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Abstract
Introduction Hepatic encephalopathy (HE) is a major complication of acute liver failure, cirrhosis and transjugular intrahepatic portosystemic shunt (TIPS) placement. Its clinical manifestations range from mild cognitive deficits to coma. Furthermore, HE is a financial burden to a patient’s family and significantly affects the patient’s quality of life. In clinical practice, proton pump inhibitors (PPIs) are widely used for the treatment of HE. The use of PPIs is associated with an increased risk of post-TIPS HE; however, findings on the risk relationship between PPIs and post-TIPS HE are inconsistent. Therefore, a systematic evaluation of the relationship is needed to further provide valid evidence for the rational use of PPIs in patients who undergo TIPS.
Methods and analysis PubMed, Web of Science, Cochrane Library and Embase will be searched extensively for relevant information. Information from 1 July 2023 to 31 July 2023 in these databases will be included. Primary outcomes will be the use of PPIs and incidence of HE after TIPS; secondary outcomes will be survival, dose dependence and adverse events. This meta-analysis will be reported in accordance with the 50 Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020. The risk of bias, heterogeneity and quality of evidence of the included studies will be evaluated prior to the data analysis. All data will be analysed using Review Manager (V.5.4.1) and Stata (V.17.0) statistical software.
Ethics and dissemination Ethical approval will not be necessary for this review and meta-analysis. The results of the study will be published in a peer-reviewed journal.
PROSPERO registration number CRD42022359208.
- Chronic Disease
- Hepatobiliary disease
- Gastroenterology
- Neurology
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STRENGTHS AND LIMITATIONS OF THIS STUDY
Search terms will consist of MeSH and free-entry terms connected by AND and OR.
If there are missing data in the included studies, the authors of the original studies will be contacted.
An appropriate risk of bias assessment tool will be selected according to the study type.
I² statistics will be used to examine the heterogeneity of the included studies.
The results of this study will be affected by the number of articles included in accordance with the study design and the methodological quality of the articles.
Introduction
Liver disease is typically a long term, insidious condition associated with several complications, including hepatic encephalopathy (HE).1 HE is a neuropsychiatric disorder caused by portosystemic shunting and/or hepatocellular dysfunction. It is categorised into minimal and overt HE; both types negatively affect patients’ quality of life.2–4 Transjugular intrahepatic portosystemic shunt (TIPS) is a minimally invasive procedure that has become a foundation in the management of portal hypertension and its complications.5 6 However, TIPS is associated with some complications, including the risk of developing HE or worsening of existing HE, which occurs in up to 50% of patients.7 8
Proton pump inhibitors (PPIs) are generally used in clinical practice, although there is a lack of evidence for their use.9 Although PPIs are typically regarded to have a high safety profile, various unfavourable adverse effects, including diarrhoea and bone disease, have been reported. Furthermore, PPI use may be an accurate indicator of mortality in patients with cirrhosis.10 11 Although the pathophysiology of HE is not completely understood, an association between HE and gut flora has long been suspected and a negative association between altered intestinal dysbiosis and the occurrence and severity of HE after TIPS has been reported. In addition, the use of PPIs in patients with cirrhosis has recently been associated with the emergence of HE.12–14
Therefore, the risk relationship between the use of PPIs and occurrence of HE after TIPS remains unclear. To provide more effective information to help clinicians manage PPI use in patients who undergo TIPS, the relationship between PPI, TIPS and HE risk will be explored through meta-analysis. In addition, during data collation, we hope to identify other valuable data that can be used for subgroup analyses, such as the effects of PPIs on the survival rate of patients with HE after TIPS and the adverse effects of PPIs on patients after TIPS. These results will provide a more comprehensive understanding of the effects of PPIs in patients who undergo TIPS.
Methods and analysis
Registration
This study will be reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement and PRISMA protocols (PRISMA-P) 2015 statement.15 16 The protocol is registered in the PROSPERO database (registration number CRD42022359208). Any alterations or additions made to the protocol throughout the review process will be reflected in the final manuscript and updated in the registration records.
Patient and public involvement
As the proposed study is a systemic review and meta-analysis of previously reported data, there will be no direct patient involvement.
Search strategy
The electronic databases PubMed, Web of Science, Cochrane Library and Embase will be searched for relevant information from 1 July 2023 to 31 July 2023. MeSH and free-entry terms joined by AND and OR will be used as search terms. Additionally, the reference lists of the search results will be manually examined to identify additional relevant studies. The publication date will not be restricted; however, the language of publication will be restricted to English. The search strategies are detailed in online supplemental table 1.
Supplemental material
Inclusion and exclusion
The systematic review and meta-analysis will include randomised control trials, case-control studies and cohort studies of patients who underwent TIPS and received PPIs. In addition, relevant studies will include a control group of patients who did not receive PPIs. Furthermore, the included studies will report on the relationship between PPIs and HE risk using relative risk (RR), incidence rate ratio (IRR), HR or OR with corresponding 95% CIs or the original data used to calculate these variables. Animal studies, conference abstracts, case reports, research protocols, comments, reviews and letters to the editor will be excluded.
Study selection
Two researchers (YS and YC) will independently review the literature, retrieve the data and cross-check the findings. A third investigator (JZ) will mediate in cases of disagreement. The literature will be managed using Endnote (V.X9; Thomson Reuters LLC, Philadelphia, Pennsylvania, USA), and the final literature included in the review and meta-analysis will be manually reviewed. The study selection process is detailed in online supplemental figure 1.
Supplemental material
Data extraction
Two researchers (YS and YC) will independently extract data from the full texts of the included studies, including general information (such as author names, year of publication, study region, study population, study design and sample size), and patient demographics (such as age, sex and comorbidities). Information regarding interventions (such as the number of PPI users and dose of PPIs), control group (such as controlled interventions and number of patients) and outcomes (such as HE risk, incidence of HE, PPI use, length of survival, length of the follow-up period and the adjusted estimates of OR, RR, IRR and HR and their corresponding 95% CIs) will be extracted. The author(s) of the original study will be contacted in cases of missing data.
Risk of bias assessment
Two researchers (YS and YC) will independently evaluate the quality of the included studies. The risk of bias in randomised controlled trials will be assessed using the Cochrane Risk of Bias Tool for randomised controlled trials, whereas the risk of bias in non-randomised controlled trials will be assessed using the Newcastle-Ottawa Scale.17 18 When substantial bias is indicated, a third researcher (JZ) will conduct an evaluation.
Statistical analysis
All statistical analyses will be conducted using Review Manager (V.5.4.1) and Stata (V.17.0). Continuous variables, such as the secondary outcomes of survival and dose dependence, will be expressed using standardised mean difference and mean difference. The effect index of dichotomous variables, such as the primary outcome, will be presented as ORs and RRs. When raw data are provided in the included studies, the RR will be calculated. The heterogeneity of the included studies will be analysed using I² statistics. I²>50% will be used to indicate a significant heterogeneity, and a random effects model will be used. I²<50% will be used to indicate the absence of heterogeneity, and a fixed effects model will be used. When significant heterogeneity exists, sensitivity analysis or subgroup analysis will be used to clarify the source of heterogeneity. If 10 or more articles are included, publication bias will be assessed using a funnel plot; if fewer than 10 articles are included, the funnel plot will no longer be applicable and publication bias will be assessed directly by the investigator based on the characteristics of the included studies.19 Statistical significance will be set at p<0.05. The Grading of Recommendations, Assessment, Development and Evaluation technique will be used to evaluate the quality of the included studies. The studies will be categorised as high, medium, low or very low quality. Randomised controlled trials will start with high quality and observational studies with low quality.20
To achieve a more efficient and accurate statistical analysis, two researchers will independently search the literature, evaluate the eligibility of all titles and abstracts and evaluate the full text of the relevant studies. In addition, we will use a meta-regression to find possible influences. Thereafter, we will perform subgroup analyses of these potential influences, including age and sex variables, or subgroup analyses based on categorical variables with significantly different clinical characteristics in the baseline data, such as with or without comorbidities, ethnicity and regional variables. The secondary outcomes will include survival, dose dependence and adverse events. In addition to examining the incidence of HE associated with the use of PPIs in patients who undergo TIPS, the effects of PPI use and dosage on the long-term survival of patients who undergo TIPS and long-term survival of patients who developed HE while using PPIs after undergoing TIPS will be assessed. The adverse effects of the use of PPIs in patients who underwent TIPS will also be analysed.
Discussion
There are few studies on the relationship between the use of PPIs and risk of HE after TIPS. To the best of our knowledge, this will be the first systematic review and meta-analysis of the association between the use of PPIs and HE after TIPS. Our meta-analysis will build on the results of earlier studies and provide more statistical evidence to assess the appropriate use of PPIs in patients with TIPS. Previous studies have shown that alterations in gut microbiota, such as small-bowel bacterial overgrowth, may lead to the production or release of chemicals such as ammonia and endotoxin, leading to cognitive dysfunction in patients with cirrhosis and HE.21 22 Dysbiosis of the intestinal flora is negatively associated with the development of HE after TIPS. Moreover, the use of PPIs may cause changes in the intestinal flora and bacterial translocation, which may account for the development of HE after TIPS in patients who receive PPIs.13 23–26
PPIs modify the intestinal flora and increase the risk of HE and changes in the intestinal flora affect the development of HE in patients who undergo TIPS; however, no comprehensive analyses have demonstrated whether PPIs increase the risk of HE in patients after TIPS. In addition, the increased risk of mortality in patients with chronic PPI use is controversial.27
This systematic review and meta-analysis protocol will examine whether the use of PPIs is associated with the risk of HE after TIPS. In addition, subgroup analyses will be conducted to further explore the association between PPI dose and the risk of HE after TIPS and the survival length of patients who undergo TIPS and receive PPIs. This study will help to guide physicians regarding the administration of PPIs, duration of PPI use and dose of PPIs in TIPS patients.
Supplemental material
Ethics statements
Patient consent for publication
Acknowledgments
We express our gratitude to the BMJ Open editors and reviewers for their insightful comments on our manuscripts.
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Contributors Concept and design: YS. PROSPERO registration: YS. Data extraction: YS, YC. Data analysis: YS, YC. Methodology: JZ. Writing: YS. Revision of writing: JZ. Monitoring and review: CY. All the authors have read and approved the manuscript for publication.
Funding This study was supported by the National Natural Science Foundationof China (No. 82260899, 82060848, 82160888), the Natural Science Foundation of Guangxi Province (No. 2020GXNSFAA297070, 2022GXNSFAA035573 and 2023GXNSFAA026361), Guangxi TCM appropriate Technology development and promotion project (No. GZSY21-16), Innovation Project of Guangxi Graduate Education of GXUCM (No. YCBXJ2023028, YCBXJ2021012, JGY2022174).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.