Retrospective Cohort Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 7, 2019; 25(33): 4933-4944
Published online Sep 7, 2019. doi: 10.3748/wjg.v25.i33.4933
Proton pump inhibitor use increases mortality and hepatic decompensation in liver cirrhosis
Marianne Anastasia De Roza, Lim Kai, Jia Wen Kam, Yiong Huak Chan, Andrew Kwek, Tiing Leong Ang, John Chen Hsiang
Marianne Anastasia De Roza, Lim Kai, Andrew Kwek, Tiing Leong Ang, John Chen Hsiang, Department of Gastroenterology and Hepatology, Changi General Hospital, Singhealth 529889, Singapore
Jia Wen Kam, Clinical Trials and Research Unit, Changi General Hospital, Singhealth 529889, Singapore
Yiong Huak Chan, Biostatistics Unit, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 160608, Singapore
Author contributions: De Roza MA and Hsiang JC designed the study and methods, and contributed to data collection, data verification, data analysis, interpretation of data, manuscript preparation, final drafting, and final approval of the version to be published; Kai L assisted with data collection and data verification; Kam JW and Chan YK performed the statistical analysis and interpretation of data; Kwek A and Ang TL contributed to the critical review of the manuscript and final approval of the version to be published.
Institutional review board statement: This study was conducted after receiving approval from the Singhealth Centralized Institutional Review Board with waiver of informed consent.
Informed consent statement: This study was approved by the Singhealth IRB for waiver of informed consent.
Conflict-of-interest statement: All authors declare there are no conflicts of interest. None of the authors received financial support or grants for this study.
Data sharing statement: Statistical coding and dataset is available from the corresponding author at
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: John Chen Hsiang, MBChB, Attending Doctor, Doctor, Senior Researcher, Department of Gastroenterology and Hepatology, Changi General Hospital, 2 Simei Street 3, Singhealth 529889, Singapore.
Telephone: +65-69302923
Received: March 25, 2019
Peer-review started: March 25, 2019
First decision: May 24, 2019
Revised: July 12, 2019
Accepted: July 19, 2019
Article in press: July 19, 2019
Published online: September 7, 2019
Research background

Proton pump inhibitor (PPI) use is associated with an increased risk of mortality but is not well studied in patients with decompensated liver cirrhosis. The impact and definition of significant dose exposure are also not known. Although previous studies have looked into this relationship, there are several unaddressed issues such as PPI users not being well defined, the presence of many confounding factors, and indications for PPIs not being adjusted for. Also, this particular patient population of decompensated cirrhotic patients has not been well studied. Our study investigated if PPI use is independently associated with increased mortality risk in decompensated liver cirrhosis after adjustment for indications, medications, baseline variables and co-morbidities, and established the impact of dose exposure on mortality.

Research motivation

PPIs are prescribed widely and for long durations even in patients with liver cirrhosis. If a convincing relationship with increased mortality risk and dose exposure is established, stopping or shortening the duration of PPIs when possible should be strongly advocated.

Research objectives

This study confirms our main objective, that PPI usage in decompensated liver cirrhosis patients is an independent factor associated with an increased risk of mortality. In addition, a longer dose exposure of more than 90 cumulative defined daily doses was found to significantly increase this risk. We hence advocate reviewing PPI use in patients with liver cirrhosis with a view to shorten or deprescribe when possible.

Research methods

This is a retrospective cohort study using a hospital database. PPI users were defined as those with more than 28 defined daily doses used within a study landmark period. Users and non-users were compared after adjusting for 43 variables including baseline characteristics, comorbidities, PPI indications, and medications.

Research results

A total of 295 patients were included for analysis in the study. PPI users had a higher mortality compared to non-users and longer PPI use with more than 90 cumulative defined daily doses was associated with higher mortality. PPI users also had a higher incidence of hospitalisation for hepatic decompensation.

Research conclusions

The impact of varying PPI dose exposure in decompensated cirrhotics has not been previously described. This study showed that a cumulative defined daily dose > 90 is associated with higher mortality in patients with decompensated liver cirrhosis. Patients with decompensated liver cirrhosis have increased intestinal permeability and decreased hepatic clearance of PPIs, which predispose to gut dysbiosis and increases the risk of severe hepatic decompensation and ultimately mortality. Higher dose exposure to PPI worsens this. PPIs can be harmful when given for long durations in patients with decompensated liver cirrhosis by increasing the risk of further decompensation and death. Longer PPI dose exposure, in particular more than 90 cumulative defined daily doses can be harmful in patients with decompensated liver cirrhosis. PPIs inhibit the bactericidal effect of gastric hydrochloric acid and predispose to gut dysbiosis. When used in patients with decompensated liver cirrhosis who have decreased hepatic clearance of PPI, there is increased dose exposure that can potentially cause more harm. PPI users were well defined in this study by using defined daily doses and a cumulative dose ≥ 28 within a landmark period. Also, users and non-users were compared after important adjustments such as indication for PPI use and medication use such as antiplatelets, which were not accounted for in prior studies. PPI use should be reviewed regularly especially in patients with liver cirrhosis. It should be stopped when there are no indications. If PPIs are indicated, dosage should be reduced to the lowest possible dose.

Research perspectives

There were potential confounding factors that could have affected the results. However, this represents real world data and the current difficulties faced. The differences were also minimised using statistical methods such as propensity adjustment or matching. Future research should be conducted to prove the mechanisms on how PPIs modulate gut microbiota causing dysbiosis and hepatic decompensations and also to determine if PPI withdrawal can reverse mortality risk. Larger cohort, prospective studies should be performed with a view on proving causality.