Table 1.

Proton pump inhibitor gastrointestinal adverse effects

Common adverse events	Abdominal pain, diarrhea, constipation, nausea, and vomiting [4]
Serious adverse events	Increased risk of gastrointestinal infection by Clostridium difficile, bone fractures, and malabsorption in the gut [34]
Clostridium difficile infection	A study performed on 136 subjects showed that one of the major risk factors for developing C. difficile infection was the long-term use of PPIs [36]
	The increased risk of infection can be explained by three proposed mechanisms: (1) the reduction in gastric acid may allow infectious organisms to reach the intestine easily, (2) antineutrophilic effect, and (3) alterations in the tight junctions between cells, allowing bacterial organisms to more freely pass from one organ to another [34]
	Inhibition of acid secretion perpetuated by PPI use can allow vegetative forms of the bacterium to survive in this less acidic environment and propagate infection [37]
	Acid secreted by parietal cells into the gastrointestinal tract serves as an innate immunological barrier; inhibition of this acid secretion by PPIs allows for increased bacterial colonization and increased opportunity for infection [38]
	PPIs also cause hypochlorhydria, which causes changes in bacterial homeostasis and growth in the GI tract, and allows for overgrowth of bacteria and perpetuation of enteric infections [39]
Bone fractures	Yang et al. showed that PPI users had a 1.5-fold increased risk of developing hip fractures compared to control groups [40]
	Hypochlorhydria caused by PPIs leads to a decrease in calcium absorption in the small intestine and, ultimately, lower calcium levels in the blood [41]
	Decreased serum calcium not only leads to disruption of bone formation performed by osteoblasts but also promotes osteoclast function and increased bone resorption [43]
	Higher gastric pH has also been hypothesized to decrease the absorption of magnesium, leading to the formation of large hydroxyapatite crystals. These crystals decrease osteoblast function and increase the number of osteoclasts [44]
	Lewis et al. showed an increased risk of fracture in patients who were taking PPIs for 1 year or more [46]
	Brozek et al. demonstrated that use of PPIs is associated with an increased risk of subsequent hip fracture after sustaining a hip fracture before initiation of a PPI; this risk was found to be greater in male PPI users than in female PPI users [47]
Malabsorption	Acquired hypochlorhydria has been found to decrease the absorption of multiple micronutrients, including vitamin B12 and iron [48]
	The suppression of gastric acid from PPI use can lead to vitamin B12 deficiency [49, 50]
	Hamano et al. demonstrated that there is an increased risk of iron deficiency anemia with PPI and H2 receptor blockers [54]