Table 3.

Proton pump inhibitor associated side effects

PPI associated adverse risks	Proposed mechanism	Evidence type	Conditional recommendations to reduce risk
Electrolyte abnormalities: Hypomagnesemia, vitamin B12, iron	Decreased acid secretion decreases intestinal absorption of minerals/vitamins	Observational studies, conflicting evidence[33,34,36,37]	Unless other risk factors present, no recommendation to increase intake of vitamins/minerals or have routine screening of levels[19]
Fracture risk/hypocalcemia	Decreased acid secretion decreases calcium carbonate absorption	Observational studies, conflicting evidence[39,40-42]	Without other risk factors for bone disease, no recommendations to increase calcium/vitamin D intake or have routine bone mineral density exam[19]
AIN/CKD/ESRD	Initiate cell mediated immune response in kidneys	Observational studies, conflicting evidence[43-46]	Without other risk factors, there is no recommendation to routinely screen for kidney function in patients on PPIs[19]
Dementia	Increase β-amyloid plaque production and increase affinity of tau proteins	Observational studies, conflicting evidence[48,49]	No recommendations on dementia prevention in patients on PPI
Gastrointestinal infections: C. diff, SIBO, SBP	Alter gut microbiota due to decreased acidic environment	Observational studies, conflicting evidence[34,51-55]	For patients who develop C.diff infection while on PPI, can consider switching to H2 blockers[55]
Community acquired Pneumonia	Increase bacterial colonization in stomach from hypochlorhydria leading to lung micro-aspiration events	Observational studies, RCTs, conflicting evidence[57-59]	No strong recommendation can be made
	Alter respiratory flora
Gastrointestinal malignancies	Hypergastrinemia resultant from decreased acid production increases ECL cell hyperplasia	Observational studies, RCTs, conflicting evidence[60-62,64,65]	Given conflicting data, no recommendation on prevention can be made
Adverse Cardiovascular effects- arrythmias, decreased clopidogrel bioavailability, increased digoxin toxicity	Hypomagnesemia- torsade de pointes	Observational studies, RCTs, conflicting evidence[59,66]	For patients with significant esophagitis (grade C or D) or with poorly controlled GERD, PPI treatment outweighs the debatable cardiovascular risks[19]
	CYP450 inhibitor- decreases drug bioavailability
	Interaction with ATP-dependent P-glycoprotein
	impair endothelial function and platelet induction

GERD: Gastro-esophageal reflux disease; PPI: Proton pump inhibitor; AIN: Acute intestinal nephritis; CKD: Chronic kidney disease; ESRD: End stage renal disease; C. diff: Clostridium difficile; SIBO: Small intestinal bacterial overgrowth; SBP: Spontaneous bacterial peritonitis; ECL: Enterochromaffin-like; RCTs: Randomized control trials.