcer disease: Gastrin, endocrine cell growth, and gastritis

BACKGROUND The effects of chronic drug-induced hypergastrinemia on the exocrine and endocrine stomach are still incompletely understood. Chronic hypergastrinemia in rats and humans is associated with gastric argyrophil cell hyperplasia. METHODS Seventy-four patients with chronic ranitidine-resistant ulcerations were treated chronically with omeprazole (median observation period 48 [6-84] months). RESULTS Median fasting serum gastrin levels increased from a pretreatment value of 74-145 pg/mL after 3 months. No further increase was observed thereafter. The finding of atrophic gastritis increased from 1.8% to 20.8% after 5 years. A doubling of the mean argyrophil cell volume density (0.36% vs. 0.74% after 5 years; P < 0.01%) was paralleled by a decrease in the normal endocrine cell growth pattern from 64.3% to 33.3% and an increase in micronodular hyperplasia (8.9% vs. 16.7%). These changes correlated with the severity of corpus gastritis and seemed to be more disease- than drug-related. No statistically significant changes were observed in the antral G- and D-cell volume densities under therapy. CONCLUSIONS Long-term omeprazole therapy in humans results in moderate hypergastrinemia and a significant argyrophil cell hyperplasia, which are correlated to the grade of corpus gastritis. Because hypergastrinemia and gastritis are closely related, it is difficult to quantitatively assess their respective role in this process.

Long-Term Omeprazole Treatment in Man: Effects on Gastric Endocrine Cell Populations

36 patients with chronic gastric or oesophageal peptic ulceration (including 6 with antrectomy), resistant to high-dose ranitidine treatment for at least 3 months, were successfully treated with 40-60 mg of omeprazole daily for periods between 1 and 2 years. Fasting serum gastrin levels were monitored at regular intervals during therapy and multiple gastric mucosal biopsies were taken during gastroscopy every 3-6 months. Gastrin levels increased significantly during the first 6 months of therapy from a medium level of 81.5 to 206 pg/ml, a slight decrease was seen thereafter. In 10 patients investigated before the start of the treatment and after 1 and 2 years, the volume density of argyrophilic cells in the oxyntic mucosa increased from 0.43 +/- 0.08 to 0.91 +/- 0.14% during the first year; this change was statistically significant. No further increase was observed thereafter. No such difference could be demonstrated between a larger group of 18 patients investigated before and after 1 year of treatment with omeprazole (0.806 +/- 0.1 vs. 0.93 +/- 0.08%) and between a larger group of 22 untreated patients and 17 patients treated for 17-24 months with omeprazole (0.73 +/- 0.1 vs. 0.86 +/- 0.09%). The volume density of argyrophilic cells found in 8 patients with gastrinoma amounted to 1.37 +/- 0.22%. No clusters of endocrine cells were found in omeprazole-treated patients. The D cell volume density in the antral mucosa decreased significantly during the first months of treatment, but steadily increased thereafter to reach pretreatment values after 17 months. There was no change in G cell volume density under therapy. No changes in gastrin levels or oxyntic argyrophilic cells were observed in the antrectomized patients. It is concluded that the hyperplasia of argyrophilic cells observed in some patients during long-term omeprazole treatment is mediated by hypergastrinaemia.

Therapy with omeprazole in patients with peptic ulcerations resistant to extended high-dose ranitidine treatment

94 patients with peptic ulcerations of duodenum, stomach, and esophagus, who did not respond to 3 or more months high-dose (450 or 600 mg) treatment with ranitidine, were treated orally with 40 mg omeprazole daily. After healing all patients were offered long-term maintenance therapy with the same dose for 5 years. In 75 patients the peptic ulcerations healed within 4 weeks, in 13 patients within 8 weeks, and in 3 patients only after an increase to 60 mg omeprazole daily. In 3 patients the ulcers did not heal. So far 83 patients have entered long-term maintenance therapy. 59 of these patients are on the drug between 1 and 4 years. During maintenance therapy with 40 mg omeprazole no relapses have occurred up to now as demonstrated by endoscopy and no drug-related adverse effects were observed. Routine laboratory tests remained without significant changes in all patients including 18 patients with concomitant liver cirrhosis. Serum gastrin levels were already elevated during the initial high-dose ranitidine treatment (106 +/- 15.4 pg/ml). 4 weeks after the start of omeprazole treatment serum gastrin levels rose to 4 times normal levels (195 +/- 28 pg/ml). Thereafter, no further increase in serum gastrin was observed even up to 4 years of continuous observation. It is therefore concluded that omeprazole is highly effective in healing ranitidine-resistant peptic ulcerations and that omeprazole maintenance therapy with 40 mg omeprazole is safe during the time observed and highly effective in the prevention of ulcer recurrence.

Session 6: Is Hypergastrinaemia Dangerous to Man?

Creutzfeldt W, Lamberts R. Is hypergastrinaemia dangerous to man? Scand J Gastroenterol 1991, 26(suppl 180), 179–191Achlorhydria 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...

Light and electron microscopical immunocytochemical localization of pancreastatin-like immunoreactivity in porcine tissues.

SummaryPancreastatin is a 49 amino acid comprising peptide isolated from porcine pancreas that is derived by proteolytic processing from chromogranin A. Using an antibody against the synthetic C-terminal fragment pancreastatin (33–49), we examined the light and electron microscopical immunocytochemical localization of this peptide in porcine tissues. Pancreastatin-like immunoreactivity (PLI) was found in pancreatic somatostatin-, insulin- and glucagon cells in varying intensities; pancreatic polypeptide cells were always negative. At the electron microscopical (EM) level the immunoreactivity was confined to the electron dense core of the secretory granules in the case of somatostatin and insulin cells or to the less electron dense “halo” of the glucagon granules. In the antrum PLI positive cells represented gastrin (G), somatostatin (D) and enterochromaffin (EC) cells, in the duodenum in addition to EC- and G-cells a small number of PLI positive cells showed a positive immunoreaction for glucagon-like peptide (GLP) I and secretin in serial sections. Both norepinephrine and epinephrine containing cells of the adrenal medulla exhibited a strong reaction for PLI. In the pituitary several cell populations stained with varying intensities, including gonadotrophs and thyrotrophs. PLI is present in a distinct and characteristic subpopulation of neuroendocrine cells in various organs. The subcellular localization may indicate a function in the granular concentration, packaging and storage of peptides and amines in the brain-gut endocrine system.

Quantitative Studies of Gastric Endocrine Cells in Patients Receiving Long-term Treatment with Omeprazole

A total of 36 patients with chronic gastric or oesophageal peptic ulceration (including 6 with antrectomy), resistant to high-dose ranitidine treatment for at least 3 months, were successfully treated with omeprazole 20-60 mg/day, for periods up to 3 years. Fasting serum gastrin levels were monitored at regular intervals during therapy and multiple gastric mucosal biopsies were taken during gastroscopy every 3-6 months. Gastrin levels increased significantly during the first 6 months of therapy from a mean of 81.5 to 206 pg/ml; a slight decrease was observed thereafter. There was no significant increase in the volume density of argyrophilic cells in the oxyntic mucosa. No clusters of endocrine cells were found in the oxyntic mucosa and no change of G-cell volume density occurred in the antral mucosa under therapy. Omeprazole therapy did not result in any changes in gastrin levels or oxyntic argyrophilic cells in the antrectomized patients. It is concluded that the moderate hypergastrinaemia observed during long-term omeprazole treatment in man does not induce hyperplasia of argyrophilic cells in the oxyntic mucosa.

Antral Helicobacter pylori-like organisms in different states of gastric acid secretion

The frequency of Helicobacter pylori (H.p.) infestation in antral mucosa and the presence of gastritis were investigated in different states of gastric acid secretion. Biopsies were stained by the Warthin-Starry technique and hematoxylin-eosin. Antral H.p. was found in similar frequencies in Zollinger-Ellison syndrome (n = 17; profound acid hypersecretion, associated with duodenal ulcer disease in most cases) and the same number of age-matched controls (35% in each group) whereas H.p. could be detected in 31 out of 33 duodenal ulcer patients (94%). The incidence of H.p. infestation in H2-blocker refractory reflux oesophagitis was low (24%). Treatment of peptic lesions with omeprazole (drug-induced hypochlorhydria) led to a reduction or disappearance of H.p. in 7 out of 10 H.p.-positive patients whereas none of 19 primarily H.p.-negative patients became infected with H.p. during prolonged omeprazole therapy. It is concluded that (1) development of duodenal ulcers (as in gastrinomas) does not necessarily require H.p., and (2) at least in some patients H.p. is reduced in antral mucosa by omeprazole.

Budd-Chiari Syndrome as the Primary Manifestation of a Fibrolamellar Hepatocellular Carcinoma

An 18-year-old female patient was admitted with ascites, right upper abdominal tenderness and peripheral edema. Angiography showed complete occlusion of the vena cava inferior up to the level of the right atrium. By open heart surgery, masses of thrombotic material were pulled out of the v. cava inferior/vv. iliacae which histologically contained tumor cell populations consistent with a hepatocellular carcinoma. Celiacography showed a highly vascularized tumor in the right hepatic lobe. Histologically, it proved to be fibrolamellar subtype hepatocellular carcinoma.

Somatostatin cells in rat antral mucosa: qualitative and quantitative ultrastructural analyses in different states of gastric acid secretion

SummaryIn the gastrointestinal tract somatostatin is localized in endocrine cells and in neurons. The antral somatostatin (D-) cell shares features of both cell types. The activity of the antral D-cell is regulated by intragastric pH. Therefore different states of gastric acidity were induced experimentally in order to study D-cell morphology at the electron microscopical level. The morphological findings were related to measurements of plasma and tissue concentrations of the peptide. The D-cell is characterized by extensive membrane interdigitations with neighbouring cells. Changes in the activity of antral D-cells are reflected by an increase in cytoplasmic secretory granule density and a shift of secretory granules towards basal cell processes. Direct endocrine cell contacts at the level of the perikarya were rarely observed. The intracellular distribution of secretory granules suggests that cell communication is more likely to take place at the level of the strongly immunoreactive cytoplasmic processes. No evidence for endocrine or exocrine (luminar) secretion was observed morphologically. This is in agreement with the concept of paracrine secretion of the antral D-cell.

Intestinal Obstruction, ProgressiveWeight Loss, and Recurrent Feverin Two Patients with Mesenteric Lesions

We describe 2 patients who presented with fever and incomplete intestinal obstruction. Previously, both patients had had laparotomies showing unresectable lesions in the root of the mesentery which were histologically diagnosed as sclerosing mesenteritis in the first and mesenteric fibromatosis in the second patient. In spite of aggressive immunosuppressive therapy the first patient deteriorated with high-grade fever and progressive weight loss. Similar symptoms occurred in the second patient. Computed tomographic scanning revealed necrotic lesions in both patients which histologically were found to be an angiocentric T-cell lymphoma in the first and a superinfected necrotizing fibroma in the second patient. It is therefore clinically and radiologically impossible to distinguish between the different causes of mesenteric lesions. Reoperation for further biopsies needs to be considered if such patients do not respond to medical treatment.