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. Author manuscript; available in PMC: 2021 Jun 1.
Published in final edited form as: Eur J Clin Pharmacol. 2020 Mar 14;76(6):851–866. doi: 10.1007/s00228-020-02854-8

Table 1.

Study characteristics of included studies

Author, year Country Study design/Data source Patients Number of part icipants Mean age (SD) Male Diabetes Etiology of liver disease/MELD score, median (range) or mean ± SD
Proton pump inhibitor use and liver cancer
Kao et al. 2019 [30] Taiwan Cohort study/Longitudinal H ealth Insuranc e Database (LH ID), 2003–2013

  1. Patients with HBV infection

  2. Patients with HCV infection
    • Inclusion: Adult patients with HBV or HCV infection, three or more ambulatory claims or one inpatient
    • Exclusion: patients with dual HBV and HCV infection, diagnosed with other forms of cancers, follow-up duration of less than one year, PPI use before 2003, diagnosed with HCC before 2003 or within a year of the cohort entry date, diagnosed with HCC after using PPIs for less than a year

  1. HBV cohort 11,154 (5,577 PPI users, 5’577, nonusers)

  2. HCV cohort 3,830 (1,915 PPI users, 1,915 nonusers)

  1. HHBV cohort PPI 48.9 (12. 8), no PPI 48.9 (13.9)

  2. HHCV cohort PPI 59.0 (13. 7), no PPI 58.9 (14.4)

  • HBV cohort PPI 61.7%

  • HCV cohort PPI 47.7%

  1. HBV cohort 9.0%

  2. HCV cohort 19.0%
  1. HBV cohort
    • ALD: 1.9%
    • NAFLD: 1.4%
    • Cirrhosis: 3.2%
  2. HCV cohort
    • ALD: 2.8%
    • NAFLD: 2.5%
    • Cirrhosis: 6.8%
Li et al. 2018 [21] US Cohort study/Electronically retrieved cohort of HCV-infected veterans (ERCHIVES), 2001–2015 Patients with HCV infection

  • Inclusion: Non-cirrhotic patients with HCV infection, at least 14 days of treatment for HCV

  • Exclusion: coinfection with HIV, positive test for HBV surface antigen (HBsAg), diagnosis of cirrhosis, hepatic decompensation event prior to baseline or known gastr oesophageal v arices, HCC any time before or up to within 6 months of baseline, missing a baseline HCV RNA or FIB- 4 score, at least one FIB-4 was not available at least 24 months after completion of HCV therapy, exposed to both PPI and H2RA, first prescription of PPI after first diagnosis of cirrhosis

 11,526 (5,752 PPI users, 5,774 nonusers) Median 53 (IQR 49–57) 96.1% 6.1% N/A
Shao et al. 2018 [20] Taiwan Nested case- control study/National Health Insurance Research Dataset (NHIRD) linked the Death Registry, 2000–2013 Patients with cirrhosis

  • Inclusion: Patients with cirrhosis and without HBV or HCV

  • Exclusion: younger than 20 years, any diagnosis of cancer, HBV or HCV or cirrhosis before 2002, received any anti-viral therapy for hepatitis throughout the study period, PPI prescription before 2001, less than 365 days of follow- up, less than 180 days follow-up after first dose of PPIs

 139,791 (5,545 PPI users, 134,2 46 nonusers) N/A N/A N/A N/A
Proton pump inhibitor use and mortality
Cole et al. 2016 [31] UK Cohort study/Scottish Liver T ransplant Unit (SLTU), 2013 Patients with liver disease

  • Inclusion: 2013 discharge list for all patients with liver disease on the Hepatology ward

  • Exclusion: non-hepatic illness, liver transplant, significant comorbidity such as HCC

 206 (114 PPI us ers, 92 nonusers) Median 56 (range 50–63) 65.5% N/A

  • ALD: 37.9%

  • HBV, HCV, and HEV: 24.8%

  • NAFLD: 18.4%

  • Autoimmune hepatitis: 4.9%

  • Encephalopathy 34.5%

  • MELD: 18 (1324)
De Roza et al. 2020 [3 4] Singapore Cohort study/Changi General Hospital, 2013–2017 Patients with cirrhosis

  • Inclusion: liver cirrhosis confirmed by histology, imaging or transient elastography and hospital admissions for hepatic decompensation

  • Exclusion: patients without hepatic decompensation

 295 (238 PPI users, 57 nonusers) PPI 63.3 (12. 4), nonusers 60.0 (13.3) 68.1% Type 2 diabetes 53.2%

  • HBV: 18.0%

  • HCV: 21.4%

  • Alcohol: 19.7%

  • NASH: 28.1%

  • Autoimmune: 2.7%

  • Median MELD: PPI 10.5 (range 8.0–14.3), nonusers 11.0 (range 8.0–14.5)
Dultz et al. 2015 [12] Germany Cohort study/German Unive rsity hospital, 2009–2011 Patients with cirrhosis

  • Inclusion: out- and in-patients with cirrhosis (confirmed by liver histopathological examination or pathognomonic results in ultrasound, CT, or MRI)

  • Exclusion: history of cancer other than HCC within the last 5 years, history of solid organ transplantation

 272 (213 PPI users, 59 nonusers) Median 57 (range 25–84) 66.9% N/A

  • ALD: 50.0%

  • HCV: 27.2%

  • HBV: 12.9%

  • NAFLD: 2.6%

  • Autoimmune hepatitis: 1.1%

  • MELD: 15 (6–40)
Hung et al. 2018 [18] Taiwan Cohort study/National Healt h Insurance Re search Databa se (NHIRD), 2010–2013 Patients with cirrhosis

  • Inclusion: patients with cirrhosis and HE, patients discharged with a main or accessory diagnosis of cirrhosis (ICD-9-CM code 571.5 or 571.2), use only first HE episode data (572.2)

  • Exclusion: esophageal variceal bleeding, panendoscopy examinations, intravenous PPI treatment during hospitalization, patients with an aDD of more than 1

 5,020 (1,004 PPI users, 4,016 nonusers) PPI users 62. 5 (13.3), nonusers 62.6 (13.6) 67.5% N/A

  • HCC: 45.4%

  • Alcoholic cirrhosis: 20.5%
Janka et al. 2019 [35] Hungary Cohort study/Referral Hepatology Center (Division of Gas troenterology, Department of Internal Medicine, Clinical center, University of Debrecen), 2006–2010 Patients with cirrhosis

  • Inclusion: patients with diagnosis of cirrhosis based on clinical, biochemical, imaging, and histological data and no signs of acute decompensation

  • Exclusion: patients with a single specialist consultation only, follow up regularly elsewhere, and follow up shorter than 3 months

 350 (196 PPI us ers, 154 nonusers) Median 56 (IQR 50–64) 53.7% N/A

  • HCC: 9.4%

  • MELD: 11.5 (816)
Kwon et al. 2014 [32] South Korea Cohort study/Seoul National University Hospital, Seoul National University Boramae Medical Center, 2003–2010 Patients with cirrhosis

  • Inclusion: cirrhotic patients with SBP, cirrhotic patients with ascites who had undergone diagnostic paracentesis after admission, cirrhosis was established by liver biopsy or clinical evidence such as varices or radiological evidence in ultrasound, CT, MRI

  • Exclusion: gastrointestinal bleeding within 14 days prior to carcinomatosis, HIVadmission, organ transplantation, unclear medical record, antibiotic use within 2 weeks prior to admission, tuberculosis peritonitis, carcinamatosis, HIV

 533 (82 PPI users, 451 nonusers) PPI users 61. 9 (9.9), nonusers 62.9 (9. 4) 76.9% 18.9%

  • HBV: 75.4%

  • HCV: 11.6%

  • ALD: 8.1%

  • HCC: 53.7%

  • MELD: PPI users 20.0±9.7, nonusers 18.8±8.9
Mandorfer et al. 2014 [33] Austria Cohort study/Medical University of Vienna, 2006–2011 Patients with cirrhosis

  • Inclusion: patients with cirrhosis who underwent their first paracentesis

  • Exclusion: other causes of ascites such as severe cardiovascular disease, renal insufficiency, extra- hepatic malignancies and noncirrhotic portal hypertension

 607 (520 PPI users, 87 nonusers) 57.5 (11.8) 70.0% N/A

  • ALD: 55%

  • Viral hepatitis: 19%

  • ALD and viral hepatitis: 8%

  • HCC: 21%

  • MELD: 17.5 (10.6)
Nardelli et al. 2019 [1 9] Italy Cohort study/Center for the Study of Portal Hypertension i n Rome, 20142016 Patients with cirrhosis

  • Inclusion: in- and out-patients with cirrhosis, the diagnosis of liver cirrhosis was based on clinical, biochemical and radiological signs

  • Exclusion: alcohol/psychoactive drug intake, unrelated neurological disease, lack of compliance with psychometric evaluation, dementia, advanced HCC, not suitable for Milan criteria

 310 (125 PPI us ers, 185 nonusers) 62.2 (11.8) 71.3% N/A

  • Viral hepatitis: 61.0%

  • Alcohol: 27.1%

  • DCC: 66.8%

  • MELD: 12.7±4.9

aDD: average number of defined doses, ALD: alcoholic liver disease, CT: computed tomography, DCC: decompensate cirrhosis, FIB-4: fibrosis-4, H2RA: histamine-2 receptor antagonist, HBV: hepatitis B virus, HCC: hepatocellular carcinoma, HCV: hepatitis C virus, HE: hepatic encephalopathy, HEV: hepatitis E virus, HIV: human immunodeficiency virus, IQR: interquartile range, MELD: model of end-stage liver disease, MRI: magnetic resonance imaging, N/A: not available, NAFLD: non-alcoholic fatty liver disease, PPI: proton pump inhibitor, RNA: ribonucleic acid, SBP: spontaneous bacterial peritonitis, NASH: non-alcoholic steatohepatitis