Letter To The Editor Open Access
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 7, 2020; 26(9): 992-994
Published online Mar 7, 2020. doi: 10.3748/wjg.v26.i9.992
Results of meta-analysis should be treated critically
Rong-Qiang Liu, Yi Shao, Department of Ophthalmology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
Rong-Qiang Liu, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510220, Guangdong Province, China
ORCID number: Rong-Qiang Liu (0000-0001-7993-8891); Yi Shao (0000-0003-1571-2433).
Author contributions: Liu RQ and Shao Y designed and performed the research, and analyzed the data; Liu RQ wrote the letter; Liu RQ revised the letter.
Supported by National Natural Science Foundation of China, No. 81400372; Youth Science Foundation of Jiangxi Province, No. 20151BAB21516; Science and Technology Plan Project of Jiangxi Province, No. 20151BBG70223; Association for Science and Technology of Jiangxi Province, No. 20111BBG70026-2; Science and Technology Plan of Jiangxi Provincial Health and Family Planning Commission, No. 20164017 and No. 20155154.
Conflict-of-interest statement: Osamu Yokosuka has received research funding from Chugai Pharma.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Yi Shao, MD, PhD, Director, Doctor, Department of Ophthalmology, The First Affiliated Hospital of Nanchang University, No. 17, YongWaiZheng Street, DongHu District, Nanchang 330006, Jiangxi Province, China. freebee99@163.com
Received: November 25, 2019
Peer-review started: November 25, 2019
First decision: December 23, 2019
Revised: January 14, 2020
Accepted: January 19, 2020
Article in press: January 19, 2020
Published online: March 7, 2020


Proton pump inhibitors use increases hepatic encephalopathy risk in patients with liver disease.

Key Words: Proton pump inhibitor, Hepatic encephalopathy, Liver disease

Core tip: Proton pump inhibitors (PPIs) have been widely used in patients with liver disease. In general, PPIs are considered safe. However, accumulating evidence indicates that long-term and excessive use of PPIs without clear indication can lead to serious adverse reactions. Some epidemiological studies have investigated the association of PPI use with the risk of hepatic encephalopathy. However, the results are controversial. The study reveals that PPI use increases hepatic encephalopathy risk in patients with liver disease. This reminds clinicians to be more cautious when using PPIs in patients with liver disease.


We read the recently published meta-analysis on the association between proton pump inhibitor (PPI) and hepatic encephalopathy (HE)[1]. The authors found that there was a significant association between PPI use and HE risk with low heterogeneity (I2 = 14.2%). In fact, a correct analysis showed an even stronger association. First, the author made an error in extracting the data. The study by Tsai et al[2] provided three dose-related odds ratios (ORs) of 1.41 (1.09-1.84), 1.51 (1.11-2.06) and 3.01 (1.78-5.10), and the meta-analysis by Ma et al[1] incorrectly used only the first OR. According to the study of Hamling et al[3], we recalculated that the correct OR was 1.59 (1.30-1.95). The results of the meta-analysis revealed that PPI use was significantly associated with the risk of HE with a pooled OR of 1.97 (95% confidence interval [CI]: 1.51–2.58) by using a random effects model (I2 = 57.1%). The forest plot is shown in Figure 1. In addition, we used the data which were given by Ma et al[1] to perform comprehensive analysis. The pooled OR was 1.97 (1.47, 2.65) instead of 1.50 (1.25, 1.75) and the I2 was 61.2% instead of 14.2%. The results are shown in Figure 2. The incorrect operations of Ma et al[1] from using software may be the cause of inconsistencies. Due to the obvious heterogeneity, subgroup analysis and meta-regression should be performed to explore the sources of heterogeneity.

Figure 1
Figure 1 Forest plot of the association between proton pump inhibitor use and hepatic encephalopathy.
Figure 2
Figure 2 Forest plot of proton pump inhibitor use and risk of hepatic encephalopathy.

The fixed effects model assumes that all the included studies have the same true effect size, while the true effect size in the random effects model varies with different studies. When the observed effect size of each study approaches or equals its true effect size, the heterogeneity is not obvious and the fixed effect model should be used. Otherwise, the random effects model is used. The Cochrane Handbook has stated that when I2 is less than 40%, a fixed effects model should be used for meta-analysis. Otherwise, a random effect model should be used. In general, the conclusions obtained by random effects models tend to be conservative, and thus can be used in any case. However, when the heterogeneity is significant, only the random effect model can be used, and further analysis is needed to find the sources of heterogeneity.

In conclusion, our results demonstrated that PPI use increased HE risk, consistent with the study of Ma et al[1]. However, the meta-analysis by Ma et al[1] is flawed. More accurate statistical analysis is necessary to improve the quality of this meta-analysis.


Manuscript source: Unsolicited manuscript

Specialty type: Gastroenterology and hepatology

Country of origin: China

Peer-review report classification

Grade A (Excellent): A

Grade B (Very good): B

Grade C (Good): 0

Grade D (Fair): 0

Grade E (Poor): E

P-Reviewer: Barreto SG, Chiu CC, Triantafyllou K S-Editor: Zhang L L-Editor: Filipodia E-Editor: Ma YJ

1.  Ma YJ, Cao ZX, Li Y, Feng SY. Proton pump inhibitor use increases hepatic encephalopathy risk: A systematic review and meta-analysis. World J Gastroenterol. 2019;25:2675-2682.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 17]  [Cited by in F6Publishing: 15]  [Article Influence: 3.0]  [Reference Citation Analysis (0)]
2.  Tsai CF, Chen MH, Wang YP, Chu CJ, Huang YH, Lin HC, Hou MC, Lee FY, Su TP, Lu CL. Proton Pump Inhibitors Increase Risk for Hepatic Encephalopathy in Patients With Cirrhosis in A Population Study. Gastroenterology. 2017;152:134-141.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 100]  [Cited by in F6Publishing: 104]  [Article Influence: 14.9]  [Reference Citation Analysis (0)]
3.  Hamling J, Lee P, Weitkunat R, Ambühl M. Facilitating meta-analyses by deriving relative effect and precision estimates for alternative comparisons from a set of estimates presented by exposure level or disease category. Stat Med. 2008;27:954-970.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 438]  [Cited by in F6Publishing: 495]  [Article Influence: 30.9]  [Reference Citation Analysis (0)]