Effects of Proton Pump Inhibitors in Cirrhotic Patients: What Do We Really Know?

Abstract

See “The association between proton pump inhibitor exposure and key liver-related outcomes in patients with cirrhosis: a Veterans Affairs cohort study,” by Mahmud N, Serper M, Taddei TH, et al, on page 257. See “The association between proton pump inhibitor exposure and key liver-related outcomes in patients with cirrhosis: a Veterans Affairs cohort study,” by Mahmud N, Serper M, Taddei TH, et al, on page 257. Proton pump inhibitors (PPIs), after they having been originally proposed in the late 1980s,1Yang Y.X. Metz D.C. Safety of proton pump inhibitor exposure.Gastroenterology. 2010; 139: 1115-1127Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar have quickly become among the most used drugs globally for the treatment of gastroesophageal reflux disease, because the public perception considers PPIs generally effective and safe.2Bardhan K.D. The role of proton pump inhibitors in the treatment of gastro-oesophageal reflux disease.Aliment Pharmacol Ther. 1995; 9: 15-25PubMed Google Scholar However, their availability as over-the-counter drugs and the relative low cost led to unforeseeable prolonged and inappropriate use, most probably contributing to the appearance of their well-known and feared side effects.3Plehhova K. Paquette N. Gould et al.Understanding the patient PPI journey: results of a survey on PPI treatment initiation and patient experience.J Prim Care Community Health. Jan-Dec 2022; 13 (21501319221088688)Crossref PubMed Scopus (2) Google Scholar PPIs adverse effects, in addition to the possible idiosyncratic effect toward PPIs, seem to be essentially linked to 2 mechanisms: the first is a direct consequence of the mechanism of action of the PPIs on gastric parietal cells, which determines hypochlorhydria and reflex hypergastrinemia with consequent reduction of absorption of important nutrients, including vitamin B12, calcium, and iron; the second mechanism is linked to the metabolism of the PPIs that, similar to other classes of drugs, occurs mainly in the liver through the cytochrome P450 pathway.4Raghunath A.S. O’Morain C. McLoughlin R.C. Review article: the long-term use of proton-pump inhibitors.Aliment Pharmacol Ther. 2005; 22: 55-63Crossref PubMed Scopus (135) Google Scholar Although evidence suggests that the use of these drugs could lead to different adverse effects, including an increased risk of fractures, interstitial nephritis, hepatic encephalopathy, anemia, and cognitive decline, most of the available data are based on observational studies and, therefore, could be susceptible to interpretation bias.5Targownik L.E. Fisher D.A. Saini S.D. AGA clinical practice update on de-prescribing of proton pump inhibitors: expert review.Gastroenterology. 2022; 162: 1334-1342Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 6Inadomi J.M. Fendrick A.M. PPI Use in the OTC era: who to treat, with what, and for how long?.Clin Gastroenterol Hepatol. 2005; 3: 208-215Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 7Scarpignato C. Pelosini I. Di Mario F. Acid suppression therapy: where do we go from here?.Dig Dis. 2006; 24: 11-46Crossref PubMed Scopus (93) Google Scholar, 8Vaezi M.F. Yang Y.-X. Howden C.W. Complications of proton pump inhibitor therapy.Gastroenterology. 2017; 153: 35-48Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar, 9Lochhead P. Hagan K. Joshi A.D. et al.Association Between proton pump inhibitor use and cognitive function in women.Gastroenterology. 2017; 153: 971-979Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar Despite a large number of studies, the overall quality of evidence for PPIs adverse effects is low to very low10Klatte D.C.F. Gasparini A. Xu H. et al.Association between proton pump inhibitor use and risk of progression of chronic kidney disease.Gastroenterology. 2017; 153: 702-710Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar and it is difficult, therefore, to rigorously establish whether the described side effects are properly attributable to the use of the drug exposure after correct prescription or whether they are a consequence of inappropriate and unregulated use.11Lo W.K. Chan W.W. Proton pump inhibitor use and the risk of small intestinal bacterial overgrowth: a meta-analysis.Clin Gastroenterol Hepatol. 2013; 11: 483-490Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar,12Freedberg D.E. Kim L.S. Yang Y.-X. The risks and benefits of long-term use of proton pump inhibitors: expert review and best practice advice from the American Gastroenterological Association.Gastroenterology. 2017; 152: 706-715Abstract Full Text Full Text PDF PubMed Scopus (439) Google Scholar Furthermore, because it remains difficult to find a consensus regarding the real side effects attributable to this class of drugs in the general population, the correct definition of these effects in patients with liver cirrhosis is even more complicated and the real effect of PPIs on cirrhotic patients remains controversial.13Goel G.A. Deshpande A. Lopez R. et al.Increased rate of spontaneous bacterial peritonitis among cirrhotic patients receiving pharmacologic acid suppression.Clin Gastroenterol Hepatol. 2012; 10: 422-427Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar, 14O’Leary J.G. Reddy K.R. Wong F. et al.on behalf of the North American Consortium for the Study of End-Stage Liver Disease. Long-term use of antibiotics and proton pump inhibitors predict development of infections in patients with cirrhosis.Clin Gastroenterol Hepatol. 2015; 13: 753-759Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 15Lu Z.N. Niu W.X. Zhang N. et al.Pantoprazole ameliorates liver fibrosis and suppresses hepatic stellate cell activation in bile duct ligation rats by promoting YAP degradation.Acta Pharmacol Sin. 2021; 42 (1808–1182)Crossref Scopus (9) Google Scholar, 16Sun S. Ye W. Zhao R. et al.Proton pump inhibitor therapy does not affect prognosis of cirrhosis patients with acute decompensation and acute-on-chronic liver failure: a single-center prospective.Study Front Med (Lausanne). 2021; 8: 763370PubMed Google Scholar, 17Sakamaki A. Kamimura K. Yokoo T. et al.The prognosis and incidence of hepatic encephalopathy of patients with liver cirrhosis treated with proton pump inhibitors.Medicine. 2021; 100: 32Crossref Scopus (2) Google Scholar Considering that liver cirrhosis is per se a condition in which it is common to find alterations in the intestinal microbiome, anemia, encephalopathy, and a greater susceptibility to infections, it is necessary to clarify what is the impact of the use of PPIs in this group of patients. Relevantly, it would be important to clarify whether there is a concentration of PPIs intake that can be considered safe and if there is a correlation between the duration of PPIs intake and the onset of side effects or even if the different classes of PPIs have any effects on the outcomes. Other crucial considerations relate the possibility that the side effects attributed to PPIs may be influenced by race, gender, body mass index, or the etiology of liver disease (Figure 1). In this regard, the valuable contribution of Mahmud et al18Mahmud N. Serper M. Taddei T.H. et al.The association between proton pump inhibitor exposure and key liver-related outcomes in patients with cirrhosis: a Veterans Affairs cohort study.Gastroenterology. 2022; 163: 257-269Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar sheds light on the association between PPI exposure and the incidence of liver decompensation, infections, and all the causes of death in a large cohort of veterans with compensated liver cirrhosis. For each outcome, the authors evaluated the exposure to PPIs either as a binary or categorical variable considering both the daily dose and the total dose per month of each PPIs class comparing the incidence of the outcome with a population of cirrhotic patients who did not use PPIs. This approach allows for a new and more complete interpretation of the outcomes deriving from exposure to PPIs, in an era in which precision medicine is playing an increasingly important role. Regarding the first and most important outcome (ie, survival), the study,18Mahmud N. Serper M. Taddei T.H. et al.The association between proton pump inhibitor exposure and key liver-related outcomes in patients with cirrhosis: a Veterans Affairs cohort study.Gastroenterology. 2022; 163: 257-269Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar evaluating patients for an average time of 49 months, concludes that despite a marginal 4% increase in the risk of all cause death in PPIs users, the PPIs reduce the risk of death when gastrointestinal bleeding is considered as the only cause of death. Remarkably, the data deriving from the stratification of the causes of mortality divided into hepatic and nonhepatic causes are significant. In fact, the statistical analysis shows that PPIs exposure was associated with a 12% decease in the risk of mortality related to nonhepatic causes and a 23% increased risk of liver-related mortality, excluding gastrointestinal bleeding. The analysis also emphasizes the role of PPIs exposure dose. Specifically, when PPI exposure is evaluated as a binary variable, there was no association with all-cause mortality. In contrast, by adopting categorical models accounting for exposure dose and cumulative dose to PPIs, a significant association (P > .001) between PPIs exposure and increased all-cause mortality has been highlighted. The role of the PPIs exposure dose has been also highlighted in the analysis of intermediate events (eg, decompensation and severe infection). In fact, in addition to the positive association between PPI exposure and severe infection or decompensation of cirrhosis, the results of the study show that the risk of spontaneous bacterial peritonitis was related to exposure to higher doses of PPIs. The finding confirms the key role of dosage and duration of PPI treatment in cirrhotic patients. These results from Mahmud et al18Mahmud N. Serper M. Taddei T.H. et al.The association between proton pump inhibitor exposure and key liver-related outcomes in patients with cirrhosis: a Veterans Affairs cohort study.Gastroenterology. 2022; 163: 257-269Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar overall show that exposure to PPIs, although it may be related to a greater risk of decompensation and infection, can have a protective effect in terms of survival if prescribed according to appropriate indications. Interestingly, the daily dose and the cumulative dose of PPIs exposure assume a key role in assessing the outcomes of cirrhotic patients. Therefore, as recommended elsewhere,5Targownik L.E. Fisher D.A. Saini S.D. AGA clinical practice update on de-prescribing of proton pump inhibitors: expert review.Gastroenterology. 2022; 162: 1334-1342Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar PPIs should only be prescribed where appropriate and at the minimum dose necessary for an adequate effect. Following the authors' contribution in clarifying the effect of PPIs on cirrhotic patients, many questions remain unresolved. It is not clear whether there is any correlation between PPI exposure and gender, or etiology of liver cirrhosis. The cohort under study18Mahmud N. Serper M. Taddei T.H. et al.The association between proton pump inhibitor exposure and key liver-related outcomes in patients with cirrhosis: a Veterans Affairs cohort study.Gastroenterology. 2022; 163: 257-269Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar was almost exclusively a male population with frequent metabolic and cardiovascular comorbidities. Another intriguing research question that arises from the study was the possible role as confounding factor of the prophylactic use of antibiotics. Unreservedly, it can be concluded that the study by Mahmud et al18Mahmud N. Serper M. Taddei T.H. et al.The association between proton pump inhibitor exposure and key liver-related outcomes in patients with cirrhosis: a Veterans Affairs cohort study.Gastroenterology. 2022; 163: 257-269Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar represents a stimulus to further investigate a topic of such significant social impact. The Association Between Proton Pump Inhibitor Exposure and Key Liver-Related Outcomes in Patients With Cirrhosis: A Veterans Affairs Cohort StudyGastroenterologyVol. 163Issue 1PreviewProton pump inhibitor use in cirrhosis is associated with increased risk of liver-related adverse outcomes, but may reduce mortality in patients hospitalized with gastrointestinal bleeding. Full-Text PDF