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.
Li DK, et al.
Aliment Pharmacol Ther. 2018;47:246–58

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 (PPI) on the progression of liver disease in noncirrhotic patients with 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. PPI 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 PPI 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. PPI 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 PPI 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.

Expert's Commentary

« The main take home message from this study is that we need to limit the use of PPI in patients with chronic HCV infection because the long term acid suppression may alter the normal gut microbiota inducing a bacterial overgrowth that can favor progression of fibrosis. The number of patients included in this analysis is the best warranty that the message may to be translated in our everyday practice. Indeed, despite potential limitations related to confounding factors, usually observed in the VA cohort, such as alcohol and obesity, the huge sample size represents the main strength of this study.

The other interesting aspect is the observed difference between PPI and H2-histamine receptor blockers. No association between H2-histamine receptor blockers and liver disease progression was observed. This evidence demonstrates that only the massive acid suppression of potent PPI is able to modify the gut microbioma.

Keeping in mind that association does not m ean cause-effect relationship, this study represents the valid premises for a randomized study on subjects with chronic HCV infection and fibrosis or cirrhosis taking PPI. In that case it would be interesting to select patients who attained SVR after DAA and are taking PPI at standard 40 mg or 20 mg daily dosages. It will be important to identify all the concomitant medications, to know the exact duration of PPI treatment and to collect data on PPI treatment adherence. »

Alessandra Mangia, San Giovanni Rotondo, Italy