Association of proton pump inhibitors with risk of hepatic encephalopathy in advanced liver disease: A meta-analysis

BACKGROUND Several studies have explored the association between the use of proton pump inhibitors (PPIs) and the risk of developing hepatic encephalopathy (HE) in patients with advanced liver disease. However, the evidence-based conclusions are controversial. We hypothesized that using PPIs may increase the risk of HE in patients with advanced liver disease. If confirmed, clinicians must strictly adhere to the indications for PPI treatment in this population. AIM To evaluate the pooled risk of HE in patients with advanced liver disease who use PPIs. METHODS Three electronic databases (PubMed, EMBASE, and the Cochrane Library) were searched from the date of database inception through January 8, 2019 to identify comparative studies evaluating the association between PPI use and the risk of HE. Data from the included studies were extracted. The random-effects model was used for pooling risk estimates and the corresponding 95% confidence intervals (CIs). Subgroup and sensitivity analyses were also performed. RESULTS In total, 4342 patients from five case-control studies and 188053 patients from four cohort studies were included in this analysis. In patients with advanced liver disease, PPI use was associated with an elevated risk of developing HE, with significant heterogeneity. The pooled odds ratio for case-control studies was 2.58 (95% CI: 1.68-3.94, I-2 = 72%). The pooled RR for cohort studies was 1.67 (95% CI: 1.30-2.14, I-2 = 67%). The results of the subgroup analyses suggested that the heterogeneity may be the result of differences in the study designs and the definitions of PPI use. The sensitivity and subgroup analyses did not alter our findings. CONCLUSION In patients with advanced liver disease, PPI use is associated with an elevated risk of HE. Future large prospective studies are needed to confirm this association.