title: Proton Pump Inhibitors Increase Risk for Hepatic Encephalopathy in Patients With Cirrhosis in A Population Study.
abstract: Hepatic encephalopathy (HE) is a serious complication of cirrhosis and is associated with gut dysbiosis. Proton pump inhibitors (PPIs), frequently prescribed to patients with cirrhosis, can contribute to small-bowel bacterial overgrowth. We investigated whether PPI predisposes patients with cirrhosis to HE using a large database of patients.
  
  
  
  We performed a case-control study nested within a sample of Taiwan National Health Insurance beneficiaries (n = 1,000,000), followed up longitudinally from 1998 through 2011. Patients with cirrhosis and an occurrence of HE (n = 1166) were selected as the case cohort and matched to patients without HE (1:1, controls) for sex, enrollment time, end point time, follow-up period, and advanced cirrhosis. Information on prescribed drugs, drug dosage, supply days, and numbers of dispensed pills was extracted from the Taiwan National Health Insurance database. PPI use was defined as more than 30 cumulative defined daily doses (cDDDs); PPI nonuse was defined as 30 cDDDs or fewer. We performed logistic regression analyses to estimate the association between PPI use and the occurrence of HE.
  
  
  
  Among patients with cirrhosis and an occurrence of HE, 38% (n = 445) had a history of PPI use before HE occurrence. We observed a relationship between dose of PPI taken and HE risk. The confounder-adjusted odd ratios were 1.41 (95% confidence interval [CI], 1.09-1.84), 1.51 (95% CI, 1.11-2.06), and 3.01 (95% CI, 1.78-5.10) for patients with 30-120 cDDDs, 120-365 cDDDs, and more than 365 cDDDs, respectively, compared with PPI nonusers. All categories of PPIs, except rabeprazole, were associated with an increased risk of HE.
  
  
  
  Based on an analysis of data from Taiwan National Health Insurance beneficiaries, we found that use of PPIs in patients with cirrhosis increases the risk for HE; risk increases with dose. It therefore is important for health care providers to carefully consider prolonged PPI use by patients with cirrhosis.
authors.affiliation: Institute of Brain Science, National Yang-Ming University School of Medicine, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Chia-Fen
authors.initials: CF
authors.lastname: Tsai
authors.affiliation: Institute of Brain Science, National Yang-Ming University School of Medicine, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Mu-Hong
authors.initials: MH
authors.lastname: Chen
authors.affiliation: Institute of Brain Science, National Yang-Ming University School of Medicine, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Yen-Po
authors.initials: YP
authors.lastname: Wang
authors.affiliation: Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Chi-Jen
authors.initials: CJ
authors.lastname: Chu
authors.affiliation: Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Yi-Hsiang
authors.initials: YH
authors.lastname: Huang
authors.affiliation: Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Han-Chieh
authors.initials: HC
authors.lastname: Lin
authors.affiliation: Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Ming-Chih
authors.initials: MC
authors.lastname: Hou
authors.affiliation: Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Fa-Yauh
authors.initials: FY
authors.lastname: Lee
authors.affiliation: Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Tung-Ping
authors.initials: TP
authors.lastname: Su
authors.affiliation: Institute of Brain Science, National Yang-Ming University School of Medicine, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan. Electronic address: cllu@ym.edu.tw.
authors.forename: Ching-Liang
authors.initials: CL
authors.lastname: Lu
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000008:administration & dosage; D000067575:Administrative Claims, Healthcare / Q000706:statistics & numerical data; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D064098:Esomeprazole / Q000008:administration & dosage; D005260:Female; D006501:Hepatic Encephalopathy / Q000453:epidemiology* / Q000209:etiology*; D006801:Humans; D015994:Incidence; D007348:Insurance, Health / Q000706:statistics & numerical data; D064747:Lansoprazole / Q000008:administration & dosage; D008103:Liver Cirrhosis / Q000150:complications*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009853:Omeprazole / Q000008:administration & dosage; D000077402:Pantoprazole; D054328:Proton Pump Inhibitors / Q000008:administration & dosage*; D064750:Rabeprazole / Q000008:administration & dosage; D013624:Taiwan / Q000453:epidemiology
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D054328:Proton Pump Inhibitors; D064747:Lansoprazole; D064750:Rabeprazole; D000077402:Pantoprazole; D009853:Omeprazole; D064098:Esomeprazole
keywords: Acid Suppression; Cognitive Dysfunction; Gut Microbiota; Liver Failure