Proton Pump Inhibitors Are Associated With Accelerated Development of Cirrhosis, Hepatic Decompensation and Hepatocellular Carcinoma in Noncirrhotic Patients With Chronic Hepatitis C Infection

Results From ERCHIVES

D. K. Li; P. Yan; A-B. Abou-Samra; R. T. Chung; A. A. Butt


Aliment Pharmacol Ther. 2018;47(2):246-258. 

In This Article

Abstract and Introduction


Background Proton pump inhibitors are among the most commonly prescribed medications in the United States. Their safety in cirrhosis has recently been questioned, but their overall effect on disease progression in noncirrhotic patients with chronic liver disease remains unclear.

Aim To determine the impact of proton pump inhibitors on the progression of liver disease in noncirrhotic patients with hepatitis C virus (HCV) infection.

Methods Using the electronically retrieved cohort of HCV-infected veterans (ERCHIVES) database, we identified all subjects who received HCV treatment and all incident cases of cirrhosis, hepatic decompensation and hepatocellular carcinoma. Proton pump inhibitor use was measured using cumulative defined daily dose. Multivariate Cox regression analysis was performed after adjusting univariate predictors of cirrhosis and various indications for proton pump inhibitor use.

Results Among 11 526 eligible individuals, we found that exposure to proton pump inhibitors was independently associated with an increased risk of developing cirrhosis (hazard ratio [HR]: 1.32; 95% confidence interval: [1.17, 1.49]). This association remained robust to sensitivity analysis in which only patients who achieved sustained virologic response were analysed as well as analysis excluding those with alcohol abuse/dependence. Proton pump inhibitor exposure was also independently associated with an increased risk of hepatic decompensation (HR: 3.79 [2.58, 5.57]) and hepatocellular carcinoma (HR: 2.01 [1.50, 2.70]).

Conclusions In patients with chronic HCV infection, increasing proton pump inhibitor use is associated with a dose-dependent risk of progression of chronic liver disease to cirrhosis, as well as an increased risk of hepatic decompensation and hepatocellular carcinoma.


Proton pump inhibitors are among the most commonly prescribed medications worldwide, representing nearly $80 billion in expenditure between the years 2007 and 2011 in the USA alone.[1] They act by irreversibly binding the H+/K+-ATPase on parietal cells, effectively suppressing acid secretion into the gastric lumen. As such, they are indicated for several conditions including gastro-oesophageal reflux disease, peptic ulcer disease and in the treatment of Helicobacter pylori infection.

In recent years, proton pump inhibitors have come under scrutiny for a rising number of associated adverse effects in the general population, including increased susceptibility to enteric infection,[2] chronic kidney disease,[3] dementia[4] and stroke.[5] Proton pump inhibitors have also garnered increasing attention for their potentially deleterious effects in patients with cirrhosis, for whom proton pump inhibitors are frequently prescribed even in the absence of an acid-related disease.[6] Specifically, a number of recent studies have uncovered associations between proton pump inhibitors and increased rates of complications in cirrhotics, including spontaneous bacterial peritonitis,[7] hepatic encephalopathy,[8] infections[9] and overall mortality,[10] although not all studies have supported such associations.[11,12] It is postulated that proton pump inhibitors mediate these effects through several mechanisms, including small intestinal bacterial overgrowth, increased intestinal permeability and bacterial translocation.

Two recent studies have shown that administration of proton pump inhibitors leads to significant alterations in the gut microbiota composition, including decreased bacterial diversity and increased numbers of potentially pathogenic bacteria.[13,14] Interestingly, decreased gut biodiversity, increased burden of pathogenic bacteria and distal translocation of upper gastrointestinal flora have all been characterised as features of the cirrhotic gut microbiome.[15–17] Whether gut dysbiosis contributes to progression of chronic liver disease remains an area of open and active investigation.

To date, most studies evaluating the link between proton pump inhibitor exposure and liver disease have focused on cirrhotics. In contrast, we sought to investigate the impact of proton pump inhibitors in a noncirrhotic cohort on the development of incident cirrhosis, hepatic decompensation and hepatocellular carcinoma by utilising a large, well-established national database of HCV-infected US veterans.