Nutrition—Acid is important in releasing vitamin B12 from food. A minor reduction in oral cyanocobalamin absorption occurs during proton-pump inhibition, potentially leading to subnormal B12 levels with prolonged therapy. Acid also promotes absorption of food-bound minerals (non-heme iron, insoluble calcium salts, magnesium). Meta-analyses of cohort and case-control studies have detected a modest increase in the risk of hip fracture in patients taking long-term PPIs. Although a causal relationship is unproven, PPIs may reduce calcium absorption or inhibit osteoclast function. All PPIs carry an FDA-mandated warning of a possible increased risk of hip, spine, and wrist fractures. Patients who require long-term PPIs—especially those with risk factors for osteoporosis—should have monitoring of bone density and should be provided calcium supplements. Cases of severe, life-threatening hypomagnesemia with secondary hypocalcemia due to PPIs have been reported, possibly due to decreased intestinal absorption.
3.
Respiratory and enteric infections—Gastric acid is an important barrier to colonization and infection of the stomach and intestine from ingested bacteria. Increases in gastric bacterial concentrations are detected in patients taking PPIs, which is of unknown clinical significance. Some studies have reported an increased risk of both community-acquired respiratory infections and nosocomial pneumonia among patients taking PPIs.
There is a twoto threefold increased risk for hospitaland community-acquired Clostridium difficile infection in patients taking PPIs. There also is a small increased risk of other enteric infections (eg, Salmonella, Shigella, Escherichia coli, Campylobacter), which should be considered particularly when traveling in underdeveloped countries.
4. Potential problems due to increased serum gastrin—
Gastrin levels are regulated by intragastric acidity. Acid suppression alters normal feedback inhibition so that median serum gastrin levels rise 1.5to twofold in patients taking PPIs. Although gastrin levels remain within normal limits in most patients, they exceed 500 pg/mL (normal, <100 pg/mL) in 3%. Upon stopping the drug, the levels normalize within 4 weeks. The rise in serum gastrin levels may stimulate hyperplasia of ECL and parietal cells, which may cause transient rebound acid hypersecretion with increased dyspepsia or heartburn after drug discontinuation, which abate within 2–4 weeks after gastrin and acid secretion normalize. In female rats given PPIs for prolonged periods, hypergastrinemia caused gastric carcinoid tumors that developed in areas of ECL hyperplasia. Although humans who take PPIs for a long time also may exhibit ECL hyperplasia, carcinoid tumor formation has not been documented. At present, routine monitoring of serum gastrin levels is not recommended in patients receiving prolonged PPI therapy.
5. Other potential problems due to decreased gastric acidity—Among patients infected with H pylori, long-term acid suppression leads to increased chronic inflammation in the gastric body and decreased inflammation in the antrum. Concerns have been raised that increased gastric inflammation may accelerate gastric gland atrophy (atrophic gastritis) and intestinal metaplasia—known risk factors for gastric adenocarcinoma. A special FDA Gastrointestinal Advisory Committee concluded that there is no evidence that prolonged PPI therapy produces the kind of atrophic gastritis (multifocal atrophic gastritis) or intestinal metaplasia that is associated with increased risk of adenocarcinoma. Routine testing for H pylori is not recommended in patients who require long-term PPI therapy. Longterm PPI therapy is associated with the development of small benign gastric fundic-gland polyps in a small number of patients, which may disappear after stopping the drug and are of uncertain clinical significance.