Clinical Drug Investigation

, Volume 39, Issue 9, pp 847–856 | Cite as

Proton Pump Inhibitor Therapy and Hepatic Encephalopathy Risk in Cirrhotic Patients: A Systematic Review with Meta-analysis

  • Dawei ShiEmail author
  • Ziye Zhou
  • Ying Dai
  • Xiaofeng Pan
  • Qinqin CaoEmail author
Systematic Review


Background and Objectives

Use of proton pump inhibitor (PPI) in patients with cirrhosis has been linked to the development of hepatic encephalopathy (HE). Little is known about the incidence rate of HE due to PPI therapy. We conducted a meta-analysis to explore the association between PPI use and the incidence of HE.


We searched PubMed, EMBASE databases and The Cochrane Library from inception to March 2019 for studies describing the association between PPI exposure and incidence of HE; we identified studies that provided the adjusted estimates of odds ratio (OR)/relative ratio (RR)/hazard ratio (HR), and the pooled RRs on the incidence of HE were calculated. Summary estimates were calculated using random effects models.


We analyzed data from 10 eligible studies; PPI users had an increased risk of HE compared with non-PPI user, with a pooled RR of 1.81 (95% CI 1.58–2.06), with notable heterogeneity (I2 = 85.2%, p <0.0001). In subgroup of considering the incidence of HE after yrans-jugular intrahepatic portosystemic shunt (TIPS), the pooled RR was 3.09 (95% CI 2.23–4.27), with no statistical heterogeneity (I2 = 0.0%, p = 0.484); another subgroup analysis was conducted for the complication of the enrolled patients with the status of ascites, the pooled RR was 1.39 (95% CI 1.10–1.77). The result of statistical heterogeneity was low (I2 = 46.2%, p = 0.156).


We found PPI therapy increased the risk of HE in cirrhotic patients, and higher risk was found in post-operative TIPS. Additional studies are warranted to inform clinical decision making.



The authors are very grateful to all staffs of the Department of Pharmacy at First Affiliated Hospital of Wenzhou Medical University and Department of Anesthesiology at Second Affiliated Hospital of Wenzhou Medical University.

Compliance with Ethical Standards


No sources of funding were received for the preparation of this study.

Conflict of interest

Dawei Shi, Ziye Zhou, Ying Dai, Xiaofeng Pan, Qinqin Cao have no conflicts of interest that are directly relevant to the content of this systematic review and meta-analysis.


Guarantor of the article: Dawei Shi.

Author contributions

DS and ZZ designed the study, then screened titles and abstracts resulting from the search. YD and QC involved in the data extraction. DS performed the statistical analysis, interpreted the results and wrote the draft. XP helped with language editing and critically revised the manuscript.

Supplementary material

40261_2019_810_MOESM1_ESM.pdf (160 kb)
Supplementary material 1 (PDF 159 kb)


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of PharmacyFirst Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
  2. 2.Department of AnesthesiologySecond Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina

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