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Proton-pump inhibitors: understanding the complications and risks

Key Points

  • Proton-pump inhibitors (PPIs) induce structural and functional changes in the gastric mucosa related to potent acid suppression, which are exaggerated during Helicobacter pylori infection; PPIs alone are unlikely to be related to gastric and gastrointestinal malignancies

  • The list of adverse events associated with PPI intake is increasing; few of these associations are plausible or proven to have a causal relationship

  • The risk of bacterial enteric infections with Clostridium difficile, Salmonella and Campylobacter is increased in patients on PPI therapy — this risk is low to modest

  • PPI use can rarely cause acute kidney injury and other morbid conditions related to idiosyncratic effects

  • Long-term PPI intake interferes with magnesium and calcium homeostasis in small subsets of patients with chronic kidney disease on diuretic therapy; the prevalence of bone fractures attributable to PPIs in older patients is low

  • The debate on whether PPIs increase the risk of coronary events in patients on clopidogrel seems to be resolved; the FDA recommends avoiding omeprazole in patients taking clopidogrel

Abstract

Proton-pump inhibitors (PPIs) are the most effective therapy for the full spectrum of gastric-acid-related diseases. However, in the past decade, a steadily increasing list of complications following long-term use of PPIs has been reported. Their potent acid-suppressive action induces several structural and functional changes within the gastric mucosa, including fundic gland polyps, enterochromaffin-like cell hyperplasia and hypergastrinaemia, which can be exaggerated in the presence of Helicobacter pylori infection. As discussed in this Review, most associations of PPIs with severe adverse events are not based on sufficient evidence because of confounding factors and a lack of plausible mechanisms. Thus, a causal relationship remains unproven in most associations, and further studies are needed. Awareness of PPI-associated risks should not lead to anxiety in patients but rather should induce the physician to consider the appropriate dosing and duration of PPI therapy, including long-term monitoring strategies in selected groups of patients because of their individual comorbidities and risk factors.

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Figure 1: Endoscopic appearance of fundic gland polyps.
Figure 2: Effect of PPIs on gastric physiology.
Figure 3: Effect of acid inhibition with PPIs on Helicobacter pylori gastritis.
Figure 4: Activation of clopidogrel via cytochrome P450.
Figure 5: PPIs and adverse events with proven and unproven causality.

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All authors contributed equally to the writing and reviewing of the draft manuscript.

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Correspondence to Peter Malfertheiner.

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P.M. is a member of the advisory boards for Allergan, Alfa Wassermann and Bayer and has taken part in speakers' bureaus for Allergan, AstraZeneca, Reckitt Benckiser and Takeda. M.V. is a member of the advisory boards for Amgen, Lilly and Nordic and has taken part in a speakers' bureau for Bayer and Merck Serono. A.K. declares no competing interests.

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Malfertheiner, P., Kandulski, A. & Venerito, M. Proton-pump inhibitors: understanding the complications and risks. Nat Rev Gastroenterol Hepatol 14, 697–710 (2017). https://doi.org/10.1038/nrgastro.2017.117

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