|
1
|
Ramsing MS, Jensen MD, Jepsen P. Use of Proton Pump Inhibitors Among Patients With Alcohol-Related Cirrhosis-A Danish Nationwide Cohort Study. Liver Int 2025; 45:e70061. [PMID: 40066903 PMCID: PMC11894920 DOI: 10.1111/liv.70061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Revised: 02/02/2025] [Accepted: 02/24/2025] [Indexed: 03/15/2025]
Abstract
BACKGROUND Use of proton pump inhibitors (PPIs) may have adverse effects in patients with alcohol-related cirrhosis (ALD cirrhosis), but PPIs continue to be used by many patients. AIMS We aimed to describe the prevalence and incidence of PPI use from filled prescriptions among patients with ALD cirrhosis and to identify predictors of PPI initiation after ALD cirrhosis diagnosis. METHODS We used Danish nationwide healthcare registries to investigate PPI use among patients diagnosed with ALD cirrhosis from 1997 to 2022. We used multivariable Cox regression to identify predictors of PPI initiation. RESULTS We identified 41 263 patients diagnosed with ALD cirrhosis in 1997-2022. In this cohort, the prevalence of PPI use rose to 40% in 2016 and plateaued at this level through 2022. Considering time since diagnosis, 26% were using PPI at the diagnosis of ALD cirrhosis, and the prevalence peaked at 38% 3 months later. Among PPI users, 79% used more than 30 defined daily doses per year on average during the follow-up. Patients older than 50 years were more likely than younger patients to initiate PPI treatment. CONCLUSION The use of PPIs continues to be prevalent among patients with ALD cirrhosis, with 40% of all patients using PPIs in 2022. Within the first 3 months after diagnosis, 38% of all patients were using PPIs. Our results provide essential background information for future RCTs on the risks and benefits of prescribing or deprescribing PPIs.
Collapse
Affiliation(s)
| | - Morten Daniel Jensen
- Department of Hepatology and GastroenterologyAarhus University HospitalAarhusDenmark
| | - Peter Jepsen
- Department of Hepatology and GastroenterologyAarhus University HospitalAarhusDenmark
- Department of Clinical EpidemiologyAarhus University HospitalAarhusDenmark
| |
Collapse
|
|
2
|
Krishnan A, Schneider CV, Walsh D. Proton pump inhibitors and all-cause mortality risk among cancer patients. World J Clin Oncol 2025; 16:99240. [PMID: 39867734 PMCID: PMC11528898 DOI: 10.5306/wjco.v16.i1.99240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 09/09/2024] [Accepted: 10/11/2024] [Indexed: 10/30/2024] Open
Abstract
BACKGROUND Proton pump inhibitors (PPIs) are widely used, including among cancer patients, to manage gastroesophageal reflux and other gastric acid-related disorders. Recent evidence suggests associations between long-term PPI use and higher risks for various adverse health outcomes, including greater mortality. AIM To investigate the association between PPI use and all-cause mortality among cancer patients by a comprehensive analysis after adjustment for various confounders and a robust methodological approach to minimize bias. METHODS This retrospective cohort study used data from the TriNetX research network, with electronic health records from multiple healthcare organizations. The study employed a new-user, active comparator design, which compared newly treated PPI users with non-users and newly treated histamine2 receptor antagonists (H2RA) users among adult cancer patients. Newly prescribed PPIs (esomeprazole, lansoprazole, omeprazole, pantoprazole, or rabeprazole) users were compared to non-users or newly prescribed H2RAs (cimetidine, famotidine, nizatidine, or ranitidine) users. The primary outcome was all-cause mortality. Each patient in the main group was matched to a patient in the control group using 1:1 propensity score matching to reduce confounding effects. Multivariable Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence interval (CI). RESULTS During the follow-up period (median 5.4 ± 1.8 years for PPI users and 6.5 ± 1.0 years for non-users), PPI users demonstrated a higher all-cause mortality rate than non-users after 1 year, 2 years, and at the end of follow up (HRs: 2.34-2.72). Compared with H2RA users, PPI users demonstrated a higher rate of all-cause mortality HR: 1.51 (95%CI: 1.41-1.69). Similar results were observed across sensitivity analyses by excluding deaths from the first 9 months and 1-year post-exposure, confirming the robustness of these findings. In a sensitivity analysis, we analyzed all-cause mortality outcomes between former PPI users and individuals who have never used PPIs, providing insights into the long-term effects of past PPI use. In addition, at 1-year follow-up, the analysis revealed a significant difference in mortality rates between former PPI users and non-users (HR: 1.84; 95%CI: 1.82-1.96). CONCLUSION PPI use among cancer patients was associated with a higher risk of all-cause mortality compared to non-users or H2RA users. These findings emphasize the need for cautious use of PPIs in cancer patients and suggest that alternative treatments should be considered when clinically feasible. However, further studies are needed to corroborate our findings, given the significant adverse outcomes in cancer patients.
Collapse
Affiliation(s)
- Arunkumar Krishnan
- Department of Supportive Oncology, Atrium Health Levine Cancer, Charlotte, NC 28204, United States
- Department of Medicine, Section of Hematology and Oncology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, United States
| | - Carolin Victoria Schneider
- Department of Medicine III, Gastroenterology, Metabolic Diseases, and Intensive Care, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Declan Walsh
- Department of Supportive Oncology, Atrium Health Levine Cancer, Charlotte, NC 28204, United States
| |
Collapse
|
|
3
|
Ho CT, Fu CC, Tan ECH, Kao WY, Lee PC, Huang YH, Huo TI, Hou MC, Wu JC, Su CW. The association between proton-pump inhibitor use and recurrence of hepatocellular carcinoma after hepatectomy. J Gastroenterol Hepatol 2024; 39:2077-2087. [PMID: 38864669 DOI: 10.1111/jgh.16640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 05/11/2024] [Accepted: 05/20/2024] [Indexed: 06/13/2024]
Abstract
BACKGROUND AND AIM The association between long-term proton-pump inhibitors (PPIs) use and malignancies had long been discussed, but it still lacks consensus. Our study investigated the association between PPI use and hepatocellular carcinoma (HCC) recurrence following curative surgery. METHODS We retrospectively enrolled 6037 patients with HCC who underwent hepatectomy. Patients were divided into four groups according to their PPI usage. (non-users: < 28 cumulative defined daily dose [cDDD]; short-term users: 28-89 cDDD; mid-term users: 90-179 cDDD, and long-term users: ≥ 180 cDDD, respectively). Recurrence-free survival (RFS) and overall survival (OS) were analyzed using Kaplan-Meier method and Cox proportional hazard models. RESULTS Among the 6037 HCC patients, 2043 (33.84%) were PPI users. PPI users demonstrated better median RFS (3.10 years, interquartile range [IQR] 1.49-5.01) compared with non-users (2.73 years, IQR 1.20-4.74; with an adjusted hazard ratio [aHR] of 0.57, 95% confidence interval [CI] 0.44-0.74, P < 0.001). When considering the cumulative dosage of PPI, only long-term PPI users had significant lower risk of HCC recurrence than non-PPI group (adj-HR: 0.50; 95% CI: 0.35-0.70; P < 0.001). Moreover, the impact of long-term PPIs use on improving RFS was significant in most of the subgroup analysis, except in patients with advanced tumor stages, with non-cirrhosis, or with a history of chronic kidney disease. However, there were no significant differences in median OS between PPI users and non-users (4.23 years, IQR 2.73-5.86 vs 4.04 years, IQR 2.51-5.82, P = 0.369). CONCLUSION Long-term PPI use (≥ 180 cDDD) may be associated with a better RFS in HCC patients after hepatectomy.
Collapse
Affiliation(s)
- Chun-Ting Ho
- Department of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chia-Chu Fu
- Department of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Elise Chia-Hui Tan
- Department of Health Service Administration, College of Public Health, China Medical University, Taichung, Taiwan
| | - Wei-Yu Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan
| | - Pei-Chang Lee
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yi-Hsiang Huang
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Clinical Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Teh-Ia Huo
- Division of Basic Research, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ming-Chih Hou
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Jaw-Ching Wu
- Institute of Clinical Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chien-Wei Su
- Department of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Clinical Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| |
Collapse
|
|
4
|
Eftimie Spitz R, Popa SL, Grad S, Dumitrascu DL, Ismaiel A, Surdea-Blaga T. The Use of Proton Pump Inhibitors in Patients with Liver Cirrhosis: Real Life Experience. J Clin Med 2024; 13:5155. [PMID: 39274368 PMCID: PMC11396469 DOI: 10.3390/jcm13175155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 08/12/2024] [Accepted: 08/28/2024] [Indexed: 09/16/2024] Open
Abstract
(1) Background: Proton pump inhibitors (PPIs) are commonly prescribed for gastric disorders. In patients with liver cirrhosis, PPI use is associated with an increased risk of spontaneous bacterial peritonitis and increased mortality rates; therefore, they should be used with caution. This study aims to evaluate the appropriateness of PPI prescriptions in hospitalized cirrhotic patients against current clinical guidelines to identify patterns of misuse and guide better prescribing practices. (2) Methods: A retrospective study was conducted on liver cirrhosis inpatients in an internal medicine department from January 2022 to May 2023. The primary measure was the proportion of PPI prescriptions aligned with clinical guidelines. Medical files were entirely reviewed by researchers to assess the appropriateness of PPI prescriptions using the current guidelines. Outcomes included the identification of common reasons for PPI prescription and the rate of inappropriate PPI use among the study population. (3) Results: The study included 189 cirrhotic patients, with PPIs prescribed to 95 (50.2%) patients during hospitalization and 75 (39.7%) patients at discharge. Among those, 47.4% of the inpatients and 34.7% at discharge had no valid indication for PPI administration. The most common reason for PPI prescription during hospital stays was gastritis, followed by antiplatelet use in high-risk patients, ulcers, and upper gastrointestinal bleeding. The most common inappropriate indication was portal hypertensive gastropathy (PHG), followed by treatment with corticosteroids and anticoagulants alone. We did not find an association between PPI administration during hospital stays and infections. Only in 4% of cases patients should have received PPIs and did not. (4) Conclusions: There is a concerning overprescription of PPIs in cirrhotic patients, often deviating from established guidelines. It subjects patients to unnecessary risks. There is an urgent need for increased awareness and adherence to clinical guidelines regarding PPI prescriptions in cirrhotic patients.
Collapse
Affiliation(s)
- Raphaël Eftimie Spitz
- Faculty of Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400000 Cluj-Napoca, Romania; (R.E.S.); (S.G.); (D.L.D.); (A.I.); (T.S.-B.)
| | - Stefan Lucian Popa
- Faculty of Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400000 Cluj-Napoca, Romania; (R.E.S.); (S.G.); (D.L.D.); (A.I.); (T.S.-B.)
- 2nd Department of Internal Medicine, Emergency County Hospital, 400003 Cluj-Napoca, Romania
| | - Simona Grad
- Faculty of Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400000 Cluj-Napoca, Romania; (R.E.S.); (S.G.); (D.L.D.); (A.I.); (T.S.-B.)
- 2nd Department of Internal Medicine, Emergency County Hospital, 400003 Cluj-Napoca, Romania
| | - Dan Lucian Dumitrascu
- Faculty of Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400000 Cluj-Napoca, Romania; (R.E.S.); (S.G.); (D.L.D.); (A.I.); (T.S.-B.)
- 2nd Department of Internal Medicine, Emergency County Hospital, 400003 Cluj-Napoca, Romania
| | - Abdulrahman Ismaiel
- Faculty of Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400000 Cluj-Napoca, Romania; (R.E.S.); (S.G.); (D.L.D.); (A.I.); (T.S.-B.)
- 2nd Department of Internal Medicine, Emergency County Hospital, 400003 Cluj-Napoca, Romania
| | - Teodora Surdea-Blaga
- Faculty of Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400000 Cluj-Napoca, Romania; (R.E.S.); (S.G.); (D.L.D.); (A.I.); (T.S.-B.)
- 2nd Department of Internal Medicine, Emergency County Hospital, 400003 Cluj-Napoca, Romania
| |
Collapse
|
|
5
|
Kosuta I, Premkumar M, Reddy KR. Review article: Evaluation and care of the critically ill patient with cirrhosis. Aliment Pharmacol Ther 2024; 59:1489-1509. [PMID: 38693712 DOI: 10.1111/apt.18016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 03/21/2024] [Accepted: 04/12/2024] [Indexed: 05/03/2024]
Abstract
BACKGROUND The increase in prevalence of liver disease globally will lead to a substantial incremental burden on intensive care requirements. While liver transplantation offers a potential life-saving intervention, not all patients are eligible due to limitations such as organ availability, resource constraints, ongoing sepsis or multiple organ failures. Consequently, the focus of critical care of patients with advanced and decompensated cirrhosis turns to liver-centric intensive care protocols, to mitigate the high mortality in such patients. AIM Provide an updated and comprehensive understanding of cirrhosis management in critical care, and which includes emergency care, secondary organ failure management (mechanical ventilation, renal replacement therapy, haemodynamic support and intensive care nutrition), use of innovative liver support systems, infection control, liver transplantation and palliative and end-of life care. METHODS We conducted a structured bibliographic search on PubMed, sourcing articles published up to 31 March 2024, to cover topics addressed. We considered data from observational studies, recommendations of society guidelines, systematic reviews, and meta-analyses, randomised controlled trials, and incorporated our clinical expertise in liver critical care. RESULTS Critical care management of the patient with cirrhosis has evolved over time while mortality remains high despite aggressive management with liver transplantation serving as a crucial but not universally available resource. CONCLUSIONS Implementation of organ support therapies, intensive care protocols, nutrition, palliative care and end-of-life discussions and decisions are an integral part of critical care of the patient with cirrhosis. A multi-disciplinary approach towards critical care management is likely to yield better outcomes.
Collapse
Affiliation(s)
- Iva Kosuta
- Department of Intensive Care Medicine, University Hospital Centre Zagreb, Zagreb, Croatia
| | - Madhumita Premkumar
- Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - K Rajender Reddy
- Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| |
Collapse
|
|
6
|
Bettinger D, Thimme R, Sturm L. Editorial: Novel insights into the prognostic relevance of high-dose PPI treatment in patients with cirrhosis. Aliment Pharmacol Ther 2024; 59:1282-1283. [PMID: 38652787 DOI: 10.1111/apt.17928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/25/2024]
Abstract
LINKED CONTENTThis article is linked to Yoon et al paper. To view this article, visit https://doi.org/10.1111/apt.17909
Collapse
Affiliation(s)
- Dominik Bettinger
- Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Robert Thimme
- Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Lukas Sturm
- Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Berta-Ottenstein-Programme, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| |
Collapse
|
|
7
|
Maimunah U, Kurniawan AA, Palayukan A. Adverse Effects of Long-term Proton Pump Inhibitors in Chronic Liver Disease Patients – A Preliminary Article Review. REVIEW OF CLINICAL PHARMACOLOGY AND PHARMACOKINETICS - INTERNATIONAL EDITION 2024; 38:87-97. [DOI: 10.61873/wway6273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
Abstract
Background: Proton pump inhibitors (PPIs) are widely prescribed medications for the management of gastroesophageal reflux disease (GERD) and peptic ulcer disease. Despite their efficacy, concerns have emerged regarding their potential adverse effects, particularly in patients with chronic liver disease (CLD). CLD patients often experience gastrointestinal symptoms and may be prescribed PPIs, but the impact of PPI use on liver function and disease progression remains uncertain. Scope: This study aims to evaluate the adverse effects of PPIs on CLD patients through a review of available literature. The scope encompasses a review of studies examining the association between PPI use and liver-related outcomes, including hepatic encephalopathy, hepatic decompensation, liver cirrhosis progression, and mortality, among CLD patients. Method: A scoping review of relevant literature were conducted to identify studies investigating the adverse effects of PPIs in CLD patients. Databases including PubMed and Google Scholar were searched for articles published up to January, 1 2023. Eligible studies were selected based on predefined inclusion criteria. Results: The review identified 27 studies meeting the inclusion criteria, comprising observational studies and meta-analysis. The review revealed a significant association between PPI use and adverse liver outcomes in CLD patients. Specifically, PPI use was associated with increased risk of SBP based on studies reviewed, while other complications remained inconclusive. Conclusion: The findings suggest that PPI use may have detrimental effects on disease progression in CLD patients, Long-term use of PPIs can lead to higher risk of SBP in CLD patients. Clinicians should exercise caution when prescribing PPIs to this vulnerable population and consider alternative treatment options or minimize PPI use to mitigate potential adverse outcomes. Further research is warranted to elucidate the underlying mechanisms, confirm the effect of PPIs toward other complications of CLD and establish guidelines for PPI use in CLD patients.
Collapse
|
|
8
|
Yoon JS, Hong JH, Park SY, Kim SU, Kim HY, Kim JY, Hur MH, Park MK, Lee YB, Lee HA, Kim GA, Sinn DH, Park SJ, Lee YJ, Kim YJ, Yoon JH, Lee JH. High-dose proton pump inhibitor treatment is associated with a higher mortality in cirrhotic patients: A multicentre study. Aliment Pharmacol Ther 2024; 59:973-983. [PMID: 38389319 DOI: 10.1111/apt.17909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Revised: 08/11/2023] [Accepted: 02/07/2024] [Indexed: 02/24/2024]
Abstract
BACKGROUND Proton pump inhibitors (PPI) are frequently used in patients with cirrhosis. AIMS This study aimed to determine whether PPI use is associated with the prognosis of cirrhotic patients. METHODS We conducted a multicentre retrospective cohort study involving 1485 patients who had experienced hepatic encephalopathy (HE) from 7 referral centres in Korea. The primary outcome was overall survival and secondary outcomes included the development of cirrhotic complications, including recurrent HE, spontaneous bacterial peritonitis (SBP), hepatorenal syndrome (HRS), and gastrointestinal bleeding. Patients treated with PPI with a mean defined daily dose (mDDD) ≥0.5 (high-dose PPI group) were compared to those treated with PPI of an mDDD < 0.5 (No or low-dose PPI group) for each outcome. RESULTS Among 1485 patients (median age, 61 years; male, 61%), 232 were assigned to the high-dose PPI group. High-dose PPI use was independently associated with a higher risk of death (adjusted HR [aHR] = 1.71, 95% confidence interval [CI] = 1.38-2.11, p < 0.001). This result was reproducible after propensity score-matching (PSM) (aHR = 1.90, 95% CI = 1.49-2.44, p < 0.001). High-dose PPI use was an independent risk factor of recurrent HE (before PSM: aHR = 2.04, 95% CI = 1.66-2.51, p < 0.001; after PSM: aHR = 2.16, 95% CI = 1.70-2.74, p < 0.001), SBP (before PSM: aHR = 1.87, 95% CI = 1.43-2.43, p < 0.001; after PSM: aHR = 1.76, 95% CI = 1.31-2.36, p = 0.002), HRS (before PSM: aHR = 1.48, 95% CI = 1.02-2.15, p = 0.04; after PSM: aHR = 1.47, 95% CI = 0.95-2.28, p = 0.09), and gastrointestinal bleeding (before PSM: aHR = 1.46, 95% CI = 1.12-1.90, p = 0.006; after PSM: aHR = 1.74, 95% CI = 1.28-2.37, p < 0.001). CONCLUSIONS The use of high-dose PPI was independently associated with increased risks of mortality and cirrhotic complications.
Collapse
Affiliation(s)
- Jun Sik Yoon
- Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea
| | - Ji Hoon Hong
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Soo Young Park
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Seung Up Kim
- Department of Internal Medicine and Yonsei Liver Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hwi Young Kim
- Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul, Republic of Korea
| | - Ju Yeon Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Moon Haeng Hur
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Min Kyung Park
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Yun Bin Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Han Ah Lee
- Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul, Republic of Korea
| | - Gi-Ae Kim
- Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Republic of Korea
| | - Dong Hyun Sinn
- Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Sung Jae Park
- Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea
| | - Youn Jae Lee
- Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea
| | - Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jung-Hwan Yoon
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jeong-Hoon Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| |
Collapse
|
|
9
|
Wong ZY, Koh JH, Muthiah M, Koh B, Ong EYH, Ong CEY, Ou KQ, Lim WH, Tan DJH, Chee D, Siah KTH, Wong Y, Kaewdech A, Wijarnpreecha K, Kulkarni AV, Nah B, Huang DQ, Noureddin M, Ng CH, Teng M. Proton Pump Inhibitors Increases Longitudinal Risk of Mortality, Decompensation, and Infection in Cirrhosis: A Meta-Analysis. Dig Dis Sci 2024; 69:289-297. [PMID: 37968557 DOI: 10.1007/s10620-023-08150-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Accepted: 10/09/2023] [Indexed: 11/17/2023]
Abstract
BACKGROUND/AIMS Proton pump inhibitors (PPIs) are frequently prescribed to cirrhotic patients, but there is limited longitudinal evidence regarding their effects. This study aimed to assess the impact of PPIs on adverse events in cirrhotic patients. METHODS A comprehensive search was conducted using the Medline and Embase databases to identify relevant articles. Pooled hazard ratios (HRs) using DerSimonian and Laird random-effects model were calculated to evaluate the risk of adverse events such as long-term mortality, hepatic decompensation, hepatic encephalopathy (HE), spontaneous bacterial peritonitis (SBP), and overall infection in cirrhotic patients with PPI use. RESULTS The analysis included 28 studies with 260,854 cirrhotic patients. The prevalence of PPI use among cirrhotic patients was 55.93%. The use of PPIs was not significantly associated with short-term mortality in cirrhotic patients. However, long-term mortality (HR 1.321, 95% CI 1.103-1.581, P = 0.002), decompensation (HR 1.646, 95% CI 1.477-1.835, P < 0.001), HE (HR 1.968, 95% CI 1.372-2.822, P < 0.001), SBP (HR 1.751, 95% CI 1.649-1.859, P < 0.001), and infection (HR 1.370, 95% CI 1.148-1.634, P < 0.001) were significantly associated with PPI use. Sensitivity analysis with prospective studies yielded similar results. CONCLUSION PPIs should be reserved for appropriate indications at lowest effective dose for cirrhotic patients due to the potential harm.
Collapse
Affiliation(s)
- Zhen Yu Wong
- Nottingham City Hospital, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Jia Hong Koh
- Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore
- National University Centre for Organ Transplantation, National University Health System, Singapore, Singapore
| | - Mark Muthiah
- Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore
- National University Centre for Organ Transplantation, National University Health System, Singapore, Singapore
| | - Benjamin Koh
- Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore
| | - Elden Yen Hng Ong
- Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore
| | - Christen En Ya Ong
- Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore
| | - Kai Qi Ou
- Nottingham City Hospital, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Wen Hui Lim
- Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore
| | - Darren Jun Hao Tan
- Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore
| | - Douglas Chee
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore
| | - Kewin Tien Ho Siah
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore
| | - Yujun Wong
- Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore
| | - Apichat Kaewdech
- Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand
| | - Karn Wijarnpreecha
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA
| | - Anand V Kulkarni
- Department of Hepatology, Asian Institute of Gastroenterology, Hyderabad, Telangana, India
| | - Benjamin Nah
- Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore
- National University Centre for Organ Transplantation, National University Health System, Singapore, Singapore
| | - Daniel Q Huang
- Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore
- Division of Gastroenterology, NAFLD Research Center, University of California at San Diego, La Jolla, CA, USA
- National University Centre for Organ Transplantation, National University Health System, Singapore, Singapore
| | | | - Cheng Han Ng
- Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore.
| | - Margaret Teng
- Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore
| |
Collapse
|
|
10
|
Sturm L, Hirose M, Stolz L, Schultheiss M, Zoldan K, Reincke M, Huber JP, Kaeser R, Boettler T, Thimme R, Albert E, Busch H, Künstner A, Bettinger D. Proton pump inhibitor treatment aggravates bacterial translocation in patients with advanced cirrhosis and portal hypertension. mBio 2023; 14:e0049223. [PMID: 37623323 PMCID: PMC10653923 DOI: 10.1128/mbio.00492-23] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 05/02/2023] [Indexed: 08/26/2023] Open
Abstract
IMPORTANCE Long-term prescription of proton pump inhibitors (PPIs) in patients with cirrhosis is common practice. However, in recent years, several observational studies have reported increased complications and negative prognostic effects of PPI treatment in these patients. Judging the significance of these associations is complicated by the fact that a plausible underlying pathomechanism has not been identified so far. In the present study, we address this important issue by investigating the impact of PPI treatment on subclinical bacterial translocation from the gut into the blood stream in patients with advanced cirrhosis and portal hypertension. Indeed, we report significantly aggravated bacterial translocation in cirrhosis patients receiving PPI treatment. This finding is highly relevant, as bacterial translocation is known to promote the development of complications and impair prognosis in patients with cirrhosis. Hence, the present study could establish a plausible link between PPI treatment and adverse effects in cirrhosis.
Collapse
Affiliation(s)
- Lukas Sturm
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
- Berta-Ottenstein-Programme, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Misa Hirose
- Luebeck Institute of Experimental Dermatology, University of Luebeck, Luebeck, Germany
| | - Laura Stolz
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
| | - Michael Schultheiss
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
- Berta-Ottenstein-Programme, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Katharina Zoldan
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
| | - Marlene Reincke
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
| | - Jan Patrick Huber
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
| | - Rafael Kaeser
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
- IMM-PACT-Programme, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Tobias Boettler
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
| | - Robert Thimme
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
| | - Elisabeth Albert
- Luebeck Institute of Experimental Dermatology, University of Luebeck, Luebeck, Germany
| | - Hauke Busch
- Luebeck Institute of Experimental Dermatology, University of Luebeck, Luebeck, Germany
- Institute for Cardiogenetics, University of Luebeck, Luebeck, Germany
| | - Axel Künstner
- Luebeck Institute of Experimental Dermatology, University of Luebeck, Luebeck, Germany
- Institute for Cardiogenetics, University of Luebeck, Luebeck, Germany
| | - Dominik Bettinger
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
| |
Collapse
|
|
11
|
Balafar M, Ghojazadeh M, Shahsavarinia K, Parsian Z, Hamedani S, Soleimanpour H. Association Between Proton Pump Inhibitor Use and Spontaneous Bacterial Peritonitis or Hepatic Encephalopathy in Cirrhotic Patients: A Systematic Review and Meta-analysis. HEPATITIS MONTHLY 2023; 23. [DOI: 10.5812/hepatmon-132642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Context: There is a link between proton pump inhibitors (PPIs) use and the occurrence of spontaneous bacterial peritonitis (SBP) in cirrhotic patients in some studies; however, in other studies, such a link does not exist. Objectives: The aim of the current systematic review and meta-analysis was to evaluate the association between PPI and the occurrence of SBP or hepatic encephalopathy (HE) in cirrhotic patients. Data Sources: A systematic search of sources was conducted in order to evaluate for any relationship between PPI and the risk of SBP in patients with liver diseases. Medline, Scopus, Ovid, ProQuest, Google Scholar, and Web of Science were searched to find any evidence in this regard from 1980 to November of 2021. Study Selection: The articles were evaluated by two independent reviewers according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses). After deleting the duplicates, first, the titles of the studies were evaluated, and then the full texts were evaluated. Any disagreement between the two researchers was solved by discussion or a third reviewer. Data Extraction: Appropriate Critical Appraisal Checklists of Joanna Briggs Institute (JBI) were used for the quality assessment of eligible studies. Statistical analysis was performed by CMA software (version 2.0), and a P-value of less than 0.05 was considered a significant level. Results: In the systematic search of sources, 3705 articles were identified. Finally, 33 studies were included in this meta-analysis study. A total of 6370 PPI users and 8037 patients in the control group experienced at least one of the complications of liver cirrhosis, including SBP or HE. According to meta-analysis, the risk of SBP or HE in the intervention group was 1.95 times higher than in the control group (RR = 1.95; 95% confidence interval [CI]: 1.53 - 2.48, P < 0.001). Conclusions: The use of PPIs is associated with a higher risk of SBP and HE in cirrhotic patients. However, the quality of included studies in the current systematic review and meta-analysis was moderate, and high-quality studies with a larger sample size are required.
Collapse
|
|
12
|
Sturm L, Gahm C, Schultheiss M, Reincke M, Huber JP, Boettler T, Thimme R, Bettinger D. Proton pump inhibitor treatment is associated with acute-on-chronic liver failure in patients with advanced cirrhosis. Hepatol Commun 2023; 7:e00178. [PMID: 37347229 PMCID: PMC10289603 DOI: 10.1097/hc9.0000000000000178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 04/15/2023] [Indexed: 06/23/2023] Open
Abstract
BACKGROUND Acute-on-chronic liver failure (ACLF) is a fatal complication of cirrhosis. Hence, identification of risk factors for ACLF is crucial. Previous studies have linked proton pump inhibitor (PPI) treatment to complications of cirrhosis, however, a possible effect of PPI treatment on the risk of ACLF has not been investigated yet. Therefore, the present study aimed to characterize the impact of PPI treatment on ACLF development. METHODS A total of 642 patients hospitalized due to complications of cirrhosis were retrospectively identified, and PPI treatment during an observation period of 3 years following the hospitalization was reviewed. Subsequently, 74 patients with newly initiated PPI treatment at the time of hospitalization (PPI group) were 1:1 propensity score matched to 74 patients who received no PPI treatment (no-PPI group). Primary end point was the development of ACLF during the observation period, and secondary endpoints were mortality and upper gastrointestinal bleeding. RESULTS PPI and no-PPI groups had comparably severe chronic liver disease at baseline. Nevertheless, the cumulative incidence of ACLF in the presence of death as competing risk was markedly higher in the PPI group compared with the no-PPI group. ACLF-related deaths contributed significantly to a higher 3-year mortality in the PPI group. Uni and multivariable competing risk regression models confirmed that PPI treatment was an independent predictor of ACLF in the study collective (subdistribution HR: 1.892, 95% CI: 1.092-3.281, p = 0.023). The impact of PPI treatment on ACLF development was particularly strong in patients with a model for end-stage liver disease score >12. Upper gastrointestinal bleeding was slightly less frequent in the PPI group. CONCLUSIONS The present results indicate that PPI treatment could be a risk factor for ACLF in patients with advanced cirrhosis.
Collapse
Affiliation(s)
- Lukas Sturm
- Department of Medicine II, Medical Center University of Freiburg, University of Freiburg, Freiburg, Germany
- Berta-Ottenstein-Program, University of Freiburg, Freiburg, Germany
| | - Chiara Gahm
- Department of Medicine II, Medical Center University of Freiburg, University of Freiburg, Freiburg, Germany
| | - Michael Schultheiss
- Department of Medicine II, Medical Center University of Freiburg, University of Freiburg, Freiburg, Germany
- Berta-Ottenstein-Program, University of Freiburg, Freiburg, Germany
| | - Marlene Reincke
- Department of Medicine II, Medical Center University of Freiburg, University of Freiburg, Freiburg, Germany
| | - Jan Patrick Huber
- Department of Medicine II, Medical Center University of Freiburg, University of Freiburg, Freiburg, Germany
| | - Tobias Boettler
- Department of Medicine II, Medical Center University of Freiburg, University of Freiburg, Freiburg, Germany
| | - Robert Thimme
- Department of Medicine II, Medical Center University of Freiburg, University of Freiburg, Freiburg, Germany
| | - Dominik Bettinger
- Department of Medicine II, Medical Center University of Freiburg, University of Freiburg, Freiburg, Germany
| |
Collapse
|
|
13
|
Nanchal R, Subramanian R, Alhazzani W, Dionne JC, Peppard WJ, Singbartl K, Truwit J, Al-Khafaji AH, Killian AJ, Alquraini M, Alshammari K, Alshamsi F, Belley-Cote E, Cartin-Ceba R, Hollenberg SM, Galusca DM, Huang DT, Hyzy RC, Junek M, Kandiah P, Kumar G, Morgan RL, Morris PE, Olson JC, Sieracki R, Steadman R, Taylor B, Karvellas CJ. Guidelines for the Management of Adult Acute and Acute-on-Chronic Liver Failure in the ICU: Neurology, Peri-Transplant Medicine, Infectious Disease, and Gastroenterology Considerations. Crit Care Med 2023; 51:657-676. [PMID: 37052436 DOI: 10.1097/ccm.0000000000005824] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/14/2023]
Abstract
OBJECTIVES To develop evidence-based recommendations for clinicians caring for adults with acute liver failure (ALF) or acute on chronic liver failure (ACLF) in the ICU. DESIGN The guideline panel comprised 27 members with expertise in aspects of care of the critically ill patient with liver failure or methodology. We adhered to the Society of Critical Care Medicine standard operating procedures manual and conflict-of-interest policy. Teleconferences and electronic-based discussion among the panel, as well as within subgroups, served as an integral part of the guideline development. INTERVENTIONS In part 2 of this guideline, the panel was divided into four subgroups: neurology, peri-transplant, infectious diseases, and gastrointestinal groups. We developed and selected Population, Intervention, Comparison, and Outcomes (PICO) questions according to importance to patients and practicing clinicians. For each PICO question, we conducted a systematic review and meta-analysis where applicable. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation approach. We used the evidence to decision framework to facilitate recommendations formulation as strong or conditional. We followed strict criteria to formulate best practice statements. MEASUREMENTS AND MAIN RESULTS We report 28 recommendations (from 31 PICO questions) on the management ALF and ACLF in the ICU. Overall, five were strong recommendations, 21 were conditional recommendations, two were best-practice statements, and we were unable to issue a recommendation for five questions due to insufficient evidence. CONCLUSIONS Multidisciplinary, international experts formulated evidence-based recommendations for the management ALF and ACLF patients in the ICU, acknowledging that most recommendations were based on low quality and indirect evidence.
Collapse
Affiliation(s)
- Rahul Nanchal
- Division of Pulmonary and Critical Care Medicine, Medical College of Wisconsin, Milwaukee, WI
| | | | - Waleed Alhazzani
- Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Joanna C Dionne
- Department of Medicine, McMaster University, Hamilton, ON, Canada
| | | | | | | | | | | | | | | | | | | | | | | | | | - David T Huang
- University of Pittsburgh Medical Center, Pittsburgh, PA
| | | | - Mats Junek
- Department of Medicine, McMaster University, Hamilton, ON, Canada
| | | | - Gagan Kumar
- Northeast Georgia Medical Center, Gainesville, GA
| | - Rebecca L Morgan
- Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada
| | - Peter E Morris
- University of Kentucky College of Medicine, Lexington, KY
| | - Jody C Olson
- Kansas University Medical Center, Kansas City, KS
| | | | - Randolph Steadman
- University of California Los Angeles Medical Center, Los Angeles, CA
| | | | - Constantine J Karvellas
- Department of Critical Care Medicine and Division of Gastroenterology (Liver Unit), University of Alberta, Edmonton, AB, Canada
| |
Collapse
|
|
14
|
China L, Tittanegro T, Crocombe D, Forrest E, Kallis Y, Ryder SD, Wright G, Freemantle N, O'Brien A. Investigating potential confounding by indication when considering the association between proton pump inhibitor use, infection, hepatic encephalopathy and mortality in hospitalised decompensated cirrhosis: a post-hoc analysis of the ATTIRE trial. EClinicalMedicine 2023; 58:101924. [PMID: 37090442 PMCID: PMC10119493 DOI: 10.1016/j.eclinm.2023.101924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 02/25/2023] [Accepted: 03/08/2023] [Indexed: 04/25/2023] Open
Abstract
Background Proton pump inhibitors (PPIs) are commonly prescribed to prevent and treat upper gastrointestinal ulceration and bleeding. Studies have identified increased incidence of spontaneous bacterial peritonitis and hepatic encephalopathy (HE) in cirrhosis patients taking PPIs. However, results are conflicting, and as PPIs are prescribed for variceal bleeding, a major risk factor for infection and HE, it is challenging to discern whether these associations are causal. Methods In this post-hoc analysis of the ATTIRE trial, we pooled all patient data to investigate the effects of PPI use on clinical outcomes. ATTIRE was a multicentre, open-label, randomised trial of targeted 20% human albumin solution (HAS) daily infusions versus standard care involving 777 adults with decompensated cirrhosis hospitalised with acute complications and albumin <30 g/L. Study recruitment was between Jan 25, 2016, and June 28, 2019, at 35 hospitals across England, Scotland, and Wales. Key exclusion criteria were advanced hepatocellular carcinoma with life expectancy <8 weeks and patients receiving palliative care. In ATTIRE, patients were grouped by PPI use at trial entry. We studied infection and HE at baseline and incidence of hospital acquired infection, new onset HE, renal dysfunction and mortality. We attempted with propensity score matching to account for differences in disease severity. Findings Overall PPI use at baseline was not associated with increased incidence of infection, renal dysfunction or mortality, but was associated with significantly increased incidence of grade III/IV HE during hospital stay (P = 0.011). This was only significant for those taking intravenous PPIs and these patients had >10 times the incidence of variceal bleeding and near double the 28-day mortality compared to non-PPI patients. However, propensity score matching was not possible as there was such a strong selection of patients for PPI use, that we could not find sufficient non-PPI patients to match to. We found no impact of PPI use on plasma markers of bacterial translocation, infection or systemic inflammation. Interpretations Our real-world data from a completed randomised trial show that PPIs are widely prescribed in the UK and judicious use appears safe in patients hospitalised with decompensated cirrhosis. However, patients prescribed PPIs had fundamentally different phenotypes to those not prescribed PPIs, a form of confounding by indication, which should be strongly considered when interpreting studies and making recommendations about their use. Funding Wellcome Trust and Department of Health and Social Care.
Collapse
Affiliation(s)
- Louise China
- Institute of Liver and Digestive Health, University College London, United Kingdom
| | - Thais Tittanegro
- Institute of Liver and Digestive Health, University College London, United Kingdom
| | - Dominic Crocombe
- Institute of Liver and Digestive Health, University College London, United Kingdom
| | - Ewan Forrest
- Glasgow Royal Infirmary, Glasgow, United Kingdom
| | - Yiannis Kallis
- Barts and the London School of Medicine and Dentistry Queen Mary University of London, United Kingdom
| | - Stephen D. Ryder
- National Institute for Health Research Nottingham Biomedical Research Centre at Nottingham University Hospitals NHS Trust and the University of Nottingham, Queens Medical Centre, Nottingham, United Kingdom
| | - Gavin Wright
- Mid and South Essex NHS Foundation Trust, Basildon & Thurrock University Hospitals NHS Foundation Trust, Gastroenterology, Hepatology and Hepatobiliary Medicine, The Royal Free Hospital, University College London, Kings College London, United Kingdom
| | - Nick Freemantle
- Comprehensive Clinical Trials Unit, University College London, United Kingdom
| | - Alastair O'Brien
- Institute of Liver and Digestive Health, University College London, United Kingdom
- Comprehensive Clinical Trials Unit, University College London, United Kingdom
| |
Collapse
|
|
15
|
Santos LAA, Lima TB, de Carvalho Nunes HR, Qi X, Romeiro FG. Two-year risedronate treatment for osteoporosis in patients with esophageal varices: a non-randomized clinical trial. Hepatol Int 2022; 16:1458-1467. [PMID: 35767173 DOI: 10.1007/s12072-022-10366-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 05/07/2022] [Indexed: 12/10/2022]
Abstract
BACKGROUND Bisphosphonates are the mainstay of osteoporosis treatment, but their use for patients with esophageal varices has been avoided due to the risk of esophagitis, which may cause variceal bleeding. Since most clinical trials assessing osteoporosis treatment last 2-3 years, this study aimed to evaluate a 2-year risedronate treatment for patients with esophageal varices and liver cirrhosis. METHODS The study received Institutional Review Board approval, and the sample was divided into two groups according to bone mineral density (BMD). Cirrhosis severity and endoscopic findings at baseline were similar between the groups. The intervention group had 51 patients with osteoporosis, who received oral risedronate 35 mg weekly plus calcium and vitamin D supplements. The control group had 51 patients with osteopenia, receiving only the supplements. Scheduled esophagogastroduodenoscopies and BMD measurements were carried out. RESULTS The adjusted esophagitis risk was higher in the intervention group; however, none of the subjects had digestive bleeding. Lumbar spine BMD increased in the intervention group (- 3.06 ± 0.71 to - 2.33 ± 0.90; p < 0.001) and in the control group (- 1.38 ± 0.77 to - 1.10 ± 1.05; p = 0.012). Femoral neck BMD did not change in the intervention group (- 1.64 ± 0.91 to - 1.71 ± 0.95; p = 0.220), but tended to decrease in the control group (- 1.00 ± 0.74 to - 1.09 ± 0.82; p = 0.053). CONCLUSION Oral risedronate was effective and did not cause gastrointestinal bleeding in cirrhotic patients with esophageal varices under endoscopic surveillance.
Collapse
Affiliation(s)
- Lívia Alves Amaral Santos
- Internal Medicine Department, Botucatu Medical School, Gastroenterology Division-São Paulo State University (UNESP), Rubião Júnior s/n, Botucatu, SP, CEP 18618-687, Brazil
| | - Talles Bazeia Lima
- Internal Medicine Department, Botucatu Medical School, Gastroenterology Division-São Paulo State University (UNESP), Rubião Júnior s/n, Botucatu, SP, CEP 18618-687, Brazil
| | | | - Xingshun Qi
- General Hospital of Shenyang Military Command, Liaoning, Sheng, China
| | - Fernando Gomes Romeiro
- Internal Medicine Department, Botucatu Medical School, Gastroenterology Division-São Paulo State University (UNESP), Rubião Júnior s/n, Botucatu, SP, CEP 18618-687, Brazil.
| |
Collapse
|
|
16
|
Elseidy SA, Sayed A, Awad AK, Mandal D, Mostafa M, Adigun A, Vorla M, Zamani Z, Iqbal A. PPI efficacy in the reduction of variceal bleeding incidence and mortality, a meta-analysis. THE EGYPTIAN JOURNAL OF INTERNAL MEDICINE 2022. [DOI: 10.1186/s43162-022-00156-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Objective
To review the efficacy and safety of proton pump inhibitors (PPIs) in gastroesophageal varices (GEVs).
Methods
We searched PubMed MEDLINE, Scopus, and Web of Science for studies that measured the effect of PPI for prophylaxis and treatment of post-band ligation ulcers up to July 20, 2021. We included studies that measured the effect of PPI as treatment or prophylaxis for post-band ligation ulcers; articles that were published in peer-reviewed international journals and had enough data for qualitative and quantitative analysis were included with no language restriction. Heterogeneity was evaluated using the inconsistency (I2) and chi-squared (χ2) test. I2 > 50% was considered substantial heterogeneity in the studies, and a P value less than 0.05 was considered statistically significant. The data was continuous, and we used the standardized mean difference (MD) and risk ratio (RR) with a 95% confidence interval to assess the estimated effect measure.
Results
A total of 7 studies with 2030 patients were included in our study of which 1480 participants were males (72%) and 550 females (18%). Mean age was 59.7 years old. Rebleeding post-band ligation was compared between PPI and placebo with significant favor for PPI (p = 0.00001). The pooled risk ratio was 0.53 (95% CI of 0.41, 0.68); furthermore, bleeding-related death at a 1-month period was compared between PPI and placebo with significant favor for PPI (p = 0.00001). The pooled risk ratio was significant at 0.33 (95% CI of 0.20, 0.53). The length of hospital stay postoperative was compared between PPI and placebo with cumulative mean difference of 0.13 (95% CI of −1.13, 1.39), yet without significance.
Conclusions
The study suggests a twofold reduction in the risk of bleeding and a threefold reduction in the risk of bleeding-related death with the use of PPI following EVL.
Collapse
|
|
17
|
Lo CH, Ni P, Yan Y, Ma W, Joshi AD, Nguyen LH, Mehta RS, Lochhead P, Song M, Curhan GC, Cao Y, Chan AT. Association of Proton Pump Inhibitor Use With All-Cause and Cause-Specific Mortality. Gastroenterology 2022; 163:852-861.e2. [PMID: 35788344 PMCID: PMC9509450 DOI: 10.1053/j.gastro.2022.06.067] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 06/18/2022] [Accepted: 06/22/2022] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS The use of proton pump inhibitors (PPIs) has increased rapidly in the past 2 decades. Concerns about the regular use of PPIs contributing to mortality have been raised. METHODS We conducted a prospective cohort study using data collected from the Nurses' Health Study (2004-2018) and the Health Professionals Follow-up Study (2004-2018). Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% CIs for mortality according to PPI use. We used a modified lag-time approach to minimize reverse causation (ie, protopathic bias). RESULTS Among 50,156 women and 21,731 men followed for 831,407 person-years and a median of 13.8 years, we documented 22,125 deaths, including 4592 deaths from cancer, 5404 from cardiovascular diseases, and 12,129 deaths from other causes. Compared with nonusers of PPIs, PPI users had significantly higher risks of all-cause mortality (HR, 1.19; 95% CI, 1.13-1.24) and mortality due to cancer (HR, 1.30; 95% CI, 1.17-1.44), cardiovascular diseases (HR, 1.13; 95% CI, 1.02-1.26), respiratory diseases (HR, 1.32; 95% CI, 1.12-1.56), and digestive diseases (HR, 1.50; 95% CI, 1.10-2.05). Upon applying lag times of up to 6 years, the associations were attenuated and no longer statistically significant (all-cause: HR, 1.04; 95% CI, 0.97-1.11; cancer: HR, 1.07; 95% CI, 0.89-1.28; cardiovascular diseases: HR, 0.94; 95% CI, 0.81-1.10; respiratory diseases: HR, 1.20; 95% CI, 0.95-1.50; digestive diseases: HR, 1.38; 95% CI, 0.88-2.18). Longer duration of PPI use did not confer higher risks for all-cause and cause-specific mortality. CONCLUSIONS After accounting for protopathic bias, PPI use was not associated with higher risks of all-cause mortality and mortality due to major causes.
Collapse
Affiliation(s)
- Chun-Han Lo
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts; Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Peiyun Ni
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
| | - Yan Yan
- Division of Biostatistics, Washington University School of Medicine in St Louis, St Louis, Missouri; Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine in St Louis, St Louis, Missouri
| | - Wenjie Ma
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts; Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts
| | - Amit D Joshi
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts; Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts
| | - Long H Nguyen
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts; Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Raaj S Mehta
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts; Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Paul Lochhead
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts; Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts
| | - Mingyang Song
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts; Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Gary C Curhan
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts; Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
| | - Yin Cao
- Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine in St Louis, St Louis, Missouri; Division of Gastroenterology, Department of Medicine, Washington University School of Medicine in St Louis, St Louis, Missouri; Alvin J. Siteman Cancer Center, Washington University School of Medicine in St Louis, St Louis, Missouri
| | - Andrew T Chan
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts; Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts; Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
| |
Collapse
|
|
18
|
Hasa E, Hartmann P, Schnabl B. Liver cirrhosis and immune dysfunction. Int Immunol 2022; 34:455-466. [PMID: 35792761 PMCID: PMC9447994 DOI: 10.1093/intimm/dxac030] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Accepted: 06/27/2022] [Indexed: 01/05/2023] Open
Abstract
Cirrhosis is end-stage liver disease resulting from various etiologies and is a common cause of death worldwide. The progression from compensated to decompensated cirrhosis to acute-on-chronic liver failure (ACLF) is due to multiple factors, including continuation of alcohol use or continued exposure to other toxins, an imbalance of the gut microbiota (dysbiosis), increased gut permeability and a disrupted immune response. This disrupted immune response is also named cirrhosis-associated immune dysfunction, which is characterized by worsening systemic inflammation with concomitant immune paralysis, as liver disease deteriorates. This review highlights central immunologic events during the exacerbation of cirrhosis and characterizes the different immune cell populations involved therein.
Collapse
|
|
19
|
Mahmud N, Serper M, Taddei TH, Kaplan DE. The Association Between Proton Pump Inhibitor Exposure and Key Liver-Related Outcomes in Patients With Cirrhosis: A Veterans Affairs Cohort Study. Gastroenterology 2022; 163:257-269.e6. [PMID: 35398042 PMCID: PMC10020994 DOI: 10.1053/j.gastro.2022.03.052] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 03/24/2022] [Accepted: 03/29/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS The impact of proton pump inhibitory (PPI) medications on adverse outcomes in cirrhosis remains controversial. We aimed to evaluate the association between PPI exposure and all-cause mortality, infection, and decompensation in a large national cohort. METHODS This was a retrospective study of patients with cirrhosis in the Veterans Health Administration. PPI exposure was classified as a time-updating variable from the index time of the cirrhosis diagnosis. Inverse probability treatment weighting-adjusted Cox regression was performed with additional adjustment for key time-varying covariates, including cardiovascular comorbidities, gastrointestinal bleeding (GIB), and statin exposure. RESULTS The study included 76,251 patients, 23,628 of whom were on a PPI at baseline. In adjusted models, binary (yes/no) PPI exposure was associated with reduced hazard of all-cause mortality in patients with hospitalization for GIB (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.84-0.91; P < .001) but had no significant association in all others (HR, 0.99; 95% CI, 0.97-1.02; P = .58). However, cumulative PPI exposure was associated with increased mortality in patients without hospitalization for GIB (HR, 1.07 per 320 mg-months [omeprazole equivalents]; 95% CI, 1.06-1.08; P < .001). PPI exposure was significantly associated with severe infection (HR, 1.21; 95% CI, 1.18-1.24; P < .001) and decompensation (HR, 1.64; 95% CI, 1.61-1.68; P < .001). In a cause-specific mortality analysis, PPI exposure was associated with increased liver-related mortality (HR, 1.23; 95% CI, 1.19-1.28) but with decreased nonliver-related mortality (HR, 0.88; 95% CI, 0.85-0.91). CONCLUSIONS PPI exposure is associated with increased risk of infection and decompensation in cirrhosis, which may mediate liver-related mortality. However, PPI use was associated with reduced all-cause mortality in those with prior GIB, suggesting benefit in the presence of an appropriate indication.
Collapse
Affiliation(s)
- Nadim Mahmud
- Division of Gastroenterology and Hepatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; Department of Medicine, Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, Pennsylvania; Leonard David Institute of Health Economics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics, Epidemiology & Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
| | - Marina Serper
- Division of Gastroenterology and Hepatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; Department of Medicine, Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, Pennsylvania; Leonard David Institute of Health Economics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Tamar H Taddei
- Division of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut; Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut
| | - David E Kaplan
- Division of Gastroenterology and Hepatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; Department of Medicine, Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, Pennsylvania
| |
Collapse
|
|
20
|
Wehmeyer MH, Horvatits T, Buchholz A, Krause L, Walter S, Zapf A, Lohse AW, Kluwe J. Stop of proton-pump inhibitor treatment in patients with liver cirrhosis (STOPPIT): study protocol for a prospective, multicentre, controlled, randomized, double-blind trial. Trials 2022; 23:302. [PMID: 35414106 PMCID: PMC9003168 DOI: 10.1186/s13063-022-06232-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 03/27/2022] [Indexed: 11/21/2022] Open
Abstract
Background Proton-pump inhibitors (PPI) are liberally prescribed in patients with liver cirrhosis. Observational studies link PPI therapy in cirrhotic patients with an increased risk for infectious complications, hepatic encephalopathy and an increased risk for hospitalization and mortality. However, patients with liver cirrhosis are also considered to be at risk for peptic ulcer bleeding. The STOPPIT trial evaluates if discontinuation of a pre-existing PPI treatment delays a composite endpoint of re-hospitalization and/or death in patients (recently) hospitalized with liver cirrhosis compared to patients on continued PPI medication. Methods The STOPPIT-trial is a prospective, multicentre, randomized, double-blinded, placebo-controlled, parallel-group trial. In total, 476 patients with complicated liver cirrhosis who already receive long-term PPI therapy without evidence-based indication are 1:1 randomized to receive either esomeprazole 20 mg (control group) or placebo (intervention group) for 360 days. Patients with an indication for PPI therapy (such as a recent diagnosis of peptic ulcers, severe reflux esophagitis, severe hemorrhagic gastritis, recent endoscopic therapy for oesophageal varices) are excluded. The primary composite endpoint is the time-to re-hospitalization and/or death. Secondary endpoints include rates of re-hospitalization, mortality, occurrence of infections, hepatic decompensation and acute-on-chronic liver failure. The safety endpoint is defined as manifestation of an evidence-based indication for PPI re-therapy. The impact of PPI continuation or discontinuation on the intestinal microbiota will be studied. The recruitment will take place at 18 study sites throughout Germany. Recruitment has started in April 2021. Discussion The STOPPIT trial is the first clinical trial to study the effects of PPI withdrawal on relevant outcome variables in patients with complicated liver cirrhosis. If the hypothesis that PPI withdrawal improves clinical outcomes of cirrhosis patients is confirmed, this would argue for a strong restriction of the currently liberal prescription practice of PPIs in this population. If, on the other hand, the trial demonstrates an increased risk of gastrointestinal bleeding events in patients after PPI withdrawal, this could create a rationale for a more liberal, prophylactic PPI treatment in patients with liver cirrhosis. Trial registration EU clinical trials register EudraCT 2019-005008-16 (registered December 27, 2019). ClinicalTrials.gov NCT04448028 (registered June 25, 2020). German Clinical Trials Register DRKS00021290 (registered March 10, 2021).
Collapse
Affiliation(s)
- Malte H Wehmeyer
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Thomas Horvatits
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Anika Buchholz
- Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Linda Krause
- Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sarah Walter
- Coordinating Center for Clinical Trials Heidelberg, University Hospital Heidelberg, Heidelberg, Germany
| | - Antonia Zapf
- Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ansgar W Lohse
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Johannes Kluwe
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | |
Collapse
|
|
21
|
Baik SH, Fung KW, McDonald CJ. The Mortality Risk of Proton Pump Inhibitors in 1.9 Million US Seniors: An Extended Cox Survival Analysis. Clin Gastroenterol Hepatol 2022; 20:e671-e681. [PMID: 33453399 DOI: 10.1016/j.cgh.2021.01.014] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 01/05/2021] [Accepted: 01/10/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Observational studies have linked proton pump inhibitors (PPIs) with increased risk of mortality and other safety outcomes, in contradiction with a recent PPI randomized controlled trial (RCT). Observational studies may be prone to reverse causality, where deaths are attributed to the treatment rather than the conditions that are treated (protopathic bias). METHODS We analyzed an incident drug user cohort of 1,930,728 elderly Medicare fee-for-service beneficiaries to evaluate the PPI-associated risk of death with a Cox regression analysis with time-varying covariates and propensity score adjustments. To correct for protopathic bias which occurs when a given drug is associated with prodromal signs of death, we implemented a lag-time approach by which any study drug taken during a 90-day look-back window before each death was disregarded. RESULTS Among 1,930,728 study individuals, 80,972 (4.2%) died during a median 3.8 years of follow-up, yielding an overall unadjusted death rate/1000 person-years of 9.85; 14.31 for PPI users and 7.93 for non- users. With no lag-time, PPI use (vs no use) was associated with 10% increased mortality risk (adjusted HR=1.10; 95% CI 1.08-1.12). However, with a lag-time of 90 days, mortality risk associated with PPI use was near zero (adjusted HR=1.01; 95% CI 0.99-1.02). CONCLUSION Given the usage patterns of PPIs in patients with conditions that may presage death, protopathic bias may explain the association of PPIs with increased risk of death reported in observational studies.
Collapse
Affiliation(s)
- Seo H Baik
- Lister Hill National Center for Biomedical Communications, National Library of Medicine, US National Institutes of Health, Bethesda, Maryland
| | - Kin-Wah Fung
- Lister Hill National Center for Biomedical Communications, National Library of Medicine, US National Institutes of Health, Bethesda, Maryland
| | - Clement J McDonald
- Lister Hill National Center for Biomedical Communications, National Library of Medicine, US National Institutes of Health, Bethesda, Maryland.
| |
Collapse
|
|
22
|
Liu YB, Chen MK. The impact of proton pump inhibitors in liver diseases and the effects on the liver. J Dig Dis 2022; 23:196-208. [PMID: 35357775 DOI: 10.1111/1751-2980.13093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 03/09/2022] [Accepted: 03/29/2022] [Indexed: 12/11/2022]
Abstract
In this systematic and comprehensive overview, we aimed to evaluate the impact of proton pump inhibitors (PPIs) on chronic liver diseases, especially on cirrhosis. A manual and comprehensive search of the PubMed database was conducted to obtain relevant literatures. PPIs altered the composition and function of the intestinal microflora and might lead to small intestinal bacterial overgrowth and bacterial translocation, which were associated with adverse effects in liver diseases. They might increase the risk of hepatic encephalopathy, spontaneous bacterial peritonitis, infections, and are related to an increased mortality in cirrhosis. PPIs might lead to an increased risk of hepatocellular carcinoma, although the mechanism is unknown, and the results are controversial. PPIs also had an impact on the direct-acting antiviral regimen in patients with chronic hepatitis C. They were associated with an increased risk of liver abscess and increased mortality. Additionally, PPIs might lead to metabolic risk events, such as liver steatosis and weight gain. PPIs are associated with several adverse outcomes in liver diseases. Cautious use of PPIs is recommended and clinicians should be aware of the indications for their use in patients with liver diseases.
Collapse
Affiliation(s)
- Yuan Bin Liu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Ming Kai Chen
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| |
Collapse
|
|
23
|
Shi L, Zhang S. Identification of Subclasses of Decompensated Cirrhotic Patients with Acute Kidney Injury with Different Responses to Fluid Input. Dig Dis 2022; 41:296-303. [PMID: 35301271 DOI: 10.1159/000524028] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Accepted: 03/07/2022] [Indexed: 02/02/2023]
Abstract
INTRODUCTION Acute kidney injury is a heterogeneous disease in decompensated cirrhotic patients. The aims of our study were to detect subphenotypes of cirrhotic patients with acute kidney injury (AKI) and explore clinical traits in patients with different subclasses. METHODS All enrolled patients were identified from a clinical database. Clinical and laboratory variables were used to perform latent profile analysis (LPA). Clinical traits in each class were compared. A multivariable logistic regression model and a Cox model were used to explore the independent association of fluid input and mortality outcome. RESULTS A total of 439 AKI patients with decompensated cirrhosis were enrolled in our study, including 113 patients in profile 1 and 326 patients in profile 2, by the LPA model. Profile 1 had higher mortality (61.1%) than profile 2 (36.81%). Moreover, profile 1 had a higher MELD score (median 39, interquartile range 34-43) than profile 2 (p < 0.001). Higher cumulative fluid input in the first 24 h for profile 1 was associated with an increased risk of hospital mortality (odds ratio 1.33, 95% CI: 1.02-1.75) and 90-day mortality (hazard ratio 1.39, 95% CI: 1.08-1.78). CONCLUSIONS In this study, two distinct subclasses of decompensated cirrhotic patients with AKI were identified, with different clinical outcomes and fluid input responses.
Collapse
Affiliation(s)
- Lin Shi
- Department of Gastroenterology, Xuzhou Central Hospital, Xuzhou, China
| | | |
Collapse
|
|
24
|
Proton pump inhibitor therapy is associated with reduced survival following first-time transarterial chemoembolization in patients with hepatocellular carcinoma. Eur J Gastroenterol Hepatol 2021; 33:e247-e253. [PMID: 33323760 DOI: 10.1097/meg.0000000000002018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND AND AIMS Several studies have reported associations of proton pump inhibitor (PPI) treatment with the incidence of complications and even increased mortality in patients with liver cirrhosis. Up to now, there are no studies on the impact of PPI treatment in patients with hepatocellular carcinoma (HCC). Therefore, the aim of our study was to investigate the prognostic effects of PPI treatment in a cohort of patients with HCC treated by transarterial chemoembolization (TACE). METHODS Three hundred fifty-eight patients with HCC that received first-time TACE were included in a retrospective analysis. We explored effects of PPI treatment using uni- and multivariable regression models. RESULTS One hundred sixty-seven of the 358 patients (46.6%) received PPI treatment. Median transplant-free survival after TACE was significantly lower in patients treated with PPIs compared to patients without PPI treatment [16.0 (10.7-21.3) months vs. 26 (22.2-29.8) months, P = 0.006]. Importantly, PPI treatment remained a significant prognostic factor for reduced survival after adjustment for patient demographics, tumor stadium and liver function [hazard ratio (HR) 1.40, 95% confidence interval (CI) 1.09-1.78, P = 0.005]. We observed a dose-dependent association of PPI treatment with survival: A higher daily PPI dose was an independent prognostic factor for reduced survival (HR 1.32, 95% CI 1.14-1.54, P < 0.001). Notably, 58.1% of patients receiving PPIs had no clear indication therefor. CONCLUSION PPI treatment is associated with reduced survival in patients with HCC in a dose-dependent manner. Thus, indication for PPI treatment should be evaluated attentively in these patients. Further, prospective studies are needed to validate the findings of this study.
Collapse
|
|
25
|
Sakamaki A, Kamimura K, Yokoo T, Osaki A, Yoshikawa S, Arao Y, Setsu T, Kamimura H, Waguri N, Takeuchi M, Funakoshi K, Terai S. The prognosis and incidence of hepatic encephalopathy of patients with liver cirrhosis treated with proton pump inhibitors: A multicenter retrospective study in Japan. Medicine (Baltimore) 2021; 100:e26902. [PMID: 34397919 PMCID: PMC8360404 DOI: 10.1097/md.0000000000026902] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 10/12/2020] [Accepted: 11/22/2020] [Indexed: 01/04/2023] Open
Abstract
Gastrointestinal bleeding, hepatic encephalopathy (HE), and hepatocarcinogenesis are associated with the prognosis of patients with liver cirrhosis (LC). Proton pump inhibitors (PPIs) have been used to prevent bleeding, however the effects of PPIs on overall survival have not yet been elucidated. Therefore, this multicenter retrospective study aimed to assess the effect of PPI on the prognosis and HE occurrence of the patients with liver cirrhosis in Japan.A total of 456 patients diagnosed with LC at the 4 institutes during the study period (2010-2014) were assessed. PPI-treated and non-treated patients were compared using propensity score matching analysis. Primary and secondary endpoints of the study were set as the occurrence of HE and overall survival, respectively.A comparison of all cases showed a significantly poorer hepatic reserve function in the PPI-treated patients. The propensity-score matching analysis was performed and 120 PPI-treated patients were 1:1 matched with non-treated patients. The analysis revealed a higher incidence of HE in the PPI-treated than in the non-treated patients (P = .032; hazard ratio [HR], 2.162; 95% confidence interval [CI], 1.066-4.176), but the prognosis of PPI-treated patients was no worse than that of non-treated patients (P = .676; HR, 1.101; 95% CI, 0.702-1.726).This retrospective study showed that PPI administration for the patients with liver cirrhosis may partly be related to the increased incidence of HE but not worsen the patient prognosis.
Collapse
Affiliation(s)
- Akira Sakamaki
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, Japan
| | - Kenya Kamimura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, Japan
| | - Takeshi Yokoo
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, Japan
| | - Akihiko Osaki
- Division of Gastroenterology and Hepatology, Niigata City General Hospital, Niigata, Niigata, Japan
| | - Seiichi Yoshikawa
- Division of Gastroenterology and Hepatology, Nagaoka Red Cross Hospital, Nagaoka, Niigata, Japan
| | - Yoshihisa Arao
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, Japan
| | - Toru Setsu
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, Japan
| | - Hiroteru Kamimura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, Japan
| | - Nobuo Waguri
- Division of Gastroenterology and Hepatology, Niigata City General Hospital, Niigata, Niigata, Japan
| | - Manabu Takeuchi
- Division of Gastroenterology and Hepatology, Nagaoka Red Cross Hospital, Nagaoka, Niigata, Japan
| | - Kazuhiro Funakoshi
- Division of Gastroenterology and Hepatology, Niigata Central Prefectural Hospital, Joetsu, Niigata, Japan
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, Japan
| |
Collapse
|
|
26
|
Brown JP, Tazare JR, Williamson E, Mansfield KE, Evans SJ, Tomlinson LA, Bhaskaran K, Smeeth L, Wing K, Douglas IJ. Proton pump inhibitors and risk of all-cause and cause-specific mortality: A cohort study. Br J Clin Pharmacol 2021; 87:3150-3161. [PMID: 33393677 PMCID: PMC11497312 DOI: 10.1111/bcp.14728] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 12/05/2020] [Accepted: 12/22/2020] [Indexed: 01/23/2023] Open
Abstract
AIM To investigate the association between proton pump inhibitors (PPIs) and both all-cause and cause-specific mortality. METHODS We conducted a cohort study using the UK Clinical Practice Research Datalink GOLD database. We compared 733 885 new users of PPIs to 124 410 new users of H2 receptor antagonists (H2Ras). In a secondary analysis we compared 689 602 PPI new users to 1 361 245 nonusers of acid suppression therapy matched on age, sex and calendar year. Hazard ratios for all-cause and cause-specific mortality were estimated using propensity score (PS) weighted Cox models. RESULTS PPI prescription was associated with increased risk of all-cause mortality, with hazard ratios decreasing considerably by increasing adjustment (unadjusted hazard ratio [HR] 1.65, 95% confidence interval [CI] 1.62-1.69; PS-weighted HR 1.38, 95% CI 1.33-1.44; high-dimensional PS-weighted HR 1.31, 95% CI 1.26-1.37). Short-term associations were observed with mortality from causes where a causal short-term association is unexpected (eg, lung cancer mortality: PS-weighted HR at 6 months 1.77, 95% CI 1.39-2.25). Adjusted hazard ratios were substantially higher when compared to nonusers (PS-weighted HR all-cause mortality 1.96, 95% CI 1.94-1.99) rather than H2RA users. CONCLUSIONS PPI prescription was strongly associated with all-cause and cause-specific mortality. However, the change in hazard ratios (a) by increasing adjustment and (b) between comparator groups indicates that residual confounding is likely to explain the association between poor health outcomes and PPI use, and fully accounting for this using observational data may not be possible.
Collapse
Affiliation(s)
- Jeremy P. Brown
- Department of Non‐Communicable Disease EpidemiologyLondon School of Hygiene and Tropical MedicineLondonUK
| | - John R. Tazare
- Department of Medical StatisticsLondon School of Hygiene and Tropical MedicineLondonUK
| | - Elizabeth Williamson
- Department of Medical StatisticsLondon School of Hygiene and Tropical MedicineLondonUK
| | - Kathryn E. Mansfield
- Department of Non‐Communicable Disease EpidemiologyLondon School of Hygiene and Tropical MedicineLondonUK
| | - Stephen J. Evans
- Department of Medical StatisticsLondon School of Hygiene and Tropical MedicineLondonUK
| | - Laurie A. Tomlinson
- Department of Non‐Communicable Disease EpidemiologyLondon School of Hygiene and Tropical MedicineLondonUK
| | - Krishnan Bhaskaran
- Department of Non‐Communicable Disease EpidemiologyLondon School of Hygiene and Tropical MedicineLondonUK
| | - Liam Smeeth
- Department of Non‐Communicable Disease EpidemiologyLondon School of Hygiene and Tropical MedicineLondonUK
| | - Kevin Wing
- Department of Non‐Communicable Disease EpidemiologyLondon School of Hygiene and Tropical MedicineLondonUK
| | - Ian J. Douglas
- Department of Non‐Communicable Disease EpidemiologyLondon School of Hygiene and Tropical MedicineLondonUK
| |
Collapse
|
|
27
|
Shaikh BA, Shaikh ZA, Shah AH, Kumar A. Determining the Risk of Spontaneous Bacterial Peritonitis due to increase use of Proton Pump Inhibitors among cirrhotic patients with ascites. Pak J Med Sci 2021; 37:1075-1079. [PMID: 34290786 PMCID: PMC8281193 DOI: 10.12669/pjms.37.4.3476] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 10/12/2020] [Accepted: 03/25/2021] [Indexed: 12/19/2022] Open
Abstract
Objectives The current study aimed to determine the Spontaneous Bacterial Peritonitis (SBP) risk due to increased use of Proton Pump Inhibitors (PPIs) among cirrhotic patients with ascites. Methods This retrospective case-control study was conducted at Chandka Medical College & Hospital, Larkana from March 2013 to February 2014, involving 215 cirrhotic patients with ascites. Paracentesis was performed to distinguish cirrhotic patients with SBP and Polymorphonuclear Neutrophil (PMN) count ≥ 250 neutrophils/mm3 (cases) and non-SBP with PMN count < 250 neutrophils/mm3 (controls). The demographic details, history of PPIs use before admission and duration of Chronic Liver Disease (CLD) were inquired and statistical analysis was carried through SPSS Version 23.0. Results Increased pre-hospital PPI intake was observed among cirrhotic patients with SBP (69.8%) as compared to those without SBP (48.8%; p = 0.014). The mean duration of PPI use was 19.16 ± 4.772 days, and it was more significant among older cirrhotic patients (p < 0.05). Increased duration of CLD was observed among PPI users, i.e. 20.47 ± 6.305 months vs. 18.95 ± 5.527 months among non-PPI users (p < 0.05). Conclusions Our results show that cirrhotic patients with ascites consuming PPIs are more likely to develop SBP as compared to non-PPI users.
Collapse
Affiliation(s)
- Bashir Ahmed Shaikh
- Bashir Ahmed Shaikh, FCPS, FRCP. Chandka Medical College Hospital, Shaheed Mohtarma Benazir Bhutto Medical University (SMBBMU), Larkana, Sindh, Pakistan
| | - Zahid Ali Shaikh
- Zahid Ali Shaikh, FCPS. Chandka Medical College Hospital, Shaheed Mohtarma Benazir Bhutto Medical University (SMBBMU), Larkana, Sindh, Pakistan
| | - Aftab Hussain Shah
- Aftab Hussain Shah, FCPS, FRCP. Chandka Medical College Hospital, Shaheed Mohtarma Benazir Bhutto Medical University (SMBBMU), Larkana, Sindh, Pakistan
| | - Aneel Kumar
- Aneel Kumar, FCPS. Chandka Medical College Hospital, Shaheed Mohtarma Benazir Bhutto Medical University (SMBBMU), Larkana, Sindh, Pakistan
| |
Collapse
|
|
28
|
Proton pump inhibitor use and mortality in patients with cirrhosis: a meta-analysis of cohort studies. Biosci Rep 2021; 40:224145. [PMID: 32406491 PMCID: PMC7276520 DOI: 10.1042/bsr20193890] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 05/12/2020] [Accepted: 05/13/2020] [Indexed: 02/06/2023] Open
Abstract
Background: Proton pump inhibitor (PPI) is commonly used in patients with cirrhosis. However, some studies demonstrated that PPI use was associated with adverse outcome in patients with cirrhosis. We aimed to perform a meta-analysis of cohort studies to evaluate the association between PPI use and mortality in cirrhotic patients. Methods: Relevant studies were obtained via search of PubMed and Embase databases. A randomized-effect model was used to pool the results. Subgroup analyses were performed to evaluate the source of heterogeneity. Results: Overall, 21 cohort studies with 20,899 patients and 7457 death events were included. The pooled results with a randomized-effect model showed that PPI use was associated with significantly increased risk of mortality in patients with cirrhosis (adjusted relative risk [RR] = RR: 1.39, P<0.001) with considerable heterogeneity (I2=73%). Subgroup analyses showed that characteristics such as patient ethnicity, sample size, definition of PPI use, and complications of patients did not affect the association. However, the association between PPI use and mortality was independent of study characteristics including patient ethnicity, sample size, complications, definition of PPI use, and follow-up duration. However, the association between PPI use and mortality in cirrhotic patients was significant in retrospective studies (RR: 1.40, P<0.001), but not in prospective studies (RR: 1.34, P=0.33). Conclusions: PPI use may be associated with moderately increased mortality in cirrhotic patients. Although prospective cohort studies are needed to validate our findings, PPI should only prescribed to cirrhotic patients with indications for the treatment.
Collapse
|
|
29
|
Drolz A, Schramm C, Seiz O, Groth S, Vettorazzi E, Horvatits T, Wehmeyer MH, Schramm C, Goeser T, Roesch T, Lohse AW, Kluwe J. Risk factors associated with bleeding after prophylactic endoscopic variceal ligation in cirrhosis. Endoscopy 2021; 53:226-234. [PMID: 32894867 DOI: 10.1055/a-1214-5355] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Prophylactic endoscopic variceal band ligation (EVL) is frequently performed in patients with liver cirrhosis. The aim of our study was to identify factors associated with early upper gastrointestinal bleeding (UGIB) in cirrhosis patients after prophylactic EVL. METHODS 787 nonemergency EVLs performed in 444 patients in two German University medical centers were analyzed retrospectively. RESULTS Within 30 days after EVL, 38 UGIBs were observed (4.8 % of all procedures). Bilirubin levels (hazard ratio [HR] 1.5, 95 % confidence interval [CI] 1.2-2.0 for a 2-fold increase) and presence of varices grade III/IV according to Paquet (HR 2.6, 95 %CI 1.3-5.0 compared with absence or smaller sized varices) were independently associated with UGIB following EVL. International normalized ratio (INR) was associated with bleeding events in the univariate analysis but did not reach statistical significance after adjustment for bilirubin and presence of varices grade III/IV (HR 1.2, 95 %CI 0.9-1.6 for an increase by 0.25). There was no statistically significant association between platelet count or fibrinogen levels and UGIB. Substitution of coagulation products did not affect incidence of bleeding after EVL, which also applied to patients with "coagulopathy" (INR > 1.5 and/or platelet count < 50 × 109/L). No association between proton pump inhibitor therapy and post-EVL UGIB was observed. CONCLUSIONS EVL is a safe procedure and immediate bleeding complications are rare. Serum bilirubin levels and size of varices, rather than coagulation indices, are associated with UGIB after EVL. Our data do not support the preventive substitution of blood or coagulation products.
Collapse
Affiliation(s)
- Andreas Drolz
- Department of Internal Medicine I, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | - Christoph Schramm
- Department of Gastroenterology and Hepatology, University Hospital Cologne, Cologne, Germany
| | - Oliver Seiz
- Department of Internal Medicine I, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | - Stefan Groth
- Department of Interdisciplinary Endoscopy, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | - Eik Vettorazzi
- Department of Medical Biometry and Epidemiology, University Medical Center, Hamburg, Germany
| | - Thomas Horvatits
- Department of Internal Medicine I, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | - Malte H Wehmeyer
- Department of Internal Medicine I, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | - Christoph Schramm
- Department of Internal Medicine I, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | - Tobias Goeser
- Department of Gastroenterology and Hepatology, University Hospital Cologne, Cologne, Germany
| | - Thomas Roesch
- Department of Interdisciplinary Endoscopy, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | - Ansgar W Lohse
- Department of Internal Medicine I, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | - Johannes Kluwe
- Department of Internal Medicine I, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| |
Collapse
|
|
30
|
Horvath A, Stadlbauer V. [Proton Pump Inhibitors and their Microbiome-Mediated Side Effects]. Zentralbl Chir 2020; 146:165-169. [PMID: 33327006 DOI: 10.1055/a-1312-7587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Proton pump inhibitors are valuable treatment options for gastric acid associated diseases, such as peptic ulcer disease or reflux diseases. Due to their irreversible inhibition of the proton pumps in the parietal cells of the stomach, gastric acid secretion can be effectively reduced. With the reduction in gastric acid, however, proton pump inhibitors also block a highly conserved, crucial part of the unspecific immune system. The gastric barrier protects the body - and here mainly the intestinal microbiome - from food-borne pathogens and oral bacteria that can reach more distal parts of the gastrointestinal tract during proton pump inhibitor therapy. Resulting changes in the intestinal microbiome, such as the reduction in microbial diversity or small intestinal bacterial overgrowth, can be linked to side effects of (long-term) proton pump inhibitor therapy, such as the increased risk of Clostridium difficile infections or gastrointestinal discomfort. In liver cirrhosis patients, the increase in oral bacteria in the intestine is associated with intestinal inflammation and permeability, and can even be used as a biomarker for 3-year liver related mortality. Therefore, microbiome-mediated side effects should be included in the risk assessment of proton pump inhibitor therapy and the evaluation of potential alternatives.
Collapse
Affiliation(s)
- Angela Horvath
- Klinische Abteilung für Gastroenterologie und Hepatologie, Medizinische Universität Graz, Österreich.,Center for Biomarker Research in Medicine, Graz, Österreich
| | - Vanessa Stadlbauer
- Klinische Abteilung für Gastroenterologie und Hepatologie, Medizinische Universität Graz, Österreich
| |
Collapse
|
|
31
|
Labenz C, Kostev K, Galle PR, Wörns MA, Labenz J, Tanislav C, Adarkwah CC. Proton pump inhibitor use is associated with a variety of infections in patients with liver cirrhosis. Medicine (Baltimore) 2020; 99:e23436. [PMID: 33327272 PMCID: PMC7738005 DOI: 10.1097/md.0000000000023436] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
There is evidence that intake of proton pump inhibitors (PPI) increases the risk for spontaneous bacterial peritonitis (SBP) in patients with liver cirrhosis. However, data regarding the impact of PPI intake on occurrence of infections other than SBP are still lacking.We hypothesized that PPI use is associated with a higher rate of infections other than SBP in patients with liver cirrhosis.The current case-control study sample included patients with liver cirrhosis from the Disease Analyzer database (IQVIA), which compiles data such as risk factors, drug prescriptions and diagnoses obtained from general practitioners and specialists in Germany. In total, 2,823 patients with infections were matched with 2,823 patients without infections by propensity scores. For quantification of PPI use the prescribed quantity of PPI during the past 12 months before index date was analyzed.Frequency of PPI users was significantly higher in patients with infections than in patients without infections (47.9% vs 37.9%). In regression analysis, PPI use was significantly associated with the occurrence of infections overall (OR 1.55, 95% CI 1.39-1.72, P < .001), and associated with the occurrence of lower respiratory tract infections, urinary tract infections and infectious gastroenteritis. There was no association between PPI use and skin infections. Pantoprazole and omeprazole were the most frequently prescribed PPIs and were both independently associated with the occurrence of infections.PPI use may be associated with infections other than SBP in patients with liver cirrhosis. Prescription of PPI should be limited to patients with a clear indication.
Collapse
Affiliation(s)
- Christian Labenz
- Department of Internal Medicine I, University Medical Centre of the Johannes Gutenberg-University, Mainz
| | | | - Peter R. Galle
- Department of Internal Medicine I, University Medical Centre of the Johannes Gutenberg-University, Mainz
| | - Marcus-Alexander Wörns
- Department of Internal Medicine I, University Medical Centre of the Johannes Gutenberg-University, Mainz
| | | | | | - Charles Christian Adarkwah
- Department of General Practice and Family Medicine, Philipps-University, Marburg
- CAPHRI School for Public Health and Primary Care, Department of Health Services Research, Maastricht University, Maastricht, The Netherlands
| |
Collapse
|
|
32
|
Association between anti-acid therapies and advanced fibrosis in type 2 diabetics with biopsy-proven non-alcoholic fatty liver disease. Indian J Gastroenterol 2020; 39:591-598. [PMID: 33219985 PMCID: PMC9254737 DOI: 10.1007/s12664-020-01087-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 08/27/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUNDS AND AIMS Data on associations of antacid therapies with advanced fibrosis (AF) in patients with non-alcoholic fatty liver disease (NAFLD) are limited. We aimed to assess the association of histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) with AF in NAFLD patients with underlying type 2 diabetes (T2D). METHODS We retrospectively reviewed patient's charts with T2D who had a liver biopsy for suspected NAFLD. Fibrosis stages were determined as F0-F4, AF being F3-4. Laboratory data and use of various medications within 24 months of liver biopsies were used for the analysis. Univariable and multivariable logistic regression analyses were performed to assess any association. RESULTS Our cohort consisted of 1008 T2D patients with biopsy-proven NAFLD. Sixty-six percent were female, 86.2% were Caucasian, and median HbA1C was 6.4%. AF was present in 32% of the patients. Thirty-four percent were on H2RAs and 60.6% were on PPI therapy (p < 0.001) for a median duration of 3.6 [0.10, 3.8] (p = 0.20) and 45.6 [0.80, 15.4] (p = 0.17) months, respectively. On multivariable logistic regression analysis being on H2RAs was associated with a 68% lower risk of AF (odds ratio [OR] [95%CI]: 0.32 [0.24, 0.44]) (p < 0.001), but use of PPIs showed a trend towards higher risk of AF (OR [95%CI]: 1.4 [1.00, 1.8]) (p = 0.053). CONCLUSION Our study suggests that H2RAs are associated with lower risk of AF in NAFLD patients with underlying diabetes and should be considered as the first-line antacid therapy in these patients. Risk stratification should be done if PPIs are indicated in high-risk diabetics with NAFLD.
Collapse
|
|
33
|
Proton-pump-inhibitor use associated with lower short-term rebleeding and mortality in patients receiving esophageal variceal band ligation: a retrospective cohort study. Eur J Gastroenterol Hepatol 2020; 32:1571-1578. [PMID: 32868651 DOI: 10.1097/meg.0000000000001905] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND The impact of proton-pump inhibitor (PPI) therapy on subsequent hemorrhage and mortality after variceal hemorrhage is unclear. AIM Evaluate the associations of PPI use with upper gastrointestinal bleeding (UGIB) and death within 30 days of undergoing esophageal variceal band ligation (EBL) separately in inpatient and outpatient settings. METHODS Retrospective review of cirrhotic patients with variceal hemorrhage who underwent EBL between 2005 and 2018. Endoscopic findings, PPI use at admission (inpatients only), PPI use at discharge (inpatients and outpatients), and adverse outcomes data (liver transplant, UGIB, transjugular intrahepatic portosystemic shunt, and death within 30 days of discharge or death during hospitalization) were reviewed. RESULTS A total of 446 patients (164 inpatients, 282 outpatients) were included. The most commonly observed outcomes were death within 30 days of discharge in inpatients (12.8%), UGIB within 30 days of discharge in inpatients (21.3%), and UGIB within 30 days of discharge in outpatients (8.5%). For inpatients, prescription of PPI at discharge was associated with a lower risk of bleeding within 30 days (odds ratio: 0.30, P = 0.025) and death within 30 days (odds ratio = 0.16, P = 0.002). No other significant associations of PPI with death or UGIB were reported. CONCLUSION Post-EBL PPI therapy is associated with reduced risk of bleeding and death within 30 days after variceal hemorrhage in hospitalized patients.
Collapse
|
|
34
|
Kim TJ, Lee H. Clinical Significance of Changes in Gut Microbiome Associated with Use of Proton Pump Inhibitors. THE KOREAN JOURNAL OF HELICOBACTER AND UPPER GASTROINTESTINAL RESEARCH 2020. [DOI: 10.7704/kjhugr.2020.0014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Proton pump inhibitors (PPIs) are commonly used for the treatment of gastric acid-related disorders, and are generally well tolerated. However, by reducing the secretion of gastric acid in the long term, PPI can increase the risk of inducing an imbalance in the gut microbiome composition. Moreover, gastric hypochlorhydria that is caused by PPIs favors the survival and migration of oral bacteria in the lower part of the gastrointestinal tract, with a possible induction of pro-inflammatory microenvironment. Therefore, gut dysbiosis that is associated with the use of PPI has been found to cause adverse infectious and inflammatory diseases. In this regard, adverse effects of the PPI-related gut dysbiosis have been reported in different observational studies, but their clinical relevance remains unclear. Therefore, the aim of this review was to explore the available data on the PPI-related gut dysbiosis in order to better understand its clinical significance.
Collapse
|
|
35
|
Labenz C, Wörns MA, Adarkwah CC, Galle PR, Schattenberg JM, Kostev K. Proton pump inhibitors increase risk of bone fractures in men with cirrhosis: a population-based study. Aliment Pharmacol Ther 2020; 52:1042-1050. [PMID: 32729625 DOI: 10.1111/apt.16008] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 06/23/2020] [Accepted: 07/10/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND Bone fractures are a frequent complication in patients with cirrhosis. Proton pump inhibitors (PPIs) are among the most frequently prescribed medications and may impair bone quality and quantity. AIMS To investigate whether PPI use predisposes patients with cirrhosis to bone fractures. METHODS We performed a population-based case-control study exploring a sample of patients with cirrhosis derived from the Disease Analyzer database. In total, 1795 cirrhotic patients with fractures were compared to 10 235 cirrhotic patients without fractures. PPI use overall and the cumulative PPI dose 5 years prior to the index date were analysed. To estimate the association between PPI use and fractures, logistic regression analyses were performed taking cofounding factors into consideration. RESULTS PPI use was more frequently seen in cirrhotic patients with fractures compared to controls (67.0% vs 53.4%, P < 0.001). In regression analyses, PPI use was associated with bone fractures after adjusting for important confounders (OR 1.34, 95% CI 1.20-1.51, P < 0.001). Importantly, the strongest effect of PPIs on bone fractures was seen in men and patients below 70 years of age. On further sensitivity analyses, we observed a dose-dependent effect for all PPIs with the strongest effect in cirrhotic patients receiving a dose of >50 000 mg during the 5 years prior to index date (OR 1.63, 95% CI 1.32-2.03). CONCLUSIONS PPI use was associated with bone fractures in a dose-dependent fashion in patients with cirrhosis. PPI use in these patients should be based on a careful risk-benefit assessment.
Collapse
Affiliation(s)
- Christian Labenz
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.,Cirrhosis Center Mainz (CCM), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Marcus-Alexander Wörns
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.,Cirrhosis Center Mainz (CCM), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Charles C Adarkwah
- Department of Health Services Research and General Practice, Faculty of Life Sciences, University of Siegen, Siegen, Germany
| | - Peter R Galle
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.,Cirrhosis Center Mainz (CCM), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Jörn M Schattenberg
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.,Cirrhosis Center Mainz (CCM), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.,Metabolic Liver Research Program, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | | |
Collapse
|
|
36
|
Martynov AI, Sheptulin AA, Mayev IV, Kazyulin AN, Karateev AY, Melekhov AV, Pal’gova LK, Raikhel’son KL. New Prospects of Cytoprotection in the Treatment and Prevention of Gastric and Intestinal Diseases (Resolution of an Expert Council and Literature Review). RUSSIAN JOURNAL OF GASTROENTEROLOGY, HEPATOLOGY, COLOPROCTOLOGY 2020; 30:7-14. [DOI: 10.22416/1382-4376-2020-30-2-7-14] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
Abstract
Aim. To generalize up-to-date information on the possibilities of cytoprotection in the treatment and prevention of gastric and intestinal diseases, as well as to present the materials of an Expert Council meeting held on February 8, 2020 in Moscow under the support of the Alium company.General provisions. The conducted Expert Council meeting was aimed at discussing the importance of improving the cytoprotective properties of the gastric and intestinal mucous membrane in the treatment of its lesions. It was shown that Rebamipide exhibits positive effects on various parts of the protective barrier of the gastrointestinal tract (GIT), primarily due to its stimulating action on the production of prostaglandins playing a key role in maintaining the cytoprotective properties of the gastrointestinal mucosa. The possibilities of applying Rebamipide for the treatment and prevention of erosive and ulcerative gastrointestinal lesions caused by non-steroidal anti-inflammatory (NSAIDs) and antithrombotic drugs were demonstrated. In the treatment of gastroesophageal reflux disease, Rebamipide is recommended for patients refractory to therapy with proton pump inhibitors (PPIs) and for those with non-acid reflux. The efficacy of Rebamipide in the treatment of Helicobacter pylori (H. pylori) infection, as well as functional dyspepsia and chronic gastritis, was confirmed.Conclusions. Rebamipid is a highly effective drug positively affecting various cytoprotection links, thus being suitable for the treatment and prevention of erosive and ulcerative lesions of the gastrointestinal tract, as well as gastroenterological diseases of various etiologies.Conflict of interest: The Expert Council meeting was supported by the Alium company.
Collapse
Affiliation(s)
- A. I. Martynov
- A.I. Yevdokimov Moscow State University of Medicine and Dentistry
| | | | - I. V. Mayev
- A.I. Yevdokimov Moscow State University of Medicine and Dentistry
| | - A. N. Kazyulin
- A.I. Yevdokimov Moscow State University of Medicine and Dentistry
| | | | | | | | | |
Collapse
|
|
37
|
Proton pump inhibitors and risk of liver cancer and mortality in patients with chronic liver disease: a systematic review and meta-analysis. Eur J Clin Pharmacol 2020; 76:851-866. [PMID: 32172363 DOI: 10.1007/s00228-020-02854-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 03/05/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Epidemiological studies investigating the use of proton pump inhibitors (PPI) on the risk of liver cancer and/or mortality among persons with chronic liver disease (CLD) have reported conflicting results. We conducted a systematic review and meta-analysis to determine the impact of PPI use on liver cancer and/or death among patients with CLD. METHODS The core databases including MEDLINE, EMBASE, and Cochrane library were searched through January 2020. We included studies, evaluating the association between PPIs and liver cancer or mortality among patients with CLD including randomized controlled, nonrandomized controlled, and observational studies. We used inverse-variance random-effects models to estimate the pooled relative risk (RR) and 95% confidence interval (CI) for liver cancer or mortality. RESULTS Eleven studies including 173,894 patients were selected. In three studies, individuals with CLD who used PPIs had a 67% greater risk of developing hepatocellular carcinoma (HCC) compared to nonusers (RR, 1.67; 95% CI, 1.12-2.50; I2 = 92%). Combining data from the eight studies relating PPI to overall mortality, we observed a 57% increased risk of mortality in PPI users with CLD compared to CLD nonusers (RR: 1.57; 95% CI, 1.24-1.99; I2 = 69%). CONCLUSION PPI use was associated with an increased risk of HCC and mortality in patients with CLD suggesting that PPI prescriptions in patients with CLD should be considered carefully.
Collapse
|
|
38
|
Wang AJ, Wang J, Zheng XL, Liao WD, Yu HQ, Gong Y, Gan N, You Y, Guo GH, Xie BS, Zhong JW, Hong JB, Liu L, Shu X, Zhu Y, Li BM, Zhu X. Second-look endoscopy-guided therapy under sedation prevents early rebleeding after variceal ligation for acute variceal bleeding. J Dig Dis 2020; 21:170-178. [PMID: 32031737 DOI: 10.1111/1751-2980.12847] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 02/04/2020] [Accepted: 02/04/2020] [Indexed: 12/11/2022]
Abstract
OBJECTIVES To investigate whether second-look endoscopy (SLE)-guided therapy could be used to prevent post-endoscopic variceal ligation (EVL) early bleeding. METHODS Consecutive cirrhotic patients with large esophageal varices (EV) receiving successful EVL for acute variceal bleeding (AVB) or secondary prophylaxis were enrolled. The patients were randomized into a SLE group and a non-SLE group (NSLE) 10 days after EVL. Additional endoscopic interventions as well as proton pump inhibitors and octreotide administration were applied based on the SLE findings. The post-EVL early rebleeding and mortality rates were compared between the two groups. RESULTS A total of 252 patients were included in the final analysis. Post-EVL early rebleeding (13.5% vs 4.8%, P = 0.016) and bleeding-caused mortality (4.8% vs 0%, P = 0.013) were more frequently observed in the NSLE group than in the SLE group. However, post-EVL early rebleeding and mortality rates were reduced by SLE in patients receiving EVL for AVB only but not in those receiving secondary prophylaxis. Patients with Child-Pugh classification B to C at randomization (hazard ratio [HR] 8.77, P = 0.034), AVB at index EVL (HR 3.62, P = 0.003), discontinuation of non-selective β-blocker after randomization (HR 4.68, P = 0.001) and non-SLE (HR 2.63, P = 0.046) were more likely to have post-EVL early rebleeding. No serious adverse events occurred during SLE. CONCLUSION SLE-guided therapy reduces post-EVL early rebleeding and mortality rates in cirrhotic patients with large EV receiving EVL for AVB.
Collapse
Affiliation(s)
- An Jiang Wang
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Jian Wang
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Xue Lian Zheng
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Wang Di Liao
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Hui Qiang Yu
- Department of Health Statistics, School of Public Health, Nanchang University, Nanchang, Jiangxi Province, China
| | - Yue Gong
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Na Gan
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Yu You
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Gui Hai Guo
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Bu Shan Xie
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Jia Wei Zhong
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Jun Bo Hong
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Li Liu
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Xu Shu
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Yin Zhu
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Bi Min Li
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Xuan Zhu
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| |
Collapse
|
|
39
|
Shi L, Zhang D. Proton Pump Inhibitor Use Before ICU Admission Is Not Associated With Mortality of Critically Ill Patients. J Clin Pharmacol 2020; 60:860-866. [PMID: 32043627 DOI: 10.1002/jcph.1585] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 01/02/2020] [Indexed: 12/17/2022]
Abstract
Some studies have shown that the long-term use of proton pump inhibitors (PPIs) is associated with many adverse events that may increase mortality; however, the relationship between premorbid PPI use and in-hospital mortality has yet to be validated in critically ill patients. Therefore, we performed this study to determine whether the preadmission use of PPIs is associated with mortality in patients admitted to the intensive care unit. This was a retrospective study with a large and freely accessible database in critical-care medicine (the Multiparameter Intelligent Monitoring in Intensive Care III project). The clinical data and outcomes of 17 473 patients, consisting of 1895 in the PPI group, 514 in the H2 -receptor antagonist group, and 15 064 control subjects, were collected during their hospital stay. The study outcome was in-hospital mortality. A total of 17 473 patients were included in our study. PPI use was associated with significantly increased in-hospital mortality in the original model without adjustment for any parameters (odds ratio 1.19; 95%CI 1.03-1.38; P = .02). However, after adjustments had been made for age, sex, Elixhauser score, Simplified Acute Physiology Score, laboratory results, vasopressor use, ventilator use, and other parameters, PPIs were not associated with significantly increased in-hospital mortality (odds ratio 1.04; 95%CI 0.87-1.26; P = .614). In the subgroup analysis among patients with renal or liver disease, we still found that PPIs were not associated with a significant increase in in-hospital mortality. We found no association between PPI use before ICU admission and increased in-hospital mortality in critically ill patients compared with control subjects.
Collapse
Affiliation(s)
- Lin Shi
- Department of Gastroenterology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Dan Zhang
- Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| |
Collapse
|
|
40
|
Abstract
OBJECTIVES Proton pump inhibitors(PPIs) are widely prescribed to patients with liver cirrhosis. We hypothesized that long-standing PPI use is associated with spontaneous bacterial peritonitis(SBP) and accelerated development of disease-specific complications and liver-related death. METHODS A 5-year follow-up observational cohort study assessed the impact of long-standing PPI use on the clinical course of cirrhosis in a large referral patient cohort. Three hundred fifty patients with cirrhosis (alcohol:69.1%, Child-Pugh stage A/B/C:206/108/36) were assigned to two groups: regular PPI users (n=196) and nonusers (n=154). Occurrence of SBP, decompensation events (ascites, hepatic encephalopathy and variceal bleeding), and liver-related death were assessed. RESULTS Regular PPI use was associated with an increased cumulative probability of SBP compared to nonusers [55% vs. 24.8%, hazard ratio(HR):4.25; P=0.05], in patients without previous SBP episode (n=84). A similar association was found between regular PPI use and decompensation events. The risk of the development of a first decompensation was higher in regular PPI users compared with nonusers, in patients with compensated clinical stage at enrollment (HR: 2.81, P= 0.008, n=146). The risk of liver-related death was also significantly increased among regular PPI users (P<0.001). In multivariate Cox-regression analysis, regular PPI use (HR:2.81, P=0.003) and MELD score (HR:1.21, P<0.001) was an independent predictor of mortality. CONCLUSION In the present follow-up cohort study, long-term PPI use was associated with the development of SBP and a progressive disease course in patients with cirrhosis that may have been caused by enhanced pathologic bacterial translocation, accelerated development of bacterial translocation-dependent disease-specific complications, and liver-related death.
Collapse
|
|
41
|
The Phylogeny and Biological Function of Gastric Juice-Microbiological Consequences of Removing Gastric Acid. Int J Mol Sci 2019; 20:ijms20236031. [PMID: 31795477 PMCID: PMC6928904 DOI: 10.3390/ijms20236031] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Revised: 11/24/2019] [Accepted: 11/25/2019] [Indexed: 12/15/2022] Open
Abstract
Gastric juice is a unique combination of hydrochloric acid (HCl), lipase, and pepsin. Acidic gastric juice is found in all vertebrates, and its main function is to inactivate microorganisms. The phylogenetic preservation of this energy-consuming and, at times, hazardous function (acid-related diseases) reflects its biological importance. Proton pump inhibitors (PPIs) are one of the most widely used drugs in the world. Due to the reduced prevalence of Helicobacter pylori infection as well as the increased use of inhibitors of gastric acid secretion, the latter has become the most important cause of gastric hypoacidity. In the present manuscript, we review the microbiological consequences of removing gastric acidity. The resulting susceptibility to infections has not been studied extensively, and focus has mainly been restricted to bacterial and parasitic agents only. The strongest evidence concerning the relationship between hypochlorhydria and predisposition to infections relates to bacterial infections affecting the gastrointestinal tract. However, several other clinical settings with increased susceptibility to infections due to inhibited gastric acidity are discussed. We also discuss the impact of hypochlorhydria on the gut microbiome.
Collapse
|
|
42
|
Min YW, Kang D, Shin JY, Kang M, Park JK, Lee KH, Lee JK, Lee KT, Rhee PL, Kim JJ, Guallar E, Cho J, Lee H. Use of proton pump inhibitors and the risk of cholangitis: a nationwide cohort study. Aliment Pharmacol Ther 2019; 50:760-768. [PMID: 31448440 DOI: 10.1111/apt.15466] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 04/09/2019] [Accepted: 07/28/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND Proton pump inhibitor (PPI) use may alter the gut microbiome and increase the risk of cholangitis. However, the association of PPI use with the risk of incident cholangitis has not been evaluated. AIM To evaluate whether PPI use was associated with a higher risk of cholangitis. METHODS This cohort study included a nationwide representative sample of the Korean general population followed up for 10 years (1 January 2003 to 31 December 2013). PPI use was identified from treatment claims and considered as a time-varying variable. Incident cholangitis was identified from hospitalisation and out-patient visit claims. RESULTS During 4 212 003 person-years of follow-up, 58,863 participants had at least one PPI prescription and 1 834 participants developed cholangitis. The age-, sex-, residential area- and income-adjusted hazard ratio (HR) for incident cholangitis comparing PPI use with non-use was 6.06 (95% CI, 4.64-7.91). The association was essentially unchanged in fully adjusted models (HR 5.75; 95% CI, 4.39-7.54). The risk was highest during PPI treatment and decreased gradually after PPI discontinuation (Ptrend <.001). CONCLUSIONS In this large cohort, PPI use was associated with an increased risk of cholangitis. Physicians prescribing PPIs should consider cholangitis as a potential complication of PPI use.
Collapse
Affiliation(s)
- Yang Won Min
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Danbee Kang
- Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University School of Medicine, Seoul, Korea
- Center for Clinical Epidemiology, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea
| | - Ju-Young Shin
- School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
| | - Minwoong Kang
- Center for Clinical Epidemiology, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea
| | - Joo Kyung Park
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Kwang Hyuck Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jong Kyun Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Kyu Taek Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Poong-Lyul Rhee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jae J Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Eliseo Guallar
- Center for Clinical Epidemiology, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea
- Departments of Epidemiology and Medicine and Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
| | - Juhee Cho
- Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University School of Medicine, Seoul, Korea
- Center for Clinical Epidemiology, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea
- Departments of Epidemiology and Medicine and Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
| | - Hyuk Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| |
Collapse
|
|
43
|
Chang TE, Huang YS, Perng CL, Huang YH, Hou MC. Use of proton pump inhibitors and the risk of hepatocellular carcinoma: A systematic review and meta-analysis. J Chin Med Assoc 2019; 82:756-761. [PMID: 31335628 DOI: 10.1097/jcma.0000000000000157] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Worldwide, proton pump inhibitors (PPIs) are commonly used for the treatment of peptic ulcer and gastro-esophageal reflux disease. Recently, concern has arisen over the potential association between PPIs and hepatocellular carcinoma (HCC). The aim of the current study was to evaluate the influence of PPI use on the risk of HCC, through a systematic review and meta-analysis. METHODS A review of all English-language literature was conducted, using the subject search terms: "hepatocellular carcinoma", "liver cancer", "hepatic tumor", and "proton pump inhibitor" in the major medical databases. A meta-analysis of the qualifying publications was then performed. RESULTS A total of five studies, which had shown that PPIs were associated with HCC (crude risk ratio [RR] = 2.27, 95% confidence interval [CI]: 1.44-3.57; p < 0.01) when an unadjusted RR were adopted, were eligible for meta-analysis. It was observed that the cumulative dose of PPIs may increase the risk of HCC in a linear model (p < 0.01). However, when using data that were adjusted by comorbidities and concurrent medications, the association between PPIs and HCC became insignificant (adjusted RR = 1.62, 95% CI: 0.89-2.93; p = 0.11) and this result was consistent in the sensitivity analysis. CONCLUSION The current meta-analysis has shown that PPI use does not significantly increase the risk of HCC after adjusting for confounding factors. However, further studies are warranted to verify the association between PPIs and HCC in special populations, such as viral or alcoholic liver diseases.
Collapse
Affiliation(s)
- Tien-En Chang
- Dvision of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taiwan, ROC
- National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
| | - Yi-Shin Huang
- Dvision of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taiwan, ROC
- National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
| | - Chin-Lin Perng
- Dvision of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taiwan, ROC
- National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
| | - Yi-Hsiang Huang
- Dvision of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taiwan, ROC
- National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
| | - Ming-Chih Hou
- Dvision of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taiwan, ROC
- National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
| |
Collapse
|
|
44
|
Hov JR. Editorial: proton pump inhibition - microbial complications beyond dysbiosis. Aliment Pharmacol Ther 2019; 50:962-963. [PMID: 31591776 DOI: 10.1111/apt.15495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Affiliation(s)
- Johannes Roksund Hov
- Norwegian PSC Research Center and Research Institute of Internal Medicine and Section of Gastroenterology, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital and University of Oslo, Oslo, Norway
| |
Collapse
|
|
45
|
Lanas-Gimeno A, Hijos G, Lanas Á. Proton pump inhibitors, adverse events and increased risk of mortality. Expert Opin Drug Saf 2019; 18:1043-1053. [DOI: 10.1080/14740338.2019.1664470] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
| | - Gonzalo Hijos
- Servicio de Aparato Digestivo, Hospital Clínico Universitario, Zaragoza, Spain
- Instituto de Investigación Sanitaria Aragón, Zaragoza, Spain
| | - Ángel Lanas
- Servicio de Aparato Digestivo, Hospital Clínico Universitario, Zaragoza, Spain
- Instituto de Investigación Sanitaria Aragón, Zaragoza, Spain
- CIBERehd, Madrid, Spain
- Department of Medicine, Universidad de Zaragoza, Zaragoza, Spain
| |
Collapse
|
|
46
|
De Roza MA, Kai L, Kam JW, Chan YH, Kwek A, Ang TL, Hsiang JC. Proton pump inhibitor use increases mortality and hepatic decompensation in liver cirrhosis. World J Gastroenterol 2019; 25:4933-4944. [PMID: 31543684 PMCID: PMC6737311 DOI: 10.3748/wjg.v25.i33.4933] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2019] [Revised: 07/12/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Proton pump inhibitors (PPIs) are widely prescribed, often without clear indications. There are conflicting data on its association with mortality risk and hepatic decompensation in cirrhotic patients. Furthermore, PPI users and PPI exposure in some studies have been poorly defined with many confounding factors.
AIM To examine if PPI use increases mortality and hepatic decompensation and the impact of cumulative PPI dose exposure.
METHODS Data from patients with decompensated liver cirrhosis were extracted from a hospital database between 2013 to 2017. PPI users were defined as cumulative defined daily dose (cDDD) ≥ 28 within a landmark period, after hospitalisation for hepatic decompensation. Cox regression analysis for comparison was done after propensity score adjustment. Further risk of hepatic decompensation was analysed by Poisson regression.
RESULTS Among 295 decompensated cirrhosis patients, 238 were PPI users and 57 were non-users. PPI users had higher mortality compared to non-users [adjusted HR = 2.10, (1.20-3.67); P = 0.009]. Longer PPI use with cDDD > 90 was associated with higher mortality, compared to non-users [aHR = 2.27, (1.10-5.14); P = 0.038]. PPI users had a higher incidence of hospitalization for hepatic decompensation [aRR = 1.61, (1.30-2.11); P < 0.001].
CONCLUSION PPI use in decompensated cirrhosis is associated with increased risk of mortality and hepatic decompensation. Longer PPI exposure with cDDD > 90 increases the risk of mortality.
Collapse
Affiliation(s)
| | - Lim Kai
- Department of Gastroenterology and Hepatology, Changi General Hospital, Singhealth 529889, Singapore
| | - Jia Wen Kam
- Clinical Trials and Research Unit, Changi General Hospital, Singhealth 529889, Singapore
| | - Yiong Huak Chan
- Biostatistics Unit, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 160608, Singapore
| | - Andrew Kwek
- Department of Gastroenterology and Hepatology, Changi General Hospital, Singhealth 529889, Singapore
| | - Tiing Leong Ang
- Department of Gastroenterology and Hepatology, Changi General Hospital, Singhealth 529889, Singapore
| | - John Chen Hsiang
- Department of Gastroenterology and Hepatology, Changi General Hospital, Singhealth 529889, Singapore
| |
Collapse
|
|
47
|
Horvath A, Rainer F, Bashir M, Leber B, Schmerboeck B, Klymiuk I, Groselj-Strele A, Durdevic M, Freedberg DE, Abrams JA, Fickert P, Stiegler P, Stadlbauer V. Biomarkers for oralization during long-term proton pump inhibitor therapy predict survival in cirrhosis. Sci Rep 2019; 9:12000. [PMID: 31427714 PMCID: PMC6700098 DOI: 10.1038/s41598-019-48352-5] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Accepted: 07/31/2019] [Indexed: 02/07/2023] Open
Abstract
Proton pump inhibitors (PPI) are an invaluable therapy option for acid related diseases; however, PPI therapy is also linked to a series of side effects in cirrhosis, such as microbiome alterations, spontaneous bacterial peritonitis and hepatic encephalopathy. Decision tools to balance benefits and risks of PPI therapy are largely missing. In this study, we tested gut-derived biomarkers to identify PPI-associated dysbiosis, its association with gut barrier function and liver-related mortality. In this observational study, faecal microbiome composition data obtained from 16S rDNA sequencing of 90 cirrhotic patients with and without long-term PPI use and additional potential biomarkers identified from the literature were evaluated for their predictive value regarding PPI-associated dysbiosis and liver-related three-year mortality. In addition, faecal calprotectin, faecal zonulin and serum lipopolysaccharides were assessed as markers for intestinal inflammation, gut permeability and bacterial translocation. Streptococcus salivarius, Veillonella parvula and the genus Streptococcus were significantly increased in patients with long-term PPI therapy and performed well as biomarkers for PPI-associated dysbiosis (accuracy: 74%, 72% and 74%, respectively). The abundance of Streptococcus salivarius was linked to intestinal inflammation and gut barrier dysfunction, whereas the abundance of Veillonella parvula showed associations with liver disease severity; both were independent predictors for liver-related three-year mortality. Gut-derived biomarkers of PPI-associated dysbiosis are linked to worse outcome and a potential option to evaluate the risks of adverse events during long-term PPI therapy.
Collapse
Affiliation(s)
- Angela Horvath
- Department of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria. .,Center for Biomarker Research in Medicine (CBmed), Graz, Austria.
| | - Florian Rainer
- Department of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria
| | - Mina Bashir
- Department of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria
| | - Bettina Leber
- Department of Transplantation Surgery, Medical University of Graz, Graz, Austria
| | - Bianca Schmerboeck
- Department of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria.,Center for Biomarker Research in Medicine (CBmed), Graz, Austria
| | - Ingeborg Klymiuk
- Center for Medical Research, Core Facility Molecular Biology, Medical University of Graz, Graz, Austria
| | - Andrea Groselj-Strele
- Center for Medical Research, Core Facility Computational Bioanalytics, Medical University of Graz, Graz, Austria
| | - Marija Durdevic
- Center for Medical Research, Core Facility Computational Bioanalytics, Medical University of Graz, Graz, Austria
| | - Daniel E Freedberg
- Division of Digestive and Liver Diseases, Columbia University Medical Center, New York, USA
| | - Julian A Abrams
- Division of Digestive and Liver Diseases, Columbia University Medical Center, New York, USA
| | - Peter Fickert
- Department of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria
| | - Philipp Stiegler
- Department of Transplantation Surgery, Medical University of Graz, Graz, Austria
| | - Vanessa Stadlbauer
- Department of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria
| |
Collapse
|
|
48
|
Nardelli S, Gioia S, Ridola L, Farcomeni A, Merli M, Riggio O. Proton Pump Inhibitors Are Associated With Minimal and Overt Hepatic Encephalopathy and Increased Mortality in Patients With Cirrhosis. Hepatology 2019; 70:640-649. [PMID: 30289992 DOI: 10.1002/hep.30304] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 10/02/2018] [Indexed: 12/12/2022]
Abstract
Minimal hepatic encephalopathy (MHE) is a subclinical cognitive impairment frequently observable in patients with cirrhosis. Proton pump inhibitors (PPIs) can contribute to small-bowel bacterial overgrowth, but no study has investigated the link between PPIs and MHE. We investigated the relationship between MHE and PPI use as well as the role of PPI use in the development of overt HE and survival. Consecutive patients with cirrhosis (n = 310) were included in the study and followed up for 14.1 ± 12.3 months. At entry, MHE was diagnosed when the Psychometric Hepatic Encephalopathy Score was ≤-4. Data were analyzed by logistic regression for the factors associated with MHE and by time-related models for overt HE development and survival. At inclusion, 131 out of 310 patients with cirrhosis (42%) were affected by MHE. One hundred and twenty-five patients (40%) were using PPIs. The variables independently associated with the presence of MHE were PPI use, previous overt HE, low albumin, low sodium, and age. During follow-up, the development of overt HE was higher (64% versus 25%, P < 0.001) and overall survival lower (41% versus 81%, P < 0.001) in PPI users than in nonusers. Variables independently associated with the development of overt HE were PPIs, history of overt HE, low albumin, MHE, and age, while variables independently associated with mortality were PPIs, development of overt HE, Model for End-Stage Liver Disease score, low sodium, and age. Conclusion: The study identifies a potentially removable factor associated with the presence of MHE and related to the development of overt HE and survival in patients with liver cirrhosis.
Collapse
Affiliation(s)
- Silvia Nardelli
- Department of Clinical Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Stefania Gioia
- Department of Clinical Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Lorenzo Ridola
- Department of Clinical Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Alessio Farcomeni
- Department of Public Health and Infectious Diseases, "Sapienza" University of Rome, Rome, Italy
| | - Manuela Merli
- Department of Clinical Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Oliviero Riggio
- Department of Clinical Medicine, "Sapienza" University of Rome, Rome, Italy
| |
Collapse
|
|
49
|
Farhat N, Fortin Y, Haddad N, Birkett N, Mattison DR, Momoli F, Wu Wen S, Krewski D. Systematic review and meta-analysis of adverse cardiovascular events associated with proton pump inhibitors used alone or in combination with antiplatelet agents. Crit Rev Toxicol 2019; 49:215-261. [DOI: 10.1080/10408444.2019.1583167] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Nawal Farhat
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada
| | - Yannick Fortin
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada
| | - Nisrine Haddad
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada
| | - Nicholas Birkett
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada
| | - Donald R. Mattison
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada
- Risk Sciences International, Ottawa, Canada
| | - Franco Momoli
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada
| | - Shi Wu Wen
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada
- Ottawa Hospital Research Institute, Ottawa, Canada
| | - Daniel Krewski
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada
- Risk Sciences International, Ottawa, Canada
| |
Collapse
|
|
50
|
Tantai XX, Yang LB, Wei ZC, Xiao CL, Chen LR, Wang JH, Liu N. Association of proton pump inhibitors with risk of hepatic encephalopathy in advanced liver disease: A meta-analysis. World J Gastroenterol 2019; 25:2683-2698. [PMID: 31210719 PMCID: PMC6558434 DOI: 10.3748/wjg.v25.i21.2683] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 04/21/2019] [Accepted: 05/03/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Several studies have explored the association between the use of proton pump inhibitors (PPIs) and the risk of developing hepatic encephalopathy (HE) in patients with advanced liver disease. However, the evidence-based conclusions are controversial. We hypothesized that using PPIs may increase the risk of HE in patients with advanced liver disease. If confirmed, clinicians must strictly adhere to the indications for PPI treatment in this population. AIM To evaluate the pooled risk of HE in patients with advanced liver disease who use PPIs. METHODS Three electronic databases (PubMed, EMBASE, and the Cochrane Library) were searched from the date of database inception through January 8, 2019 to identify comparative studies evaluating the association between PPI use and the risk of HE. Data from the included studies were extracted. The random-effects model was used for pooling risk estimates and the corresponding 95% confidence intervals (CIs). Subgroup and sensitivity analyses were also performed. RESULTS In total, 4342 patients from five case-control studies and 188053 patients from four cohort studies were included in this analysis. In patients with advanced liver disease, PPI use was associated with an elevated risk of developing HE, with significant heterogeneity. The pooled odds ratio for case-control studies was 2.58 (95%CI: 1.68-3.94, I 2 = 72%). The pooled RR for cohort studies was 1.67 (95%CI: 1.30-2.14, I 2 = 67%). The results of the subgroup analyses suggested that the heterogeneity may be the result of differences in the study designs and the definitions of PPI use. The sensitivity and subgroup analyses did not alter our findings. CONCLUSION In patients with advanced liver disease, PPI use is associated with an elevated risk of HE. Future large prospective studies are needed to confirm this association.
Collapse
Affiliation(s)
- Xin-Xing Tantai
- Division of Gastroenterology, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
| | - Long-Bao Yang
- Division of Gastroenterology, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
| | - Zhong-Cao Wei
- Division of Gastroenterology, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
| | - Cai-Lan Xiao
- Division of Gastroenterology, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
| | - Li-Rong Chen
- Division of Gastroenterology, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
| | - Jin-Hai Wang
- Division of Gastroenterology, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
| | - Na Liu
- Division of Gastroenterology, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
| |
Collapse
|