Table 1 Concerns about long-term therapy with proton pump inhibitors (PPIs): Digestive System

Consequences of long-term PPI-induced hypergastrinemia

• PPI-induced hypergastrinemia is enhanced in H. pylori-infected patients [448], where the antisecretory effect is increased

• No controlled human data support the increased risk of gastric cancer [92, 449]

• More and higher quality studies are needed to confirm or refute any causal link with gastric cancer [450, 451]

• No data support the increased risk of colorectal cancer [452]

• An increased frequency of fundic gland (inflammatory) polyps has been reported [451, 453]

• Rebound acid hypersecretion (and increased frequency of acid-related symptoms) is of uncertain clinical relevance [83]

• Despite unclear biological mechanism(s), two large observational studies [454, 455] reported conflicting results concerning the putative risk of pancreatic carcinoma in PPI users

Infectious consequences of long-term PPI-induced hypochlorhydria

• Growing evidence suggests that acid suppression increases the risk of enteric infections by C. difficile [456–458] and other pathogens [456, 459]

• Increased Candida infections in the mouth, esophagus, stomach, and upper small intestine of PPI users have been documented [460]

• PPI users are at increased risk of small intestinal bacterial overgrowth (SIBO) [461], while cirrhotic patients, taking these drugs, are at higher risk of spontaneous bacterial peritonitis [354, 355]

Non-infectious consequences of long-term PPI-induced hypochlorhydria

• According to a single case-control study [462], exposure to antisecretory drugs, including PPIs, was associated with an increased rate of subsequent diagnosis of celiac disease, but the biological plausibility is unclear

Dysbiosis

• Dysbiosis probably represents the most consistent adverse effect of PPIs, responsible – besides enteric infections and SIBO – for gas-related symptoms as well as aggravation of NSAID-enteropathy [463, 464]

Consequences of long-term PPI-induced hypochlorhydria on electrolyte and nutrient absorption

• No consistent effects on calcium or iron absorption have been reported [394, 395]

• Severe symptomatic hyponatremia has been reported as a consequence of the syndrome of inappropriate ADH secretion [465]

• Data support an increased risk of developing significant B₁₂ deficiency [466], but this is a clinical concern only in elderly or malnourished patients

Idiosyncratic reactions to PPIs

• Magnesium intestinal transport is inhibited by PPIs and may lead to rare but potentially life-threatening hypo-magnesiemia [467, 468]

• Lansoprazole-induced microscopic colitis has been described [469], with complete resolution after drug discontinuation; however, recent data suggest a class effect [470]

• Despite some case reports, epidemiological studies showing an association between PPI intake and acute pancreatitis have given conflicting results [44]