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

Abstract

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.

Adverse Effects of Proton Pump Inhibitors—Evidence and Plausibility

“…PPI use increases the risk of developing HE in patients with cirrhosis [104] as well as the severity of HE [105]. Two recent meta-analyses confirmed the association [106,107] and the proposed mechanism is that PPIs induce bacterial overgrowth in the intestine [108]. It is known that PPIs do not only change the bacterial composition in the stomach, but also in faeces with a significant shift towards oral flora in principal coordinate analyses (PCoA) [109,110], demonstrating that the entire gastrointestinal tract is affected downstream of gastric hypoacidity.…”

Are proton pump inhibitors suitable medicines to prevent upper gastrointestinal events due to non-steroidal anti-inflammatory drugs?

“…PPIs are independent risk factors for small intestinal injury or exacerbated NSAIDsinduced small intestinal injury 2 . After the review was published, systematic review and/or meta-analysis reported that there were adverse effect of hepatic encephalopathy in advanced liver disease 3 , gastric cancer 4 , and myocardial infarction/stroke 5 , etc. I believe that, at least in countries where rebamipide 2 can be used, PPIs should not be used to prevent upper gastrointestinal events due to NSAIDs.…”

Letter: mind the gap – search and publication date of systematic reviews and meta‐analysis

“…New articles on contemporary topics such as PPI safety are regularly added to the global medical literature, which may make it difficult to sum- With this letter, we would like to expand on the work of Salvo et al by mentioning six more recent meta-analyses that were published after their search date. [3][4][5][6][7][8] (Table 1) Several additional adverse effects of PPIs have been evaluated such as increased risk of hepatocellular carcinoma, pancreatic cancer, congenital malformations, and complications in patients with cirrhosis including spontaneous bacterial peritonitis, pneumonia and hepatic encephalopathy.…”