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Achlorhydria, determined by the augmented histamine test, is the functional expression of the most severe atrophic gastritis and is followed by a 4- to 6-fold increased risk of gastric cancer, as we found 5 cancers in 114 patients after a mean observation period of 8.4 years. The cancers developed from 1 to 17 years after achlorhydria diagnosis--three cases after more than 9 years. The study showed no difference in gastric cancer risk between patients with and without pernicious anaemia. Spontaneous achlorhydria is the late result of atrophic gastritis, which should be regarded the premalignant condition. The development of gastric cancer from pharmacologically reduced acid secretion must be regarded as highly hypothetical, since this is not followed by atrophic gastritis.

Verner and Morrison, in 1958, reported non-insulin-secreting tumours of the pancreas that were associated with a syndrome of refractory diarrhea, achlorhydria and hypokalemia. Surgical resection of such tumours results in rebound acid hypersecretion and cessation of the watery diarrhea. The authors report the case of an 84-year-old man who had three of the four major criteria for diagnosis of the Verner Morrison syndrome. Hypokalemia was absent, but this was possibly due to the large doses of potassium chloride that he was taking in conjunction with diuretics. After resection of the tumour severe obstipation with resultant bowel obstruction developed in addition to rebound hypersecretion and relief of watery diarrhea. Treatment, consisting of bulk laxatives in appropriate amounts, alleviated the obstipation.

A pathogenetic mechanism to explain the increased incidence of gastric cancer in patients with pernicious anaemia (P.A.) is proposed. Mean nitrite concentration in gastric juice from thirteen fasting patients with P.A. was nearly fiftyfold greater than that of age-matched controls. The number of bacteria in the gastric juice of P.A. patients was also greatly increased. Small amounts of volatile nitrosamines were detected in simulated P.A. gastric juice in vitro, after addition of nitrite to achieve a concentration approximating to that found in vivo. If similar nitrosation occurs in vivo, the intragastric production of carcinogenic N-nitroso compounds could explain the high incidence of gastric cancer in patients with P.A.

Reduction in acid secretion in atrophic gastritis allows bacterial colonization of the stomach, most extremely in achlorhydric patients with pernicious anaemia, in whom overgrowth may cause nitrate reduction and formation of potentially carcinogenic N-nitroso compounds. Subsequent bacterial contamination of the upper small intestine can induce mucosal damage and malabsorption. The situation is similar after gastrectomy. In achlorhydria and after gastrectomy, the risk of gastric cancer is increased. There is controversy as to the risks of long-term treatment with H2-receptor antagonists. Increase in nitrate-reducing bacteria, nitrite and N-nitrosamine have been observed in patients by some investigators but not in volunteers and patients by others. Bacterial concentrations after cimetidine are inversely related to pretreatment acid secretory capacity. Demonstration of increased mutagenicity of gastric juice after H2-receptor antagonists gives grounds for caution. Drastic acid reduction may in future be reserved for short-term and intermittent treatment and mild or moderate reduction for long-term treatment of peptic ulcer and ulcer prevention.

Forty-two patients with pernicious anemia (PA) and 35 patients with achlorhydria but without PA were investigated by means of serum gastrin determination and estimation of circulating parietal cell and thyroidal autoantibodies. In 38 of the 77 patients, gastroscopic and histopathological examinations of the antral and corpus mucosa were performed. The patient groups were similar with regard to distribution of high and normal serum gastrin levels, the frequencey of autoantibodies and antrum-sparing atrophic gastritis. In the present selection of patients, therefore, the achlorhydria group was supposed to represent a precursor state of the group with PA. A minor proportion of patients with severe atrophic gastritis of the antrum as well as of the corpus mucosa was found in the two groups.