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

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Abstract

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.

Methods

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.

Results

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).

Conclusions

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.

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References

  1. Wijdicks EFM. Hepatic encephalopathy. N Engl J Med. 2016;375:1660–70.

    Article  CAS  PubMed  Google Scholar 

  2. Jepsen P, Ott P, Andersen PK, et al. Clinical course of alcoholic liver cirrhosis: a Danish population-based cohort study. Hepatology. 2010;51:1675–82.

    Article  PubMed  Google Scholar 

  3. Zhu J, Qi X, Yu H, et al. Acid suppression in patients treated with endoscopic therapy for the management of gastroesophageal varices: a systematic review and meta-analysis. Expert Rev Gastroenterol Hepatol. 2018;2018(17474124):1456918.

    Google Scholar 

  4. Malfertheiner P, Kandulski A, Venerito M. Proton-pump inhibitors: understanding the complications and risks. Nat Rev Gastroenterol Hepatol. 2017;14:697–710.

    Article  CAS  PubMed  Google Scholar 

  5. Moayyedi P, Leontiadis GI. The risks of PPI therapy. Nat Rev Gastroenterol Hepatol. 2012;9:132–9.

    Article  CAS  PubMed  Google Scholar 

  6. Schoenfeld AJ, Grady D. Adverse effects associated with proton pump inhibitors. JAMA Intern Med. 2016;176:172–4.

    Article  PubMed  Google Scholar 

  7. Zhu J, Yu H, Mancuso A, Qi X. Proton pump inhibitors in liver cirrhosis: a review of benefits and harms. AME Med J. 2017;2:36.

    Article  Google Scholar 

  8. Deshpande A, Pasupuleti V, Thota P, et al. Acid-suppressive therapy is associated with spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis. J Gastroenterol Hepatol. 2013;28:235–42.

    Article  CAS  PubMed  Google Scholar 

  9. Tsai CF, Chen MH, Wang YP, et al. Proton pump inhibitors increase risk for hepatic encephalopathy in patients with cirrhosis in a population study. Gastroenterology. 2017;152:134–41.

    Article  CAS  PubMed  Google Scholar 

  10. Imhann F, Bonder MJ, Vich Vila A, et al. Proton pump inhibitors affect the gut microbiome. Gut. 2016;65:740–8.

    Article  CAS  PubMed  Google Scholar 

  11. Reddymasu SC, Sostarich S, Mccallum RW. Small intestinal bacterial overgrowth in irritable bowel syndrome: are there any predictors? BMC Gastroenterol. 2010;10:23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. O’Leary JG, Reddy KR, Wong F, et al. Long-term use of antibiotics and proton pump inhibitors predict development of infections in patients with cirrhosis. Clin Gastroenterol Hepatol. 2015;13(753–9):e2.

    Google Scholar 

  13. Min YW, Lim KS, Min BH, et al. Proton pump inhibitor use significantly increases the risk of spontaneous bacterial peritonitis in 1965 patients with cirrhosis and ascites: a propensity score matched cohort study. Aliment Pharmacol Ther. 2014;40:695–704.

    Article  CAS  PubMed  Google Scholar 

  14. Ratelle M, Perreault S, Villeneuve JP, et al. Association between proton pump inhibitor use and spontaneous bacterial peritonitis in cirrhotic patients with ascites. Can J Gastroenterol Hepatol. 2016;28:330–4.

    Article  Google Scholar 

  15. Bian J, Wang A, Lin J, et al. Association between proton pump inhibitors and hepatic encephalopathy. Medicine (Baltimore). 2017;96:e6723.

    Article  CAS  Google Scholar 

  16. Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions (version 5.0.1). London: The Cochrane Collaboration; 2011.

    Google Scholar 

  17. Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000;283:2008–12.

    Article  CAS  PubMed  Google Scholar 

  18. Wells GA, Shea B, O’Connell D, et al. The Newcastle–Ottawa Scale (NOS) for assessing the quality if nonrandomized studies in meta-analyses [EB/OL]. http://www.ohri.ca/programs/clinical_epidemiology/oxford.htm. Accessed 30 Mar 2019.

  19. Rostom A, Dube C, Cranney A, et al. Celiac disease. Rockville (MD): agency for healthcare research and quality (US); 2004 Sep. (Evidence Reports/Technology Assessments, No. 104.) Appendix D. Quality assessment forms. http://www.ncbi.nlm.nih.gov/books/NBK35156. Accessed 30 Mar 2019.

  20. Zhang J, Yu KF. What’s the relative risk? A method of correcting the odds ratio in cohort studies of common outcomes. JAMA. 1998;280:1690–1.

    Article  CAS  PubMed  Google Scholar 

  21. Vilstrup H, Amodio P, Bajaj J, et al. Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology. 2014;60:715–35.

    Article  PubMed  Google Scholar 

  22. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88.

    Article  CAS  PubMed  Google Scholar 

  23. Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–58.

    Article  PubMed  Google Scholar 

  24. Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Begg C, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088–101.

    Article  CAS  PubMed  Google Scholar 

  26. Lewis DS, Lee TH, Konanur M, et al. Proton pump inhibitor use is associated with an increased frequency of new or worsening hepatic encephalopathy after transjugular intrahepatic portosystemic shunt creation. J Vasc Interv Radiol. 2019;30:163–9.

    Article  PubMed  Google Scholar 

  27. Sturm L, Bettinger D, Giesler M, et al. Treatment with proton pump inhibitors increases the risk for development of hepatic encephalopathy after implantation of transjugular intrahepatic portosystemic shunt (TIPS). United Eur Gastroenterol J. 2018;6:1380–90.

    Article  CAS  Google Scholar 

  28. Nardelli S, Gioia S, Ridola L, et al. Proton pump inhibitors are associated to minimal and overt hepatic encephalopathy and increase mortality in cirrhotics. Hepatology. 2018. https://doi.org/10.1002/hep.30304 (In press).

    Article  Google Scholar 

  29. Tergast TL, Wranke A, Laser H, et al. Dose dependent impact of proton pump inhibitors on the clinical course of spontaneous bacterial peritonitis. Liver Int. 2018;38:1602–13.

    Article  CAS  PubMed  Google Scholar 

  30. Shanab AA, Smith A, Abbas M, et al. Proton pump inhibitors-a risk factor for hepatic encephalopathy in patients listed for liver transplantation? Hepatology. 2018;68:1176A.

    Google Scholar 

  31. Tapper EB, Henderson J, Baki J, et al. Incidence and predictors of hepatic encephalopathy in a population-based cohort of older Americans with cirrhosis: role of opiates, benzodiazepines and proton-pump inhibitors (PPIs). Hepatology. 2018;68:138A.

    Article  CAS  Google Scholar 

  32. Dam G, Vilstrup H, Watson H, et al. Proton pump inhibitors as a risk factor for hepatic encephalopathy and spontaneous bacterial peritonitis in cirrhosis patients with ascites. Hepatology. 2016;64:1265–72.

    Article  CAS  PubMed  Google Scholar 

  33. Zhu J, Qi X, Yu H, et al. Association of proton pump inhibitors with the risk of hepatic encephalopathy during hospitalization for liver cirrhosis. United Eur Gastroenterol J. 2018;6:1179–87.

    Article  CAS  Google Scholar 

  34. Matei D, Pasca S, David A, et al. Proton pump inhibitors increase the risk for hepatic encephalopathy in patients with cirrhosis and ascites. J Hepatol. 2017;66:S136.

    Article  Google Scholar 

  35. Weersink RA, Bouma M, Burger DM, et al. Safe use of proton pump inhibitors in patients with cirrhosis. Br J Clin Pharmacol. 2018;84:1806–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Freedberg DE, Kim LS, Yang YX. The risks and benefits of long-term use of proton pump inhibitors: expert review and best practice advice from the American Gastroenterological Association. Gastroenterology. 2017;152:706–15.

    Article  CAS  PubMed  Google Scholar 

  37. Dhanasekaran R, West JK, Gonzales PC, et al. Transjugular intrahepatic portosystemic shunt for symptomatic refractory hepatic hydrothorax in patients with cirrhosis. Am J Gastroenterol. 2010;105:635–41.

    Article  PubMed  Google Scholar 

  38. Kikolski SG, Aryafar H, Rose SC, et al. Transjugular intrahepatic portosystemic shunt for treatment of cirrhosis-related chylothorax and chylous ascites: single-institution retrospective experience. Cardiovasc Interv Radiol. 2013;36:992–7.

    Article  Google Scholar 

  39. Garcia-Pagan JC, Caca K, Bureau C, et al. Early use of TIPS in patients with cirrhosis and variceal bleeding. N Engl J Med. 2010;362:2370–9.

    Article  CAS  PubMed  Google Scholar 

  40. Bonnel AR, Bunchorntavakul C, Rajender Reddy K. Transjugular intrahepatic portosystemic shunts in liver transplant recipients. Liver Transpl. 2014;20:130–9.

    Article  PubMed  Google Scholar 

  41. Huang KW, Kuan YC, Luo JC, et al. Impact of long-term gastric acid suppression on spontaneous bacterial peritonitis in patients with advanced decompensated liver cirrhosis. Eur J Intern Med. 2016;32:91–5.

    Article  PubMed  Google Scholar 

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Acknowledgements

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.

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Authors and Affiliations

  1. Department of Pharmacy, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China

    Dawei Shi, Ziye Zhou, Ying Dai & Xiaofeng Pan

  2. Department of Anesthesiology, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China

    Qinqin Cao

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Correspondence to Dawei Shi or Qinqin Cao.

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Funding

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.

Authorship

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.

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Shi, D., Zhou, Z., Dai, Y. et al. Proton Pump Inhibitor Therapy and Hepatic Encephalopathy Risk in Cirrhotic Patients: A Systematic Review with Meta-analysis. Clin Drug Investig 39, 847–856 (2019). https://doi.org/10.1007/s40261-019-00810-8

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