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Idalsoaga F, Ayares G, Blaney H, Cabrera D, Chahuan J, Monrroy H, Matar A, Halawi H, Arrese M, Arab JP, Díaz LA. Neurogastroenterology and motility disorders in patients with cirrhosis. Hepatol Commun 2025; 9:e0622. [PMID: 39773873 PMCID: PMC11717532 DOI: 10.1097/hc9.0000000000000622] [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: 11/08/2024] [Accepted: 11/21/2024] [Indexed: 01/11/2025] Open
Abstract
Neurogastroenterology and motility disorders are complex gastrointestinal conditions that are prevalent worldwide, particularly affecting women and younger individuals. These conditions significantly impact the quality of life of people suffering from them. There is increasing evidence linking these disorders to cirrhosis, with a higher prevalence compared to the general population. However, the link between neurogastroenterology and motility disorders and cirrhosis remains unclear due to undefined mechanisms. In addition, managing these conditions in cirrhosis is often limited by the adverse effects of drugs commonly used for these disorders, presenting a significant clinical challenge in the routine management of patients with cirrhosis. This review delves into this connection, exploring potential pathophysiological links and clinical interventions between neurogastroenterology disorders and cirrhosis.
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Affiliation(s)
- Francisco Idalsoaga
- Departamento De Gastroenterología, Escuela De Medicina, Pontificia Universidad Católica De Chile, Santiago, Chile
- Department of Medicine, Division of Gastroenterology, Schulich School of Medicine, Western University & London Health Sciences Centre, London, Ontario, Canada
| | - Gustavo Ayares
- Departamento De Gastroenterología, Escuela De Medicina, Pontificia Universidad Católica De Chile, Santiago, Chile
- Universidad Finis Terrae, Escuela de Medicina, Facultad de Medicina, Universidad Fines Terrae, Santiago, Chile
| | - Hanna Blaney
- MedStar Georgetown University Hospital, Medstar Transplant Hepatology Institute, Washington, District of Columbia, USA
| | - Daniel Cabrera
- Faculty of Medicine, Universidad de los Andes, Santiago, Chile
- Centro de Estudios e Investigación en Salud y Sociedad, Escuela de Medicina, Facultad de Ciencias Médicas, Universidad Bernardo O Higgins, Santiago, Chile
| | - Javier Chahuan
- Departamento De Gastroenterología, Escuela De Medicina, Pontificia Universidad Católica De Chile, Santiago, Chile
| | - Hugo Monrroy
- Departamento De Gastroenterología, Escuela De Medicina, Pontificia Universidad Católica De Chile, Santiago, Chile
| | - Ayah Matar
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Houssam Halawi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Marco Arrese
- Departamento De Gastroenterología, Escuela De Medicina, Pontificia Universidad Católica De Chile, Santiago, Chile
| | - Juan Pablo Arab
- Departamento De Gastroenterología, Escuela De Medicina, Pontificia Universidad Católica De Chile, Santiago, Chile
- Department of Internal Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Luis Antonio Díaz
- Departamento De Gastroenterología, Escuela De Medicina, Pontificia Universidad Católica De Chile, Santiago, Chile
- MASLD Research Center, Division of Gastroenterology and Hepatology, University of California San Diego, San Diego, California, USA
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El-Azab G. Proton Pump Inhibitors in Patients with Cirrhosis: Pharmacokinetics, Benefits and Drawbacks. Curr Gastroenterol Rep 2024; 26:323-334. [PMID: 39167119 DOI: 10.1007/s11894-024-00943-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/01/2024] [Indexed: 08/23/2024]
Abstract
PURPOSE OF REVIEW This review explores the pharmacokinetics, benefits, and risks of proton pump inhibitors (PPIs) in cirrhotic patients, focusing on the appropriateness of their use and potential adverse effects. RECENT FINDINGS Recent studies highlight significant pharmacokinetic alterations in PPIs among cirrhotic patients, with marked increases in lansoprazole and pantoprazole exposure and relatively stable levels of esomeprazole. While effective for managing acid-related disorders and post-band ulcer rebleeding, evidence supporting PPI use for portal hypertension-related bleeding is lacking. Emerging research suggests potential adverse effects such as hepatic decompensation, spontaneous bacterial peritonitis, hepatic encephalopathy, and increased mortality, possibly linked to dysbiosis and bacterial translocation. PPI use in cirrhotic patients alters pharmacokinetics significantly, with esomeprazole potentially safer in advanced cirrhosis. The review advises caution in routine PPI use beyond acid-related conditions due to limited evidence and substantial risks. It underscores the need for careful risk-benefit assessments and exploration of alternative therapies. Future research should aim to identify safer management strategies for portal hypertension complications and to develop evidence-based guidelines for PPI use in patients with cirrhosis.
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Affiliation(s)
- Gasser El-Azab
- Hepatology and Gastroenterology Department, National Liver Institute, Menoufia University, Shebin El-Kom, Menoufia, Egypt.
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Idalsoaga F, Díaz LA, Ayares G, Cabrera D, Chahuan J, Monrroy H, Halawi H, Arrese M, Arab JP. Letter: Potential impact of Helicobacter pylori infection on oesophageal disorders in chronic liver disease-Authors' reply. Aliment Pharmacol Ther 2024; 60:1141-1142. [PMID: 39223757 DOI: 10.1111/apt.18246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
LINKED CONTENTThis article is linked to Idalsoaga et al papers. To view these articles, visit https://doi.org/10.1111/apt.18193 and https://doi.org/10.1111/apt.18220
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Affiliation(s)
- Francisco Idalsoaga
- Departamento De Gastroenterología, Escuela De Medicina, Pontificia Universidad Católica De Chile, Santiago, Chile
- Division of Gastroenterology and Hepatology, London Health Sciences Centre, Western University, London, Ontario, Canada
| | - Luis Antonio Díaz
- Departamento De Gastroenterología, Escuela De Medicina, Pontificia Universidad Católica De Chile, Santiago, Chile
- Division of Gastroenterology and Hepatology, MASLD Research Center, University of California San Diego, San Diego, California, USA
| | - Gustavo Ayares
- Departamento De Gastroenterología, Escuela De Medicina, Pontificia Universidad Católica De Chile, Santiago, Chile
| | - Daniel Cabrera
- Faculty of Medicine, Universidad de los Andes, Santiago, Chile
- Centro de Estudios e Investigación en Salud y Sociedad, Escuela de Medicina, Facultad de Ciencias Médicas, Universidad Bernardo O Higgins, Santiago, Chile
| | - Javier Chahuan
- Departamento De Gastroenterología, Escuela De Medicina, Pontificia Universidad Católica De Chile, Santiago, Chile
| | - Hugo Monrroy
- Departamento De Gastroenterología, Escuela De Medicina, Pontificia Universidad Católica De Chile, Santiago, Chile
| | - Houssam Halawi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Marco Arrese
- Departamento De Gastroenterología, Escuela De Medicina, Pontificia Universidad Católica De Chile, Santiago, Chile
| | - Juan Pablo Arab
- Departamento De Gastroenterología, Escuela De Medicina, Pontificia Universidad Católica De Chile, Santiago, Chile
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
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Idalsoaga F, Díaz LA, Ayares G, Cabrera D, Chahuan J, Monrroy H, Halawi H, Arrese M, Arab JP. Review article: Oesophageal disorders in chronic liver disease. Aliment Pharmacol Ther 2024; 60:715-726. [PMID: 39082463 DOI: 10.1111/apt.18193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 07/03/2024] [Accepted: 07/20/2024] [Indexed: 08/29/2024]
Abstract
BACKGROUND Oesophageal disorders and chronic liver disease are common worldwide and significantly impact quality of life. The intricate link between these conditions, including how oesophageal disorders like GERD, Barrett's oesophagus and oesophageal cancer affect and are affected by chronic liver disease, remains poorly understood. AIMS To review the relationship between oesophageal disorders and chronic liver disease, evaluating epidemiology, pathophysiology and therapeutic factors. METHODS We reviewed the literature on the relationship between oesophageal disorders and chronic liver disease, including cirrhosis, using the PubMed database RESULTS: Oesophageal disorders such as gastroesophageal reflux disease, Barrett's oesophagus, oesophageal cancer, oesophageal motor disorders and oesophageal candidiasis are prevalent among individuals with cirrhosis, exacerbating the burden of liver disease. These diseases have a multifaceted symptomatology and pathogenic basis, posing a significant challenge in cirrhotic patients that necessitates careful diagnosis and management. Additionally, therapies frequently used for these diseases, such as proton pump inhibitors, require careful consideration in cirrhotic patients due to potential adverse effects and altered pharmacokinetics. Managing oesophageal disorders in cirrhotic patients requires a cautious approach due to possible interactions with medications and the risk of adverse effects. Furthermore, symptoms associated with these conditions are often exacerbated by common interventions in patients with cirrhosis, such as band ligation for oesophageal varices. CONCLUSIONS Oesophageal disorders are common in cirrhosis and increase the disease burden. These conditions require careful management due to complex symptoms and treatment risks. Proton pump inhibitors and other therapies must be used cautiously, as cirrhosis interventions can worsen symptoms.
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Affiliation(s)
- Francisco Idalsoaga
- Departamento De Gastroenterología, Escuela De Medicina, Pontificia Universidad Católica De Chile, Santiago, Chile
| | - Luis Antonio Díaz
- Departamento De Gastroenterología, Escuela De Medicina, Pontificia Universidad Católica De Chile, Santiago, Chile
| | - Gustavo Ayares
- Departamento De Gastroenterología, Escuela De Medicina, Pontificia Universidad Católica De Chile, Santiago, Chile
| | - Daniel Cabrera
- Faculty of Medicine, Universidad de los Andes, Santiago, Chile
- Centro de Estudios e Investigación en Salud y Sociedad, Escuela de Medicina, Facultad de Ciencias Médicas, Universidad Bernardo O Higgins, Santiago, Chile
| | - Javier Chahuan
- Departamento De Gastroenterología, Escuela De Medicina, Pontificia Universidad Católica De Chile, Santiago, Chile
| | - Hugo Monrroy
- Departamento De Gastroenterología, Escuela De Medicina, Pontificia Universidad Católica De Chile, Santiago, Chile
| | - Houssam Halawi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Marco Arrese
- Departamento De Gastroenterología, Escuela De Medicina, Pontificia Universidad Católica De Chile, Santiago, Chile
| | - Juan Pablo Arab
- Departamento De Gastroenterología, Escuela De Medicina, Pontificia Universidad Católica De Chile, Santiago, Chile
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
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Hayashi S, Moriyama T, Ito Y, Harada Y, Dodo H, Kumahara K, Yogi T, Ohashi N, Higashi R, Mori A. Proton-Pump Inhibitors and Risk of Bloodstream Infection without an Identifiable Source: a Hospital-Based Case-Control Study. Jpn J Infect Dis 2024; 77:205-212. [PMID: 38296545 DOI: 10.7883/yoken.jjid.2023.253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/26/2024]
Abstract
The association between proton-pump inhibitor (PPI) use and systemic infections caused by bacterial translocation is unclear. This study aimed to investigate whether patients receiving PPI therapy have a higher risk of bloodstream infections (BSI) without an identifiable source of infection. We conducted a hospital-based case-control study which enrolled all patients aged 20 years and older who were hospitalized in Ichinomiya Nishi Hospital with BSI confirmed by two sets of positive blood cultures in 2019. Patient data were collected from medical records, and the bacterial translocation-type (BT-type) BSI group was defined as patients with BSI without an identifiable source of infection, whereas those with a BSI from an identifiable source were assigned to the control group based on the diagnostic criteria for each infectious disease. Data from 309 patients, including 66 cases and 243 controls, were analyzed. Compared with PPI non-users, PPI users had a 2.4-fold higher risk of developing BT-type BSI after controlling for potential confounders (adjusted odds ratio: 2.41, 95% confidence interval: 1.29-4.51, P = 0.006). In conclusion, PPI use is associated with a higher risk of BSI without an identifiable source; therefore, PPI use might increase the risk of BSI secondary to bacterial translocation.
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Affiliation(s)
- Shintaro Hayashi
- Department of Gastroenterology, Ichinomiya Nishi Hospital, Japan
| | | | - Yuichiro Ito
- Department of Gastroenterology, Ichinomiya Nishi Hospital, Japan
| | - Yuta Harada
- Department of Gastroenterology, Ichinomiya Nishi Hospital, Japan
| | - Hiroki Dodo
- Department of Gastroenterology, Ichinomiya Nishi Hospital, Japan
| | - Kana Kumahara
- Department of Gastroenterology, Ichinomiya Nishi Hospital, Japan
| | - Tatsuji Yogi
- Department of Gastroenterology, Ichinomiya Nishi Hospital, Japan
| | - Noritsugu Ohashi
- Department of Gastroenterology, Ichinomiya Nishi Hospital, Japan
| | - Reiji Higashi
- Department of Gastroenterology, Ichinomiya Nishi Hospital, Japan
| | - Akihiro Mori
- Department of Gastroenterology, Ichinomiya Nishi Hospital, Japan
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Maimunah U, Kurniawan AA, Palayukan A. Adverse Effects of Long-term Proton Pump Inhibitors in Chronic Liver Disease Patients – A Preliminary Article Review. REVIEW OF CLINICAL PHARMACOLOGY AND PHARMACOKINETICS - INTERNATIONAL EDITION 2024; 38:87-97. [DOI: 10.61873/wway6273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
Abstract
Background: Proton pump inhibitors (PPIs) are widely prescribed medications for the management of gastroesophageal reflux disease (GERD) and peptic ulcer disease. Despite their efficacy, concerns have emerged regarding their potential adverse effects, particularly in patients with chronic liver disease (CLD). CLD patients often experience gastrointestinal symptoms and may be prescribed PPIs, but the impact of PPI use on liver function and disease progression remains uncertain. Scope: This study aims to evaluate the adverse effects of PPIs on CLD patients through a review of available literature. The scope encompasses a review of studies examining the association between PPI use and liver-related outcomes, including hepatic encephalopathy, hepatic decompensation, liver cirrhosis progression, and mortality, among CLD patients. Method: A scoping review of relevant literature were conducted to identify studies investigating the adverse effects of PPIs in CLD patients. Databases including PubMed and Google Scholar were searched for articles published up to January, 1 2023. Eligible studies were selected based on predefined inclusion criteria. Results: The review identified 27 studies meeting the inclusion criteria, comprising observational studies and meta-analysis. The review revealed a significant association between PPI use and adverse liver outcomes in CLD patients. Specifically, PPI use was associated with increased risk of SBP based on studies reviewed, while other complications remained inconclusive. Conclusion: The findings suggest that PPI use may have detrimental effects on disease progression in CLD patients, Long-term use of PPIs can lead to higher risk of SBP in CLD patients. Clinicians should exercise caution when prescribing PPIs to this vulnerable population and consider alternative treatment options or minimize PPI use to mitigate potential adverse outcomes. Further research is warranted to elucidate the underlying mechanisms, confirm the effect of PPIs toward other complications of CLD and establish guidelines for PPI use in CLD patients.
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Prabhoo RY, Pai UA, Wadhwa A, Pillai BV, D'souza C, Wadhawan M, Bhatnagar M, Prabhoo MR, Shetty S, Seshadri VP, Bhatnagar S, Manchanda SC, Kher V. Multidisciplinary Consensus for Rationalizing the Use of Acid Suppressants in Children and Adults: CONFOR. Euroasian J Hepatogastroenterol 2024; 14:99-119. [PMID: 39022200 PMCID: PMC11249898 DOI: 10.5005/jp-journals-10018-1430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Accepted: 04/22/2024] [Indexed: 07/20/2024] Open
Abstract
The use of acid suppression therapy (AST) is a common approach for managing a wide spectrum of acid peptic disorders. Histamine type 2-receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) are the most widely prescribed AST in routine clinical practice. However, an exponential surge in the prescriptions of PPIs, such as Omeprazole, Esomeprazole, Pantoprazole, Lansoprazole in recent years and their associated adverse effects have raised concern about their inappropriate and overuse, both in children and adults. To address these issues, a three-step modified Delphi polling process was employed to establish best practice consensus statements for rationalizing the use of acid suppressants. A multidisciplinary expert panel of 13 health professionals across medical specialties, including gastroenterologists, hepatologists, pediatric gastroenterologists, pediatricians, otolaryngologists, cardiologists, nephrologists, gynecologist and orthopedists actively contributed to this collaborative process of consensus development. The expert panel proposed 21 consensus statements providing best practice points on the general use and safety of acid suppressants based on a comprehensive review of scientific literature and clinical expertise. The panel also collaboratively developed a PPI deprescribing algorithm. Altogether, this consensus paper offers evidence-based recommendations and guidance for the rational use of acid suppressants with a blueprint for deprescribing PPIs. This consensus paper contributes to aiding primary care practitioners in improving patient outcomes and minimizing healthcare costs. Additionally, it enhances patient safety and curtail inappropriate usage. How to cite this article Prabhoo RY, Pai UA, Wadhwa A, et al. Multidisciplinary Consensus for Rationalizing the Use of Acid Suppressants in Children and Adults: CONFOR. Euroasian J Hepato-Gastroenterol 2024;14(1):99-119.
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Affiliation(s)
- Ram Y Prabhoo
- Department of Orthopedics, Mukund Hospital, Mumbai, Maharashtra, India
| | - Uday A Pai
- Department of Pediatrics, Sai Kutti Clinic, Mumbai, Maharashtra, India
| | - Arun Wadhwa
- Department of Pediatrics, Arun Wadhwa Clinic, New Delhi, India
| | - Bhanu V Pillai
- Department of Pediatric Gastroenterology, Amrita Institute of Medical Sciences, Kochi, Kerala, India
| | - Chris D'souza
- Department of ENT, Holy Family Hospital, Mumbai, Maharashtra, India
| | - Manav Wadhawan
- Department of Hepatology and Liver Transplant, BLK-Max Super Speciality Hospital, Delhi, India
| | - Manish Bhatnagar
- Department of Gastroenterology, Orchid Mediservices, Ahmedabad, Gujarat, India
| | - Meena R Prabhoo
- Department of Gynecology, Mukund Hospital, Mumbai, Maharashtra, India
| | - Sadanand Shetty
- Department of Cardiology, Somaiya Super Specialty Institute, Mumbai, Maharashtra, India
| | | | - Shrish Bhatnagar
- Department of Pediatric Gastroenterology, Era's Lucknow Medical College and Hospital, Lucknow, Uttar Pradesh, India
| | | | - Vijay Kher
- Department of Nephrology and Transplant Medicine, Epitome Kidney and Urology Institute, New Delhi, India
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Kim JW, Jung HK, Lee B, Shin CM, Gong EJ, Hong J, Youn YH, Lee KJ. Risk of gastric cancer among long-term proton pump inhibitor users: a population-based cohort study. Eur J Clin Pharmacol 2023; 79:1699-1708. [PMID: 37861752 DOI: 10.1007/s00228-023-03580-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 10/07/2023] [Indexed: 10/21/2023]
Abstract
PURPOSE To elucidate whether long-term proton pump inhibitor (PPI) users have an increased gastric cancer (GC) risk. METHODS We searched the 2009-2019 Korean National Health Insurance Services Database for patients aged > 40 years who claimed for Helicobacter pylori eradication (HPE) during 2009-2014. The GC incidence following a PPI exposure of > 180 cumulative defined daily dose (cDDD) and that following an exposure of < 180 cDDD were compared. The outcome was GC development at least 1 year following HPE. A propensity score (PS)-matched dataset was used for analysis within the same quartiles of the follow-up duration. Additionally, dose-response associations were assessed, and the mortality rates were compared between long-term PPI users and non-users. RESULTS After PS matching, 144,091 pairs of PPI users and non-users were analyzed. During a median follow-up of 8.3 (interquartile range, 6.8-9.6) years, 1053 and 948 GC cases in PPI users and non-users, respectively, were identified, with the GC incidence (95% confidence interval (CI)) being 0.90 (0.85-0.96) and 0.81 (0.76-0.86) per 1000 person-years, respectively. The adjusted hazard ratio (aHR) for GC with PPI use was 1.15 (95% CI, 1.06-1.25). Among PPI users, patients in the highest tertile for annual PPI dose showed higher GC development than those in the lowest tertile (aHR (95% CI): 3.87 (3.25-4.60)). GC-related mortality did not differ significantly between PPI users and non-users. CONCLUSION In this nationwide analysis in Korea, where the GC prevalence is high, long-term PPI use after HPE showed a significant increase in GC, with a positive dose-response relationship.
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Affiliation(s)
- Jong Wook Kim
- Department of Internal Medicine, Inje University Ilsan Paik Hospital, Goyang, Korea
| | - Hye-Kyung Jung
- Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul, Korea.
| | - Bora Lee
- Institute of Health & Environment, Seoul National University, Seoul, Korea
| | - Cheol Min Shin
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Eun Jeong Gong
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Korea
| | - Jitaek Hong
- Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul, Korea
| | - Young Hoon Youn
- Department of Internal Medicine, Yonsei University Gangnam Severance Hospital, Seoul, Korea
| | - Kwang Jae Lee
- Department of Gastroenterology, Ajou University School of Medicine & Graduate School of Medicine, Suwon, Korea
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Dutta AK, Jain A, Jearth V, Mahajan R, Panigrahi MK, Sharma V, Goenka MK, Kochhar R, Makharia G, Reddy DN, Kirubakaran R, Ahuja V, Berry N, Bhat N, Dutta U, Ghoshal UC, Jain A, Jalihal U, Jayanthi V, Kumar A, Nijhawan S, Poddar U, Ramesh GN, Singh SP, Zargar S, Bhatia S. Guidelines on optimizing the use of proton pump inhibitors: PPI stewardship. Indian J Gastroenterol 2023; 42:601-628. [PMID: 37698821 DOI: 10.1007/s12664-023-01428-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 07/10/2023] [Indexed: 09/13/2023]
Abstract
Proton pump inhibitors (PPIs) have been available for over three decades and are among the most commonly prescribed medications. They are effective in treating a variety of gastric acid-related disorders. They are freely available and based on current evidence, use of PPIs for inappropriate indications and duration appears to be common. Over the years, concerns have been raised on the safety of PPIs as they have been associated with several adverse effects. Hence, there is a need for PPI stewardship to promote the use of PPIs for appropriate indication and duration. With this objective, the Indian Society of Gastroenterology has formulated guidelines on the rational use of PPIs. The guidelines were developed using a modified Delphi process. This paper presents these guidelines in detail, including the statements, review of literature, level of evidence and recommendations. This would help the clinicians in optimizing the use of PPIs in their practice and promote PPI stewardship.
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Affiliation(s)
- Amit Kumar Dutta
- Department of Gastroenterology, Christian Medical College and Hospital, Vellore, 632 004, India.
| | | | - Vaneet Jearth
- Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Ramit Mahajan
- Dayanand Medical College and Hospital, Ludhiana, 141 001, India
| | | | - Vishal Sharma
- Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | | | | | - Govind Makharia
- All India Institute of Medical Sciences, New Delhi, 110 029, India
| | | | - Richard Kirubakaran
- Center of Biostatistics and Evidence Based Medicine, Vellore, 632 004, India
| | - Vineet Ahuja
- All India Institute of Medical Sciences, New Delhi, 110 029, India
| | - Neha Berry
- BLK Institute of Digestive and Liver Disease, New Delhi, 201 012, India
| | - Naresh Bhat
- Aster CMI Hospital, Bengaluru, 560 092, India
| | - Usha Dutta
- Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Uday Chand Ghoshal
- Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, 226 014, India
| | - Ajay Jain
- Choithram Hospital and Research Center, Indore, 452 014, India
| | | | - V Jayanthi
- Sri Ramachandra Medical College, Chennai, 600 116, India
| | - Ajay Kumar
- Institute of Digestive and Liver Diseases, BLK - Max Superspeciality Hospital, New Delhi, 201 012, India
| | | | - Ujjal Poddar
- Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, 226 014, India
| | | | - Shivram P Singh
- Kalinga Gastroenterology Foundation, Cuttack, 753 001, India
| | - Showkat Zargar
- Department of Gastroenterology, Sher-i-Kashmir Institute of Medical Sciences, Kashmir, 190 011, India
| | - Shobna Bhatia
- Sir H N Reliance Foundation Hospital, Mumbai, 400 004, India
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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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Bao J, Zhou L, Xu M, Ma J. The impact of pharmacist intervention on the intravenous-to-oral switch therapy of proton pump inhibitors in cardiovascular surgery. Expert Opin Drug Saf 2023; 22:611-619. [PMID: 36714924 DOI: 10.1080/14740338.2023.2172162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 12/08/2022] [Indexed: 01/31/2023]
Abstract
BACKGROUND The prescriptions of proton pump inhibitors (PPIs) have been widely concerned due to both huge increase in medical costs and possible long-term adverse events (AEs) caused by the improper route of drug administration. The aim of this study was to assess the effectiveness of pharmacist interventions on the clinical outcome and safety of switching from intravenous (IV) to oral PPIs therapy. PATIENTS AND METHODS A retrospective, single-center, pre- intervention (early -stage)- and intervention (later -stage) study was performed in a Chinese hospital. RESULTS A total of 1736 patients were included in the study. After 12 months of interventions, significant improvements in the number of rational IV to oral switch in patients with oral switch indications were found. The median duration of oral therapy was increased, while the duration of PPIs therapy was decreased. Pharmacist interventions led to significant reductions in mean PPI costs, mean total drug costs, mean hospitalization costs, and the risk for long-term adverse events. CONCLUSION This study provides important evidence on the beneficial effect of pharmacist interventions on promoting an optimal IV to oral switch of PPIs and substantial cost saving by shortening the duration of IV PPIs therapy and reducing the risk for long-term AEs.
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Affiliation(s)
- Jianan Bao
- Department of Pharmacy, Medical Center of Soochow University, Dushu Lake Hospital Affiliated to Soochow University, Suzhou, Jiangsu, China
| | - Ling Zhou
- Department of Pharmacy, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Mengying Xu
- Department of Pharmacy, Medical Center of Soochow University, Dushu Lake Hospital Affiliated to Soochow University, Suzhou, Jiangsu, China
| | - Jingjing Ma
- Department of Pharmacy, Medical Center of Soochow University, Dushu Lake Hospital Affiliated to Soochow University, Suzhou, Jiangsu, China
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12
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Zhang J, Zhang C, Zhang Q, Yu L, Chen W, Xue Y, Zhai Q. Meta-analysis of the effects of proton pump inhibitors on the human gut microbiota. BMC Microbiol 2023; 23:171. [PMID: 37337143 DOI: 10.1186/s12866-023-02895-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 05/16/2023] [Indexed: 06/21/2023] Open
Abstract
Mounting evidence has linked changes in human gut microbiota to proton pump inhibitor (PPI) use. Accordingly, multiple studies have analyzed the gut microbiomes of PPI users, but PPI-microbe interactions are still understudied. Here, we performed a meta-analysis of four studies with available 16S rRNA gene amplicon sequencing data to uncover the potential changes in human gut microbes among PPI users. Despite some differences, we found common features of the PPI-specific microbiota, including a decrease in the Shannon diversity index and the depletion of bacteria from the Ruminococcaceae and Lachnospiraceae families, which are crucial short-chain fatty acid-producers. Through training based on multiple studies, using a random forest classification model, we further verified the representativeness of the six screened gut microbial genera and 20 functional genes as PPI-related biomarkers, with AUC values of 0.748 and 0.879, respectively. Functional analysis of the PPI-associated 16S rRNA microbiome revealed enriched carbohydrate- and energy-associated genes, mostly encoding fructose-1,6-bisphosphatase and pyruvate dehydrogenase, among others. In this study, we have demonstrated alterations in bacterial abundance and functional metabolic potential related to PPI use, as a basis for future studies on PPI-induced adverse effects.
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Affiliation(s)
- Jiayi Zhang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, 214122, People's Republic of China
- School of Food Science and Technology, Jiangnan University, Wuxi, 214122, Jiangsu, China
| | - Chengcheng Zhang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, 214122, People's Republic of China
- School of Food Science and Technology, Jiangnan University, Wuxi, 214122, Jiangsu, China
| | - Qingsong Zhang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, 214122, People's Republic of China
- School of Food Science and Technology, Jiangnan University, Wuxi, 214122, Jiangsu, China
| | - Leilei Yu
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, 214122, People's Republic of China
- School of Food Science and Technology, Jiangnan University, Wuxi, 214122, Jiangsu, China
| | - Wei Chen
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, 214122, People's Republic of China
- School of Food Science and Technology, Jiangnan University, Wuxi, 214122, Jiangsu, China
| | - Yuzheng Xue
- Department of Gastroenterology, Affiliated Hospital of Jiangnan University, Jiangsu Province, Wuxi, China.
| | - Qixiao Zhai
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, 214122, People's Republic of China.
- School of Food Science and Technology, Jiangnan University, Wuxi, 214122, Jiangsu, China.
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13
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China L, Tittanegro T, Crocombe D, Forrest E, Kallis Y, Ryder SD, Wright G, Freemantle N, O'Brien A. Investigating potential confounding by indication when considering the association between proton pump inhibitor use, infection, hepatic encephalopathy and mortality in hospitalised decompensated cirrhosis: a post-hoc analysis of the ATTIRE trial. EClinicalMedicine 2023; 58:101924. [PMID: 37090442 PMCID: PMC10119493 DOI: 10.1016/j.eclinm.2023.101924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 02/25/2023] [Accepted: 03/08/2023] [Indexed: 04/25/2023] Open
Abstract
Background Proton pump inhibitors (PPIs) are commonly prescribed to prevent and treat upper gastrointestinal ulceration and bleeding. Studies have identified increased incidence of spontaneous bacterial peritonitis and hepatic encephalopathy (HE) in cirrhosis patients taking PPIs. However, results are conflicting, and as PPIs are prescribed for variceal bleeding, a major risk factor for infection and HE, it is challenging to discern whether these associations are causal. Methods In this post-hoc analysis of the ATTIRE trial, we pooled all patient data to investigate the effects of PPI use on clinical outcomes. ATTIRE was a multicentre, open-label, randomised trial of targeted 20% human albumin solution (HAS) daily infusions versus standard care involving 777 adults with decompensated cirrhosis hospitalised with acute complications and albumin <30 g/L. Study recruitment was between Jan 25, 2016, and June 28, 2019, at 35 hospitals across England, Scotland, and Wales. Key exclusion criteria were advanced hepatocellular carcinoma with life expectancy <8 weeks and patients receiving palliative care. In ATTIRE, patients were grouped by PPI use at trial entry. We studied infection and HE at baseline and incidence of hospital acquired infection, new onset HE, renal dysfunction and mortality. We attempted with propensity score matching to account for differences in disease severity. Findings Overall PPI use at baseline was not associated with increased incidence of infection, renal dysfunction or mortality, but was associated with significantly increased incidence of grade III/IV HE during hospital stay (P = 0.011). This was only significant for those taking intravenous PPIs and these patients had >10 times the incidence of variceal bleeding and near double the 28-day mortality compared to non-PPI patients. However, propensity score matching was not possible as there was such a strong selection of patients for PPI use, that we could not find sufficient non-PPI patients to match to. We found no impact of PPI use on plasma markers of bacterial translocation, infection or systemic inflammation. Interpretations Our real-world data from a completed randomised trial show that PPIs are widely prescribed in the UK and judicious use appears safe in patients hospitalised with decompensated cirrhosis. However, patients prescribed PPIs had fundamentally different phenotypes to those not prescribed PPIs, a form of confounding by indication, which should be strongly considered when interpreting studies and making recommendations about their use. Funding Wellcome Trust and Department of Health and Social Care.
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Affiliation(s)
- Louise China
- Institute of Liver and Digestive Health, University College London, United Kingdom
| | - Thais Tittanegro
- Institute of Liver and Digestive Health, University College London, United Kingdom
| | - Dominic Crocombe
- Institute of Liver and Digestive Health, University College London, United Kingdom
| | - Ewan Forrest
- Glasgow Royal Infirmary, Glasgow, United Kingdom
| | - Yiannis Kallis
- Barts and the London School of Medicine and Dentistry Queen Mary University of London, United Kingdom
| | - Stephen D. Ryder
- National Institute for Health Research Nottingham Biomedical Research Centre at Nottingham University Hospitals NHS Trust and the University of Nottingham, Queens Medical Centre, Nottingham, United Kingdom
| | - Gavin Wright
- Mid and South Essex NHS Foundation Trust, Basildon & Thurrock University Hospitals NHS Foundation Trust, Gastroenterology, Hepatology and Hepatobiliary Medicine, The Royal Free Hospital, University College London, Kings College London, United Kingdom
| | - Nick Freemantle
- Comprehensive Clinical Trials Unit, University College London, United Kingdom
| | - Alastair O'Brien
- Institute of Liver and Digestive Health, University College London, United Kingdom
- Comprehensive Clinical Trials Unit, University College London, United Kingdom
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14
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Hakuta R, Nakai Y, Oyama H, Noguchi K, Kanai S, Nomura Y, Suzuki T, Ishigaki K, Saito K, Saito T, Hamada T, Takahara N, Mizuno S, Kogure H, Moriya K, Fujishiro M. Increased risk of biliary infection after biliary stent placement in users of proton pump inhibitors. DEN OPEN 2023; 3:e129. [PMID: 35898828 PMCID: PMC9307719 DOI: 10.1002/deo2.129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 04/23/2022] [Accepted: 04/28/2022] [Indexed: 04/08/2023]
Abstract
OBJECTIVES Proton pump inhibitors (PPIs) are widely prescribed medications for gastric acid-induced diseases. Despite the effectiveness of PPIs, recent evidence suggested an increased risk of various bacterial infections in PPI users. The current study was conducted to evaluate the risk of biliary infection after endoscopic biliary stent placement in regular users of PPIs. METHODS Consecutive patients with a native papilla who underwent endoscopic retrograde cholangiopancreatography and stent placement for biliary stricture between January 2010 and August 2019 were included in this retrospective study. The cumulative incidences of biliary infection were compared between regular and non-regular PPI users. RESULTS During the study period, 270 regular PPI users and 146 non-regular PPI users were included in the analyses. Age, gender, and indication of endoscopic retrograde cholangiopancreatography were not different between the two groups. The incidences of biliary infection were 43% in regular PPI users and 36% in non-regular PPI users but the time to biliary infection was significantly shorter in regular PPI users than in non-regular users (28 vs. 87 days, p = 0.01). The cumulative incidence of biliary infection was significantly higher in regular PPI users compared with non-regular users (p = 0.008). The multivariable Cox regression analysis also showed a significantly higher hazard ratio of biliary infection in regular PPI users (1.62 [95% confidence interval 1.16-2.26; p = 0.005]). CONCLUSIONS Regular PPI use was associated with a higher risk of biliary infection after endoscopic biliary drainage. Inappropriate PPI use should be avoided.
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Affiliation(s)
- Ryunosuke Hakuta
- Department of GastroenterologyGraduate School of MedicineThe University of TokyoTokyoJapan
- Department of Endoscopy and Endoscopic SurgeryThe University of TokyoTokyoJapan
| | - Yousuke Nakai
- Department of GastroenterologyGraduate School of MedicineThe University of TokyoTokyoJapan
- Department of Endoscopy and Endoscopic SurgeryThe University of TokyoTokyoJapan
| | - Hiroki Oyama
- Department of GastroenterologyGraduate School of MedicineThe University of TokyoTokyoJapan
| | - Kensaku Noguchi
- Department of GastroenterologyGraduate School of MedicineThe University of TokyoTokyoJapan
| | - Sachiko Kanai
- Department of GastroenterologyGraduate School of MedicineThe University of TokyoTokyoJapan
| | - Yusuke Nomura
- Department of Infection Control and PreventionGraduate School of MedicineThe University of TokyoTokyoJapan
| | - Tatsunori Suzuki
- Department of GastroenterologyGraduate School of MedicineThe University of TokyoTokyoJapan
| | - Kazunaga Ishigaki
- Department of GastroenterologyGraduate School of MedicineThe University of TokyoTokyoJapan
| | - Kei Saito
- Department of GastroenterologyGraduate School of MedicineThe University of TokyoTokyoJapan
| | - Tomotaka Saito
- Department of GastroenterologyGraduate School of MedicineThe University of TokyoTokyoJapan
| | - Tsuyoshi Hamada
- Department of GastroenterologyGraduate School of MedicineThe University of TokyoTokyoJapan
| | - Naminatsu Takahara
- Department of GastroenterologyGraduate School of MedicineThe University of TokyoTokyoJapan
| | - Suguru Mizuno
- Department of GastroenterologyGraduate School of MedicineThe University of TokyoTokyoJapan
| | - Hirofumi Kogure
- Department of GastroenterologyGraduate School of MedicineThe University of TokyoTokyoJapan
| | - Kyoji Moriya
- Department of Infection Control and PreventionGraduate School of MedicineThe University of TokyoTokyoJapan
| | - Mitsuhiro Fujishiro
- Department of GastroenterologyGraduate School of MedicineThe University of TokyoTokyoJapan
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15
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Zhang Y, Li J, Chen Z, Liu L, Zhan X, Peng F, Zhou Q, Wu X, Zeng Y, Zhu L, Xie Y, Lai X, Wang Z, Wen Y, Feng X, Liang J. Proton pump inhibitor usage associates with higher risk of first episodes of pneumonia and peritonitis in peritoneal dialysis patients. Ren Fail 2022; 44:1623-1631. [PMID: 36195979 PMCID: PMC9542879 DOI: 10.1080/0886022x.2022.2129064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
Background A large number of studies have shown that proton pump inhibitors (PPIs) are associated with infection events. Therefore, we retrospectively evaluated the association of PPI therapy with the occurrence of first pneumonia and peritoneal dialysis(PD)-related peritonitis events in the maintenance PD patients. Methods We collected PD patients in two large hospitals from January 1, 2012 to December 31, 2016, and divided them into the PPI group and the non-PPI group. Multivariate Cox proportional hazards models were applied to evaluate the cumulative incidence and hazard ratios (HRs). Inverse probability of treatment weight (IPTW) method was used to adjust for covariate imbalance between the two groups and further confirm our findings. Results Finally, 656 PD patients were included for data analysis, and the results showed that PPI usage was associated with an increased risk of pneumonia [HR 1.71; 95% CI 1.06-2.76; p = 0.027] and peritonitis [HR 1.73; 95% CI 1.24-2.40; p = 0.001]. IPTW-adjusted HRs for the association of PPIs with pneumonia and peritonitis were 1.58 (95% CI:1.18-2.12; p = 0.002) and 2.33 (95% CI:1.91-2.85; p < 0.001), respectively. Moreover, the competitive risk model proved that under the conditions of competition for other events(including transfer to hemodialysis therapy, kidney transplant, transfer from our research center, loss to follow-up, and death), the differences in endpoints events between the two groups were still statistically significant (p = 0.009, p < 0.001, respectively). Conclusions PPIs was associated with an increased risk of first pneumonia and PD-related peritonitis events in PD patients, which reminds clinicians to be cautious when prescribing acid-suppressing drugs for PD patients.
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Affiliation(s)
- Yujing Zhang
- Department of Nephrology, The Second Affiliated Hospital Guangzhou Medical University, Guangzhou, China
| | - Jiao Li
- Department of Nephrology, The Second Affiliated Hospital Guangzhou Medical University, Guangzhou, China.,Department of Cardiology, The Second Affiliated Hospital Guangzhou Medical University, Guangzhou, China
| | - Zijun Chen
- Department of Nephrology, Affiliated Dongguan People's Hospital Southern Medical University, Guangdong, China
| | - Lingling Liu
- Department of General Medicine, The Third Affiliated Hospital Sun Yat-sen University, Guangzhou, China
| | - Xiaojiang Zhan
- Department of Nephrology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Fenfen Peng
- Department of Nephrology, Zhujiang Hospital Southern Medical University, Guangzhou, China
| | - Qian Zhou
- Department of Medical Statistics, Clinical Trials Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xianfeng Wu
- Department of Nephrology, Affiliated Sixth People's Hospital Shanghai Jiao Tong University, Shanghai, China
| | - Yingsi Zeng
- Department of Nephrology, The Second Affiliated Hospital Guangzhou Medical University, Guangzhou, China
| | - Liya Zhu
- Department of Nephrology, The Second Affiliated Hospital Guangzhou Medical University, Guangzhou, China
| | - Yuxin Xie
- Department of Nephrology, The Second Affiliated Hospital Guangzhou Medical University, Guangzhou, China
| | - Xiaochun Lai
- Department of Nephrology, The Second Affiliated Hospital Guangzhou Medical University, Guangzhou, China
| | - Zebin Wang
- Department of Nephrology, The Second Affiliated Hospital Guangzhou Medical University, Guangzhou, China
| | - Yueqiang Wen
- Department of Nephrology, The Second Affiliated Hospital Guangzhou Medical University, Guangzhou, China
| | - Xiaoran Feng
- Department of Nephrology, Jiujiang NO.1 people's Hospital, Jiujiang, China
| | - Jianbo Liang
- Department of Nephrology, The Second Affiliated Hospital Guangzhou Medical University, Guangzhou, China
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16
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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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17
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Chinzon D, Domingues G, Tosetto N, Perrotti M. SAFETY OF LONG-TERM PROTON PUMP INHIBITORS: FACTS AND MYTHS. ARQUIVOS DE GASTROENTEROLOGIA 2022; 59:219-225. [PMID: 35830032 DOI: 10.1590/s0004-2803.202202000-40] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 01/06/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND Proton pump inhibitors (PPIs) are one of the most prescribed drugs in the world. Frequent use and long-term maintenance of these drugs drew the attention of researchers for sporadic adverse effects reports. OBJECTIVE The purpose of this narrative review is to discuss appropriate data and causality related to these adverse events and PPIs. METHODS A narrative review was conducted by systematizing information about safety and adverse events on PPIs from 2015 to 2020. A structured search on Pubmed was performed to identify systematic reviews and meta-analysis investigating the following situations: a) gastric cancer; b) micronutrients deficiency; c) acid rebound; d) infections; e) fractures; f) dementia; g) kidney disease; and h) sudden death and cardiovascular changes. RESULTS Recent studies have potentially associated PPIs with some adverse events as osteoporosis-related fractures. There are also reports of intestinal infections, including Clostridium difficile, besides poor vitamins absorption and minerals such as vitamin B12, magnesium, and iron. Furthermore, there are some dementia, pneumonia, kidney disease, myocardial infarction, and stroke reports. For kidney diseases, studies consistently suggest that the use of PPI may be associated with an increased risk of adverse kidney events, especially in the elderly, with long-term PPI use and pre-existing kidney disease. Another additional question is whether chronic PPI use would also lead to the onset of gastric cancer. The abrupt discontinuation of PPIs is also related to increased gastric acid production above pre-PPI treatment levels; this phenomenon is called acid rebound. CONCLUSION The key to mitigate adverse effects is the rational use of PPIs at the lowest effective dose and in the shortest possible duration. Although these adverse effects have a potential clinical impact, their causal association is still subject to validation.
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Affiliation(s)
- Decio Chinzon
- Faculdade de Medicina da Universidade de São Paulo, Departamento de Gastroenterologia, São Paulo, SP, Brasil
| | - Gerson Domingues
- Faculdade de Medicina da Universidade do Estado do Rio Janeiro, Departamento de Gastroenterologia, Rio de Janeiro, RJ, Brasil
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18
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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] [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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19
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Veettil SK, Sadoyu S, Bald EM, Chandran VP, Khuu SAT, Pitak P, Lee YY, Nair AB, Antony PT, Ford AC, Chaiyakunapruk N. Association of proton-pump inhibitor use with adverse health outcomes: A systematic umbrella review of meta-analyses of cohort studies and randomised controlled trials. Br J Clin Pharmacol 2022; 88:1551-1566. [PMID: 34622475 DOI: 10.1111/bcp.15103] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 09/20/2021] [Accepted: 09/22/2021] [Indexed: 12/13/2022] Open
Abstract
AIMS The aim was to perform an umbrella review to summarise the existing evidence on proton-pump inhibitor (PPI) use and adverse outcomes and to grade the certainty of evidence. METHODS Electronic databases were searched up to July 2021 for meta-analyses of cohort studies and/or randomised controlled trials (RCTs). Summary effect sizes from a random-effects model, between-study heterogeneity, 95% prediction interval, small-study effect, excess significance and credibility ceilings were devised to classify the credibility of evidence from meta-analyses of cohort studies, whereas the GRADE approach was used for meta-analyses of RCTs. RESULTS In meta-analyses of cohort studies, 52 of the 91 examined associations were statistically significant (P ≤ .05). Convincing evidence emerged from main analysis for the association between PPI use and risk of all-site fracture and chronic kidney disease in the elderly population. However, none of these associations remained supported by convincing evidence after sensitivity analyses. The use of PPI is also associated with an increased risk of mortality due to COVID-19 infection and other related adverse outcomes, but the quality of evidence was weak. In meta-analyses of RCTs, 38 of the 63 examined associations were statistically significant. However, no associations were supported by high or moderate-quality evidence. CONCLUSION This study's findings imply that most putative adverse outcomes associated with PPI use may not be supported by high-quality evidence and are likely to have been affected by underlying confounding factors. Future research is needed to confirm the causal association between PPI use and risk of fracture and chronic kidney disease.
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Affiliation(s)
- Sajesh K Veettil
- Department of Pharmacotherapy, College of Pharmacy, University of Utah, Salt Lake City, UT, USA
| | - Saranrat Sadoyu
- Department of Pharmacy, Pakchongnana Hospital, Pakchong, Thailand
| | - Elizabeth M Bald
- College of Pharmacy, University of Utah, Salt Lake City, UT, USA
| | - Viji P Chandran
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | | | | | - Yeong Yeh Lee
- School of Medical Sciences, Universiti Sains Malaysia, Kota Bharu, Malaysia
- GI Function and Motility Unit, Hospital USM, Universiti Sains Malaysia, Kota Bharu, Malaysia
| | - Athira Balakrishnan Nair
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Paul T Antony
- Department of Rheumatology, Amala Institute of Medical Sciences, Kerala, India
| | - Alexander C Ford
- Leeds Gastroenterology Institute, St. James's University Hospital, Leeds, UK
- Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, UK
| | - Nathorn Chaiyakunapruk
- Department of Pharmacotherapy, College of Pharmacy, University of Utah, Salt Lake City, UT, USA
- School of Pharmacy, University of Wisconsin, Madison, WI, USA
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20
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ACG Clinical Guideline for the Diagnosis and Management of Gastroesophageal Reflux Disease. Am J Gastroenterol 2022; 117:27-56. [PMID: 34807007 PMCID: PMC8754510 DOI: 10.14309/ajg.0000000000001538] [Citation(s) in RCA: 377] [Impact Index Per Article: 125.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 08/30/2021] [Indexed: 01/30/2023]
Abstract
Gastroesophageal reflux disease (GERD) continues to be among the most common diseases seen by gastroenterologists, surgeons, and primary care physicians. Our understanding of the varied presentations of GERD, enhancements in diagnostic testing, and approach to patient management have evolved. During this time, scrutiny of proton pump inhibitors (PPIs) has increased considerably. Although PPIs remain the medical treatment of choice for GERD, multiple publications have raised questions about adverse events, raising doubts about the safety of long-term use and increasing concern about overprescribing of PPIs. New data regarding the potential for surgical and endoscopic interventions have emerged. In this new document, we provide updated, evidence-based recommendations and practical guidance for the evaluation and management of GERD, including pharmacologic, lifestyle, surgical, and endoscopic management. The Grading of Recommendations, Assessment, Development, and Evaluation system was used to evaluate the evidence and the strength of recommendations. Key concepts and suggestions that as of this writing do not have sufficient evidence to grade are also provided.
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21
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Walia N, Rao N, Garrett M, Yates K, Malone S, Holmes C. Proton pump inhibitor use and the risk of peritoneal dialysis associated peritonitis. Intern Med J 2021; 53:397-403. [PMID: 34719853 DOI: 10.1111/imj.15601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 10/28/2021] [Accepted: 10/28/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND The use of proton-pump inhibitors (PPI) has been associated with an increased risk of developing spontaneous bacterial peritonitis in patients with cirrhosis. Whether PPI use confers a similar risk in developing peritonitis in peritoneal dialysis (PD) patients remains unclear. METHODS Patients on PD were retrospectively identified. Data such as PPI use during PD, underlying diagnoses, comorbidities, and baseline serum tests were collected. Univariable and multivariable analysis was conducted using logistic regression to assess whether PPI use and other factors were associated with PD peritonitis. RESULTS 57 patients were identified with a median(interquartile range(IQR)) age of 65.0(51.5-74.0) years. The median(IQR) time on PD was 29.0(17.5-45.0) months. 28 patients were on a PPI during PD. 57% of the PPI group went on to develop peritonitis, compared to 31% of patients without PPI exposure (OR=2.96, 95% CI:[1.00, 8.78], p=0.050). Months on PD (OR=1.03, 95% CI:[1.00, 1.06], p=0.026), serum urea (OR=0.88, 95% CI:[0.80, 0.97], p=0.017), congestive cardiac failure (OR=5.44, 95% CI:[1.29, 23.00], p=0.021) and renovascular disease (OR=14.59, 95% CI:[1.68, 126.67], p=0.015) were identified as possible risk factors for peritonitis on univariable analysis. Following adjustment for covariates, serum urea, but not PPI use, was associated with PD peritonitis (OR=0.87, 95% CI:[0.78,0.98], p=0.020). CONCLUSION PPI use during PD was not associated with peritonitis. Due to the small number of patients and the limited number of studies investigating the effect of PPI use on PD peritonitis, further research is needed. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- N Walia
- Renal Department, Bendigo Health, VIC, Australia.,Austin Health, Melbourne, VIC, Australia
| | - N Rao
- Renal Department, Bendigo Health, VIC, Australia
| | - M Garrett
- Home Dialysis, Bendigo Health, Bendigo, VIC, Australia
| | - K Yates
- Home Dialysis, Bendigo Health, Bendigo, VIC, Australia
| | - S Malone
- Home Dialysis, Bendigo Health, Bendigo, VIC, Australia
| | - C Holmes
- Renal Department, Bendigo Health, VIC, Australia.,Monash Rural Health, Monash University, Bendigo, VIC, Australia
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22
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Kuo CJ, Lin CY, Chen CW, Hsu CY, Hsieh SY, Chiu CT, Lin WR. Risk of Enteric Infection in Patients with Gastric Acid Supressive Drugs: A Population-Based Case-Control Study. J Pers Med 2021; 11:jpm11111063. [PMID: 34834415 PMCID: PMC8621954 DOI: 10.3390/jpm11111063] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 09/20/2021] [Accepted: 10/19/2021] [Indexed: 12/13/2022] Open
Abstract
Long-term use of gastric-acid-suppressive drugs is known to be associated with several adverse effects. However, the association between enteric infection and acid suppression therapy is still uncertain. This study aimed to evaluate the association between gastric acid suppression and the risk of enteric infection. Materials and Methods: We conducted a population-based case-control study using the data from Chang Gung Research Database (CGRD) in Taiwan. Between January 2008 and December 2017, a total of 154,590 adult inpatients (age > 18) were identified. A pool of potential eligible controls according to four propensity scores matching by sex, age, and index year were extracted (n = 89,925). Subjects with missing data or who received less than 7 days of proton pump inhibitors (PPIs) and/or H2-receptor antagonists (H2RAs) were excluded. Finally, 17,186 cases and 69,708 corresponding controls were selected for analysis. The use of PPIs and H2RAs, the result of microbiological samples, and co-morbidity conditions have been analyzed. Confounders were controlled by conditional logistic regression. Results: 32.84% of patients in the case group used PPIs, compared with 7.48% in the control group. Of patients in the case group, 9.9% used H2RAs, compared with 6.9% in the control group. Of patients in the case group, 8.3% used a combination of PPIs and H2RAs, compared with 2.7% in the control group. The most common etiological pathogens were Enterococcus (44.8%), Clostridioides difficile (34.5%), and Salmonella spp. (10.2%). The adjusted odds ratio (OR) for PPI use with enteric infection was 5.526 (95% confidence interval [CI], 5.274–5.791). For H2RAs, the adjusted odds ratio was 1.339 (95% confidence interval [CI], 1.261–1.424). Compared to the control group, persons with enteric infection had more frequent acid-suppressive agent usage. Conclusions: This study demonstrates that gastric-acid-suppressive drug use is associated with an increased risk of enteric infection after adjusting for potential biases and confounders.
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Affiliation(s)
- Chia-Jung Kuo
- Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (C.-J.K.); (C.-Y.L.); (C.-W.C.); (S.-Y.H.); (C.-T.C.)
- Department of Gastroenterology, Chang Gung Memorial Hospital at Linkou, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
- Chang Gung Microbiota Therapy Center, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Cheng-Yu Lin
- Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (C.-J.K.); (C.-Y.L.); (C.-W.C.); (S.-Y.H.); (C.-T.C.)
- Department of Gastroenterology, Chang Gung Memorial Hospital at Linkou, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Chun-Wei Chen
- Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (C.-J.K.); (C.-Y.L.); (C.-W.C.); (S.-Y.H.); (C.-T.C.)
- Department of Gastroenterology, Chang Gung Memorial Hospital at Linkou, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Chiu-Yi Hsu
- Center for Big Data Analytics and Statistics, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan;
| | - Sen-Yung Hsieh
- Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (C.-J.K.); (C.-Y.L.); (C.-W.C.); (S.-Y.H.); (C.-T.C.)
- Department of Gastroenterology, Chang Gung Memorial Hospital at Linkou, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Cheng-Tang Chiu
- Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (C.-J.K.); (C.-Y.L.); (C.-W.C.); (S.-Y.H.); (C.-T.C.)
- Department of Gastroenterology, Chang Gung Memorial Hospital at Linkou, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
- Chang Gung Microbiota Therapy Center, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Wey-Ran Lin
- Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (C.-J.K.); (C.-Y.L.); (C.-W.C.); (S.-Y.H.); (C.-T.C.)
- Department of Gastroenterology, Chang Gung Memorial Hospital at Linkou, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, 5, Fushin Street, Kweishan, Taoyuan 333, Taiwan
- Correspondence: ; Tel.: +886-3-3281200 (ext. 8102); Fax: +886-3-3272236
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23
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Hakuta R, Nakai Y, Hamada T, Nomura Y, Saito T, Takahara N, Mizuno S, Kogure H, Moriya K, Koike K. Use of proton pump inhibitors and cholangitis complicated with multi-drug resistant bacteria. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2021; 29:230-238. [PMID: 34382333 DOI: 10.1002/jhbp.1035] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 07/13/2021] [Accepted: 07/30/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND Multidrug-resistant bacteria (MDRB) has rapidly spread worldwide and become a serious problem. Proton pump inhibitors (PPIs) are a class of commonly prescribed medications, but recent studies have suggested the increased risk of infection with MDRB in PPI users. We evaluated the association between PPI use and incidence of cholangitis with MDRB. METHODS Consecutive patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) between January 2010 and August 2019 were included in this retrospective study. The incidence of cholangitis with MDRB was compared between regular and non-regular PPI users. RESULTS A total of 1224 regular PPI users and 1528 non-regular PPI users were identified. There was no clinically significant difference in age and sex between the groups. Indication of ERCP was different between the groups. The number of ERCP sessions during the study periods was higher in regular PPI users. The incidence of cholangitis with MDRB was significantly higher in regular PPI users (3.0% vs 1.1%; P < .001). Multivariable-adjusted odds ratio for cholangitis with MDRB comparing regular PPI users to non-regular users was 2.19 (95% confidence interval 1.20-4.00; P = .01). CONCLUSIONS Regular PPI use was associated with a higher risk of cholangitis with MDRB.
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Affiliation(s)
- Ryunosuke Hakuta
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Department of Endoscopy and Endoscopic Surgery, The University of Tokyo, Tokyo, Japan
| | - Yousuke Nakai
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Department of Endoscopy and Endoscopic Surgery, The University of Tokyo, Tokyo, Japan
| | - Tsuyoshi Hamada
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yusuke Nomura
- Department of Infection Control and Prevention, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tomotaka Saito
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Naminatsu Takahara
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Suguru Mizuno
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hirofumi Kogure
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kyoji Moriya
- Department of Infection Control and Prevention, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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24
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Shaevitz MH, Moore GE, Fulkerson CM. A prospective, randomized, placebo-controlled, double-blinded clinical trial comparing the incidence and severity of gastrointestinal adverse events in dogs with cancer treated with piroxicam alone or in combination with omeprazole or famotidine. J Am Vet Med Assoc 2021; 259:385-391. [PMID: 34337965 DOI: 10.2460/javma.259.4.385] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To assess the impact of prophylactic omeprazole and famotidine on the incidence and severity of gastrointestinal (GI) adverse events (AEs) in dogs with cancer treated with single agent piroxicam. ANIMALS 39 dogs with a cytologic or histologic diagnosis of cancer with no history of GI disease and received piroxicam. PROCEDURES A prospective, randomized, placebo-controlled, double-blinded clinical trial was performed. All dogs received piroxicam (0.3 mg/kg [0.14 mg/lb], PO, q 24 h) and either omeprazole (1 mg/kg [0.45 mg/lb], PO, q 12 h), famotidine (1 mg/kg, PO, q 12 h), or placebo (lactose; PO, q 12 h). Monthly assessments of GI AEs were performed and scored by using the Veterinary Comparative Oncology Group's Common Terminology Criteria for Adverse Events (version 1.1). RESULTS Compared with dogs in the placebo group, more dogs in the omeprazole group (84.6% vs 36.4%) and famotidine group (80.0% vs 36.4%) experienced GI AEs by day 56. The severity of GI AEs was higher in the omeprazole group, compared with the placebo group. CONCLUSIONS AND CLINICAL RELEVANCE Omeprazole was not helpful in reducing the frequency or severity of GI AEs and was associated with more frequent and severer GI AEs in dogs with cancer treated with single agent piroxicam. Proton-pump inhibitors and H2-receptor antagonists should not be prescribed as prophylaxis with NSAIDs for dogs with cancer.
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25
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Shaikh BA, Shaikh ZA, Shah AH, Kumar A. Determining the Risk of Spontaneous Bacterial Peritonitis due to increase use of Proton Pump Inhibitors among cirrhotic patients with ascites. Pak J Med Sci 2021; 37:1075-1079. [PMID: 34290786 PMCID: PMC8281193 DOI: 10.12669/pjms.37.4.3476] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 10/12/2020] [Accepted: 03/25/2021] [Indexed: 12/19/2022] Open
Abstract
Objectives The current study aimed to determine the Spontaneous Bacterial Peritonitis (SBP) risk due to increased use of Proton Pump Inhibitors (PPIs) among cirrhotic patients with ascites. Methods This retrospective case-control study was conducted at Chandka Medical College & Hospital, Larkana from March 2013 to February 2014, involving 215 cirrhotic patients with ascites. Paracentesis was performed to distinguish cirrhotic patients with SBP and Polymorphonuclear Neutrophil (PMN) count ≥ 250 neutrophils/mm3 (cases) and non-SBP with PMN count < 250 neutrophils/mm3 (controls). The demographic details, history of PPIs use before admission and duration of Chronic Liver Disease (CLD) were inquired and statistical analysis was carried through SPSS Version 23.0. Results Increased pre-hospital PPI intake was observed among cirrhotic patients with SBP (69.8%) as compared to those without SBP (48.8%; p = 0.014). The mean duration of PPI use was 19.16 ± 4.772 days, and it was more significant among older cirrhotic patients (p < 0.05). Increased duration of CLD was observed among PPI users, i.e. 20.47 ± 6.305 months vs. 18.95 ± 5.527 months among non-PPI users (p < 0.05). Conclusions Our results show that cirrhotic patients with ascites consuming PPIs are more likely to develop SBP as compared to non-PPI users.
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Affiliation(s)
- Bashir Ahmed Shaikh
- Bashir Ahmed Shaikh, FCPS, FRCP. Chandka Medical College Hospital, Shaheed Mohtarma Benazir Bhutto Medical University (SMBBMU), Larkana, Sindh, Pakistan
| | - Zahid Ali Shaikh
- Zahid Ali Shaikh, FCPS. Chandka Medical College Hospital, Shaheed Mohtarma Benazir Bhutto Medical University (SMBBMU), Larkana, Sindh, Pakistan
| | - Aftab Hussain Shah
- Aftab Hussain Shah, FCPS, FRCP. Chandka Medical College Hospital, Shaheed Mohtarma Benazir Bhutto Medical University (SMBBMU), Larkana, Sindh, Pakistan
| | - Aneel Kumar
- Aneel Kumar, FCPS. Chandka Medical College Hospital, Shaheed Mohtarma Benazir Bhutto Medical University (SMBBMU), Larkana, Sindh, Pakistan
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26
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Proton pump inhibitor use and mortality in patients with cirrhosis: a meta-analysis of cohort studies. Biosci Rep 2021; 40:224145. [PMID: 32406491 PMCID: PMC7276520 DOI: 10.1042/bsr20193890] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 05/12/2020] [Accepted: 05/13/2020] [Indexed: 02/06/2023] Open
Abstract
Background: Proton pump inhibitor (PPI) is commonly used in patients with cirrhosis. However, some studies demonstrated that PPI use was associated with adverse outcome in patients with cirrhosis. We aimed to perform a meta-analysis of cohort studies to evaluate the association between PPI use and mortality in cirrhotic patients. Methods: Relevant studies were obtained via search of PubMed and Embase databases. A randomized-effect model was used to pool the results. Subgroup analyses were performed to evaluate the source of heterogeneity. Results: Overall, 21 cohort studies with 20,899 patients and 7457 death events were included. The pooled results with a randomized-effect model showed that PPI use was associated with significantly increased risk of mortality in patients with cirrhosis (adjusted relative risk [RR] = RR: 1.39, P<0.001) with considerable heterogeneity (I2=73%). Subgroup analyses showed that characteristics such as patient ethnicity, sample size, definition of PPI use, and complications of patients did not affect the association. However, the association between PPI use and mortality was independent of study characteristics including patient ethnicity, sample size, complications, definition of PPI use, and follow-up duration. However, the association between PPI use and mortality in cirrhotic patients was significant in retrospective studies (RR: 1.40, P<0.001), but not in prospective studies (RR: 1.34, P=0.33). Conclusions: PPI use may be associated with moderately increased mortality in cirrhotic patients. Although prospective cohort studies are needed to validate our findings, PPI should only prescribed to cirrhotic patients with indications for the treatment.
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Anti-Acid Drug Treatment Induces Changes in the Gut Microbiome Composition of Hemodialysis Patients. Microorganisms 2021; 9:microorganisms9020286. [PMID: 33573326 PMCID: PMC7910989 DOI: 10.3390/microorganisms9020286] [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] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 01/15/2021] [Accepted: 01/26/2021] [Indexed: 12/13/2022] Open
Abstract
Anti-acid drugs, proton pump inhibitor (PPI) and histamine-2 blocker (H2-blocker), are commonly prescribed to treat gastrointestinal disorders. These anti-acid drugs alter gut microbiota in the general population, but their effects are not known in hemodialysis patients. Hence, we investigated the microbiota composition in hemodialysis patients treated with PPIs or H2-blocker. Among 193 hemodialysis patients, we identified 32 H2-blocker users, 23 PPI users, and 138 no anti-acid drug subjects. Fecal samples were obtained to analyze the gut microbiome using 16S RNA amplicon sequencing. Differences in the microbial composition of the H2-blocker users, PPI users, and controls were assessed using linear discriminant analysis effect size and the random forest algorithm. The species richness or evenness (α-diversity) was similar among the three groups, whereas the inter-individual diversity (β-diversity) was different between H2-blocker users, PPI users, and controls. Hemodialysis patients treated with H2-blocker and PPIs had a higher microbial dysbiosis index than the controls, with a significant increase in the genera Provetella 2, Phascolarctobacterium, Christensenellaceae R-7 group, and Eubacterium oxidoreducens group in H2-blocker users, and Streptococcus and Veillonella in PPI users. In addition, compared to the H2-blocker users, there was a significant enrichment of the genera Streptococcus in PPI users, as confirmed by the random forest analysis and the confounder-adjusted regression model. In conclusion, PPIs significantly changed the gut microbiota composition in hemodialysis patients compared to H2-blocker users or controls. Importantly, the Streptococcus genus was significantly increased in PPI treatment. These findings caution against the overuse of PPIs.
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28
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Labenz C, Kostev K, Galle PR, Wörns MA, Labenz J, Tanislav C, Adarkwah CC. Proton pump inhibitor use is associated with a variety of infections in patients with liver cirrhosis. Medicine (Baltimore) 2020; 99:e23436. [PMID: 33327272 PMCID: PMC7738005 DOI: 10.1097/md.0000000000023436] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
There is evidence that intake of proton pump inhibitors (PPI) increases the risk for spontaneous bacterial peritonitis (SBP) in patients with liver cirrhosis. However, data regarding the impact of PPI intake on occurrence of infections other than SBP are still lacking.We hypothesized that PPI use is associated with a higher rate of infections other than SBP in patients with liver cirrhosis.The current case-control study sample included patients with liver cirrhosis from the Disease Analyzer database (IQVIA), which compiles data such as risk factors, drug prescriptions and diagnoses obtained from general practitioners and specialists in Germany. In total, 2,823 patients with infections were matched with 2,823 patients without infections by propensity scores. For quantification of PPI use the prescribed quantity of PPI during the past 12 months before index date was analyzed.Frequency of PPI users was significantly higher in patients with infections than in patients without infections (47.9% vs 37.9%). In regression analysis, PPI use was significantly associated with the occurrence of infections overall (OR 1.55, 95% CI 1.39-1.72, P < .001), and associated with the occurrence of lower respiratory tract infections, urinary tract infections and infectious gastroenteritis. There was no association between PPI use and skin infections. Pantoprazole and omeprazole were the most frequently prescribed PPIs and were both independently associated with the occurrence of infections.PPI use may be associated with infections other than SBP in patients with liver cirrhosis. Prescription of PPI should be limited to patients with a clear indication.
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Affiliation(s)
- Christian Labenz
- Department of Internal Medicine I, University Medical Centre of the Johannes Gutenberg-University, Mainz
| | | | - Peter R. Galle
- Department of Internal Medicine I, University Medical Centre of the Johannes Gutenberg-University, Mainz
| | - Marcus-Alexander Wörns
- Department of Internal Medicine I, University Medical Centre of the Johannes Gutenberg-University, Mainz
| | | | | | - Charles Christian Adarkwah
- Department of General Practice and Family Medicine, Philipps-University, Marburg
- CAPHRI School for Public Health and Primary Care, Department of Health Services Research, Maastricht University, Maastricht, The Netherlands
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Association between anti-acid therapies and advanced fibrosis in type 2 diabetics with biopsy-proven non-alcoholic fatty liver disease. Indian J Gastroenterol 2020; 39:591-598. [PMID: 33219985 PMCID: PMC9254737 DOI: 10.1007/s12664-020-01087-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 08/27/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUNDS AND AIMS Data on associations of antacid therapies with advanced fibrosis (AF) in patients with non-alcoholic fatty liver disease (NAFLD) are limited. We aimed to assess the association of histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) with AF in NAFLD patients with underlying type 2 diabetes (T2D). METHODS We retrospectively reviewed patient's charts with T2D who had a liver biopsy for suspected NAFLD. Fibrosis stages were determined as F0-F4, AF being F3-4. Laboratory data and use of various medications within 24 months of liver biopsies were used for the analysis. Univariable and multivariable logistic regression analyses were performed to assess any association. RESULTS Our cohort consisted of 1008 T2D patients with biopsy-proven NAFLD. Sixty-six percent were female, 86.2% were Caucasian, and median HbA1C was 6.4%. AF was present in 32% of the patients. Thirty-four percent were on H2RAs and 60.6% were on PPI therapy (p < 0.001) for a median duration of 3.6 [0.10, 3.8] (p = 0.20) and 45.6 [0.80, 15.4] (p = 0.17) months, respectively. On multivariable logistic regression analysis being on H2RAs was associated with a 68% lower risk of AF (odds ratio [OR] [95%CI]: 0.32 [0.24, 0.44]) (p < 0.001), but use of PPIs showed a trend towards higher risk of AF (OR [95%CI]: 1.4 [1.00, 1.8]) (p = 0.053). CONCLUSION Our study suggests that H2RAs are associated with lower risk of AF in NAFLD patients with underlying diabetes and should be considered as the first-line antacid therapy in these patients. Risk stratification should be done if PPIs are indicated in high-risk diabetics with NAFLD.
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30
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Macke L, Schulz C, Koletzko L, Malfertheiner P. Systematic review: the effects of proton pump inhibitors on the microbiome of the digestive tract-evidence from next-generation sequencing studies. Aliment Pharmacol Ther 2020; 51:505-526. [PMID: 31990420 DOI: 10.1111/apt.15604] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Revised: 09/03/2019] [Accepted: 11/13/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Proton pump inhibitors (PPI) are widely used to treat acid-related disorders of the upper gastrointestinal tract. However, large observational studies have raised concerns about PPI-associated adverse events. In recent years, data from next-generation sequencing studies suggested that PPIs affect the composition of the intestinal microbiota, while a balanced gut microbiome is essential for maintaining health. AIM To review the available evidence from next-generation sequencing studies on the effect of PPIs on the intestinal microbiome and to discuss possible implications of PPI-induced dysbiosis in health and disease. METHODS A systematic review was conducted following the recommendations of the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement. A PubMed query yielded 197 results. 19 publications met the prespecified eligibility criteria. RESULTS Twelve observational study cohorts with 708 PPI users and 11 interventional cohorts with 180 PPI users were included in the review. In most studies, PPI treatment did not affect microbiological richness and diversity, but was associated with distinct taxonomic alterations: In the upper gastrointestinal tract, PPI users showed overgrowth of orally derived bacteria, mostly Streptococcaceae (findings based on six independent cohorts with 126 PPI users). In faecal samples, PPIs increased multiple taxa from the orders Bacillales (eg, Staphylococcaceae), Lactobacillales (eg, Enterococcaceae, Lactobacillaceae, Streptococcaceae) and Actinomycetales (eg, Actinomycetaceae, Micrococcaceae), the families Pasteurellaceae and Enterobacteriaceae and the genus Veillonella. Taxa decreased by PPIs include Bifidobacteriaceae, Ruminococcaceae, Lachnospiraceae and Mollicutes (findings in faecal samples based on 19 independent cohorts with 790 PPI users). CONCLUSION PPI use is associated with moderate alterations to upper and distal gut microbiota. The available data suggest that PPI-induced hypochlorhydria facilitates colonization of more distal parts of the digestive tract by upper gastrointestinal microbiota.
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Affiliation(s)
- Lukas Macke
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Christian Schulz
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Leandra Koletzko
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Peter Malfertheiner
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany.,Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
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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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32
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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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Teng S, Hsu C, Hsu C, Shin J, Huang J. Association of gastric acid suppressants with the development of spontaneous bacterial peritonitis in cirrhotic patients with ascites. ADVANCES IN DIGESTIVE MEDICINE 2019. [DOI: 10.1002/aid2.13164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Shih‐Lun Teng
- Division of Gastroenterology, Department of Internal Medicine Cheng Ching Hospital, Chung Kang Branch Taichung Taiwan
| | - Che‐Han Hsu
- Department of Healthcare Administration Central Taiwan University of Sciences and Technology Taichung Taiwan
| | - Chia‐Chun Hsu
- Department of Healthcare Administration Central Taiwan University of Sciences and Technology Taichung Taiwan
| | - Jeng‐Shiann Shin
- Division of Gastroenterology, Department of Internal Medicine Cheng Ching Hospital, Chung Kang Branch Taichung Taiwan
| | - Jen‐Chieh Huang
- Division of Gastroenterology, Department of Internal Medicine Cheng Ching Hospital, Chung Kang Branch Taichung Taiwan
- Department of Health Business Administration Hung Kuang University Taichung Taiwan
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The Phylogeny and Biological Function of Gastric Juice-Microbiological Consequences of Removing Gastric Acid. Int J Mol Sci 2019; 20:ijms20236031. [PMID: 31795477 PMCID: PMC6928904 DOI: 10.3390/ijms20236031] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Revised: 11/24/2019] [Accepted: 11/25/2019] [Indexed: 12/15/2022] Open
Abstract
Gastric juice is a unique combination of hydrochloric acid (HCl), lipase, and pepsin. Acidic gastric juice is found in all vertebrates, and its main function is to inactivate microorganisms. The phylogenetic preservation of this energy-consuming and, at times, hazardous function (acid-related diseases) reflects its biological importance. Proton pump inhibitors (PPIs) are one of the most widely used drugs in the world. Due to the reduced prevalence of Helicobacter pylori infection as well as the increased use of inhibitors of gastric acid secretion, the latter has become the most important cause of gastric hypoacidity. In the present manuscript, we review the microbiological consequences of removing gastric acidity. The resulting susceptibility to infections has not been studied extensively, and focus has mainly been restricted to bacterial and parasitic agents only. The strongest evidence concerning the relationship between hypochlorhydria and predisposition to infections relates to bacterial infections affecting the gastrointestinal tract. However, several other clinical settings with increased susceptibility to infections due to inhibited gastric acidity are discussed. We also discuss the impact of hypochlorhydria on the gut microbiome.
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Abstract
A substantial volume of literature exists linking proton pump inhibitor (PPI) use with a multitude of serious adverse events. There is uncertainty, however, over whether these associations are clinically important. Excessive concern about PPI-related adverse events may leave patients at risk of harm by leaving acid-related upper gastrointestinal disease untreated. Conversely, the risk of treatments may outweigh the benefits if any of the purported adverse events are directly caused by PPI use; this is of particular concern where indications for PPI use are not present. In this paper, we review the studies which have reported associations between adverse events and PPI use, discuss the proposed mechanisms of action, grade the confidence in whether these associations are truly causal, and provide advice regarding balancing the benefits of PPI use against their possible harms.
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Affiliation(s)
- Evan Elias
- Section of Gastroenterology, Department of Internal Medicine, Rady School of Medicine, University of Manitoba, 805G-715 McDermot Avenue, Winnipeg, MB, R3E 3P4, Canada
| | - Laura E Targownik
- Section of Gastroenterology, Department of Internal Medicine, Rady School of Medicine, University of Manitoba, 805G-715 McDermot Avenue, Winnipeg, MB, R3E 3P4, Canada.
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Properly prescribed, proton pump inhibitors are largely safe, but precautions are needed to prevent potential problems, overuse and misuse. DRUGS & THERAPY PERSPECTIVES 2019. [DOI: 10.1007/s40267-019-00671-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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Lanas-Gimeno A, Hijos G, Lanas Á. Proton pump inhibitors, adverse events and increased risk of mortality. Expert Opin Drug Saf 2019; 18:1043-1053. [DOI: 10.1080/14740338.2019.1664470] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
| | - Gonzalo Hijos
- Servicio de Aparato Digestivo, Hospital Clínico Universitario, Zaragoza, Spain
- Instituto de Investigación Sanitaria Aragón, Zaragoza, Spain
| | - Ángel Lanas
- Servicio de Aparato Digestivo, Hospital Clínico Universitario, Zaragoza, Spain
- Instituto de Investigación Sanitaria Aragón, Zaragoza, Spain
- CIBERehd, Madrid, Spain
- Department of Medicine, Universidad de Zaragoza, Zaragoza, Spain
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Pineda-Peña EA, Meza-Pérez DG, Chávez-Piña AE, Velázquez-Moyado JA, Tavares-Carvalho JC, Navarrete Castro A. Pharmacodynamic interaction of 3α-hydroxymasticadienonic acid and diligustilide against indomethacin-induced gastric damage in rats. Drug Dev Res 2019; 80:585-594. [PMID: 30957263 DOI: 10.1002/ddr.21535] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 02/13/2019] [Accepted: 03/17/2019] [Indexed: 01/02/2025]
Abstract
The aims of the study were to evaluate the pharmacodynamic interaction between 3α-hydroxymasticadienonic acid and diligustilide (DLG), isolated from the plants Amphiptherygium adstringens and Ligusticum porteri, respectively, using the indomethacin-induced gastric injury model, as well as their individual gastroprotective efficacy in this model. Male Wistar rats were orally administered with 3α-hydroxymasticadienonic acid, DLG or the mixture of 3α-hydroxymasticadienonic acid-DLG (at a fixed-ratio combination of 1:1, 1:3, and 3:1). Thirty minutes later, the gastric damage was induced by a single oral dose of indomethacin (30 mg/kg). Three hours later, the gastric injury (mm2 ) was determined. 3α-hydroxymasticadienonic acid and DLG as individual compounds showed a gastroprotective effect against indomethacin-induced gastric damage (p < .05). The effective dose (ED50 ) values for each compound were 6.96 ± 1.25 mg/kg for 3α-hydroxymasticadienonic acid and 2.63 ± 0.37 mg/kg for DLG. The isobolographic analysis performed showed that the combination exhibited super-additive interaction as the experimental ED50 values (Zexp) were lower than theoretical additive dose values (Zadd; p < .05). Our results identify the super-additive (synergist) interaction between 3α-hydroxymasticadienonic acid and DLG and the gastric safety of both compounds in the indomethacin-induced gastric injury model, suggesting their potential in the future as a strategy to decrease the gastric damage associated to the chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs).
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Affiliation(s)
- Elizabeth A Pineda-Peña
- Facultad de Química, Departamento de Farmacia, Universidad Nacional Autónoma de México, Ciudad Universitaria, Ciudad de México, Mexico
| | - Dulce G Meza-Pérez
- Facultad de Química, Departamento de Farmacia, Universidad Nacional Autónoma de México, Ciudad Universitaria, Ciudad de México, Mexico
| | - Aracely E Chávez-Piña
- Laboratorio de Farmacología, Programa Institucional en Biomedicina Molecular, Escuela, Nacional de Medicina y Homeopatía del Instituto Politécnico Nacional, Ciudad de México, Mexico
| | - Josué A Velázquez-Moyado
- Facultad de Química, Departamento de Farmacia, Universidad Nacional Autónoma de México, Ciudad Universitaria, Ciudad de México, Mexico
- Laboratório de Pesquisa em Fármacos, Curso de Farmácia, Departamento de Ciências Biológicas e da Saúde, Universidade Federal do Amapá, Macapá, Amapá, Brazil
| | - José C Tavares-Carvalho
- Laboratório de Pesquisa em Fármacos, Curso de Farmácia, Departamento de Ciências Biológicas e da Saúde, Universidade Federal do Amapá, Macapá, Amapá, Brazil
| | - Andrés Navarrete Castro
- Facultad de Química, Departamento de Farmacia, Universidad Nacional Autónoma de México, Ciudad Universitaria, Ciudad de México, Mexico
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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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Ribiere S, Guillaumot MA, Barré A, Abou Ali E, Barret M, Chaussade S, Coriat R. Quel est le VRAI risque au long cours des inhibiteurs de la pompe à protons ? Presse Med 2019; 48:503-510. [PMID: 30926204 DOI: 10.1016/j.lpm.2019.02.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Accepted: 02/11/2019] [Indexed: 11/30/2022] Open
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Effects of Proton Pump Inhibitors on the Gastrointestinal Microbiota in Gastroesophageal Reflux Disease. GENOMICS PROTEOMICS & BIOINFORMATICS 2019; 17:52-63. [PMID: 31028880 PMCID: PMC6520915 DOI: 10.1016/j.gpb.2018.12.004] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Revised: 06/28/2018] [Accepted: 12/28/2018] [Indexed: 02/06/2023]
Abstract
Proton pump inhibitors (PPIs) are commonly used to lessen symptoms in patients with gastroesophageal reflux disease (GERD). However, the effects of PPI therapy on the gastrointestinal microbiota in GERD patients remain unclear. We examined the association between the PPI usage and the microbiota present in gastric mucosal and fecal samples from GERD patients and healthy controls (HCs) using 16S rRNA gene sequencing. GERD patients taking PPIs were further divided into short-term and long-term PPI user groups. We showed that PPI administration lowered the relative bacterial diversity of the gastric microbiota in GERD patients. Compared to the non-PPI-user and HC groups, higher abundances of Planococcaceae, Oxalobacteraceae, and Sphingomonadaceae were found in the gastric microbiota from the PPI-user group. In addition, the Methylophilus genus was more highly abundant in the long-term PPI user group than in the short-term PPI-user group. Despite the absence of differences in alpha diversity, there were significant differences in the fecal bacterial composition of between GERD patients taking PPIs and those not taking PPIs. There was a higher abundance of Streptococcaceae, Veillonellaceae, Acidaminococcaceae, Micrococcaceae, and Flavobacteriaceae present in the fecal microbiota from the PPI-user group than those from the non-PPI-user and HC groups. Additionally, a significantly higher abundance of Ruminococcus was found in GERD patients on long-term PPI medication than that on short-term PPI medication. Our study indicates that PPI administration in patients with GERD has a significant effect on the abundance and structure of the gastric mucosal microbiota but only on the composition of the fecal microbiota.
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Zhong HJ, Lin D, Lu ZY, Yang WY, Chen Y. Use of gastric-acid suppressants may be a risk factor for enteric peritonitis in patients undergoing peritoneal dialysis: A meta-analysis. J Clin Pharm Ther 2019; 44:209-215. [PMID: 30332507 DOI: 10.1111/jcpt.12769] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 08/23/2018] [Accepted: 09/13/2018] [Indexed: 12/14/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE Mounting evidence suggests that long-term use of gastric-acid suppressants (GASs) may be associated with adverse effects. Whether GAS use increases the risk of enteric peritonitis in patients undergoing peritoneal dialysis (PD) is not known. The aim of this meta-analysis was to evaluate the association between GAS use and enteric peritonitis in PD patients. METHODS We searched PubMed, Embase and Cochrane Library databases from inception to 23 January 2018 to identify eligible studies. The primary outcome was an association between GAS use and enteric peritonitis in PD patients. RESULTS AND DISCUSSION Six studies involving 829 people were included in this meta-analysis. Pooled data showed that GAS use in PD patients was associated with an increased risk of enteric peritonitis (odds ratio [OR] = 1.27; 95% confidence interval [CI]: 1.02-1.57, I2 = 48%). Subgroup analyses based on GAS type revealed that histamine-2 receptor antagonists (H2 RAs) might increase the risk of enteric peritonitis in PD patients (OR = 1.40; 95% CI: 1.01-1.93; I2 = 8%), but proton pump inhibitors (PPIs) might not (1.13; 0.72-1.77; 6; 34%). WHAT IS NEW AND CONCLUSION Gastric-acid suppressants use might be a risk factor for enteric peritonitis in PD patients. In particular, H2 RAs increased the risk of enteric peritonitis, but PPIs did not. Therefore, to prevent enteric peritonitis, H2 RAs should probably be prescribed with caution for PD patients.
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Affiliation(s)
- Hao-Jie Zhong
- Department of Gastroenterology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangdong, China
- Guangdong Medical University, Guangdong, China
| | - Da Lin
- Department of Gastroenterology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangdong, China
| | - Zhi-Yong Lu
- Department of Dermatology, Qingyuan Hospital of Traditional Chinese Medicine, Guangdong, China
| | | | - Yu Chen
- Department of Gastroenterology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangdong, China
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Fernandes SR, Tato Marinho R. The Dark Side of the Long-Term Use of Proton Pump Inhibitors in Chronic Liver Disease. GE PORTUGUESE JOURNAL OF GASTROENTEROLOGY 2019; 26:79-80. [PMID: 30976610 PMCID: PMC6454383 DOI: 10.1159/000489640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Accepted: 04/26/2018] [Indexed: 06/09/2023]
Affiliation(s)
| | - Rui Tato Marinho
- Serviço de Gastrenterologia e Hepatologia, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, Portugal
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44
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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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Spontaneous bacterial peritonitis - therapeutic challenges in the era of increasing drug resistance of bacteria. Clin Exp Hepatol 2018; 4:224-231. [PMID: 30603669 PMCID: PMC6311748 DOI: 10.5114/ceh.2018.80123] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2018] [Accepted: 11/04/2018] [Indexed: 12/17/2022] Open
Abstract
Spontaneous bacterial peritonitis (SBP) is one of the most common bacterial infections in patients with liver cirrhosis and it significantly contributes to the deterioration of the prognosis and increased risk of mortality. Previous data suggested that the most common pathogens causing SBP are G-negative aerobic bacteria and treatment recommended by the international guidelines (EASL, AASLD) is highly effective. In recent years, due to the widespread use of antibiotic prophylaxis and the increased frequency of hospitalization along with the use of invasive procedures in patients with cirrhosis, the involvement of Gram-positive cocci and multi-drug resistant bacteria in the etiology of SBP is increasing. This is related to the lowering of the effectiveness of the first-line therapy used so far and worsening of the prognosis, increasing in-hospital mortality. In this work we summarize current data on the characteristics of pathogens responsible for SBP in the context of currently recommended treatment regimens.
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Marks SL, Kook PH, Papich MG, Tolbert MK, Willard MD. ACVIM consensus statement: Support for rational administration of gastrointestinal protectants to dogs and cats. J Vet Intern Med 2018; 32:1823-1840. [PMID: 30378711 PMCID: PMC6271318 DOI: 10.1111/jvim.15337] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Revised: 08/24/2018] [Accepted: 09/05/2018] [Indexed: 12/12/2022] Open
Abstract
The gastrointestinal (GI) mucosal barrier is continuously exposed to noxious toxins, reactive oxygen species, microbes, and drugs, leading to the development of inflammatory, erosive, and ultimately ulcerative lesions. This report offers a consensus opinion on the rational administration of GI protectants to dogs and cats, with an emphasis on proton pump inhibitors (PPIs), histamine type-2 receptor antagonists (H2 RAs), misoprostol, and sucralfate. These medications decrease gastric acidity or promote mucosal protective mechanisms, transforming the management of dyspepsia, peptic ulceration, and gastroesophageal reflux disease. In contrast to guidelines that have been established in people for the optimal treatment of gastroduodenal ulcers and gastroesophageal reflux disease, effective clinical dosages of antisecretory drugs have not been well established in the dog and cat to date. Similar to the situation in human medicine, practice of inappropriate prescription of acid suppressants is also commonplace in veterinary medicine. This report challenges the dogma and clinical practice of administering GI protectants for the routine management of gastritis, pancreatitis, hepatic disease, and renal disease in dogs and cats lacking additional risk factors for ulceration or concerns for GI bleeding. Judicious use of acid suppressants is warranted considering recent studies that have documented adverse effects of long-term supplementation of PPIs in people and animals.
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Affiliation(s)
- Stanley L. Marks
- Department of Medicine & EpidemiologySchool of Veterinary Medicine, University of California, DavisDavisCalifornia
| | - Peter H. Kook
- Vetsuisse Faculty, Clinic for Small Animal Internal Medicine, Vetsuisse FacultyUniversity of ZurichZurichSwitzerland
| | - Mark G. Papich
- Department of Molecular Biomedical SciencesNorth Carolina State University, College of Veterinary MedicineRaleighNorth Carolina
| | - M. K. Tolbert
- Department of Small Animal Clinical SciencesCollege of Veterinary Medicine, Texas A & M UniversityCollege StationTexas
| | - Michael D. Willard
- Department of Small Animal Clinical SciencesCollege of Veterinary Medicine, Texas A & M UniversityCollege StationTexas
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KASL clinical practice guidelines for liver cirrhosis: Ascites and related complications. Clin Mol Hepatol 2018; 24:230-277. [PMID: 29991196 PMCID: PMC6166105 DOI: 10.3350/cmh.2018.1005] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 04/06/2018] [Indexed: 02/07/2023] Open
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Naito Y, Kashiwagi K, Takagi T, Andoh A, Inoue R. Intestinal Dysbiosis Secondary to Proton-Pump Inhibitor Use. Digestion 2018; 97:195-204. [PMID: 29316555 DOI: 10.1159/000481813] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Gut dysbiosis associated with the use of proton-pump inhibitors (PPIs) has been found to lead to the occurrence of infectious and inflammatory adverse events. A longitudinal observational cohort study has demonstrated the heightened risk of death associated with PPI use. SUMMARY We evaluated meta-analyses to determine the association between PPI use and infectious and inflammatory diseases. Meta-analyses showed that PPI use is a potential risk for the development of enteric infections caused by Clostridium difficile, as well as small intestinal bacterial overgrowth, spontaneous bacterial peritonitis, community-acquired pneumonia, hepatic encephalopathy, and adverse outcomes in inflammatory bowel disease. We also examined changes in the composition and function of the gut microbiota with the use of PPIs. PPI use significantly increased the presence of Streptococcaceae and Enterococcaceae, which are risk factors for C. difficile infection, and decreased that of Faecalibacterium, a commensal anti-inflammatory microorganism. Key Message: High-throughput, microbial 16S rRNA gene sequencing has allowed us to investigate the association between the gut microbiome and PPI use. Future prospective comparison studies are necessary to confirm this association, and to develop new strategies to prevent complications of PPI use.
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Affiliation(s)
- Yuji Naito
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
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Singh A, Cresci GA, Kirby DF. Proton Pump Inhibitors: Risks and Rewards and Emerging Consequences to the Gut Microbiome. Nutr Clin Pract 2018; 33:614-624. [PMID: 30071147 DOI: 10.1002/ncp.10181] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
In recent years, proton pump inhibitors (PPIs) have been criticized for their various adverse interactions and side effects, creating a dilemma among practitioners regarding their use. Our goal is to review the proper use and possible side effects that might be caused by or associated with PPI use. Conclusions were drawn based on the evidence supporting or refuting short-term and long-term adverse events associated with PPI use. We also looked for the evidence regarding effects of PPIs on gut microbiota and their overall safety profile. Although there are significant discrepancies in the current literature regarding various adverse effects associated with PPI use, current data suggest that PPI use is not associated with an increased risk of bone fractures, community-acquired pneumonia, cardiovascular events, hypocalcemia, and gastric malignancies. A mild increased risk of vitamin B12 deficiency and chronic kidney disease, and a moderate increase in the risk of rebound hypersecretion, small intestinal bacterial overgrowth, and enteric infections, including Clostridium difficile, has been noted with PPI therapy. PPI's link with dementia and spontaneous bacterial peritonitis is not clear and requires further investigation. When used appropriately, PPIs are safe medications and are associated with minimal side effects. A clear indication and potential short-term and long-term side effects should be considered before starting PPI therapy.
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Affiliation(s)
- Amandeep Singh
- Department of Gastroenterology and Hepatology, Center for Human Nutrition, Diegstive Disease and Survery Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Gail A Cresci
- Department of Gastroenterology and Hepatology, Center for Human Nutrition, Diegstive Disease and Survery Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Department Gastroenterology, Pediatric Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Pathobiology, Learner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Donald F Kirby
- Department of Gastroenterology and Hepatology, Center for Human Nutrition, Diegstive Disease and Survery Institute, Cleveland Clinic, Cleveland, Ohio, USA
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Savarino E, Marabotto E, Zentilin P, Furnari M, Bodini G, Pellegatta G, Lorenzon G, Della Coletta M, Ghisa M, Coppo C, Marinelli C, Savarino V. A safety review of proton pump inhibitors to treat acid-related digestive diseases. Expert Opin Drug Saf 2018; 17:785-794. [DOI: 10.1080/14740338.2018.1497155] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Edoardo Savarino
- Gastrointestinal Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Elisa Marabotto
- Gastrointestinal Unit, Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy
| | - Patrizia Zentilin
- Gastrointestinal Unit, Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy
| | - Manuele Furnari
- Gastrointestinal Unit, Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy
| | - Giorgia Bodini
- Gastrointestinal Unit, Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy
| | - Gaia Pellegatta
- Gastrointestinal Unit, Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy
| | - Greta Lorenzon
- Gastrointestinal Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Marco Della Coletta
- Gastrointestinal Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Matteo Ghisa
- Gastrointestinal Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Claudia Coppo
- Gastrointestinal Unit, Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy
| | - Carla Marinelli
- Gastrointestinal Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Vincenzo Savarino
- Gastrointestinal Unit, Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy
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