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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.
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Association Between Proton Pump Inhibitor Therapy and Spontaneous Bacterial Peritonitis Occurrence in Cirrhotic Patients: A Clinical Review. Curr Med Sci 2022; 42:673-680. [PMID: 35870102 DOI: 10.1007/s11596-022-2607-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Accepted: 01/20/2022] [Indexed: 11/26/2022]
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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.
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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
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Zhang M, Xu X, Liu W, Zhang Z, Cheng Q, Yang Z, Liu T, Liu Y, Ning Q, Chen T, Qi J. Proton Pump Inhibitor Therapy Increases the Risk of Spontaneous Bacterial Peritonitis in Patients with HBV-Related Acute-on-Chronic Liver Failure. Adv Ther 2021; 38:4675-4694. [PMID: 34308513 DOI: 10.1007/s12325-021-01844-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 06/24/2021] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Spontaneous bacterial peritonitis (SBP) is a common infection in patients with hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). SBP significantly increases the mortality rate and medical costs. The association between proton pump inhibitor (PPI) use and SBP remains unclear. We conducted a retrospective study to investigate the association between PPI use and SBP in patients with HBV-related ACLF and to explore the risk factors for SBP. METHODS We compared the SBP incidence between the PPI and non-PPI groups before and after propensity score matching and explored the association between the duration and type of PPI and SBP occurrence. Risk factors for SBP occurrence were determined by univariate and multivariate logistic regression analysis. RESULTS The SBP incidence was higher in the PPI group than in the non-PPI group before and after propensity score matching. The SBP incidence increased for elevated MELD scores in PPI users. There was a similar SBP incidence in both different types and durations of PPI users. MELD score, old age, male sex, and high WBC count were significant independent risk factors for SBP in PPI users with HBV-related ACLF in the hospital. CONCLUSIONS PPI therapy increases the risk of SBP development in patients with HBV-related ACLF. MELD score, old age, male sex, and high WBC count could serve as predictors of SBP in PPI users. Caution should be taken regarding PPI use, especially for patients with MELD scores > 30.
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Affiliation(s)
- Meng Zhang
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095, Jiefang Avenue, Wuhan, 430030, People's Republic of China
| | - Xin Xu
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095, Jiefang Avenue, Wuhan, 430030, People's Republic of China
| | - Wei Liu
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095, Jiefang Avenue, Wuhan, 430030, People's Republic of China
| | - Zhongwei Zhang
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095, Jiefang Avenue, Wuhan, 430030, People's Republic of China
| | - Qiuyu Cheng
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095, Jiefang Avenue, Wuhan, 430030, People's Republic of China
| | - Zhongyuan Yang
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095, Jiefang Avenue, Wuhan, 430030, People's Republic of China
| | - Tingting Liu
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095, Jiefang Avenue, Wuhan, 430030, People's Republic of China
| | - Yunhui Liu
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095, Jiefang Avenue, Wuhan, 430030, People's Republic of China
| | - Qin Ning
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095, Jiefang Avenue, Wuhan, 430030, People's Republic of China
| | - Tao Chen
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095, Jiefang Avenue, Wuhan, 430030, People's Republic of China.
| | - Junying Qi
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095, Jiefang Avenue, Wuhan, 430030, People's Republic of China.
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Campbell KA, Trivedi HD, Chopra S. Infections in Cirrhosis: A Guide for the Clinician. Am J Med 2021; 134:727-734. [PMID: 33607090 DOI: 10.1016/j.amjmed.2021.01.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 12/31/2020] [Accepted: 01/25/2021] [Indexed: 12/13/2022]
Abstract
Cirrhosis contributes significantly to morbidity and mortality worldwide. Infections in patients with cirrhosis are common and significantly impact health-related quality of life. As our understanding of immune dysfunction associated with cirrhosis grows and as rates of drug-resistant organisms increase, the management of infections in cirrhosis has become increasingly nuanced. In this review, we discuss the current understanding of cirrhosis-associated immune deficiency, review the most common infections in patients with cirrhosis, and highlight techniques for the general clinician in the prevention and treatment of infections in this high-risk population.
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Affiliation(s)
- Kirsti A Campbell
- Beth Israel Deaconess Medical Center, Boston, Mass; Harvard Medical School, Boston, Mass.
| | - Hirsh D Trivedi
- Beth Israel Deaconess Medical Center, Boston, Mass; Harvard Medical School, Boston, Mass
| | - Sanjiv Chopra
- Beth Israel Deaconess Medical Center, Boston, Mass; Harvard Medical School, Boston, Mass
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Alhumaid S, Al Mutair A, Al Alawi Z, Zaidi ARZ, Rabaan AA, Elhazmi A, Al-Omari A. Proton pump inhibitors use and risk of developing spontaneous bacterial peritonitis in cirrhotic patients: A systematic review and meta-analysis. Gut Pathog 2021; 13:17. [PMID: 33741033 PMCID: PMC7977161 DOI: 10.1186/s13099-021-00414-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 03/11/2021] [Indexed: 02/06/2023] Open
Abstract
Background Spontaneous bacterial peritonitis (SBP) is one of the most common infectious diseases in patients with cirrhosis and is associated with serious prognosis. A prevailing dogma posits that SBP is exacerbated by the frequent use of proton pump inhibitors (PPIs). Aims To re-assess the association between PPIs use and SBP incidence with larger and better-quality data. Method The studies were identified by searching Proquest, Medline, and Embase for English language articles published between January 2008 and March 2020 using the following keywords alone or in combination: anti-ulcer agent, antacid, proton pump inhibitor, proton pumps, PPI, omeprazole, rabeprazole, lansoprazole, pantoprazole, esomeprazole, peritonitis, spontaneous bacterial peritonitis, SBP, ascites, cirrhosis, ascitic and cirrhotic. Three authors critically reviewed all of the studies retrieved and selected those judged to be the most relevant. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was followed. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Sub-group analyses were done to decrease the heterogeneity. Results A total of twenty-three studies: seven case–control, and sixteen cohorts, involving 10,386 patients were analyzed. The overall results showed a statistically significant association between SBP and PPIs use (pooled odds ratio (OR): 1.80, 95% CI of 1.41 to 2.31). Substantial heterogeneity was observed. On subgroup analysis involving cohort studies, the association was weaker (OR: 1.55 with 95% CI of 1.16 to 2.06 p < 0.00001) but still statistically significant and with high heterogeneity (Chi2p = 57.68; I2 = 74%). For case–control studies, the OR was 2.62 with a 95% CI of 1.94 to 3.54. The funnel plot was asymmetric and Egger’s test confirmed asymmetry suggesting publication bias (intercept = − 0.05, SE = 0.27, P = 0.850 two-tailed). Conclusion This meta-analysis sheds light on the conflicting results raised by previous studies regarding the association of SBP with PPIs use. Our meta-analysis showed that there is a weak association, although statistically significant, between SBP and PPIs use. However, the magnitude of the possible association diminished when analysis focused on higher quality data that were more robust. Thus, this updated meta-analysis suggests judicious use of PPIs among cirrhotic patients with ascites.
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Affiliation(s)
- Saad Alhumaid
- Administration of Pharmaceutical Care, Al-Ahsa Health Cluster, Ministry of Health, Al-Ahsa, Saudi Arabia.
| | - Abbas Al Mutair
- Research Center, Almoosa Specialist Hospital, Al-Ahsa, Saudi Arabia.,College of Nursing, Princess Nourah Bint Abdul Rahman University, Riyadh, Saudi Arabia.,School of Nursing, University of Wollongong, Wollongong, Australia
| | - Zainab Al Alawi
- Department of Paediatrics, College of Medicine, King Faisal University, Al-Ahsa, Saudi Arabia
| | - Abdul Rehman Zia Zaidi
- Research Center, Dr. Sulaiman Al Habib Medical Group, Riyadh, Saudi Arabia.,College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Ali A Rabaan
- Molecular Diagnostic Laboratory, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia
| | - Alyaa Elhazmi
- Research Center, Dr. Sulaiman Al Habib Medical Group, Riyadh, Saudi Arabia
| | - Awad Al-Omari
- Research Center, Dr. Sulaiman Al Habib Medical Group, Riyadh, Saudi Arabia.,College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
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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.
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Lin L, Hou L, Deng Y, Zhao T, Wang B, Sun C. Acid suppression therapy and its association with spontaneous bacterial peritonitis incidence: A systemic review and meta-analysis. Hepatol Res 2020; 50:233-245. [PMID: 31667938 DOI: 10.1111/hepr.13447] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 10/02/2019] [Accepted: 10/04/2019] [Indexed: 12/16/2022]
Abstract
AIM It is well known that the use of proton pump inhibitor (PPI) is widespread in patients with liver cirrhosis. PPI counteracts H2 receptor inhibitor (H2 RA) with its strong acid suppression effect. However, there is always a concern that PPI use may increase spontaneous bacteria peritonitis (SBP) development in cirrhotic patients. We aimed to investigate the association between acid suppression therapy (i.e. PPI or H2 RA) and SBP through meta-analysis. METHODS We searched PubMed, Medline, Web of Science, Cochrane library, and Embase for relevant studies published up to April 2019. Pooled OR and 95% CI were calculated by a random-effects model. Funnel plots and Egger's tests were performed for the evaluation of publication bias. Non-parametric "trim-and-fill" tests were conducted for sensitivity analysis. RESULTS A total of 20 original articles including 9566 cirrhotic patients were analyzed. The overall meta-analysis highlighted that PPI use was associated with the risk of SBP (pooled OR 1.77, 95% CI 1.49-2.11). The conclusion was irrespective of study methods, whereas the result was inconsistent only in South America. However, the conclusion might not be stable enough and should be extrapolated with caution. Unlike PPI, we found H2 RA was not associated with SBP (pooled OR 1.06, 95% CI 0.75-1.48). CONCLUSIONS In conclusion, PPI use, but not H2 RA, will increase the incidence of SBP in cirrhotic patients. In addition, H2 RA might be beneficial for patients who require long-term acid suppression therapy.
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Affiliation(s)
- Lin Lin
- Department of Gastroenterology, Tianjin Medical University General Hospital Airport Hospital, Tianjin, China
| | - Lijun Hou
- Department of Gastroenterology, Tianjin Medical University General Hospital Airport Hospital, Tianjin, China
| | - You Deng
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Tianming Zhao
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Bangmao Wang
- Department of Gastroenterology, Tianjin Medical University General Hospital Airport Hospital, Tianjin, China
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Chao Sun
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
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Frieling T. Gastroösophageale Refluxkrankheit. JOURNAL FÜR GASTROENTEROLOGISCHE UND HEPATOLOGISCHE ERKRANKUNGEN 2019; 17:28-37. [DOI: 10.1007/s41971-019-0047-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Elzouki AN, Neffati N, Rasoul FA, Abdallah A, Othman M, Waness A. Increased Risk of Spontaneous Bacterial Peritonitis in Cirrhotic Patients Using Proton Pump Inhibitors. GE PORTUGUESE JOURNAL OF GASTROENTEROLOGY 2019; 26:83-89. [PMID: 30976612 PMCID: PMC6454390 DOI: 10.1159/000487963] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Accepted: 02/23/2018] [Indexed: 12/21/2022]
Abstract
BACKGROUND The association between bacterial infections and proton pump inhibitors (PPIs) has recently been studied with debatable results. AIM The aim of this study was to investigate the relationship between PPIs and the development of spontaneous bacterial peritonitis (SBP) or other bacterial infections in cirrhotic patients. MATERIALS AND METHODS Consecutive cirrhotic patients hospitalized from 2007 through 2012 to Hamad General Hospital-, Doha, Qatar, were enrolled and classified as PPI users or non-users according to PPI consumption in the 90 days prior to hospitalization. Cirrhosis was clinically diagnosed by a combination of physical, biochemical, radiological, and endoscopic findings, or by liver biopsy. RESULTS A total of 333 patients were included in this study, of whom 171 (51.4%) used PPIs and 162 (48.6%) did not use PPIs. PPI users were significantly older in age (p = 0.001). There was no statistical difference between the 2 groups in sex distribution and etiology of cirrhosis (p > 0.05 for both parameters). PPI users had a significantly higher incidence of overall bacterial infection (38%) than non-PPI users (13.6%), p = 0.0001. Statistical significance is observed specifically for SBP and chest infection (p = 0.0006 and p = 0.01, respectively). In multivariate analysis, older age (> 60 years; OR = 1.246, 95% CI 1.021-08.486; p = 0.02), and PPI use (OR = 2.149, 95% CI 1.124-06.188; p = 0.01) were independent predicting factors for SBP and overall bacterial infection. CONCLUSION The present study shows that PPI use, as well as older age (> 60 years), was an independent predicting factor for the development of overall infection and SBP in hospitalized cirrhotic patients. Unless it is indicated, PPI therapy should be avoided in this group of patients, particularly in those older than 60 years of age.
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Affiliation(s)
- Abdel-Naser Elzouki
- aDepartment of Medicine, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar
- bWeill Cornell Medical College, Doha, Qatar
| | - Nadia Neffati
- aDepartment of Medicine, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar
| | - Fatma A. Rasoul
- aDepartment of Medicine, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar
| | - Ali Abdallah
- aDepartment of Medicine, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar
| | - Muftah Othman
- aDepartment of Medicine, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar
| | - Abdelkarim Waness
- aDepartment of Medicine, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar
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Dam G, Vilstrup H, Andersen PK, Bossen L, Watson H, Jepsen P. Effect of proton pump inhibitors on the risk and prognosis of infections in patients with cirrhosis and ascites. Liver Int 2019; 39:514-521. [PMID: 30472808 DOI: 10.1111/liv.14012] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 10/30/2018] [Accepted: 11/17/2018] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Many patients with cirrhosis use proton pump inhibitors. We aimed to determine their effects on the risk and prognosis of infections in patients with cirrhosis and ascites. METHODS We used data from three 1-year trials of satavaptan treatment of ascites (N = 1198) to compare incidence and 90-day mortality of first-time infections between users and nonusers of proton pump inhibitors. With standard and marginal structural Cox models, we adjusted for differences in gender, age, cirrhosis aetiology, Model for End-stage Liver Disease score, serum albumin, lactulose use, severity of ascites, and history of spontaneous bacterial peritonitis or variceal bleeding. RESULTS During the follow-up, 446 patients had an infection. At inclusion, 524 patients (44%) used proton pump inhibitors, and 645 (54%) used them at some point during the follow-up. Proton pump inhibitor use increased the rate of infections overall (adjusted hazard ratio = 1.43, 95% CI 1.18-1.74), and it also increased the rate of all specific types of infections except upper respiratory tract infections of presumably viral origin. The estimated cumulative risk of infections was 36.4% for proton pump inhibitor users vs 25.1% for nonusers at 6 months (relative risk = 1.45, 95% CI 1.22-1.73), and 45.2% vs 37.7% at 1 year (relative risk = 1.20, 95% 0.97-1.40). Use of proton pump inhibitors did not affect mortality during the 90 days following infection (adjusted hazard ratio = 0.83, 95% CI 0.53-1.31). CONCLUSIONS Approximately half of patients with cirrhosis and ascites use proton pump inhibitors. This use increases their risk of bacterial infections, but does not affect their prognosis after an infection occurs.
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Affiliation(s)
- Gitte Dam
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Hendrik Vilstrup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | | | - Lars Bossen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | | | - Peter Jepsen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.,Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
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Weersink RA, Bouma M, Burger DM, Drenth JPH, Harkes-Idzinga SF, Hunfeld NGM, Metselaar HJ, Monster-Simons MH, van Putten SAW, Taxis K, Borgsteede SD. Safe use of proton pump inhibitors in patients with cirrhosis. Br J Clin Pharmacol 2018; 84:1806-1820. [PMID: 29688583 PMCID: PMC6046475 DOI: 10.1111/bcp.13615] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 04/09/2018] [Accepted: 04/10/2018] [Indexed: 12/16/2022] Open
Abstract
Aims Proton pump inhibitors (PPIs) belong to the most frequently used drugs, also in patients with cirrhosis. PPIs are extensively metabolized by the liver, but practice guidance on prescribing in cirrhosis is lacking. We aim to develop practical guidance on the safe use of PPIs in patients with cirrhosis. Methods A systematic literature search identified studies on the safety (i.e. adverse events) and pharmacokinetics of PPIs in cirrhotic patients. This evidence and data from the product information was reviewed by an expert panel who classified drugs as safe; no additional risks known; additional risks known; unsafe; or unknown. Guidance was aimed at the oral use of PPIs and categorized by the severity of cirrhosis, using the Child–Turcotte–Pugh (CTP) classification. Results A total of 69 studies were included. Esomeprazole, omeprazole and rabeprazole were classified as having ‘no additional risks known’. A reduction in maximum dose of omeprazole and rabeprazole is recommended for CTP A and B patients. For patients with CTP C cirrhosis, the only PPI advised is esomeprazole at a maximum dosage of 20 mg per day. Pantoprazole and lansoprazole were classified as unsafe because of 4‐ to 8‐fold increased exposure. The use of PPIs in cirrhotic patients has been associated with the development of infections and hepatic encephalopathy and should be carefully considered. Conclusions We suggest using esomeprazole, omeprazole or rabeprazole in patients with CTP A or B cirrhosis and only esomeprazole in patients with CTP C. Pharmacokinetic changes are also important to consider when prescribing PPIs to vulnerable, cirrhotic patients.
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Affiliation(s)
- Rianne A Weersink
- Health Base Foundation, Houten, The Netherlands.,Department of Pharmacy, Unit of Pharmacotherapy, -Epidemiology & -Economics, University of Groningen, Groningen, The Netherlands
| | - Margriet Bouma
- Department of Guideline Development, Dutch College of General Practice, Utrecht, The Netherlands
| | - David M Burger
- Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Joost P H Drenth
- Department of Gastroenterology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - S Froukje Harkes-Idzinga
- Center for Information on Medicines, Royal Dutch Pharmacists Association (KNMP), The Hague, The Netherlands
| | - Nicole G M Hunfeld
- Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands.,Department of Intensive Care, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Herold J Metselaar
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Margje H Monster-Simons
- Dutch Medicines Evaluation Board, Utrecht, The Netherlands.,Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, The Netherlands
| | | | - Katja Taxis
- Department of Pharmacy, Unit of Pharmacotherapy, -Epidemiology & -Economics, University of Groningen, Groningen, The Netherlands
| | - Sander D Borgsteede
- Health Base Foundation, Houten, The Netherlands.,Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands
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Lázaro-Pacheco IB, Servín-Caamaño AI, Pérez-Hernández JL, Rojas-Loureiro G, Servín-Abad L, Tijera FHDELA. PROTON PUMP INHIBITORS INCREASE THE OVERALL RISK OF DEVELOPING BACTERIAL INFECTIONS IN PATIENTS WITH CIRRHOSIS. ARQUIVOS DE GASTROENTEROLOGIA 2018; 55:28-32. [PMID: 29561973 DOI: 10.1590/s0004-2803.201800000-09] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/23/2017] [Accepted: 11/28/2017] [Indexed: 12/15/2022]
Abstract
BACKGROUND Acid suppression has been associated with adverse events; such as, enteric infections. Proton pump inhibitors (PPI) are frequently prescribed in patients with cirrhosis, but is unclear if PPI are associated with the development of bacterial infections in these patients. OBJECTIVE To assess the impact of PPI intake on the development of bacterial, viral and fungal infections in patients with cirrhosis. METHODS An observational, retrospective, historic cohort study. The exposed cohort included patients with cirrhosis with chronic use of PPI. The non-exposed cohort had not been using PPI. The follow-up period was 3 years, searching in the medical records for any events of bacterial infection confirmed by bacteriological culture. RESULTS One hundred and thirteen patients met the selection criteria, 44 (39%) had chronic use of PPI; of them, 28 (63.6%) patients had not a clear clinical indication to justify the prescription of PPI. Twenty four (21.2%) patients developed bacterial infections during the follow-up period. In the univariate analysis, decompensated cirrhosis (Child B/C), presence of ascites, history of variceal bleeding, and chronic consumption of PPI were risk factors related to the development of infections. But, in the adjusted multivariate analysis only the chronic use of PPI was associated with development of infections (RR=3.6; 95% CI=1.1-12.3; P=0.04). CONCLUSION There is an over-prescription of PPI without a justified clinical indication. The long-term consumption of PPI in patients with cirrhosis is associated with the development of bacterial infections; therefore these drugs must be carefully prescribed in this specific population.
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Affiliation(s)
- Illce B Lázaro-Pacheco
- Gastroenterology and Hepatology Department, Hospital General de México Dr. Eduardo Liceaga, Mexico City, Mexico
| | - Alfredo I Servín-Caamaño
- Internal Medicine Department, Hospital General de México Dr. Eduardo Liceaga, Mexico City, Mexico
| | - José L Pérez-Hernández
- The Liver Clinic´s Research Group from Gastroenterology and Hepatology Department, Hospital General de México Dr. Eduardo Liceaga, Mexico City, Mexico
| | - Gabriela Rojas-Loureiro
- Gastroenterology and Hepatology Department, Hospital General de México Dr. Eduardo Liceaga, Mexico City, Mexico
| | - Luis Servín-Abad
- Gastroenterology Department, Lakeland Regional Medical Center, United States of America
| | - Fátima Higuera-DE LA Tijera
- The Liver Clinic´s Research Group from Gastroenterology and Hepatology Department, Hospital General de México Dr. Eduardo Liceaga, Mexico City, Mexico
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Miozzo SAS, John JA, Appel-da-Silva MC, Dossin IA, Tovo CV, Mattos AA. Influence of proton pump inhibitors in the development of spontaneous bacterial peritonitis. World J Hepatol 2017; 9:1278-1285. [PMID: 29290909 PMCID: PMC5740091 DOI: 10.4254/wjh.v9.i35.1278] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Revised: 08/25/2017] [Accepted: 11/03/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate whether the use of proton pump inhibitors (PPIs) increases the incidence of spontaneous bacterial peritonitis (SBP) in patients with cirrhosis and ascites. METHODS An historical cohort study was carried out in cirrhotic outpatients with ascites followed in a specialized clinic at a tertiary hospital in Southern Brazil. Patient charts were reviewed to collect information on the variables of interest as the use of PPIs. Primary outcome was defined as development of SBP during the study period. SBP was diagnosed based on ascitic fluid polymorphonuclear cell count ≥ 250 cells/mm³ without evidence of an intra-abdominal, surgically treatable source of infection. RESULTS Of 738 cirrhotic patients, 582 (58.2% male) were enrolled, with mean age of 53.6 ± 12 years. Hepatitis C virus infection (36.2%) and alcohol abuse (25.6%) were the main etiologies of cirrhosis. The presence of ascites was detected in 299 (51.4%) patients during the development of the study. Nineteen patients with previous diagnosis of SBP undergoing secondary prophylaxis and 22 patients with insufficient PPI data were further excluded. Of 258 patients with ascites, 151 used PPIs, and 34 developed SBP (22.5%). Among 107 non-users of PPIs, 23 developed SBP (21.5%) (HR = 1.44, 95%CI: 0.85-2.47, P = 0.176). The median follow-up time of patients using PPI was 27 mo vs 32 mo for non-users. Univariate analysis of the risk factors associated with the development of SBP revealed a significant association of SPB with the severity of liver disease according to the Child-Turcotte-Pugh (CTP) score. Multivariate analysis confirmed that CTP score was the only independent variable influencing the occurrence of SBP. Survival at 60 mo (Kaplan-Meier analysis) was similar in users and non-users of PPI, independently of the presence of SBP (58.4% vs 62.7% respectively, P = 0.66). For patients with SBP, survival at 60 mo was 55.1%, vs 61.7% in patients without SBP (P = 0.34). CONCLUSION In conclusion, the rate of SBP was not significantly different in users or non-users of PPIs in this cohort of cirrhotic with ascites.
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Affiliation(s)
- Suelen A S Miozzo
- Graduate Program in Medicine, Hepatology, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre CEP 90430-080, Brazil
| | - Jorge A John
- Graduate Program in Medicine, Hepatology, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre CEP 90430-080, Brazil
| | - Marcelo C Appel-da-Silva
- Graduate Program in Medicine, Hepatology, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre CEP 90430-080, Brazil
| | - Isabella A Dossin
- Graduate Program in Medicine, Hepatology, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre CEP 90430-080, Brazil
| | - Cristiane V Tovo
- Graduate Program in Medicine, Hepatology, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre CEP 90430-080, Brazil.
| | - Angelo A Mattos
- Graduate Program in Medicine, Hepatology, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre CEP 90430-080, Brazil
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Kim JH, Lim KS, Min YW, Lee H, Min BH, Rhee PL, Kim JJ, Koh KC, Paik SW. Proton pump inhibitors do not increase the risk for recurrent spontaneous bacterial peritonitis in patients with cirrhosis. J Gastroenterol Hepatol 2017; 32:1064-1070. [PMID: 28449345 DOI: 10.1111/jgh.13637] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Revised: 10/03/2016] [Accepted: 10/27/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIM The present study aimed to assess the real impact of proton pump inhibitor (PPI) use on incidence of recurrent spontaneous bacterial peritonitis (SBP) in a homogenous population composed of cirrhotic patients with a previous SBP where differences related with SBP incidence between PPI users and non-users are less likely to exist. METHODS This retrospective cohort study enrolled 307 cirrhotic patients taking diuretics for ascites control and had a previous SBP. Patients who took any PPI for at least 1 week prior to a second SBP were included in the PPI group. The incidence of a second SBP was a primary outcome and was compared between PPI group and non-PPI group before and after propensity score matching. Risk factors for a second SBP were investigated by multivariate analysis. RESULTS Second SBP occurred in 17 patients (29.3%) during mean 52.1 ± 5.2 months of PPI group and in 60 patients (24.1%) during mean 61.9 ± 4.8 months of non-PPI group, which did not differ (P = .185). In the matched cohort, second SBP similarly occurred in both groups [29.3% of PPI group vs 26.8% of non-PPI group (P = .271)]. According to the multivariate analysis, Child-Pugh score was the only significant risk factor for a second SBP (hazard ratio 1.68, 95% confidence interval, 1.13-2.50, P = .001). Isolated bacteria and clinical outcomes such as of mortality, presence of sepsis, and hospital stay did not differ between the two groups in the matched cohort. CONCLUSION Proton pump inhibitor use is not a risk factor for recurrent SBP in cirrhotic patients.
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Affiliation(s)
- Jung Hee Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kyung Sook Lim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yang Won Min
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hyuk Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Byung-Hoon Min
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Poong-Lyul Rhee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jae J Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kwang Cheol Koh
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seung Woon Paik
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Correlation between proton pump inhibitors and risk of pyogenic liver abscess. Eur J Clin Pharmacol 2017; 73:1019-1025. [PMID: 28434021 DOI: 10.1007/s00228-017-2256-9] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Accepted: 04/18/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND/OBJECTIVE Little is known about the relationship between proton pump inhibitors use and pyogenic liver abscess. The objective of this study was to evaluate the correlation between proton pump inhibitors use and pyogenic liver abscess in Taiwan. METHODS This was a population-based case-control study using the database of the Taiwan National Health Insurance Program since 2000 to 2011. Subjects aged 20 to 84 who experienced their first episode of pyogenic liver abscess were enrolled as the case group (n = 1372). Randomly selected subjects aged 20 to 84 without pyogenic liver abscess were enrolled as the control group (n = 1372). Current use, early use, and late use of proton pump inhibitors was defined as subjects whose last one tablet for proton pump inhibitors was noted ≤30 days, between 31 to 90 days and ≥91 days before the date of admission for pyogenic liver abscess. Subjects who never received a prescription for proton pump inhibitors were defined as nonusers of proton pump inhibitors. A multivariable unconditional logistic regression model was used to measure the odds ratio and 95% confidence interval to evaluate the correlation between proton pump inhibitors use and pyogenic liver abscess. RESULTS After adjusting for confounders, the adjusted odds ratio of pyogenic liver abscess was 7.59 for subjects with current use of proton pump inhibitors (95% confidence interval 5.05, 11.4), when compared with nonusers. CONCLUSIONS Current use of proton pump inhibitors is associated with a greater risk of pyogenic liver abscess.
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Triantos C, Kalafateli M, Spantidea PI, Goukos D, Koutroumpakis E, Konstantakis C, Assimakopoulos SF, Gogos C, Mouzaki A, Daikos G, Thomopoulos K. Bacterial load and cytokine profile in patients with cirrhosis following therapy with proton pump inhibitors: a prospective cohort study. Ann Gastroenterol 2017; 30:450-456. [PMID: 28655984 PMCID: PMC5480000 DOI: 10.20524/aog.2017.0142] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Accepted: 03/08/2017] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND The aim of this study was to explore the presence of bacterial products and the cytokine profile in outpatients with cirrhosis before and after short-term (4-8 weeks) administration of proton pump inhibitors (PPIs). METHODS Seventeen patients with cirrhosis-male/female: 12/5; age: median 59.2 years (49-65); etiology: HBV±HDV 23.5%, HCV 17.7%, alcohol 41.2%, other 17.6%; Child-Pugh score: median 7.5 (5-12); Model for End-stage Liver Disease: 10.5 (7-21); ascites (%): 3 (17.7)-attending the outpatient clinics were included. None had hepatocellular carcinoma. Indications for PPIs were: esophagitis (n=6, 35.3%), peptic ulcer (n=10, 58.6%) and other (n=1, 5.9%). Bacterial DNA in serum and the levels of endotoxin, lipopolysaccharide binding protein, transforming growth factor-β, interleukin -1β, -6, -8, -12, -10, tumor necrosis factor-α and nitric oxide were assessed at baseline (time 1) and at the end of treatment (time 2). The Wilcoxon signed rank test was used to evaluate significant differences in the parameters assayed before and after PPI administration. RESULTS No patients developed infection during the study period. Bacterial DNA was not detected before or after treatment. No significant differences were observed between the concentrations of any indices between times 1 and 2 (P>0.05). Subgroup analysis according to Child-Pugh stage yielded similar results. CONCLUSION Short-term administration of PPIs had no effect on bacterial DNA, bacterial products or cytokine concentrations in patients with liver cirrhosis.
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Affiliation(s)
- Christos Triantos
- Department of Gastroenterology, University Hospital of Patras (Christos Triantos, Maria Kalafateli, Efstratios Koutroumpakis, Christos Konstantakis, Konstantinos Thomopoulos)
| | - Maria Kalafateli
- Department of Gastroenterology, University Hospital of Patras (Christos Triantos, Maria Kalafateli, Efstratios Koutroumpakis, Christos Konstantakis, Konstantinos Thomopoulos)
| | - Panagiota I. Spantidea
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras (Panagiota Spadidea, Athanasia Mouzaki)
| | - Dimitrios Goukos
- Department of Propedeutic Medicine, Laiko General Hospital, Athens (Dimitrios Goukos, Georgios Daikos)
| | - Efstratios Koutroumpakis
- Department of Gastroenterology, University Hospital of Patras (Christos Triantos, Maria Kalafateli, Efstratios Koutroumpakis, Christos Konstantakis, Konstantinos Thomopoulos)
| | - Christos Konstantakis
- Department of Gastroenterology, University Hospital of Patras (Christos Triantos, Maria Kalafateli, Efstratios Koutroumpakis, Christos Konstantakis, Konstantinos Thomopoulos)
| | - Stelios F. Assimakopoulos
- Department of Internal Medicine, University Hospital of Patras (Stelios Assimakopoulos, Charalambos Gogos), Greece
| | - Charalambos Gogos
- Department of Internal Medicine, University Hospital of Patras (Stelios Assimakopoulos, Charalambos Gogos), Greece
| | - Athanasia Mouzaki
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras (Panagiota Spadidea, Athanasia Mouzaki)
| | - Georgios Daikos
- Department of Propedeutic Medicine, Laiko General Hospital, Athens (Dimitrios Goukos, Georgios Daikos)
| | - Konstantinos Thomopoulos
- Department of Gastroenterology, University Hospital of Patras (Christos Triantos, Maria Kalafateli, Efstratios Koutroumpakis, Christos Konstantakis, Konstantinos Thomopoulos)
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de la Coba Ortiz C, Argüelles Arias F, Martín de Argila de Prados C, Júdez Gutiérrez J, Linares Rodríguez A, Ortega Alonso A, Rodríguez de Santiago E, Rodríguez-Téllez M, Vera Mendoza MI, Aguilera Castro L, Álvarez Sánchez Á, Andrade Bellido RJ, Bao Pérez F, Castro Fernández M, Giganto Tomé F. Proton-pump inhibitors adverse effects: a review of the evidence and position statement by the Sociedad Española de Patología Digestiva. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2017; 108:207-24. [PMID: 27034082 DOI: 10.17235/reed.2016.4232/2016] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION In the last few years a significant number of papers have related the use of proton-pump inhibitors (PPIs) to potential serious adverse effects that have resulted in social unrest. OBJECTIVE The goal of this paper was to provide a literature review for the development of an institutional position statement by Sociedad Española de Patología Digestiva (SEPD) regarding the safety of long-term PPI use. MATERIAL AND METHODS A comprehensive review of the literature was performed to draw conclusions based on a critical assessment of the following: a) current PPI indications; b) vitamin B12 deficiency and neurological disorders; c) magnesium deficiency; d) bone fractures; e) enteric infection and pneumonia; f) interactions with thienopyridine derivatives; e) complications in cirrhotic patients. RESULTS Current PPI indications have remained unchanged for years now, and are well established. A general screening of vitamin B12 levels is not recommended for all patients on a PPI; however, it does seem necessary that magnesium levels be measured at therapy onset, and then monitored in subjects on other drugs that may induce hypomagnesemia. A higher risk for bone fractures is present, even though causality cannot be concluded for this association. The association between PPIs and infection with Clostridium difficile is mild to moderate, and the risk for pneumonia is low. In patients with cardiovascular risk receiving thienopyridines derivatives it is prudent to adequately consider gastrointestinal and cardiovascular risks, given the absence of definitive evidence regardin potential drug-drug interactions; if gastrointestinal risk is found to be moderate or high, effective prevention should be in place with a PPI. PPIs should be cautiously indicated in patients with decompensated cirrhosis. CONCLUSIONS PPIs are safe drugs whose benefits outweigh their potential side effects both short-term and long-term, provided their indication, dosage, and duration are appropriate.
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Affiliation(s)
| | | | | | - Javier Júdez Gutiérrez
- Departamento de Gestión del Conocimiento, Sociedad Española de Patología Digestiva SEPD, España
| | | | - Aida Ortega Alonso
- UGC Enfermedades Digestivas, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, España
| | | | - Manuel Rodríguez-Téllez
- UGC Intercentros de Aparato Digestivo , Hospital Universitario Virgen de la Macarena (HUVM), España
| | | | | | - Ángel Álvarez Sánchez
- Servicio de Aparato Digestivo, Hospital Clínico San Carlos. Universidad Complutense de Madrid., España
| | - Raúl Jesús Andrade Bellido
- Unidad de Gestión Clinica de Aparato Digestivo, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, España
| | | | | | - Froilán Giganto Tomé
- Servicio de Aparato Digestivo, Hospital Universitario Central de Asturias, España
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Dam G, Vilstrup H, Watson H, Jepsen P. Proton pump inhibitors as a risk factor for hepatic encephalopathy and spontaneous bacterial peritonitis in patients with cirrhosis with ascites. Hepatology 2016; 64:1265-72. [PMID: 27474889 DOI: 10.1002/hep.28737] [Citation(s) in RCA: 133] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Accepted: 07/05/2016] [Indexed: 12/12/2022]
Abstract
UNLABELLED Proton pump inhibitors (PPIs) may be a risk factor for hepatic encephalopathy (HE) in patients with cirrhosis, possibly through translocation of gut bacteria, which can also lead to spontaneous bacterial peritonitis (SBP). We examined the associations between PPIs and development of HE or SBP in patients with cirrhosis with ascites. We used data from three 1-year trials of satavaptan for ascites control. We used Cox regression to compare HE and SBP rates between users and nonusers of PPIs. At inclusion, 39% of the 865 patients with cirrhosis with ascites used PPIs, 52% used them at some point during the follow-up, and the proportion of current users was always in the 30%-39% range. There were 189 first-time HE episodes during the follow-up, and the cumulative 1-year risk was 31% for those who used PPIs at baseline versus 25% for those who did not. The confounder-adjusted hazard ratio (HR) of HE for current PPI use versus current nonuse was 1.36 (95% confidence interval [CI], 1.01-1.84). The HR for overt HE was higher (adjusted HR = 1.88; 95% CI, 1.21-1.91). During the follow-up, 86 patients developed SBP. The adjusted HR of SBP for current PPI users versus nonusers was 1.72 (95% CI, 1.10-2.69). CONCLUSION PPIs were used by 52% of this international cirrhosis cohort during a 1-year period and was a risk factor for developing HE and SBP. These findings are consistent with the hypothesis that PPIs may increase translocation of gut bacteria. (Hepatology 2016;64:1265-1272).
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Affiliation(s)
- Gitte Dam
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
| | - Hendrik Vilstrup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | | | - Peter Jepsen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
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Huang KW, Kuan YC, Luo JC, Lin CL, Liang JA, Kao CH. Impact of long-term gastric acid suppression on spontaneous bacterial peritonitis in patients with advanced decompensated liver cirrhosis. Eur J Intern Med 2016; 32:91-5. [PMID: 27139916 DOI: 10.1016/j.ejim.2016.04.016] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Revised: 03/25/2016] [Accepted: 04/15/2016] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Recent studies have presented conflicting results on the association between gastric acid suppression and spontaneous bacterial peritonitis (SBP). The long-term effects of gastric acid suppression on SBP in cirrhotic patients remain unclear. This study evaluated the risk of SBP in advanced decompensated cirrhotic patients with long-term gastric acid suppression. METHODS Using the Taiwan National Health Insurance Research Database, we identified 4788 patients with decompensated cirrhosis from 1998 to 2011. The SBP incidence rate was compared among proton pump inhibitor (PPI), H2-receptor antagonist (H2RA), and control cohorts. Multivariate Cox proportional hazards regressions analysis was conducted to confirm the association between gastric acid suppression and SBP. RESULTS Totally, 4788 patients were analyzed: 1870 in the PPI cohort, 1728 in the H2RA cohort, and 1190 in the control cohort. The overall incidences of SBP were 16.8, 11.9, and 9.80 per 1000 person-years in the PPI, H2RA, and control cohorts, respectively. The adjusted hazard ratio (aHR) of SBP during the follow-up period was 1.16- (95% confidence interval [CI], 0.72-1.86) and 1.00-fold (95% CI, 0.63-1.57) higher in the PPI and H2RA cohorts, respectively, than in the control cohort; the result was non-significant. Compared with the control cohort, patients with >180days of PPI therapy had significantly higher risks of SBP, with an aHR of 2.28 (95% CI, 1.37-3.78). CONCLUSIONS Long-term PPI use is associated with a high risk of SBP in advanced decompensated cirrhotic patients. Well-designed prospective studies are necessary to evaluate the safety of long-term PPI use in such patients.
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Affiliation(s)
- Kuang-Wei Huang
- Division of Gastroenterology, Department of Internal Medicine, Taipei Beitou Health Management Hospital, Taipei, Taiwan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yi-Chun Kuan
- Department of Neurology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan; Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Jiing-Chyuan Luo
- Division of Gastroenterology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Cheng-Li Lin
- Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan; College of Medicine, China Medical University, Taichung, Taiwan
| | - Ji-An Liang
- Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, No. 2, Yuh-Der Road, Taichung 40447, Taiwan; Department of Radiation Oncology, China Medical University Hospital, Taichung, Taiwan
| | - Chia-Hung Kao
- Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, No. 2, Yuh-Der Road, Taichung 40447, Taiwan; Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan
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Proton pump inhibitor therapy and its association with spontaneous bacterial peritonitis incidence and mortality: A meta-analysis. Dig Liver Dis 2016; 48:353-9. [PMID: 26795544 DOI: 10.1016/j.dld.2015.12.009] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2015] [Revised: 10/26/2015] [Accepted: 12/15/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Previous meta-analyses reported proton pump inhibitor (PPI) therapy is associated with increased incidence of spontaneous bacterial peritonitis (SBP) in cirrhotic patients. However, this conclusion was based on case-control studies. Moreover, the association between PPI use and mortality of SBP has not yet been confirmed. AIMS To evaluate the association between PPI use and SBP incidence and mortality using case-control and cohort studies. METHODS We searched Medline, Embase and Web of Knowledge for relevant articles published up to January 2015. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using a random-effects model. RESULTS A total of 10 case-control and six cohort studies involving 8145 patients were analyzed. The overall analysis indicated that PPI use was associated with SBP (OR=2.11, 95% CI: 1.46-3.06). The association was limited in case-control studies (OR=2.97, 95% CI: 2.06-4.26) but not in cohort studies (OR=1.18, 95% CI: 0.99-1.14). PPI therapy was not associated with mortality during hospitalization or within 30 days after SBP (OR=1.54, 95% CI: 0.92-2.59). CONCLUSIONS We could not establish causality that PPI use increases the incidence or mortality of SBP.
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Bunchorntavakul C, Chamroonkul N, Chavalitdhamrong D. Bacterial infections in cirrhosis: A critical review and practical guidance. World J Hepatol 2016; 8:307-321. [PMID: 26962397 PMCID: PMC4766259 DOI: 10.4254/wjh.v8.i6.307] [Citation(s) in RCA: 141] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Revised: 11/23/2015] [Accepted: 01/29/2016] [Indexed: 02/06/2023] Open
Abstract
Bacterial infection is common and accounts for major morbidity and mortality in cirrhosis. Patients with cirrhosis are immunocompromised and increased susceptibility to develop spontaneous bacterial infections, hospital-acquired infections, and a variety of infections from uncommon pathogens. Once infection develops, the excessive response of pro-inflammatory cytokines on a pre-existing hemodynamic dysfunction in cirrhosis further predispose the development of serious complications such as shock, acute-on-chronic liver failure, renal failure, and death. Spontaneous bacterial peritonitis and bacteremia are common in patients with advanced cirrhosis, and are important prognostic landmarks in the natural history of cirrhosis. Notably, the incidence of infections from resistant bacteria has increased significantly in healthcare-associated settings. Serum biomarkers such as procalcitonin may help to improve the diagnosis of bacterial infection. Preventive measures (e.g., avoidance, antibiotic prophylaxis, and vaccination), early recognition, and proper management are required in order to minimize morbidity and mortality of infections in cirrhosis.
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Systematic review and meta-analysis of the possible association between pharmacological gastric acid suppression and spontaneous bacterial peritonitis. Eur J Gastroenterol Hepatol 2015; 27:1327-36. [PMID: 26313401 DOI: 10.1097/meg.0000000000000448] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Observational studies have presented conflicting results with regard to an association between gastric acid suppression and spontaneous bacterial peritonitis (SBP). Our aim was to carry out a meta-analysis investigating the possible association between the use of proton pump inhibitors or H2-receptor antagonists and SBP. METHODS We searched several databases from inception through 15 December 2014 to identify observational studies that provided data on the association of gastric acid suppression with SBP as their primary outcome, and carried out random effects meta-analyses. RESULTS Fourteen observational studies (six case-control and eight cohort) evaluating the association between proton pump inhibitors and SBP revealed a pooled odds ratio (OR) of 2.32 [95% confidence interval (CI) 1.57-3.42, I(2)=82%]. The subgroup analysis based on study design revealed a pooled OR of 2.52 (95% CI 1.71-3.71, I(2)=16%) for case-control studies, and a pooled OR of 2.18 (95% CI 1.24-3.82, I(2)=89%) for cohort studies. Sensitivity analysis including only the peer-reviewed publications in the cohort subgroup revealed a pooled OR of 1.49 (95% CI 1.15-1.95, I(2)=27%). The subgroup analysis for high-quality studies revealed a pooled OR of 1.49 (95% CI 1.19-1.88, I(2)=21%). The pooled OR for H2-receptor antagonists and SBP was 1.93 (95% CI 1.15-3.24, I(2)=0%). CONCLUSIONS There appear to be statistically significant, but quantitatively small, associations between gastric acid suppression and SBP. However, the magnitude of the possible association diminished when analysis focused on higher quality data that were more robust. Furthermore, the quality evidence in support of the association, as per the GRADE framework, was very low.
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Abstract
BACKGROUND Microbial infections are a relevant problem for patients with liver cirrhosis. Different types of bacteria are responsible for different kinds of infections: Escherichia coli and Klebsiella pneumoniae are frequently observed in spontaneous bacterial peritonitis or urinary tract infections, and Streptococcus pneumoniae and Mycoplasma pneumoniae in pulmonary infections. Mortality is up to 4-fold higher in infected patients with liver cirrhosis than in patients without infections. Key Messages: Infections in patients with liver cirrhosis are due to three major reasons: bacterial translocation, immune deficiency and an increased incidence of systemic infections. Nonparenchymal liver cells like Kupffer cells, sinusoidal endothelial cells and hepatic stellate cells are the first liver cells to come into contact with microbial products when systemic infection or bacterial translocation occurs. Kupffer cell (KC) activation by Toll-like receptor (TLR) agonists and endothelial sinusoidal dysfunction have been shown to be important mechanisms increasing portal pressure following intraperitoneal lipopolysaccharide pretreatment in cirrhotic rat livers. Reduced intrahepatic vasodilation and increased intrahepatic vasoconstriction are the relevant pathophysiological pathways. Thromboxane A2 and leukotriene (LT) C4/D4 have been identified as important vasoconstrictors. Accordingly, treatment with montelukast to inhibit the cysteinyl-LT1 receptor reduced portal pressure in cirrhotic rat livers. Clinical studies have demonstrated that activation of KCs, estimated by the amount of soluble CD163 in the blood, correlates with the risk for variceal bleeding. Additionally, intestinal decontamination with rifaximin in patients with alcohol-associated liver cirrhosis reduced the portal pressure and the risk for variceal bleeding. CONCLUSIONS TLR activation of nonparenchymal liver cells by pathogens results in portal hypertension. This might explain the pathophysiologic correlation between microbial infections and portal hypertension in patients with liver cirrhosis. These findings are the basis for both better risk stratifying and new treatment options, such as specific inhibition of TLR for patients with liver cirrhosis and portal hypertension.
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Affiliation(s)
- Christian J Steib
- Department of Medicine II, University Hospital LMU Munich, Liver Center Munich, Munich, Germany
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Lo EAG, Wilby KJ, Ensom MHH. Use of proton pump inhibitors in the management of gastroesophageal varices: a systematic review. Ann Pharmacother 2015; 49:207-19. [PMID: 25583938 DOI: 10.1177/1060028014559244] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
OBJECTIVE To review the efficacy and safety of proton pump inhibitors (PPIs) in gastroesophageal varices (GEVs). DATA SOURCES MEDLINE (1946 to September 2014), EMBASE (1974 to September 2014), International Pharmaceutical Abstracts (1970 to September 2014), Cochrane Central Register of Controlled Trials (1991 to September 2014), Google, and Google Scholar were searched using the following terms: esophageal varices, gastroesophageal varices, variceal hemorrhage, variceal bleeding, banding ligation, endoscopic variceal ligation, sclerotherapy, proton pump inhibitor, PPI, omeprazole, pantoprazole, lansoprazole, dexlansoprazole, rabeprazole, and esomeprazole. STUDY SELECTION AND DATA EXTRACTION Published and unpublished studies evaluating the clinical outcomes of PPI use for GEVs were included regardless of study design. Non-English and nonhuman studies were excluded. DATA SYNTHESIS Of 1156 studies, 20 were included after assessment. There was wide methodological heterogeneity and moderately high risk of bias among studies. Level I evidence suggests that PPIs reduce esophageal ulcer size post-elective esophageal ligation; the clinical importance of such findings is not known given the self-limiting nature of esophageal ulcer. Available evidence does not support a role of PPIs for long-term prophylaxis of portal hypertension-related bleeding and high-dose infusion for acute management of GEV hemorrhage. Retrospective data demonstrate a potential increase in the incidence of spontaneous bacterial peritonitis in patients with cirrhosis receiving PPIs. CONCLUSIONS The best available evidence supports the use of short-course (10 days) PPI post-endoscopic variceal ligation to reduce ulcer size if ulcer healing is a concern. Practices such as high-dose infusion and prolonged use should be discouraged until evidence of benefit becomes available.
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Affiliation(s)
- Elaine A G Lo
- University of British Columbia, Vancouver, British Columbia, Canada
| | | | - Mary H H Ensom
- University of British Columbia, Vancouver, British Columbia, Canada Children's and Women's Health Centre of British Columbia, Vancouver, British Columbia, Canada
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Chang SS, Lai CC, Lee MTG, Lee YC, Tsai YW, Hsu WT, Lee CC. Risk of spontaneous bacterial peritonitis associated with gastric Acid suppression. Medicine (Baltimore) 2015; 94:e944. [PMID: 26039135 PMCID: PMC4616349 DOI: 10.1097/md.0000000000000944] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
The primary objective of this study was to determine the association between the use of gastric acid suppressants (GAS) and the risk of developing spontaneous bacterial peritonitis (SBP) in patients with advanced liver cirrhosis (LC). A case-control study nested within a cohort of 480,000 representatives of Taiwan National Health Insurance beneficiaries was carried out. A case was matched with 100 controls on age, gender, and index date of SBP diagnosis. GAS use was identified from the 1-year period before the index date. Conditional logistic regression analysis was used to adjust for various unbalanced covariates between users and nonusers of GAS. A total of 947 cases of SBP were identified among the 86,418 patients with advanced LC. A significant increased risk of developing SBP was found to be associated with current (within 30 days), and recent (within 30-90 day) use of 2 different classes of GAS: proton pump inhibitors (PPIs) and histamine 2 receptor antagonists (H2RAs). The confounder adjusted rate ratio (aRR) for the current use of PPIs was 2.77 (95% CI: 1.90-4.04) and H2RAs was 2.62 (95% CI: 2.00-3.42). The risk of SBP attenuated for the recent use of PPIs (aRR: 2.20, 95%CI: 1.60-3.02) or H2RAs (aRR: 1.72, 95% CI: 1.25-2.37). In addition, sensitivity analysis using hospitalized SBP as the primary outcome showed a similar risk for the current use of PPIs (aRR, 3.24; 95% CI: 2.08-5.05) and H2RAs (aRR 2.43; 95% CI 1.71-3.46). Furthermore, higher cumulative days of gastric acid suppression were associated with a higher risk of SBP (trend P < 0.0001). To conclude, exposure to GAS was associated with an increased risk of SBP in patients with advanced LC. The association was more pronounced in current PPI users compared with nonusers.
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Affiliation(s)
- Shy-Shin Chang
- From the Department of Family Medicine, Chang Gung Memorial Hospital, Linkou, (S-SC, Y-CL, Y-WT); Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan City (S-SC); Chang Gung University College of Medicine, Taoyuan City (S-SC, Y-CL, Y-WT); Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying Dis., Tainan City (C-CLai); Department of Emergency Medicine, National Taiwan University Hospital, Taipei City (M-tGL, W-TH, C-CLee); and Department of Emergency Medicine and General Medicine, National Taiwan University Hospital Yunlin Branch, Douliou, Taiwan (R.O.C.) (C-CLee)
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Terg R, Casciato P, Garbe C, Cartier M, Stieben T, Mendizabal M, Niveyro C, Benavides J, Marino M, Colombato L, Berbara D, Silva M, Salgado P, Barreyro F, Fassio E, Gadano A. Proton pump inhibitor therapy does not increase the incidence of spontaneous bacterial peritonitis in cirrhosis: a multicenter prospective study. J Hepatol 2015; 62:1056-60. [PMID: 25481567 DOI: 10.1016/j.jhep.2014.11.036] [Citation(s) in RCA: 92] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2013] [Revised: 11/11/2014] [Accepted: 11/24/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIM Retrospective studies show an association between proton pump inhibitor (PPI) therapy and spontaneous bacterial peritonitis (SBP). We investigate the relationship between PPI and SBP in decompensated cirrhotic patients in a large nationwide prospective study. METHODS Seven hundred seventy patients with a diagnosis of decompensated cirrhosis were admitted consecutively in 23 hospitals in Argentina from March 2011 to April 2012; the patients were carefully investigated for PPI consumption in the previous 3 months. In total, 251 patients were excluded because of active gastrointestinal hemorrhage, antibiotic use during the preceding weeks, HIV-positive status and immunosuppressive therapy. RESULTS Two hundred twenty-six out of 519 patients (43.5%) had received PPI therapy within the last 3 months. In 135 patients, PPIs were administered for longer than 2 weeks. A bacterial infection was shown in 255 patients (49.1%). SBP was diagnosed in 95 patients out of 394 patients with ascites (24.7%). There was no significant difference in the rate of PPI consumption between the infected and the non-infected patients (44.3% vs. 42.8%) or between the SBP patients and the patients with ascites without SBP (46% vs. 42%). In the SBP patients, the duration of PPI administration did not influence the rate of SBP occurrence. The type of bacteria and the origin of SBP infection were similar in the patients with and without PPI. CONCLUSION In the current large, multicenter, prospective study, PPI therapy, specifically evaluated at admission of consecutive cirrhotic patients, was not associated with a higher risk of SBP.
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Affiliation(s)
- Rubén Terg
- Hospital Bonorino Udaondo, Buenos Aires, Argentina
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Wu D, Qiu T, Zhang Q, Kang H, Yuan S, Zhu L, Zhu R. Systematic toxicity mechanism analysis of proton pump inhibitors: an in silico study. Chem Res Toxicol 2015; 28:419-30. [PMID: 25626140 DOI: 10.1021/tx5003782] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Proton pump inhibitors (PPIs) are extensively used for the treatment of gastric acid-related disorders. PPIs appear to be well tolerated and almost have no short-term side effects. However, the clinical adverse reactions of long-term PPI usage are increasingly reported in recent years. So far, there is no study that elucidates the side effect mechanisms of PPIs comprehensively and systematically. In this study, a well-defined small molecule perturbed microarray data set of 344 compounds and 1695 samples was analyzed. With this high-throughput data set, a new index (Identity, I) was designed to identify PPI-specific differentially expressed genes. Results indicated that (1) up-regulated genes, such as RETSAT, CYP1A1, CYP1A2, and UGT, enhanced vitamin A's metabolism processes in the cellular retinol metabolism pathway; and that (2) down-regulated genes, such as C1QA, C1QC, C4BPA, C4BPB, CFI, and SERPING1, enriched in the complement and coagulation cascades pathway. In addition, strong association was observed between these PPI-specific differentially expressed genes and the reported side effects of PPIs by the gene-disease association network analysis. One potential toxicity mechanism of PPIs as suggested from this systematic PPI-specific gene expression analysis is that PPIs are enriched in acidic organelles where they are activated and inhibit V-ATPases and acid hydrolases, and consequently block the pathways of antigen presentation, the synthesis and secretion of cytokines, and complement component proteins and coagulation factors. The strategies developed in this work could be extended to studies on other drugs.
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Affiliation(s)
- Dingfeng Wu
- Department of Bioinformatics, Tongji University , Shanghai, P.R. China
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Merli M, Lucidi C, Di Gregorio V, Giannelli V, Giusto M, Ceccarelli G, Riggio O, Venditti M. The chronic use of beta-blockers and proton pump inhibitors may affect the rate of bacterial infections in cirrhosis. Liver Int 2015; 35:362-9. [PMID: 24836902 DOI: 10.1111/liv.12593] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2014] [Accepted: 05/11/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Bacterial infections are among the most common and life-threatening complications in cirrhosis. Qualitative and quantitative modifications of the gut microbiota, dysfunction of the intestinal barrier and multiple immune defects are factors that contribute to a pathological 'bacterial translocation' (BT), leading to a higher susceptibility to infections in cirrhotic patients. Long-term therapies, commonly adopted in cirrhotic patients, may influence BT and modify the risk of infection in these patients. To investigate the influence of chronic therapies on the prevalence and microbiological characteristics of infections in cirrhosis. METHODS Consecutive cirrhotic patients hospitalised from 2008 to 2013 were enrolled. All previous treatments were carefully recorded. Infections were actively sought out, patients were actively monitored for infection, and possible risk factors were evaluated. RESULTS Four hundred cirrhotic patients were included. The most frequent therapies were proton pump inhibitors (PPIs) (67%), non-absorbable-disaccharides (44%), beta-blockers (BBs) (39%) and non-absorbable-antibiotics (10%). Child-Pugh C (P < 0.001; OR 5; 95%CI: 2.6-9.9) and PPI therapy (P = 0.008; OR 2; 95% CI: 1.2-3.2) were found to be independent predictors of infection, and the use of BBs was a protective factor (P = 0.001; OR 0.46; 95%CI: 0.3-0.7). Cirrhotic patients with bacterial infection showed lower morbidity and mortality when taking BBs. CONCLUSIONS Proton pump inhibitors increase the risk of infection in cirrhosis and should not be prescribed in these patients without specific indications. In contrast, the use of BBs is associated with a lower rate of infection and attenuates the consequences of infections in cirrhotic patients.
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Affiliation(s)
- Manuela Merli
- Gastroenterology, Department of Clinical Medicine, 'Sapienza' University of Rome, Rome, Italy
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Proton pump inhibitor intake neither predisposes to spontaneous bacterial peritonitis or other infections nor increases mortality in patients with cirrhosis and ascites. PLoS One 2014; 9:e110503. [PMID: 25369194 PMCID: PMC4219684 DOI: 10.1371/journal.pone.0110503] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2014] [Accepted: 09/14/2014] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND AND AIM The aim of this study was to assess the impact of proton pump inhibitor (PPI) intake on the development of spontaneous bacterial peritonitis (SBP) or other infections, as well as on mortality, in a thoroughly documented cohort of patients with cirrhosis and ascites. PATIENTS AND METHODS We performed a retrospective analysis of follow-up data from 607 consecutive patients with cirrhosis undergoing their first paracentesis at a tertiary center. A binary logistic regression model investigating the association between PPI intake and SBP at the first paracentesis was calculated. Competing risk analyses and Cox models were used to investigate the effect of PPIs on the cumulative incidence of SBP or other infections and transplant-free survival, respectively. Adjustments were made for age, hepatocellular carcinoma, history of variceal bleeding, varices and model of end-stage liver disease score. RESULTS Eighty-six percent of patients were receiving PPIs. After adjusting for potential confounding factors, PPI intake was neither associated with increased SBP prevalence at the first paracentesis (odds ratio (OR):1.11,95% confidence interval (95%CI):0.6-2.06; P = 0.731) nor cumulative incidence of SBP (subdistribution hazard ratio (SHR): 1.38; 95%CI:0.63-3.01; P = 0.42) and SBP or other infections (SHR:1.71; 95%CI:0.85-3.44; P = 0.13) during follow-up. Moreover, PPI intake had no impact on transplant-free survival in both the overall cohort (hazard ratio (HR):0.973,95%CI:0.719-1.317; P = 0.859) as well as in the subgroups of patients without SBP (HR:1.01,95%CI:0.72-1.42; P = 0.971) and without SBP or other infections at the first paracentesis (HR:0.944,95%CI:0.668-1.334; P = 0.742). CONCLUSIONS The proportion of cirrhotic patients with PPI intake was higher than in previous reports, suggesting that PPI indications were interpreted liberally. In our cohort with a particularly high prevalence of PPI intake, we observed no association between PPIs and SBP or other infections, as well as mortality. Thus, the severity of liver disease and other factors, rather than PPI treatment per se may predispose for infectious complications.
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Moreau R. The burden of extended-spectrum β-lactamase-producing Enterobacteriaceae in patients with cirrhosis. Hepatol Int 2014. [DOI: 10.1007/s12072-014-9567-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Min YW, Lim KS, Min BH, Gwak GY, Paik YH, Choi MS, Lee JH, Kim JJ, Koh KC, Paik SW, Yoo BC, Rhee PL. Proton pump inhibitor use significantly increases the risk of spontaneous bacterial peritonitis in 1965 patients with cirrhosis and ascites: a propensity score matched cohort study. Aliment Pharmacol Ther 2014; 40:695-704. [PMID: 25078671 DOI: 10.1111/apt.12875] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Revised: 05/28/2014] [Accepted: 06/23/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND The risk of spontaneous bacterial peritonitis (SBP) associated with proton pump inhibitor (PPI) use has been raised in cirrhotic patients with ascites. However, this is based on case-control studies, often with a small series. AIM To determine whether PPI use increases the risk of SBP using a large cohort. METHODS This retrospective cohort study included 1965 cirrhotic patients with ascites diagnosed between January 2005 and December 2009. The SBP incidence rate was compared between the PPI and non-PPI groups before and after propensity score matching to reduce the effect of selection bias and potential confounders. Multivariate analysis was conducted to confirm the association of PPI use with SBP. RESULTS After excluding 411 patients, 1554 were analysed. Among them, 512 patients (32.9%) were included in the PPI group. The annual SBP incidence rate was higher in the PPI group than in the non-PPI group (10.6% and 5.8%, P = 0.002) before matching. Indications for PPI use and dose of PPI were similar between patients with and without SBP. In the propensity score matched cohort (402 pairs), the SBP incidence rate was also higher in the PPI group than in the non-PPI group (10.8% vs. 6.0%, P = 0.038). Multivariate analysis revealed that PPI use (Hazard ratio 1.396; 95% confidence interval, 1.057-1.843; P = 0.019) was the independent risk factor for SBP. CONCLUSIONS Proton pump inhibitor use significantly increases the risk of spontaneous bacterial peritonitis in cirrhotic patients with ascites. Proton pump inhibitor use should be undertaken with greater caution and appropriately in patients with cirrhosis.
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Affiliation(s)
- Y W Min
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Association between proton pump inhibitor use and spontaneous bacterial peritonitis in cirrhotic patients with ascites. Can J Gastroenterol Hepatol 2014; 28:330-4. [PMID: 24945188 PMCID: PMC4072237 DOI: 10.1155/2014/751921] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND There are data suggesting a link between proton pump inhibitor (PPI) use and the development of spontaneous bacterial peritonitis (SBP) in cirrhotic patients with ascites; however, these data are controversial. OBJECTIVE To assess whether the use of PPIs in cirrhotic patients with ascites is associated with an increased risk for SBP. METHODS A retrospective case-control study (June 2004 to June 2010) was conducted at the Centre Hospitalier de l'Université de Montréal in Montreal, Quebec. Fifty-one cirrhotic patients admitted with paracentesis-proven SBP (≥250 neutrophils/mm3), occurring within seven days of hospital admission, met the inclusion criteria. These patients were matched 1:2 (for age, Child-Pugh class and year of admission) with 102 comparable cirrhotic patients with ascites who were admitted for conditions other than SBP. RESULTS Patients with SBP had a significantly higher rate of pre-hospital PPI use (60.8%) compared with cirrhotic patients without SBP (42.2%; P=0.03). On multivariate analysis, PPI use was the only factor independently associated with SBP (OR 2.09 [95% CI 1.04 to 4.23]; P=0.04). Thirty-five (35%) patients in both groups had no documented indication for PPI use in their charts. Forty-five percent of the remaining cirrhotic patients with SBP had an inappropriate indication, as defined in the protocol, for PPI use compared with 25% of controls. CONCLUSIONS Cirrhotic patients with SBP were twice as likely to have taken PPIs than patients without SBP. These findings reinforce the association between PPI use and SBP observed in other studies. A high percentage of cirrhotic patients were taking a PPI without any documented indication.
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Lin ZN, Zuo YQ, Hu P. Association of Proton Pump Inhibitor Therapy with Hepatic Encephalopathy in Hepatitis B Virus-related Acute-on-Chronic Liver Failure. HEPATITIS MONTHLY 2014; 14:e16258. [PMID: 24748895 PMCID: PMC3989600 DOI: 10.5812/hepatmon.16258] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Revised: 01/20/2014] [Accepted: 02/14/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND Hepatic encephalopathy (HE) is an important neuropsychiatry complication of acute-on-chronic liver failure (ACLF). PPI therapy may increase the intestinal bacterial overgrowth and infections. OBJECTIVES The aim of this study was to assess whether PPI use in ACLF is associated with HE. PATIENTS AND METHODS A retrospective case-control study was performed. Fifty five admitted patients with hepatitis B virus (HBV)-related ACLF complicated by Stage II-IV HE developed after admission between January 2008 and December 2012 were matched (by sex, age, and MELD score) with comparable HBV-related ACLF patients (n = 110) who did not develop this complication during hospitalization. We excluded combined HE upon admission and other neurological disorders in patients with ACLF. Univariate and multivariate analyses of 30 variables (laboratory examination, predisposition, treatment, etc.) before the occurrence of HE were carried out to identify the factors predictive of HE. RESULTS In univariate analysis, patients with HE in ACLF had a significantly higher rate of PPI use (89.1%) compared with non-HE (63.6%, P = 0.001). In addition, clinical and standard laboratory variables were significantly different between the two groups regarding the infection rate, hyponatremia, alpha-fetoprotein (AFP), Arginine Hydrochloride use and Lactulose use. Logistic regression analysis was used to examine the combined effects of the variables with HE as the outcome. HE in ACLF was associated with hyponatremia (odds ratio (OR) = 6. 318, 95% confidence interval (CI) = 2. 803-14.241; P = 0. 000), PPI use was independently associated with HE (OR = 4. 392, CI = 1. 604-12.031; P = 0. 004), and lactulose use was protective (OR = 0. 294, CI = 0. 136-0.675; P = 0. 003). CONCLUSIONS The occurrence of HE is associated with hyponatremia and PPI use in patients with ACLF.
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Affiliation(s)
- Zhao-Ni Lin
- Department of Infectious Diseases, Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yong-Qing Zuo
- Department of Infectious Diseases, Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Peng Hu
- Department of Infectious Diseases, Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Corresponding Author: Peng Hu, Department of Infectious Diseases, Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China. Tel: +86-2363693289, Fax: +86-2363703790, E-mail:
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Kwon JH, Koh SJ, Kim W, Jung YJ, Kim JW, Kim BG, Lee KL, Im JP, Kim YJ, Kim JS, Yoon JH, Lee HS, Jung HC. Mortality associated with proton pump inhibitors in cirrhotic patients with spontaneous bacterial peritonitis. J Gastroenterol Hepatol 2014; 29:775-81. [PMID: 24219827 DOI: 10.1111/jgh.12426] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/01/2013] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM The aims of this study were to investigate whether acid suppressive therapy increases the risk of spontaneous bacterial peritonitis (SBP) and to define factors associated with mortality in cirrhotic patients with SBP. METHODS Cirrhotic patients who had undergone paracentesis after hospitalization were included. Those patients were divided into two groups according to the presence or absence of SBP. Factors associated with the development of SBP were analyzed. Mortality rates during hospitalization or within 30 days after SBP and the factors associated with mortality were also analyzed. RESULTS A total of 1140 patients (median age, 62; men, 75%; model for end-stage liver disease [MELD] score, 17) were included. Five hundred thirty-three patients were identified as having SBP. In the logistic regression, the use of histamine-2 receptor antagonists, the use of proton pump inhibitors (PPIs), a high admission MELD score, and old age were associated with the development of SBP. The use of PPIs within 30 days (adjusted odds ratio [aOR] 1.960; 95% confidence interval [CI] 1.190-3.227; P = 0.008), a higher admission MELD score (aOR 1.054; 95% CI 1.032-1.076; P < 0.001), and hepatocellular carcinoma (aOR 1.852; 95% CI 1.256-2.730; P = 0.002) were associated with mortality after SBP. CONCLUSIONS Acid suppressive therapy is associated with the development of SBP in cirrhotic patients with ascites. The use of PPIs is associated with mortality after SBP independent of the severity of the underlying liver disease in our retrospective cohort study.
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Affiliation(s)
- Jee Hye Kwon
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Corleto VD, Festa S, Di Giulio E, Annibale B. Proton pump inhibitor therapy and potential long-term harm. Curr Opin Endocrinol Diabetes Obes 2014; 21:3-8. [PMID: 24310148 DOI: 10.1097/med.0000000000000031] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
PURPOSE OF REVIEW This review summarizes the recent literature on the potential side-effects of proton pump inhibitors (PPIs) and known interactions with the metabolism/absorption of other drugs. RECENT FINDINGS Data confirm that PPIs are a very well tolerated drug class. Their high safety, efficacy and wide distribution lead to overuse, inappropriate dosage or excessive duration of treatment. Despite the absorption of micronutrients or other plausible effects on the development of bacterial infections linked to PPI-induced hypochlorhydria, it is difficult to demonstrate an association between PPI and specific symptoms. A possible negative effect of PPIs on bone integrity appears weak, but hypomagnesemia is likely a PPI drug class effect. A higher risk of Clostridium difficile infection and other infectious diseases such as small intestinal bacterial overgrowth and spontaneous bacterial peritonitis remain controversial in PPI users. However, the careful use of PPIs in cirrhotic or otherwise fragile patients is mandatory. Short-term or long-term PPI use may trigger microscopic colitis, and the management of this condition may include PPI withdrawal. The effect of PPIs on stimulating exocrine or endocrine gastric cell proliferation is poorly understood. A diagnostic delay or masking of diseases such as gastrinoma is difficult to evaluate. SUMMARY Short-term standard dose PPI treatment is low risk. Long-term PPI use may complicate health conditions by various mechanisms linked to PPIs and/or to hypochlorhydria.
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Affiliation(s)
- Vito Domenico Corleto
- aDepartment of Gastroenterology and Digestive Endoscopy, School of Medicine and Psychology, Sapienza University of Rome, Sant'Andrea Hospital bCentro Ricerche S. Pietro, Ospedale S. Pietro, Rome, Italy
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Miura K, Tanaka A, Yamamoto T, Adachi M, Takikawa H. Proton pump inhibitor use is associated with spontaneous bacterial peritonitis in patients with liver cirrhosis. Intern Med 2014; 53:1037-42. [PMID: 24827481 DOI: 10.2169/internalmedicine.53.2021] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
OBJECTIVE Accumulating evidence suggests that the use of proton pump inhibitors (PPIs) is associated with spontaneous bacterial peritonitis (SBP) in cirrhotic patients, although the results are inconsistent. We aimed to examine whether PPI use is associated with SBP in Japan, where the administration of PPIs is strictly regulated. METHODS In this single-center retrospective study, we reviewed 65 patients with liver cirrhosis who were admitted between January 2008 and January 2013 due to ascites. The administration of any PPI for at least one week prior to admission was regarded as PPI use. RESULTS Eighteen cirrhotic patients with SBP and 47 without SBP were identified. Both the serum bilirubin levels and international normalized ratio (INR) values were significantly elevated in the patients with SBP (p=0.007, 0.002). The model for end-stage liver disease scores (mean±SD) were 16.1±9.9 and 12.5±9.3 in those with and without SBP (p=0.009), respectively. PPIs were used in 16 out 18 in patients with SBP and 27 of 47 patients without SBP (p=0.002). A multivariate analysis identified INR (odds ratio (OR)=15.3, 95% CI 2.96-76.9, p=0.001) and PPI use (OR=6.41, 95% CI=1.16-35.7, p=0.033) to be independent risk factors for SBP. CONCLUSION The use of PPIs in cirrhotic patients with ascites is independently associated with SBP in the Japanese clinical setting.
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Affiliation(s)
- Kotaro Miura
- Department of Medicine, Teikyo University School of Medicine, Japan
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Tang RSY, Wu JCY. Managing peptic ulcer and gastroesophageal reflux disease in elderly Chinese patients--focus on esomeprazole. Clin Interv Aging 2013; 8:1433-43. [PMID: 24187492 PMCID: PMC3810197 DOI: 10.2147/cia.s41350] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Peptic ulcer disease (PUD) and gastroesophageal reflux disease (GERD) are not uncommon in elderly patients. Clinical presentations of these acid-related disorders may be atypical in the geriatric population. Older individuals are at increased risk for poor outcomes in complicated PUD and for development of GERD complications. Multiple risk factors (eg, Helicobacter pylori [HP], use of nonsteroidal anti-inflammatory drugs [NSAIDs], aspirin) contribute to the development of PUD. Recent data has shown that HP-negative, NSAID-negative idiopathic peptic ulcers are on the rise and carry a higher risk of recurrent ulcer bleeding and mortality. Effective management of PUD in the geriatric population relies on identification and modification of treatable risk factors. Elderly patients with GERD often require long-term acid suppressive therapy. Proton pump inhibitors (PPI) including esomeprazole are effective in the treatment of reflux esophagitis, maintenance of GERD symptomatic control, and management of PUD as well as its complications. Potential safety concerns of long-term PPI use have been reported in the literature. Clinicians should balance the risks and benefits before committing elderly patients to long-term PPI therapy.
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Affiliation(s)
- Raymond S Y Tang
- Institute of Digestive Disease, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong
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de Vos M, De Vroey B, Garcia BG, Roy C, Kidd F, Henrion J, Deltenre P. Role of proton pump inhibitors in the occurrence and the prognosis of spontaneous bacterial peritonitis in cirrhotic patients with ascites. Liver Int 2013; 33:1316-23. [PMID: 23730823 DOI: 10.1111/liv.12210] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2012] [Accepted: 05/05/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND Proton pump inhibitors (PPIs) facilitate intestinal bacterial translocation. No robust data exist demonstrating that PPIs increase the risk of spontaneous bacterial peritonitis (SBP) and that PPIs worsen the prognosis of SBP patients. PPI use might be unsuitable for cirrhotic patients. AIMS To analyse: (i) the role of PPIs in the occurrence of SBP in cirrhotic patients; (ii) their impact on the prognosis of SBP patients; and (iii) the suitability of their use. METHODS In this retrospective case-control study, PPI use was first assessed in cirrhotic patients consecutively admitted with SBP (group I) and in a control group that included the same number of uninfected cirrhotic patients with ascites (group II). Afterwards, the impact of PPIs on SBP was assessed in group I by comparing survival of patients with and without PPIs. RESULTS A total of 102 patients were included, 51 in each group. (i) SBP patients were more frequently treated by PPIs than controls (49 vs. 25%, P = 0.014). (ii) In group I, patients with (n = 25) and without (n = 26) PPIs had similar survival rates at 1 month (64.0 ± 9.6% vs. 59.4 ± 10.0%), 3 months (41.2 ± 10.2% vs. 44.6 ± 10.6%), and 1 year (26.6 ± 9.6% vs. 28.9 ± 10.1%), and similar median age at death (53 vs. 57 years). (iii) The reason for PPI use was inappropriate or undocumented in 34% of group I and II. CONCLUSIONS Proton pump inhibitors were more frequently used in SBP patients than in controls, but did not influence the prognosis in SBP. Overuse of PPIs was encountered in one-third of cirrhotic patients and should be avoided.
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Affiliation(s)
- Marie de Vos
- Service d'Hépato-Gastroentérologie, Hôpital de Jolimont, Haine-Saint-Paul, Belgium
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Johnson DA, Oldfield EC. Reported side effects and complications of long-term proton pump inhibitor use: dissecting the evidence. Clin Gastroenterol Hepatol 2013; 11:458-e38. [PMID: 23247326 DOI: 10.1016/j.cgh.2012.11.031] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2012] [Revised: 11/27/2012] [Accepted: 11/27/2012] [Indexed: 02/07/2023]
Affiliation(s)
- David A Johnson
- Gastroenterology Division, Department of Medicine, Eastern Virginia Medical School, Norfolk, Virginia 23505, USA.
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41
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Deshpande A, Pasupuleti V, Thota P, Pant C, Mapara S, Hassan S, Rolston DDK, Sferra TJ, Hernandez AV. Acid-suppressive therapy is associated with spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis. J Gastroenterol Hepatol 2013. [PMID: 23190338 DOI: 10.1111/jgh.12065] [Citation(s) in RCA: 100] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM Proton pump inhibitors (PPI) and H(2) -receptor antagonists (H2RA) are frequently prescribed in hospitalized patients with cirrhosis. There are conflicting reports regarding the role of acid-suppressive therapy in predisposing hospitalized patients with cirrhosis to spontaneous bacterial peritonitis (SBP). The aim of this meta-analysis was to evaluate the association between acid-suppressive therapy and the risk of SBP in hospitalized patients with cirrhosis. METHODS We searched MEDLINE and four other databases for subject headings and text words related to SBP and acid-suppressive therapy. All observational studies that investigated the risk of SBP associated with PPI/H2RA therapy and utilized SBP as an endpoint were considered eligible. Data from the identified studies were combined by means of a random-effects model and odds ratios (ORs) were calculated. RESULTS Eight studies (n = 3815 patients) met inclusion criteria. The risk of hospitalized cirrhotic patients developing SBP increased when using acid-suppressive therapy. The risk was greater with PPI therapy (n = 3815; OR 3.15, 95% confidence interval 2.09-4.74) as compared to those on H2RA therapy (n = 562; OR 1.71, 95% confidence interval 0.97-3.01). CONCLUSIONS Pharmacologic acid suppression was associated with a greater risk of SBP in hospitalized patients with cirrhosis. Cirrhotic patients receiving a PPI have approximately three times the risk of developing SBP compared with those not receiving this medication. Prospective studies may help clarify this relationship and shed light on the mechanism(s) by which acid-suppressive therapy increases the risk of SBP in hospitalized patients with cirrhosis.
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Affiliation(s)
- Abhishek Deshpande
- Department of Medicine, Division of Infectious Diseases, Case Western Reserve University, Cleveland, Ohio 44106-4984, USA.
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Pleguezuelo M, Benitez JM, Jurado J, Montero JL, De la Mata M. Diagnosis and management of bacterial infections in decompensated cirrhosis. World J Hepatol 2013; 5:16-25. [PMID: 23383362 PMCID: PMC3562722 DOI: 10.4254/wjh.v5.i1.16] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2012] [Revised: 08/29/2012] [Accepted: 11/25/2012] [Indexed: 02/06/2023] Open
Abstract
Bacterial infections are one of the most frequent complications in cirrhosis and result in high mortality rates. Patients with cirrhosis have altered and impaired immunity, which favours bacterial translocation. Episodes of infections are more frequent in patients with decompensated cirrhosis than those with compensated liver disease. The most common and life-threatening infection in cirrhosis is spontaneous bacterial peritonitis followed by urinary tract infections, pneumonia, endocarditis and skin and soft-tissue infections. Patients with decompensated cirrhosis have increased risk of developing sepsis, multiple organ failure and death. Risk factors associated with the development of infections are severe liver failure, variceal bleeding, low ascitic protein level and prior episodes of spontaneous bacterial peritonitis (SBP). The prognosis of these patients is closely related to a prompt and accurate diagnosis. An appropriate treatment decreases the mortality rates. Preventive strategies are the mainstay of the management of these patients. Empirical antibiotics should be started immediately following the diagnosis of SBP and the first-line antibiotic treatment is third-generation cephalosporins. However, the efficacy of currently recommended empirical antibiotic therapy is very low in nosocomial infections including SBP, compared to community-acquired episodes. This may be associated with the emergence of infections caused by Enterococcus faecium and extended-spectrum β-lactamase-producing Enterobacteriaceae, which are resistant to the first line antimicrobial agents used for treatment. The emergence of resistant bacteria, underlines the need to restrict the use of prophylactic antibiotics to patients with the greatest risk of infections. Nosocomial infections should be treated with wide spectrum antibiotics. Further studies of early diagnosis, prevention and treatment are needed to improve the outcomes in patients with decompensated cirrhosis.
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Affiliation(s)
- Maria Pleguezuelo
- Maria Pleguezuelo, Jose Manuel Benitez, Juan Jurado, Jose Luis Montero, Manuel De la Mata, Liver Research Unit, Reina Sofia University Hospital, Avda Menendez Pidal s/n, 14004 Cordoba, Spain
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Terg R. Spontaneous bacterial peritonitis and pharmacologic acid suppression in patients with cirrhosis. Hepatology 2013; 57:411-3. [PMID: 23297071 DOI: 10.1002/hep.26098] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Revised: 10/02/2012] [Accepted: 10/04/2012] [Indexed: 12/07/2022]
Affiliation(s)
- Ruben Terg
- Universidad del Salvador Hospital de Gastroenterología Bonorino Udaondo, Buenos Aires, Argentina
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44
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Siple JF, Morey JM, Gutman TE, Weinberg KL, Collins PD. Proton pump inhibitor use and association with spontaneous bacterial peritonitis in patients with cirrhosis and ascites. Ann Pharmacother 2012; 46:1413-8. [PMID: 23032651 DOI: 10.1345/aph.1r174] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE To evaluate the literature regarding the efficacy and safety of proton pump inhibitors (PPIs) when they are used in patients with cirrhosis and ascites. DATA SOURCES A literature search was conducted using MEDLINE (1966-May 2012) and Web of Science (1990-May 2012) with the terms proton pump inhibitor, antisecretory therapy, cirrhosis, ascites, spontaneous bacterial peritonitis, and Clostridium difficile. The search was restricted to articles published in English on the use of PPIs in humans. Reference citations from identified published articles were reviewed for relevant information. STUDY SELECTION AND DATA EXTRACTION All articles in English identified from the data sources were evaluated for inclusion. One case series, 8 retrospective case-control trials, and 1 meta-analysis were identified. DATA SYNTHESIS Cirrhosis may cause complications such as portal hypertension, esophageal varices, and ascites. Patients may be prescribed PPIs without clear indications or because of their propensity to develop upper gastrointestinal symptoms and bleeding. However, gastric acidity is a major nonspecific defense mechanism and there is insufficient evidence on the need for chronic acid suppression in patients with cirrhosis. It is postulated that the portal hypertensive environment in cirrhosis and the acid suppression from PPIs can increase the risk of spontaneous bacterial peritonitis and C. difficile infection in patients with cirrhosis with ascites. Several retrospective studies and 1 meta-analysis have confirmed this association. CONCLUSIONS Patients with cirrhosis and ascites should be monitored carefully while on PPIs for a possible increased risk of infection from spontaneous bacterial peritonitis and C. difficile. Prospective randomized trials are needed to confirm this association. Clinicians should be aware of this lesser known adverse effect of PPIs.
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Affiliation(s)
- Jolene F Siple
- Vancouver Primary Care, Portland Veterans Affairs Medical Center, WA, USA.
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45
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van Vlerken LG, Huisman EJ, van Hoek B, Renooij W, de Rooij FWM, Siersema PD, van Erpecum KJ. Bacterial infections in cirrhosis: role of proton pump inhibitors and intestinal permeability. Eur J Clin Invest 2012; 42:760-7. [PMID: 22288900 DOI: 10.1111/j.1365-2362.2011.02643.x] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Cirrhotic patients are at considerable risk for bacterial infections, possibly through increased intestinal permeability and bacterial overgrowth. Proton pump inhibitors (PPIs) may increase infection risk. We aimed to explore the potential association between PPI use and bacterial infection risk in cirrhotic patients and potential underlying mechanisms in complementary patient and animal models. MATERIALS AND METHODS Bacterial overgrowth was determined in jejunum of 30 rats randomly allocated to 6-week PPI treatment, gastrectomy or no treatment. In 84 consecutive cirrhotic patients, bacterial infection risk was prospectively assessed and related to PPI use. Intestinal permeability was determined by polyethylene glycol (PEG) test in nine healthy individuals and 12 cirrhotic patients. RESULTS Bacterial overgrowth was much more common in jejunum of rats treated with PPI or gastrectomy compared with nontreated rats. Twenty-four patients (29%) developed a bacterial infection during a median follow-up of 28 months. Although PPI users tended to experience infection more often than patients without PPI therapy, PPI use was not an independent predictor of bacterial infection (HR 1·2, 95% CI 0·5-3·0, P = 0·72), after correction for Child-Pugh class (HR 3·6, 95% CI 1·5-8·7, P = 0·004) and age (HR 1·05, 95%CI 1·01-1·09, P = 0·02). In cirrhotic patients, 24-h urinary recovery of PEGs 1500 and 3350 was significantly higher compared with healthy controls. CONCLUSIONS Although in our animal model PPIs induced intestinal overgrowth, stage of liver disease rather than PPI use was the predominant factor determining infection risk in cirrhotic patients. Increased intestinal permeability may be a factor contributing to infection risk.
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Affiliation(s)
- Lotte G van Vlerken
- Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands
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Increased rate of spontaneous bacterial peritonitis among cirrhotic patients receiving pharmacologic acid suppression. Clin Gastroenterol Hepatol 2012; 10:422-7. [PMID: 22155557 DOI: 10.1016/j.cgh.2011.11.019] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2011] [Revised: 09/30/2011] [Accepted: 11/18/2011] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Patients with cirrhosis frequently receive proton pump inhibitor (PPI) or H2-receptor antagonist therapies. We investigated whether acid-suppressive therapy is associated with spontaneous bacterial peritonitis (SBP) in cirrhotic patients with ascites. METHODS We compared data from 65 hospitalized cirrhotic patients with paracentesis-proven SBP, collected from 2006 to 2009, with those of 65 contemporaneous, hospitalized cirrhotic patients without SBP (controls). We evaluated PPI use and analyzed the effects of covariates. RESULTS Patients with SBP had a significantly higher incidence of recent (past 7 days) PPI use (71%) than controls (42%). Of patients with SBP, 68% had no documented indication for PPI therapy. Based on multivariable logistic regression analysis, subjects who had not taken PPIs in the past 90 days were almost 70% less likely to develop SBP than those who had taken PPIs in the previous 7 days. Subjects who took PPIs within 8 to 90 days before hospitalization were 79% less likely to develop SBP than those who took PPIs within 7 days before hospitalization. There was no significant difference between patients who received no PPI therapy in the previous 90 days versus those who had taken PPIs in the previous 8 to 90 days (P = .58). Hyponatremia was associated significantly with SBP. There were no significant differences in length of hospital stay or 30-day survival for the SBP and control groups. CONCLUSIONS Pharmacologic acid suppression is associated with SBP in patients with advanced cirrhosis. Prospective studies are needed to determine the mechanism of this association and to determine whether reduced use of PPIs and H2-receptor antagonists reduce the incidence of SBP.
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Hermos JA, Young MM, Fonda JR, Gagnon DR, Fiore LD, Lawler EV. Risk of community-acquired pneumonia in veteran patients to whom proton pump inhibitors were dispensed. Clin Infect Dis 2011; 54:33-42. [PMID: 22100573 DOI: 10.1093/cid/cir767] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Observational studies linking proton pump inhibitor (PPI) exposure with community-acquired pneumonia (CAP) have reported either modest or no associations. Accordingly, we studied PPI exposure and CAP in veteran patients, using a retrospective, nested case-control design. METHODS From linked pharmacy and administrative databases of the New England Veterans Healthcare System, we identified 71985 outpatients newly prescribed PPIs between 1998 and 2007; 1544 patients met criteria for CAP subsequent to PPI initiation; 15440 controls were matched through risk-set sampling by age and time under observation. Crude and adjusted odds ratios comparing current with past PPI exposures, as well as tests for interactions, were conducted for the entire and stratified samples. RESULTS Current PPI use associated with CAP (adjusted odds ratio [OR], 1.29 [95% confidence interval {CI}, 1.15-1.45]). Risks were not substantially altered by age or year of diagnosis. Dementia (n = 85; P = .062 for interaction) and sedative/tranquilizer use (n = 224; P = .049 for interaction) were likely effect modifiers increasing a PPI-CAP association; conversely, for some chronic medical conditions, PPI-associated CAP risks were reversed. PPI exposures between 1 and 15 days increased CAP risks, compared with longer exposures, but PPI initiation also frequently occurred shortly after CAP diagnoses. Prescribed PPI doses >1 dose/day also increased PPI-associated CAP risks. CONCLUSIONS Among the veterans studied, current compared with past PPI exposures associated modestly with increased risks of CAP. However, our observations that recent treatment initiation and higher PPI doses were associated with greater risks, and the inconsistent PPI-CAP associations between patient subgroups, indicate that further inquiries are needed to separate out coincidental patterns of associations.
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Affiliation(s)
- John A Hermos
- Pharmaco-Epidemiology Group, Massachusetts Veterans Epidemiology Research and Information Center, VA Cooperative Studies Program, VA Boston Healthcare System, Boston, Massachusetts 02130, USA.
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Steed H, Macfarlane GT, Blackett KL, Macfarlane S, Miller MH, Bahrami B, Dillon JF. Bacterial translocation in cirrhosis is not caused by an abnormal small bowel gut microbiota. ACTA ACUST UNITED AC 2011; 63:346-54. [PMID: 22092561 DOI: 10.1111/j.1574-695x.2011.00857.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2011] [Revised: 07/28/2011] [Accepted: 08/04/2011] [Indexed: 11/29/2022]
Abstract
Sepsis is common in liver cirrhosis, and animal studies have shown the gut to be the principal source of infection, through bacterial overgrowth and translocation in the small bowel. A total of 33 patients were recruited into this study, 10 without cirrhosis and 23 with cirrhotic liver disease. Six distal duodenal biopsies were obtained and snap frozen for RNA and DNA extraction, or frozen for FISH. Peripheral venous bloods were obtained from 30 patients, including 17 chronic liver disease patients. Samples were analysed by real-time PCR, to assess total bacteria, bifidobacteria, bacteroides, enterobacteria, staphylococci, streptococci, lactobacilli, enterococci, Helicobacter pylori and moraxella, as well as TNF-α, IL-8 and IL-18. There was no evidence of bacterial overgrowth with respect to any of the individual bacterial groups, with the exception of enterococci, which were present in higher numbers in cirrhotic patients (P = 0.04). There were no significant differences in any of the cytokines compared to the controls. The small intestinal mucosal microbiota in cirrhotic patients was qualitatively and quantitatively normal, and this shifts the focus of disease aetiology to factors that reduce gut integrity, failure of mechanisms to remove translocating bacteria, or the large bowel as the source of sepsis.
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Affiliation(s)
- Helen Steed
- Dundee University Gut Group, Ninewells Hospital and Medical School, UK
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Trikudanathan G, Israel J, Cappa J, O'Sullivan DM. Association between proton pump inhibitors and spontaneous bacterial peritonitis in cirrhotic patients - a systematic review and meta-analysis. Int J Clin Pract 2011; 65:674-8. [PMID: 21564440 DOI: 10.1111/j.1742-1241.2011.02650.x] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Acid suppressive therapy, in the form of proton pump inhibitor (PPI), is widely used in cirrhotic patients, often in indications which are not clearly justified. PPI facilitates enteric bacterial colonisation, overgrowth and translocation, which might predispose to spontaneous bacterial peritonitis. However, observational studies evaluating the association of PPI and SBP in cirrhotic patients have yielded inconsistent results. We therefore conducted a meta-analysis of relevant clinical studies to determine the nature of this association. Observational studies assessing the association between SBP and PPI in cirrhosis, conducted in adult population and published in all languages, were identified through systematic search in the MEDLINE, EMBASE and manual reviews of all major gastroenterology meeting proceedings up to May 2010. The relevant studies were pooled using traditional meta-analytic techniques with a random-effects model. Four studies were identified and included in the meta-analysis. The pooled analysis, involving a total of 772 patients, found a significant association between the use of PPI and the development of SBP (OR 2.77, 95% CI 1.82-4.23). There was very little degree of heterogeneity as reflected by an I(2) value of 22% and the visual inspection of the funnel plot. There is a potential association between use of PPI and development of SBP. Therefore, PPIs should be used judiciously and only when clearly indicated in cirrhotics. Further studies are essential to clarify this relationship and elucidate the underlying mechanisms.
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Affiliation(s)
- G Trikudanathan
- Department of Internal Medicine, University of Connecticut Medical Center, Farmington, CT, USA.
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Choi EJ, Lee HJ, Kim KO, Lee SH, Eun JR, Jang BI, Kim TN. Association between acid suppressive therapy and spontaneous bacterial peritonitis in cirrhotic patients with ascites. Scand J Gastroenterol 2011; 46:616-20. [PMID: 21275825 DOI: 10.3109/00365521.2011.551891] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Proton pump inhibitor (PPI) or histamine-2 receptor antagonist (H2RA) therapy may cause intestinal bacterial overgrowth and translocation. Therefore, acid suppressive therapy may increase the risk of spontaneous bacterial peritonitis (SBP) in cirrhotic patients with ascites. MATERIAL AND METHODS A total of 176 cirrhotic patients with ascites who underwent diagnostic paracentesis between September 2004 and April 2009 were included in the analysis. Patients with gastrointestinal hemorrhage and/or antibiotic therapy within 2 weeks prior to hospital admission were excluded. SBP was defined as ≥250/mm(3) polymorphonuclear white blood cells with or without a positive culture from the ascitic fluid. Eighty-three patients (mean age 56.1 years, 63 males) had SBP and 93 (mean age 54.7 years, 75 males) did not. RESULTS On the multivariate analysis, a Child-Pugh class C (OR = 2.890, 95% CI 1.443-5.786; p = 0.003), high MELD scores (≥ 20, OR = 3.540, 95% CI 1.155-10.849; p = 0.027), and PPI use (OR = 3.443, 95% CI 1.164-10.188; p = 0.025) were risk factors for SBP. H2RA was not associated with SBP. CONCLUSIONS PPI use, as well as Child-Pugh class C and high MELD scores, was an independent risk factor for the development of SBP in cirrhotic patients with ascites. Further prospective studies are warranted to clarify this issue.
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Affiliation(s)
- Eun Jung Choi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Republic of Korea
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