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Damianos JA. Response to Endogenous Ethanol Production in the Human Alimentary Tract: A Literature Review. J Gastroenterol Hepatol 2025; 40:1317-1318. [PMID: 40017434 DOI: 10.1111/jgh.16924] [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: 02/03/2025] [Accepted: 02/23/2025] [Indexed: 03/01/2025]
Affiliation(s)
- John A Damianos
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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2
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Xu XT, Jiang MJ, Fu YL, Xie F, Li JJ, Meng QH. Incidence and efficacy of strategies for preventing hepatic encephalopathy following transjugular intrahepatic portosystemic shunt: A meta-analysis. World J Hepatol 2025; 17:104890. [PMID: 40308821 PMCID: PMC12038425 DOI: 10.4254/wjh.v17.i4.104890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Revised: 02/27/2025] [Accepted: 04/07/2025] [Indexed: 04/25/2025] Open
Abstract
BACKGROUND Hepatic encephalopathy (HE) is a primary complication following transjugular intrahepatic portosystemic shunt (TIPS), but the utility of pharmacological prophylaxis for HE is unclear. AIM To assess the HE incidence post-TIPS across various groups and the prophylactic efficacies of various medications. METHODS A thorough literature search was performed in PubMed, Web of Science, EMBASE, and the Cochrane Library databases from their inception to November 24, 2024, to collect data regarding HE incidence. The main outcome was HE incidence post-TIPS. A meta-analysis using a random effects model was performed to obtain odds ratios (ORs) and 95% confidence intervals. Statistical analyses were conducted using Stata and RevMan software. RESULTS This meta-analysis included nine studies with 1140 patients; 647 received pharmacological agents including lactulose, rifaximin, albumin, and l-ornithin-l-aspartate, and 493 did not (controls). (1) In the single-group meta-analysis, the control group had higher short- and long-term HE rates than the drug intervention group. Among patients with and without prior HE, the non-intervention group's HE rates were also higher; (2) Pharmacological prevention post-TIPS significantly reduced HE incidence [OR = 0.59 (0.45, 0.77), P = 0.0001]. Compared with the no prophylaxis, rifaximin reduced the risk of HE after TIPS [OR = 0.52 (0.29, 0.95), P = 0.03], but lactulose did not; (3) In patients without prior HE, pharmacological prevention significantly reduced post-TIPS HE incidence [OR = 0.62 (0.41,0.95), P = 0.03]; and (4) Network meta-analysis showed no significant differences among five prevention strategies. CONCLUSION The HE incidence after TIPS was relatively high, and the use of drugs after TIPS may reduce the HE incidence. However, research, especially large-scale randomized controlled trials, is still lacking.
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Affiliation(s)
- Xiao-Tong Xu
- Hepatic Disease and Oncology Minimally Invasive Interventional Center, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Min-Jie Jiang
- Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Yun-Lai Fu
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Fang Xie
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Jian-Jun Li
- Hepatic Disease and Oncology Minimally Invasive Interventional Center, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Qing-Hua Meng
- Hepatic Disease and Oncology Minimally Invasive Interventional Center, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China.
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Xu X, Zhu T, Jing C, Jiang M, Fu Y, Xie F, Meng Q, Li J. Hepatic encephalopathy treatment after transjugular intrahepatic portosystemic shunt: a new perspective on the gut microbiota. Front Med (Lausanne) 2025; 12:1423780. [PMID: 40124683 PMCID: PMC11926149 DOI: 10.3389/fmed.2025.1423780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Accepted: 02/24/2025] [Indexed: 03/25/2025] Open
Abstract
Transjugular intrahepatic portosystemic shunt (TIPS) placement alleviates portal hypertension symptoms. Hepatic encephalopathy (HE) is a common complication of TIPS, impacting patient quality of life and the healthcare burden. Post-TIPS HE is associated with portosystemic shunting, elevated blood ammonia levels, and inflammation. Increasing attention has been given to the liver and intestinal circulation in recent years. An imbalance in intestinal microecology plays a role in the occurrence of HE and may be a new target for treatment. This review discusses the causes, diagnosis, and treatment strategies for post-TIPS HE and focuses on exploring treatment strategies and their relationships with the gut microbiota, suggesting an innovative approach to address this complication.
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Affiliation(s)
- Xiaotong Xu
- Department of Oncology, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Tong Zhu
- Interventional Therapy Center for Oncology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Changyou Jing
- Interventional Therapy Center for Oncology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Minjie Jiang
- Department of Oncology, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Yunlai Fu
- Department of Oncology, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Fang Xie
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Qinghua Meng
- Department of Oncology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Jianjun Li
- Interventional Therapy Center for Oncology, Beijing Youan Hospital, Capital Medical University, Beijing, China
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Zhou Y, Pu S, Xiao J, Luo J, Xue L. Meta-analysis of probiotics efficacy in the treatment of minimum hepatic encephalopathy. Liver Int 2024; 44:3164-3173. [PMID: 39267392 PMCID: PMC11586888 DOI: 10.1111/liv.16081] [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: 05/30/2024] [Revised: 07/26/2024] [Accepted: 08/12/2024] [Indexed: 09/17/2024]
Abstract
OBJECTIVE This study aims to systematically evaluate the efficacy of probiotics in treating minimum hepatic encephalopathy (MHE). METHODS A systematic search was conducted across three major databases: PubMed, China National Knowledge Infrastructure and Wanfang. The search period spanned from the inception of each database to 9 March 2023. The objective was to identify all randomised controlled trials (RCTs) examining the efficacy of probiotic preparations in treating MHE. The search terms included 'probiotics' along with other clinically relevant terms to comprehensively capture all pertinent studies. RESULTS A total of 18 RCTs were included. The meta-analysis showed that probiotic treatment outperformed control groups in reducing blood ammonia levels (standard mean difference [MD] = -2.68, 95% confidence interval [CI]: -3.90 to -1.46, p < .0001), improving the remission rate of MHE (risk ratio [RR] = 2.79, 95% CI: 1.23-6.35, p = .01) and lowering alanine aminotransferase levels (MD = -11.10, 95% CI: -16.17 to -6.03, p < .0001). It also significantly reduced the Model for End-Stage Liver Disease scores (MD = -2.55, 95% CI: -3.56 to -1.54, p < .00001) and the incidence of MHE (RR = .18, 95% CI: .09-.34, p < .00001). CONCLUSION Our study demonstrates that probiotics effectively improve blood ammonia levels, liver function and cognitive function in patients with MHE. They significantly enhance the remission rate of MHE and effectively reduce its incidence, providing solid new evidence for treating MHE with probiotics.
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Affiliation(s)
- Yu‐Lian Zhou
- Department of Clinical LaboratoryMianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of ChinaMianyangSichuanChina
| | - Shu‐Tao Pu
- Department of Clinical LaboratoryMianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of ChinaMianyangSichuanChina
| | - Jian‐Bo Xiao
- Department of Clinical LaboratoryMianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of ChinaMianyangSichuanChina
| | - Jun Luo
- Department of Clinical LaboratoryMianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of ChinaMianyangSichuanChina
| | - Li Xue
- Department of Clinical LaboratoryMianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of ChinaMianyangSichuanChina
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5
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Gil-Gómez A, Muñoz-Hernández R, Martínez F, Jiménez F, Romero-Gómez M. Hepatic encephalopathy: experimental drugs in development and therapeutic potential. Expert Opin Investig Drugs 2024; 33:1219-1230. [PMID: 39588934 DOI: 10.1080/13543784.2024.2434053] [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: 09/19/2024] [Accepted: 11/21/2024] [Indexed: 11/27/2024]
Abstract
INTRODUCTION Hepatic encephalopathy (HE) presents a complex pathophysiology, creating multiple potential treatment avenues. This review covers current and emerging treatments for HE. AREAS COVERED Standard therapies, including non-absorbable disaccharides and rifaximin, are widely used but show inconsistent efficacy. Alternatives such as polyethylene glycol and L-ornithine L-aspartate have been effective in certain cases. Advancements in understanding HE reveal a growing need for personalized treatments. Novel approaches targeting immune modulation and neuroinflammation are under investigation, though clinical translation is slow. Nutritional interventions and fecal microbiota transplantation show potential but lack robust evidence. Innovative therapies like gene and cell therapies, as well as extracellular vesicles from mesenchymal stem cells, present promising avenues for liver disease treatment, potentially benefiting HE. EXPERT OPINION A key challenge in HE research is the design of randomized clinical trials, which often suffer from small sample sizes, heterogeneity in patient population, and inconsistent blinding. Additionally, the multifactorial nature of HE, together with a high spontaneous response rate, complicates efforts to isolate treatment effects. Despite current limitations, ongoing research and technological advances hold promise for more effective and individualized HE treatments in the future.
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Affiliation(s)
- Antonio Gil-Gómez
- SeLiver Group at Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital/CSIC/University of Seville, Seville, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Rocío Muñoz-Hernández
- SeLiver Group at Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital/CSIC/University of Seville, Seville, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
- Departamento de Fisiología, Facultad de Biología, Universidad de Sevilla, Seville, Spain
| | - Filomeno Martínez
- UCM Digestive Diseases, Virgen del Rocío University Hospital, Seville, Spain
| | - Fernando Jiménez
- UCM Digestive Diseases, Virgen del Rocío University Hospital, Seville, Spain
| | - Manuel Romero-Gómez
- SeLiver Group at Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital/CSIC/University of Seville, Seville, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
- UCM Digestive Diseases, Virgen del Rocío University Hospital, Seville, Spain
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Lai JC, Ring M, Dhruva A, Yeh GY. A patient-centered approach to dietary supplements for patients with chronic liver disease. Hepatol Commun 2024; 8:e0552. [PMID: 39445862 PMCID: PMC11512633 DOI: 10.1097/hc9.0000000000000552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 08/25/2024] [Indexed: 10/25/2024] Open
Abstract
The use of dietary supplements by patients with chronic liver disease is prevalent and rising. Despite the known risks of dietary supplements, including hepatotoxicity, adulteration, and contamination, patients with chronic liver disease often turn to dietary supplements to support their liver and/or overall health but are not necessarily empowered with the information or guidance from their liver practitioner to do so. This article provides practitioners with a framework for balancing the risks and benefits of dietary supplements in patients with chronic liver disease, offering examples of independent resources and certifications to use this framework in clinical practice. We offer 3 common clinical scenarios to highlight how the use of this framework can improve communication and decision-making in clinical practice. By adapting principles from Integrative Medicine, this article advocates for a patient-centered approach to dietary supplements in patients with chronic liver disease, encouraging open dialogue between clinicians and their patients to facilitate informed decision-making and personalized care.
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Affiliation(s)
- Jennifer C. Lai
- Department of Medicine, University of California-San Francisco, San Francisco, California, USA
| | - Melinda Ring
- Osher Center for Integrative Health at Northwestern University, Chicago, Illinois, USA
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Anand Dhruva
- Osher Center for Integrative Health, University of California-San Francisco, San Francisco, California, USA
- Department of Medicine, Division of Hematology and Oncology, University of California-San Francisco, San Francisco, California, USA
- Helen Diller Family Comprehensive Cancer Center, University of California-San Francisco, San Francisco, California, USA
| | - Gloria Y. Yeh
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
- Osher Center for Integrative Health, Harvard Medical School, Boston, Massachusetts, USA
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Smith ML, Wade JB, Wolstenholme J, Bajaj JS. Gut microbiome-brain-cirrhosis axis. Hepatology 2024; 80:465-485. [PMID: 36866864 PMCID: PMC10480351 DOI: 10.1097/hep.0000000000000344] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 02/10/2023] [Indexed: 03/04/2023]
Abstract
Cirrhosis is characterized by inflammation, degeneration, and fibrosis of liver tissue. Along with being the most common cause of liver failure and liver transplant, cirrhosis is a significant risk factor for several neuropsychiatric conditions. The most common of these is HE, which is characterized by cognitive and ataxic symptoms, resulting from the buildup of metabolic toxins with liver failure. However, cirrhosis patients also show a significantly increased risk for neurodegenerative diseases such as Alzheimer and Parkinson diseases, and for mood disorders such as anxiety and depression. In recent years, more attention has been played to communication between the ways the gut and liver communicate with each other and with the central nervous system, and the way these organs influence each other's function. This bidirectional communication has come to be known as the gut-liver-brain axis. The gut microbiome has emerged as a key mechanism affecting gut-liver, gut-brain, and brain-liver communication. Clinical studies and animal models have demonstrated the significant patterns of gut dysbiosis when cirrhosis is present, both with or without concomitant alcohol use disorder, and have provided compelling evidence that this dysbiosis also influences the cognitive and mood-related behaviors. In this review, we have summarized the pathophysiological and cognitive effects associated with cirrhosis, links to cirrhosis-associated disruption of the gut microbiome, and the current evidence from clinical and preclinical studies for the modulation of the gut microbiome as a treatment for cirrhosis and associated neuropsychiatric conditions.
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Affiliation(s)
- Maren L Smith
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, USA
- Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - James B Wade
- Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Jennifer Wolstenholme
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, USA
- Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Jasmohan S Bajaj
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and Central Virginia Veterans Healthcare System, Richmond, Virginia, USA
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8
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Turner BRH, Jenkinson PI, Huttman M, Mullish BH. Inflammation, oxidative stress and gut microbiome perturbation: A narrative review of mechanisms and treatment of the alcohol hangover. ALCOHOL, CLINICAL & EXPERIMENTAL RESEARCH 2024; 48:1451-1465. [PMID: 38965644 DOI: 10.1111/acer.15396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 05/17/2024] [Accepted: 06/03/2024] [Indexed: 07/06/2024]
Abstract
Alcohol is the most widely abused substance in the world, the leading source of mortality in 15-49-year-olds, and a major risk factor for heart disease, liver disease, diabetes, and cancer. Despite this, alcohol is regularly misused in wider society. Consumers of excess alcohol often note a constellation of negative symptoms, known as the alcohol hangover. However, the alcohol hangover is not considered to have long-term clinical significance by clinicians or consumers. We undertook a critical review of the literature to demonstrate the pathophysiological mechanisms of the alcohol hangover. Hereafter, the alcohol hangover is re-defined as a manifestation of sickness behavior secondary to alcohol-induced inflammation, using the Bradford-Hill criteria to demonstrate causation above correlation. Alcohol causes inflammation through oxidative stress and endotoxemia. Alcohol metabolism is oxidative and increased intake causes relative tissue hypoxia and increased free radical generation. Tissue damage ensues through lipid peroxidation and the formation of DNA/protein adducts. Byproducts of alcohol metabolism such as acetaldehyde and congeners, sleep deprivation, and the activation of nonspecific inducible CYP2E1 in alcohol-exposed tissues exacerbate free radical generation. Tissue damage and cell death lead to inflammation, but in the intestine loss of epithelial cells leads to intestinal permeability, allowing the translocation of pathogenic bacteria to the systemic circulation (endotoxemia). This leads to a well-characterized cascade of systemic inflammation, additionally activating toll-like receptor 4 to induce sickness behavior. Considering the evidence, it is suggested that hangover frequency and severity may be predictors of the development of later alcohol-related diseases, meriting formal confirmation in prospective studies. In light of the mechanisms of alcohol-mediated inflammation, research into gut permeability and the gut microbiome may be an exciting future therapeutic avenue to prevent alcohol hangover and other alcohol-related diseases.
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Affiliation(s)
| | - Poppy I Jenkinson
- Department of Anaesthetics, Royal Surrey County Hospital, Surrey, UK
| | - Marc Huttman
- Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK
| | - Benjamin H Mullish
- Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
- Department of Hepatology, St Mary's Hospital, Imperial College Healthcare NHS Trust, London, UK
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Coluzzi F, Scerpa MS, Loffredo C, Borro M, Pergolizzi JV, LeQuang JA, Alessandri E, Simmaco M, Rocco M. Opioid Use and Gut Dysbiosis in Cancer Pain Patients. Int J Mol Sci 2024; 25:7999. [PMID: 39063241 PMCID: PMC11276997 DOI: 10.3390/ijms25147999] [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: 04/30/2024] [Revised: 07/11/2024] [Accepted: 07/18/2024] [Indexed: 07/28/2024] Open
Abstract
Opioids are commonly used for the management of severe chronic cancer pain. Their well-known pharmacological effects on the gastrointestinal system, particularly opioid-induced constipation (OIC), are the most common limiting factors in the optimization of analgesia, and have led to the wide use of laxatives and/or peripherally acting mu-opioid receptor antagonists (PAMORAs). A growing interest has been recently recorded in the possible effects of opioid treatment on the gut microbiota. Preclinical and clinical data, as presented in this review, showed that alterations of the gut microbiota play a role in modulating opioid-mediated analgesia and tolerability, including constipation. Moreover, due to the bidirectional crosstalk between gut bacteria and the central nervous system, gut dysbiosis may be crucial in modulating opioid reward and addictive behavior. The microbiota may also modulate pain regulation and tolerance, by activating microglial cells and inducing the release of inflammatory cytokines and chemokines, which sustain neuroinflammation. In the subset of cancer patients, the clinical meaning of opioid-induced gut dysbiosis, particularly its possible interference with the efficacy of chemotherapy and immunotherapy, is still unclear. Gut dysbiosis could be a new target for treatment in cancer patients. Restoring the physiological amount of specific gut bacteria may represent a promising therapeutic option for managing gastrointestinal symptoms and optimizing analgesia for cancer patients using opioids.
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Affiliation(s)
- Flaminia Coluzzi
- Department of Medical-Surgical Sciences and Translational Medicine, Sapienza University of Rome, 00189 Rome, Italy
- Unit of Anaesthesia, Intensive Care, and Pain Medicine, Sant’Andrea University Hospital, 00189 Rome, Italy
| | - Maria Sole Scerpa
- Unit of Anaesthesia, Intensive Care, and Pain Medicine, Sant’Andrea University Hospital, 00189 Rome, Italy
| | - Chiara Loffredo
- Unit of Anaesthesia, Intensive Care, and Pain Medicine, Sant’Andrea University Hospital, 00189 Rome, Italy
| | - Marina Borro
- Department of Neuroscience, Mental Health and Sense Organs NESMOS, Sapienza University of Rome, 00185 Rome, Italy
| | | | | | - Elisa Alessandri
- Unit of Anaesthesia, Intensive Care, and Pain Medicine, Sant’Andrea University Hospital, 00189 Rome, Italy
| | - Maurizio Simmaco
- Unit of Anaesthesia, Intensive Care, and Pain Medicine, Sant’Andrea University Hospital, 00189 Rome, Italy
- Department of Neuroscience, Mental Health and Sense Organs NESMOS, Sapienza University of Rome, 00185 Rome, Italy
| | - Monica Rocco
- Department of Medical-Surgical Sciences and Translational Medicine, Sapienza University of Rome, 00189 Rome, Italy
- Unit of Anaesthesia, Intensive Care, and Pain Medicine, Sant’Andrea University Hospital, 00189 Rome, Italy
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10
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Samanta A, Sen Sarma M. Fecal microbiota transplantation in the treatment of hepatic encephalopathy: A perspective. World J Hepatol 2024; 16:678-683. [PMID: 38818298 PMCID: PMC11135264 DOI: 10.4254/wjh.v16.i5.678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 03/06/2024] [Accepted: 04/16/2024] [Indexed: 05/22/2024] Open
Abstract
Due to its complex pathogenesis, treatment of hepatic encephalopathy (HE) continues to be a therapeutic challenge. Of late, gut microbiome has garnered much attention for its role in the pathogenesis of various gastrointestinal and liver diseases and its potential therapeutic use. New evidence suggests that gut microbiota plays a significant role in cerebral homeostasis. Alteration in the gut microbiota has been documented in patients with HE in a number of clinical and experimental studies. Research on gut dysbiosis in patients with HE has opened newer therapeutic avenues in the form of probiotics, prebiotics and the latest fecal microbiota transplantation (FMT). Recent studies have shown that FMT is safe and could be effective in improving outcomes in advanced liver disease patients presenting with HE. However, questions over the appropriate dose, duration and route of administration for best treatment outcome remains unsettled.
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Affiliation(s)
- Arghya Samanta
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Moinak Sen Sarma
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India.
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11
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Singh J, Ibrahim B, Han SH. Nontraditional Treatment of Hepatic Encephalopathy. Clin Liver Dis 2024; 28:297-315. [PMID: 38548441 DOI: 10.1016/j.cld.2024.01.007] [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: 04/02/2024]
Abstract
The pathophysiology of hepatic encephalopathy (HE) is complex, with hyperammonemia playing a central role in its development. Traditional therapies for HE have targeted ammonia and include medications such as lactulose and rifaximin. Although these agents are considered standard of care, nontraditional treatments seek to affect other factors in the pathogenesis of HE. Finally, procedural therapies include albumin dialysis, shunt closure, and the ultimate cure for HE, which is liver transplant. The treatments discussed provide alternative options for patients who have failed standard of care. However, more high-quality studies are needed to routinely recommend many of these agents.
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Affiliation(s)
- Jasleen Singh
- Department of Medicine, University of California at Los Angeles; Los Angeles, CA, USA.
| | - Brittney Ibrahim
- Department of Surgery, University of California at Los Angeles; Los Angeles, CA, USA
| | - Steven-Huy Han
- Department of Medicine, University of California at Los Angeles; Los Angeles, CA, USA; Department of Surgery, University of California at Los Angeles; Los Angeles, CA, USA
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12
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Román E, Kaür N, Sánchez E, Poca M, Padrós J, Nadal MJ, Cuyàs B, Alvarado E, Vidal S, Ortiz MÀ, Hernández E, Santesmases R, Urgell E, Juanes E, Ferrero-Gregori A, Escorsell À, Guarner C, Soriano G. Home exercise, branched-chain amino acids, and probiotics improve frailty in cirrhosis: A randomized clinical trial. Hepatol Commun 2024; 8:e0443. [PMID: 38701490 PMCID: PMC11073778 DOI: 10.1097/hc9.0000000000000443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 03/04/2024] [Indexed: 05/05/2024] Open
Abstract
BACKGROUND Frailty is a predictive factor of hospitalization, falls, and mortality in patients with cirrhosis, regardless of the degree of liver failure. The aim was to analyze whether a multifactorial intervention consisting of home-based exercise, branched-chain amino acids, and a multistrain probiotic can improve frailty in these patients. METHODS Outpatients with cirrhosis were classified according to the Liver Frailty Index (LFI). Prefrail and frail patients were randomized into 2 groups. The intervention group was assigned to a multifactorial intervention consisting of exercise at home, branched-chain amino acid supplements, and a multistrain probiotic for 12 months. The control group received standard care. All patients were prospectively followed up every 3 months for 1 year to determine LFI, incidence of falls, emergency room visits, hospitalizations, and mortality. RESULTS Thirty-two patients were included: 17 patients were assigned to the intervention group and 15 to the control group. In the intervention group, the baseline LFI decreased at 3, 6, 9, and 12 months (p = 0.019 for overall change with respect to the control group). The change in LFI (ΔLFI) at 12 months was -0.71 ± 0.24 in the intervention group and -0.09 ± 0.32 in the control group (p<0.001). During follow-up, patients in the intervention group had a lower 1-year probability of falls (6% vs. 47%, p = 0.03) and emergency room visits (10% vs. 44%, p = 0.04) than patients in the control group. CONCLUSIONS A long-term multifactorial intervention that included exercise at home, branched-chain amino acids, and a multistrain probiotic improved frailty in outpatients with cirrhosis and was associated with a decrease in the incidence of clinical events such as falls and emergency room visits.
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Affiliation(s)
- Eva Román
- University Nursing School EUI-Sant Pau, Barcelona, Spain
- Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
- Universitat Autònoma de Barcelona, Barcelona, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Naujot Kaür
- Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Elisabet Sánchez
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
- Institut de Recerca Sant Pau (IR Sant Pau), Barcelona, Spain
| | - Maria Poca
- Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Josep Padrós
- Department of Physical Medicine and Rehabilitation, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Maria Josep Nadal
- Department of Physical Medicine and Rehabilitation, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Berta Cuyàs
- Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Edilmar Alvarado
- Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Silvia Vidal
- Universitat Autònoma de Barcelona, Barcelona, Spain
- Institut de Recerca Sant Pau (IR Sant Pau), Barcelona, Spain
| | | | - Elvira Hernández
- University Nursing School EUI-Sant Pau, Barcelona, Spain
- Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Rosalía Santesmases
- University Nursing School EUI-Sant Pau, Barcelona, Spain
- Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Eulàlia Urgell
- Department of Biochemistry, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Elena Juanes
- Department of Pharmacy at Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | | | - Àngels Escorsell
- Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Carlos Guarner
- Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
- Universitat Autònoma de Barcelona, Barcelona, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Germán Soriano
- Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
- Universitat Autònoma de Barcelona, Barcelona, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
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13
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Di Vincenzo F, Del Gaudio A, Petito V, Lopetuso LR, Scaldaferri F. Gut microbiota, intestinal permeability, and systemic inflammation: a narrative review. Intern Emerg Med 2024; 19:275-293. [PMID: 37505311 PMCID: PMC10954893 DOI: 10.1007/s11739-023-03374-w] [Citation(s) in RCA: 207] [Impact Index Per Article: 207.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 07/10/2023] [Indexed: 07/29/2023]
Abstract
The intestine is the largest interface between the internal body and the external environment. The intestinal barrier is a dynamic system influenced by the composition of the intestinal microbiome and the activity of intercellular connections, regulated by hormones, dietary components, inflammatory mediators, and the enteric nervous system (ENS). Over the years, it has become increasingly evident that maintaining a stable intestinal barrier is crucial to prevent various potentially harmful substances and pathogens from entering the internal environment. Disruption of the barrier is referred to as 'leaky gut' or leaky gut wall syndrome and seems to be characterized by the release of bacterial metabolites and endotoxins, such as lipopolysaccharide (LPS), into the circulation. This condition, mainly caused by bacterial infections, oxidative stress, high-fat diet, exposure to alcohol or chronic allergens, and dysbiosis, appear to be highly connected with the development and/or progression of several metabolic and autoimmune systemic diseases, including obesity, non-alcoholic fatty liver disease (NAFLD), neurodegeneration, cardiovascular disease, inflammatory bowel disease, and type 1 diabetes mellitus (T1D). In this review, starting from a description of the mechanisms that enable barrier homeostasis and analyzing the relationship between this complex ecosystem and various pathological conditions, we explore the role of the gut barrier in driving systemic inflammation, also shedding light on current and future therapeutic interventions.
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Affiliation(s)
- Federica Di Vincenzo
- UOS Malattie Infiammatorie Croniche Intestinali, Centro Malattie Apparato Digerente (CeMAD), Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, L.go A. Gemelli 8, Rome, Italy.
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, L.go F. Vito 1, Rome, Italy.
| | - Angelo Del Gaudio
- UOS Malattie Infiammatorie Croniche Intestinali, Centro Malattie Apparato Digerente (CeMAD), Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, L.go A. Gemelli 8, Rome, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, L.go F. Vito 1, Rome, Italy
| | - Valentina Petito
- UOS Malattie Infiammatorie Croniche Intestinali, Centro Malattie Apparato Digerente (CeMAD), Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, L.go A. Gemelli 8, Rome, Italy
| | - Loris Riccardo Lopetuso
- UOS Malattie Infiammatorie Croniche Intestinali, Centro Malattie Apparato Digerente (CeMAD), Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, L.go A. Gemelli 8, Rome, Italy
| | - Franco Scaldaferri
- UOS Malattie Infiammatorie Croniche Intestinali, Centro Malattie Apparato Digerente (CeMAD), Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, L.go A. Gemelli 8, Rome, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, L.go F. Vito 1, Rome, Italy
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14
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Maftei NM, Raileanu CR, Balta AA, Ambrose L, Boev M, Marin DB, Lisa EL. The Potential Impact of Probiotics on Human Health: An Update on Their Health-Promoting Properties. Microorganisms 2024; 12:234. [PMID: 38399637 PMCID: PMC10891645 DOI: 10.3390/microorganisms12020234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 01/17/2024] [Accepted: 01/17/2024] [Indexed: 02/25/2024] Open
Abstract
Probiotics, known to be live microorganisms, have been shown to improve or restore the gut microbiota, which in turn has been linked to improved health. It is believed that probiotics are the modern equivalent of a panacea, with claims that they may treat or prevent different diseases both in children and adults (e.g., from colic in babies to cardiovascular disease, respiratory infection, and cancer in adults). Ever since the early 2000s, probiotic-based fermented foods have had a resurgence in popularity, mostly due to claims made regarding their health benefits. Fermented foods have been associated with the prevention of irritable bowel syndrome, lactose intolerance, gastroenteritis, and obesity, but also other conditions such as chronic diarrhea, allergies, dermatitis, and bacterial and viral infections, all of which are closely related to an unhealthy lifestyle. Recent and ongoing developments in microbiome/microbiota science have given us new research directions for probiotics. The new types, mechanisms, and applications studied so far, and those currently under study, have a great potential to change scientific understanding of probiotics' nutritional applications and human health care. The expansion of fields related to the study of the microbiome and the involvement of probiotics in its improvement foreshadow an era of significant changes. An expanding range of candidate probiotic species is emerging that can address newly elucidated data-driven microbial niches and host targets. In the probiotic field, new variants of microbiome-modulating interventions are being developed, including prebiotics, symbiotics, postbiotics, microbial consortia, live biotherapeutic products, and genetically modified organisms, with renewed interest in polyphenols, fibers, and fermented foods to ensure human health. This manuscript aims to analyze recent, emerging, and anticipated trends in probiotics (sources, doses, mechanism of action, diseases for which probiotics are administered, side effects, and risks) and create a vision for the development of related areas of influence in the field.
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Affiliation(s)
- Nicoleta-Maricica Maftei
- Department of Pharmaceutical Sciences, Faculty of Medicine, and Pharmacy, “Dunărea de Jos” University, 800010 Galati, Romania; (N.-M.M.); (E.L.L.)
- Clinic Laboratory Department, Clinical Hospital of Children Hospital “Sf. Ioan”, 800487 Galati, Romania
- Research Centre in the Medical-Pharmaceutical Field, “Dunarea de Jos” University of Galati, 800010 Galati, Romania
| | - Cosmin Raducu Raileanu
- Department of Morphological and Functional Sciences, Faculty of Medicine, and Pharmacy, “Dunărea de Jos” University, 800010 Galati, Romania; (C.R.R.); (L.A.)
| | - Alexia Anastasia Balta
- Medical Department Faculty of Medicine and Pharmacy, “Dunărea de Jos” University, 800010 Galati, Romania;
| | - Lenuta Ambrose
- Department of Morphological and Functional Sciences, Faculty of Medicine, and Pharmacy, “Dunărea de Jos” University, 800010 Galati, Romania; (C.R.R.); (L.A.)
| | - Monica Boev
- Department of Pharmaceutical Sciences, Faculty of Medicine, and Pharmacy, “Dunărea de Jos” University, 800010 Galati, Romania; (N.-M.M.); (E.L.L.)
- Research Centre in the Medical-Pharmaceutical Field, “Dunarea de Jos” University of Galati, 800010 Galati, Romania
| | - Denisa Batîr Marin
- Department of Pharmaceutical Sciences, Faculty of Medicine, and Pharmacy, “Dunărea de Jos” University, 800010 Galati, Romania; (N.-M.M.); (E.L.L.)
- Research Centre in the Medical-Pharmaceutical Field, “Dunarea de Jos” University of Galati, 800010 Galati, Romania
| | - Elena Lacramioara Lisa
- Department of Pharmaceutical Sciences, Faculty of Medicine, and Pharmacy, “Dunărea de Jos” University, 800010 Galati, Romania; (N.-M.M.); (E.L.L.)
- Research Centre in the Medical-Pharmaceutical Field, “Dunarea de Jos” University of Galati, 800010 Galati, Romania
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15
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Gilbert MC, Setayesh T, Wan YJY. The contributions of bacteria metabolites to the development of hepatic encephalopathy. LIVER RESEARCH 2023; 7:296-303. [PMID: 38221945 PMCID: PMC10786625 DOI: 10.1016/j.livres.2022.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Over 20% of mortality during acute liver failure is associated with the development of hepatic encephalopathy (HE). Thus, HE is a complication of acute liver failure with a broad spectrum of neuropsychiatric abnormalities ranging from subclinical alterations to coma. HE is caused by the diversion of portal blood into systemic circulation through portosystemic collateral vessels. Thus, the brain is exposed to intestinal-derived toxic substances. Moreover, the strategies to prevent advancement and improve the prognosis of such a liver-brain disease rely on intestinal microbial modulation. This is supported by the findings that antibiotics such as rifaximin and laxative lactulose can alleviate hepatic cirrhosis and/or prevent HE. Together, the significance of the gut-liver-brain axis in human health warrants attention. This review paper focuses on the roles of bacteria metabolites, mainly ammonia and bile acids (BAs) as well as BA receptors in HE. The literature search conducted for this review included searches for phrases such as BA receptors, BAs, ammonia, farnesoid X receptor (FXR), G protein-coupled bile acid receptor 1 (GPBAR1 or TGR5), sphingosine-1-phosphate receptor 2 (S1PR2), and cirrhosis in conjunction with the phrase hepatic encephalopathy and portosystemic encephalopathy. PubMed, as well as Google Scholar, was the search engines used to find relevant publications.
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Affiliation(s)
- Miranda Claire Gilbert
- Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA, USA
| | - Tahereh Setayesh
- Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA, USA
| | - Yu-Jui Yvonne Wan
- Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA, USA
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16
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Jiang H, Xu N, Zhang W, Wei H, Chen Y, Jiang Q, Zhou Y. Do gut microbiome-targeted therapies improve liver function in cirrhotic patients? A systematic review and meta-analysis. J Gastroenterol Hepatol 2023; 38:1900-1909. [PMID: 37582506 DOI: 10.1111/jgh.16329] [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: 05/10/2023] [Revised: 07/19/2023] [Accepted: 08/02/2023] [Indexed: 08/17/2023]
Abstract
BACKGROUND AND AIM Microbiome-targeted therapies (MTTs) are considered as promising interventions for cirrhosis, but the impact of gut microbiome modulation on liver function and disease severity has not been fully assessed. We comprehensively evaluated the efficacy of MTTs in patients with liver cirrhosis. METHODS Data from randomized controlled trials were collected through MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrial.gov from inception to February 20, 2023. Clinical outcomes were pooled and expressed in terms of risk ratios or mean differences (MD). Additional subgroup and sensitivity analyses were performed to validate the robustness of findings. A trial sequential analysis was applied to calculate the required information size and evaluate the credibility of the meta-analysis results. RESULTS Twenty-one studies with a total of 1699 cirrhotic patients were included for meta-analysis. MTTs were associated with a significant reduction in aspartate aminotransferase (MD, -3.62; 95% CI, -6.59 to -0.65), the risk of hepatic encephalopathy (risk ratio = 0.56, 95% CI: 0.46 to 0.68), model for end-stage liver disease score (MD, -0.90; 95% CI, -1.17 to -0.11), ammonia (MD, -11.86; 95% CI, -16.39 to -7.33), and endotoxin (MD, -0.14; 95% CI, -0.23 to -0.04). The trial sequential analysis yielded reliable results of these outcomes. No effects were observed on the changes of other hepatic function indicators. CONCLUSION MTTs appeared to be associated with a slowed deterioration in liver cirrhosis, which could provide reference for clinicians in treatment of cirrhotic patients based on their conditions.
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Affiliation(s)
- Honglin Jiang
- School of Public Health, Fudan University, Shanghai, China
- Key Laboratory of Public Health Safety, Ministry of Education, Fudan University, Shanghai, China
- Fudan University Center for Tropical Disease Research, Shanghai, China
| | - Ning Xu
- School of Public Health, Fudan University, Shanghai, China
- Key Laboratory of Public Health Safety, Ministry of Education, Fudan University, Shanghai, China
- Fudan University Center for Tropical Disease Research, Shanghai, China
| | - Wei Zhang
- Department of Reference, Medical Library of Fudan University, Shanghai, China
| | - Hongjian Wei
- Department of Gastroenterology, The Third People's Hospital of Hunan, Yueyang, China
| | - Yue Chen
- School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, Canada
| | - Qingwu Jiang
- School of Public Health, Fudan University, Shanghai, China
- Key Laboratory of Public Health Safety, Ministry of Education, Fudan University, Shanghai, China
- Fudan University Center for Tropical Disease Research, Shanghai, China
| | - Yibiao Zhou
- School of Public Health, Fudan University, Shanghai, China
- Key Laboratory of Public Health Safety, Ministry of Education, Fudan University, Shanghai, China
- Fudan University Center for Tropical Disease Research, Shanghai, China
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17
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Gao J, Nie R, Chang H, Yang W, Ren Q. A meta-analysis of microbiome therapies for hepatic encephalopathy. Eur J Gastroenterol Hepatol 2023; 35:927-937. [PMID: 37505972 DOI: 10.1097/meg.0000000000002596] [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: 07/30/2023]
Abstract
Microbiome therapies may be reported to be effective in hepatic encephalopathy (HE). We thus did a meta-analysis of randomized controlled trials to assess the effect of microbiome therapies for HE. We systematically searched PubMed, Web of Science, EMBASE, and Cochrane Library for randomized controlled trials that compared the different treatments for HE including probiotics, symbiotics, and fecal microbiota transplant (FMT). Meta-analysis was performed to calculate pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Twenty-one studies met our inclusion criteria (N = 1746 participants). Probiotics, synbiotics and FMT significantly reversed minimal HE (MHE) (OR: 0.41, 95% CI: 0.19-0.90, P = 0.03), reduced overt HE (OHE) development (OR, 0.41; 95% CI: 0.28-0.61 P < 0.00001)and the frequency of serious adverse events(SAEs) (OR:0.14, 95% CI: 0.04-0.47, P = 0.001), meanwhile decreased ammonia levels (WMD: -9.26, 95% CI: -16.92 to -1.61; P = 0.02), NCT level (MD = -4.41, 95% CI: -0.87 to -0.22, P = 0.04) and hospitalization rates (OR, 0.38; 95% CI: 0.19-0.79, P = 0.009) compared with placebo/no treatment. Finally, we conclude that microbiome therapies were more effective in improving MHE and preventing progression to OHE, reducing the frequency of SAEs, and decreasing ammonia levels, NCT level, and hospitalization rates when compared to placebo/no treatment.
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Affiliation(s)
- Jie Gao
- Lanzhou University
- Department of Gastroenterology, the First Hospital of Lanzhou University
| | - Rui Nie
- Lanzhou University
- Department of Gastroenterology, the First Hospital of Lanzhou University
| | - Hong Chang
- Lanzhou University
- Department of Gastroenterology, the First Hospital of Lanzhou University
| | - Wei Yang
- Lanzhou University
- Department of Gastroenterology, the First Hospital of Lanzhou University
- Key Laboratory for Gastrointestinal Diseases of Gansu Province, Lanzhou University, Lanzhou, China
| | - Qian Ren
- Lanzhou University
- Department of Gastroenterology, the First Hospital of Lanzhou University
- Key Laboratory for Gastrointestinal Diseases of Gansu Province, Lanzhou University, Lanzhou, China
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18
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Shalaby N, Samocha-Bonet D, Kaakoush NO, Danta M. The Role of the Gastrointestinal Microbiome in Liver Disease. Pathogens 2023; 12:1087. [PMID: 37764895 PMCID: PMC10536540 DOI: 10.3390/pathogens12091087] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 08/14/2023] [Accepted: 08/21/2023] [Indexed: 09/29/2023] Open
Abstract
Liver disease is a major global health problem leading to approximately two million deaths a year. This is the consequence of a number of aetiologies, including alcohol-related, metabolic-related, viral infection, cholestatic and immune disease, leading to fibrosis and, eventually, cirrhosis. No specific registered antifibrotic therapies exist to reverse liver injury, so current treatment aims at managing the underlying factors to mitigate the development of liver disease. There are bidirectional feedback loops between the liver and the rest of the gastrointestinal tract via the portal venous and biliary systems, which are mediated by microbial metabolites, specifically short-chain fatty acids (SCFAs) and secondary bile acids. The interaction between the liver and the gastrointestinal microbiome has the potential to provide a novel therapeutic modality to mitigate the progression of liver disease and its complications. This review will outline our understanding of hepatic fibrosis, liver disease, and its connection to the microbiome, which may identify potential therapeutic targets or strategies to mitigate liver disease.
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Affiliation(s)
- Nicholas Shalaby
- School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, St Vincent’s Healthcare Campus, Darlinghurst, NSW 2010, Australia
| | - Dorit Samocha-Bonet
- School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, St Vincent’s Healthcare Campus, Darlinghurst, NSW 2010, Australia
- Clinical Insulin Resistance Group, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia
| | - Nadeem O. Kaakoush
- School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Kensington, NSW 2033, Australia
| | - Mark Danta
- School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, St Vincent’s Healthcare Campus, Darlinghurst, NSW 2010, Australia
- Department of Gastroenterology and Hepatology, St Vincent’s Hospital, Darlinghurst, NSW 2010, Australia
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19
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Gairing SJ, Schleicher EM, Galle PR, Labenz C. Prediction and prevention of the first episode of overt hepatic encephalopathy in patients with cirrhosis. Hepatol Commun 2023; 7:02009842-202304010-00007. [PMID: 36930868 PMCID: PMC10027066 DOI: 10.1097/hc9.0000000000000096] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 12/13/2022] [Indexed: 03/19/2023] Open
Abstract
Hepatic encephalopathy (HE) is one of the most important complications of patients with liver cirrhosis. In addition, HE is associated with a dismal prognosis and has detrimental effects on patients' quality of life. Thus, it is of pivotal importance to identify patients at high risk for overt HE (OHE) in whom primary prophylaxis may be justified. In this narrative review, we aim to provide insight into predictors and prediction tools for a first-time episode of OHE and to scrutinize the current level of evidence of primary prophylaxis. In recent decades, several cognitive tests, composite scores, and blood-based biomarkers have been demonstrated to be predictive of a first-time episode of OHE. Among the best validated are the established tests for minimal HE, such as the Psychometric Hepatic Encephalopathy Score, determination of the critical flicker frequency, Stroop EncephalApp, or the Animal Naming Test. Individualized risk stratification using blood-based biomarkers and cross-sectional imaging (sarcopenia and spontaneous portosystemic shunts) is coming to the fore, but validation in larger multicenter cohorts is often lacking. On the basis of current evidence, a recommendation for primary prophylaxis of a first episode of OHE cannot be made in general. Only 2 studies have investigated the prevention of a first-time OHE episode as the primary endpoint. In this narrative review, we provide a concise overview of the current evidence levels on prediction tools and pharmacological prevention of a first episode of OHE. In addition, we give an outlook on future research targets to improve knowledge on this important topic.
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Affiliation(s)
- Simon J Gairing
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
- Cirrhosis Center Mainz (CCM), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Eva M Schleicher
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
- Cirrhosis Center Mainz (CCM), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Peter R Galle
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
- Cirrhosis Center Mainz (CCM), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Christian Labenz
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
- Cirrhosis Center Mainz (CCM), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
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20
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Huang L, Yu Q, Peng H, Zhen Z. Alterations of gut microbiome and effects of probiotic therapy in patients with liver cirrhosis: A systematic review and meta-analysis. Medicine (Baltimore) 2022; 101:e32335. [PMID: 36595801 PMCID: PMC9794299 DOI: 10.1097/md.0000000000032335] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Alterations in the gut microbiome usually occur in liver cirrhosis. Gut microbiome dysregulation damages the liver and accelerates the development of liver fibrosis. Probiotic treatment has gradually become a major method for improving the prognosis of liver cirrhosis and reducing its complications. However, alterations in the gut microbiome have revealed different results, and the therapeutic effects of various probiotics are inconsistent. METHODS We searched the PubMed, Medline, EMBASE, ScienceDirect, and Cochrane databases up to August 2022 and conducted a systematic review and meta-analysis of 17 relevant studies. RESULTS The counts of Enterobacter (standardized mean difference [SMD] -1.79, 95% confidence interval [CI]: -3.08 to -0.49) and Enterococcus (SMD -1.41, 95% CI: -2.26 to -0.55) increased significantly in patients with cirrhosis, while the counts of Lactobacillus (SMD 0.63, 95% CI: 0.12-1.15) and Bifidobacterium (SMD 0.44, 95% CI: 0.12-0.77) decreased significantly. Blood ammonia (weighted mean difference [WMD] 14.61, 95% CI: 7.84-21.37) and the incidence of hepatic encephalopathy (WMD 0.40, 95% CI: 0.27-0.61) were significantly decreased in the probiotic group. As for mortality (MD 0.75, 95% CI: 0.48-1.16) and the incidence of spontaneous bacterial peritonitis (WMD -0.02, 95% CI: -0.07 to 0.03), no significant differences were found between the probiotic and placebo groups. CONCLUSION In summary, the gut microbiome in cirrhosis manifests as decreased counts of Lactobacillus and Bifidobacterium and increased counts of Enterobacter and Enterococcus. Targeted supplementation of probiotics in cirrhosis, including Lactobacillus combined with Bifidobacterium or Bifidobacterium alone, can reduce blood ammonia and the incidence of hepatic encephalopathy. The effect is similar to that of lactulose, but it has no obvious effect on mortality and spontaneous bacterial peritonitis.
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Affiliation(s)
- Long Huang
- Department of No. 1 Surgery, The First Hospital Affiliated to Anhui University of Traditional Chinese Medicine, Hefei, Anhui Province, China
- * Correspondence: Long Huang, The First Hospital Affiliated to Anhui University of Traditional Chinese Medicine, No. 117 Meishan Road, Hefei, Anhui Province 230031, China (e-mail: )
| | - Qingsheng Yu
- Department of No. 1 Surgery, The First Hospital Affiliated to Anhui University of Traditional Chinese Medicine, Hefei, Anhui Province, China
| | - Hui Peng
- Department of No. 1 Surgery, The First Hospital Affiliated to Anhui University of Traditional Chinese Medicine, Hefei, Anhui Province, China
| | - Zhou Zhen
- Department of Surgery, The Second Hospital Affiliated to Anhui University of Traditional Chinese Medicine, Hefei, Anhui Province, China
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21
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Jiang H, Peng Y, Zhang W, Chen Y, Jiang Q, Zhou Y. Gut microbiome-targeted therapies in liver cirrhosis: a protocol for systematic review and meta-analysis. Syst Rev 2022; 11:181. [PMID: 36042459 PMCID: PMC9429623 DOI: 10.1186/s13643-022-02059-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 08/23/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Microbiome-targeted therapies (MTTs), including probiotics, prebiotics, synbiotics, and fecal microbiota transplantation (FMT), have been proposed as a potential treatment for cirrhosis via modulation of gut microbiome, while the impact of gut microflora alteration on liver function in cirrhosis trajectory is unclear, and no related systematic review has been published. We aim to comprehensively assess the effects of MTTs in patients with liver cirrhosis. METHODS We will search databases of MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) with no time restriction. Only randomized controlled trials published in English will be included. Two independent reviewers will be responsible for study identification and selection, data extraction, and risk of bias assessment, with discrepancies resolved by consensus or referral to a third author. Heterogeneity of studies will be examined using Cochrane Q-test and I2 statistics. The data will be pooled using either a fixed- or random-effects model based on I2 statistics. The results will be presented as risk ratios (RR) or mean differences (MD) with 95% confidence intervals (CI). We will perform subgroup analysis on the type of MTTs and assess the reporting biases. Sensitivity analysis will be conducted to test the stability of each outcome result. DISCUSSION There is no current study about the role of MTTs in developing the liver function, and the therapeutic effects of MTTs are inconsistent. By investigating the liver-specific indicators when treating with multiple MTTs on course of cirrhosis, our findings will give more conclusive and stronger evidence about the efficacy of MTTs and provide new insight into the action mechanisms of these MTTs. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42021253198.
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Affiliation(s)
- Honglin Jiang
- Fudan University School of Public Health, Building 8, 130 Dong'an Road, Shanghai, 200032, China.,Key Laboratory of Public Health Safety, Fudan University, Ministry of Education, Building 8, 130 Dong'an Road, Shanghai, 200032, China.,Fudan University Center for Tropical Disease Research, Building 8, 130 Dong'an Road, Shanghai, 200032, China
| | - Yan Peng
- Department of Nutrition, Beijing Fangshan District Liangxiang Hospital, No. 45 Gongchen Street, Fangshan, Beijing, 102401, China
| | - Wei Zhang
- Department of Reference, Medical Library of Fudan University, Building 8, 130 Dong'an Road, Shanghai, 200032, China
| | - Yue Chen
- School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, 600 Peter Morand Crescent, Ottawa, Ontario, K1G 5Z3, Canada
| | - Qingwu Jiang
- Fudan University School of Public Health, Building 8, 130 Dong'an Road, Shanghai, 200032, China.,Key Laboratory of Public Health Safety, Fudan University, Ministry of Education, Building 8, 130 Dong'an Road, Shanghai, 200032, China.,Fudan University Center for Tropical Disease Research, Building 8, 130 Dong'an Road, Shanghai, 200032, China
| | - Yibiao Zhou
- Fudan University School of Public Health, Building 8, 130 Dong'an Road, Shanghai, 200032, China. .,Key Laboratory of Public Health Safety, Fudan University, Ministry of Education, Building 8, 130 Dong'an Road, Shanghai, 200032, China. .,Fudan University Center for Tropical Disease Research, Building 8, 130 Dong'an Road, Shanghai, 200032, China.
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22
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Shi D, Turroni S, Gong L, Wu W, Yim HCH. Editorial: Manipulation of gut microbiota as a key target to intervene on the onset and progression of digestive system diseases. Front Med (Lausanne) 2022; 9:999005. [PMID: 36106327 PMCID: PMC9465376 DOI: 10.3389/fmed.2022.999005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 07/29/2022] [Indexed: 11/23/2022] Open
Affiliation(s)
- Ding Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China
- *Correspondence: Ding Shi
| | - Silvia Turroni
- Unit of Microbiome Science and Biotechnology, Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Lan Gong
- Microbiome Research Centre, St George and Sutherland Clinical Campus, School of Clinical Medicine, University of New South Wales, Sydney, NSW, Australia
| | - Wenrui Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China
| | - Howard Chi Ho Yim
- Microbiome Research Centre, St George and Sutherland Clinical Campus, School of Clinical Medicine, University of New South Wales, Sydney, NSW, Australia
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23
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Malone J, Jung J, Tran L, Zhao C. Periodontal Disease and Risk of Dementia in Medicare Patients with Hepatitis C Virus. J Alzheimers Dis 2021; 85:1301-1308. [PMID: 34924375 DOI: 10.3233/jad-210666] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Periodontal disease and hepatitis C virus (HCV) represent chronic infectious states that are common in elderly adults. Both conditions have independently been associated with an increased risk for dementia. Chronic infections are thought to lead to neurodegenerative changes in the central nervous system possibly by promoting a proinflammatory state. This is consistent with growing literature on the etiological role of infections in dementia. Few studies have previously evaluated the association of periodontal disease with dementia in HCV patients. OBJECTIVE To examine whether periodontal disease increases the risk of developing Alzheimer's disease and related dementias (ADRD) among HCV patients in Medicare claims data. METHODS We used Medicare claims data for HCV patients to assess the incidence rate of ADRD with and without exposure to periodontal disease between 2014 and 2017. Cox multivariate regression was used to estimate the association between periodontal disease and development of ADRD, controlling for age, gender, race, ZIP-level income and education, and medical comorbidities. RESULTS Of 439,760 HCV patients, the incidence rate of ADRD was higher in patients with periodontal diseases compared to those without (10.84% versus 9.26%, p < 0.001), and those with periodontal disease developed ADRD earlier compared to those without periodontal disease (13.99 versus 21.60 months, p < 0.001). The hazard of developing ADRD was 1.35 times higher in those with periodontal disease (95% CI, 1.30 to 1.40, p < 0.001) after adjusting for all covariates, including age. CONCLUSION Periodontal disease increased the risk of developing ADRD among HCV patients in a national Medicare claims dataset.
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Affiliation(s)
- Joseph Malone
- Department of Neurology, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Jeah Jung
- Department of Health Policy and Administration, College of Health and Human Development, Pennsylvania State University, University Park, PA, USA
| | - Linh Tran
- Department of Health Policy and Administration, College of Health and Human Development, Pennsylvania State University, University Park, PA, USA
| | - Chen Zhao
- Department of Neurology, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA.,Department of Public Health Sciences, Pennsylvania State University College of Medicine, Hershey, PA, USA
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24
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Influence of Probiotics Administration Before Liver Resection in Patients with Liver Disease: A Randomized Controlled Trial. World J Surg 2021; 46:656-665. [PMID: 34837121 DOI: 10.1007/s00268-021-06388-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/24/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND By inhibiting the growth of pathogenic bacteria and modulating the local intestinal immune system, probiotics may reduce bacterial translocation and systemic endotoxaemia, factors partially responsible for post-operative complications following liver resection for hepatocellular carcinoma in patients with cirrhosis. METHODS Patients with resectable hepatocellular carcinoma developed in the setting of chronic liver disease were prospectively divided into two equal-sized groups: one receiving probiotic treatment 14 days prior to surgery and the other receiving placebo. The primary endpoint was the level of circulating endotoxins after hepatectomy. Secondary endpoints were systemic inflammation (inflammatory cytokine levels), post-operative liver function and overall post-operative complication rate. RESULTS From May 2013 to December 2018, 64 patients were randomized, and 54 patients were included in the analysis, 27 in each arm. No significant change in endotoxin levels was observed over time in either group (P = 0.299). No difference between the groups in terms of post-operative liver function and overall complication rates was observed. The only differences observed were significant increases in the levels of TNFalpha (P = 0.019) and interleukin 1-b (P = 0.028) in the probiotic group in the post-operative period. CONCLUSION Contrary to the modest data reported in the literature, the administration of probiotics before minor liver resection for hepatocellular carcinoma developed in the setting of compensated chronic liver disease does not seem to have an impact on circulating endotoxin levels or post-operative complication rates. TRIAL REGISTRATION Trial registration: NCT02021253.
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25
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Flatt E, McLin VA, Braissant O, Pierzchala K, Mastromarino P, Mitrea SO, Sessa D, Gruetter R, Cudalbu C. Probiotics combined with rifaximin influence the neurometabolic changes in a rat model of type C HE. Sci Rep 2021; 11:17988. [PMID: 34504135 PMCID: PMC8429411 DOI: 10.1038/s41598-021-97018-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 08/12/2021] [Indexed: 02/07/2023] Open
Abstract
Type C hepatic encephalopathy (HE) is a neuropsychiatric disease caused by chronic liver disease. Management of type C HE remains an important challenge because treatment options are limited. Both the antibiotic rifaximin and probiotics have been reported to reduce the symptoms of HE, but longitudinal studies assessing their effects on brain metabolism are lacking and the molecular mechanisms underpinning their effects are not fully understood. Therefore, we evaluated in detail the effects of these different treatments on the neurometabolic changes associated with type C HE using a multimodal approach including ultra-high field in vivo 1H MRS. We analyzed longitudinally the effect of rifaximin alone or in combination with the probiotic Vivomixx on the brain metabolic profile in the hippocampus and cerebellum of bile duct ligated (BDL) rats, an established model of type C HE. Overall, while rifaximin alone appeared to induce no significant effect on the neurometabolic profile of BDL rats, its association with the probiotic resulted in more attenuated neurometabolic alterations in BDL rats followed longitudinally (i.e. a smaller increase in Gln and milder decrease in Glu and Cr levels). Given that both rifaximin and some probiotics are used in the treatment of HE, the implications of these findings may be clinically relevant.
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Affiliation(s)
- Emmanuelle Flatt
- Laboratory for Functional and Metabolic Imaging, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Valérie A McLin
- Swiss Pediatric Liver Center, Department of Pediatrics, Gynecology and Obstetrics, University Hospitals Geneva, University of Geneva, Geneva, Switzerland
| | - Olivier Braissant
- Service of Clinical Chemistry, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
| | - Katarzyna Pierzchala
- CIBM Center for Biomedical Imaging, Lausanne, Switzerland.,Animal Imaging and Technology, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Paola Mastromarino
- Section of Microbiology, Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | | | - Dario Sessa
- Swiss Pediatric Liver Center, Department of Pediatrics, Gynecology and Obstetrics, University Hospitals Geneva, University of Geneva, Geneva, Switzerland
| | - Rolf Gruetter
- Laboratory for Functional and Metabolic Imaging, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Cristina Cudalbu
- CIBM Center for Biomedical Imaging, Lausanne, Switzerland. .,Animal Imaging and Technology, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
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26
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Yoshiji H, Nagoshi S, Akahane T, Asaoka Y, Ueno Y, Ogawa K, Kawaguchi T, Kurosaki M, Sakaida I, Shimizu M, Taniai M, Terai S, Nishikawa H, Hiasa Y, Hidaka H, Miwa H, Chayama K, Enomoto N, Shimosegawa T, Takehara T, Koike K. Evidence-based clinical practice guidelines for Liver Cirrhosis 2020. J Gastroenterol 2021; 56:593-619. [PMID: 34231046 PMCID: PMC8280040 DOI: 10.1007/s00535-021-01788-x] [Citation(s) in RCA: 189] [Impact Index Per Article: 47.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 02/25/2021] [Indexed: 02/07/2023]
Abstract
The first edition of the clinical practice guidelines for liver cirrhosis was published in 2010, and the second edition was published in 2015 by the Japanese Society of Gastroenterology (JSGE). The revised third edition was recently published in 2020. This version has become a joint guideline by the JSGE and the Japan Society of Hepatology (JSH). In addition to the clinical questions (CQs), background questions (BQs) are new items for basic clinical knowledge, and future research questions (FRQs) are newly added clinically important items. Concerning the clinical treatment of liver cirrhosis, new findings have been reported over the past 5 years since the second edition. In this revision, we decided to match the international standards as much as possible by referring to the latest international guidelines. Newly developed agents for various complications have also made great progress. In comparison with the latest global guidelines, such as the European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases (AASLD), we are introducing data based on the evidence for clinical practice in Japan. The flowchart for nutrition therapy was reviewed to be useful for daily medical care by referring to overseas guidelines. We also explain several clinically important items that have recently received focus and were not mentioned in the last editions. This digest version describes the issues related to the management of liver cirrhosis and several complications in clinical practice. The content begins with a diagnostic algorithm, the revised flowchart for nutritional therapy, and refracted ascites, which are of great importance to patients with cirrhosis. In addition to the updated antiviral therapy for hepatitis B and C liver cirrhosis, the latest treatments for non-viral cirrhosis, such as alcoholic steatohepatitis/non-alcoholic steatohepatitis (ASH/NASH) and autoimmune-related cirrhosis, are also described. It also covers the latest evidence regarding the diagnosis and treatment of liver cirrhosis complications, namely gastrointestinal bleeding, ascites, hepatorenal syndrome and acute kidney injury, hepatic encephalopathy, portal thrombus, sarcopenia, muscle cramp, thrombocytopenia, pruritus, hepatopulmonary syndrome, portopulmonary hypertension, and vitamin D deficiency, including BQ, CQ and FRQ. Finally, this guideline covers prognosis prediction and liver transplantation, especially focusing on several new findings since the last version. Since this revision is a joint guideline by both societies, the same content is published simultaneously in the official English journal of JSGE and JSH.
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Affiliation(s)
- Hitoshi Yoshiji
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan.
- Department of Gastroenterology, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan.
| | - Sumiko Nagoshi
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Takemi Akahane
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Yoshinari Asaoka
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Yoshiyuki Ueno
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Koji Ogawa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Takumi Kawaguchi
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Masayuki Kurosaki
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Isao Sakaida
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Masahito Shimizu
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Makiko Taniai
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Shuji Terai
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Hiroki Nishikawa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Yoichi Hiasa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Hisashi Hidaka
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Hiroto Miwa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Kazuaki Chayama
- The Japan Society of Hepatology, Kashiwaya 2 Building 5F, 3-28-10 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Nobuyuki Enomoto
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Tooru Shimosegawa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Tetsuo Takehara
- The Japan Society of Hepatology, Kashiwaya 2 Building 5F, 3-28-10 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Kazuhiko Koike
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
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27
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Yoshiji H, Nagoshi S, Akahane T, Asaoka Y, Ueno Y, Ogawa K, Kawaguchi T, Kurosaki M, Sakaida I, Shimizu M, Taniai M, Terai S, Nishikawa H, Hiasa Y, Hidaka H, Miwa H, Chayama K, Enomoto N, Shimosegawa T, Takehara T, Koike K. Evidence-based clinical practice guidelines for liver cirrhosis 2020. Hepatol Res 2021; 51:725-749. [PMID: 34231046 DOI: 10.1111/hepr.13678] [Citation(s) in RCA: 100] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 05/26/2021] [Indexed: 12/14/2022]
Abstract
The first edition of the clinical practice guidelines for liver cirrhosis was published in 2010, and the second edition was published in 2015 by the Japanese Society of Gastroenterology (JSGE). The revised third edition was recently published in 2020. This version has become a joint guideline by the JSGE and the Japanese Society of Hepatology (JSH). In addition to the clinical questions (CQs), background questions (BQs) are new items for basic clinical knowledge, and future research questions (FRQs) are newly added clinically important items. Concerning the clinical treatment of liver cirrhosis, new findings have been reported over the past 5 years since the second edition. In this revision, we decided to match the international standards as much as possible by referring to the latest international guidelines. Newly developed agents for various complications have also made great progress. In comparison with the latest global guidelines, such as the European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases (AASLD), we are introducing data based on the evidence for clinical practice in Japan. The flowchart for nutrition therapy was reviewed to be useful for daily medical care by referring to overseas guidelines. We also explain several clinically important items that have recently received focus and were not mentioned in the last editions. This digest version describes the issues related to the management of liver cirrhosis and several complications in clinical practice. The content begins with a diagnostic algorithm, the revised flowchart for nutritional therapy, and refracted ascites, which are of great importance to patients with cirrhosis. In addition to the updated antiviral therapy for hepatitis B and C liver cirrhosis, the latest treatments for non-viral cirrhosis, such as alcoholic steatohepatitis/non-alcoholic steatohepatitis (ASH/NASH) and autoimmune-related cirrhosis, are also described. It also covers the latest evidence regarding the diagnosis and treatment of liver cirrhosis complications, namely gastrointestinal bleeding, ascites, hepatorenal syndrome and acute kidney injury, hepatic encephalopathy, portal thrombus, sarcopenia, muscle cramp, thrombocytopenia, pruritus, hepatopulmonary syndrome, portopulmonary hypertension, and vitamin D deficiency, including BQ, CQ and FRQ. Finally, this guideline covers prognosis prediction and liver transplantation, especially focusing on several new findings since the last version. Since this revision is a joint guideline by both societies, the same content is published simultaneously in the official English journal of JSGE and JSH.
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Affiliation(s)
- Hitoshi Yoshiji
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan.,Department of Gastroenterology, Nara Medical University, Nara, Japan
| | - Sumiko Nagoshi
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Takemi Akahane
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Yoshinari Asaoka
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Yoshiyuki Ueno
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Koji Ogawa
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Takumi Kawaguchi
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Masayuki Kurosaki
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Isao Sakaida
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Masahito Shimizu
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Makiko Taniai
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Shuji Terai
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Hiroki Nishikawa
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Yoichi Hiasa
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Hisashi Hidaka
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Hiroto Miwa
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | | | - Nobuyuki Enomoto
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Tooru Shimosegawa
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | | | - Kazuhiko Koike
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
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28
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Moran S, López-Sánchez M, Milke-García MDP, Rodríguez-Leal G. Current approach to treatment of minimal hepatic encephalopathy in patients with liver cirrhosis. World J Gastroenterol 2021; 27:3050-3063. [PMID: 34168407 PMCID: PMC8192295 DOI: 10.3748/wjg.v27.i22.3050] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 04/01/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023] Open
Abstract
Minimal hepatic encephalopathy (MHE) corresponds to the earliest stage of hepatic encephalopathy (HE). MHE does not present clinically detectable neurological-psychiatric abnormalities but is characterized by imperceptible neurocognitive alterations detected during routine clinical examination via neuropsychological or psychometrical tests. MHE may affect daily activities and reduce job performance and quality of life. MHE can increase the risk of accidents and may develop into overt encephalopathy, worsening the prognosis of patients with liver cirrhosis. Despite a lack of consensus on the therapeutic indication, interest in finding novel strategies for prevention or reversion has led to numerous clinical trials; their results are the main objective of this review. Many studies address the treatment of MHE, which is mainly based on the strategies and previous management of overt HE. Current alternatives for the management of MHE include measures to maintain nutritional status while avoiding sarcopenia, and manipulation of intestinal microbiota with non-absorbable disaccharides such as lactulose, antibiotics such as rifaximin, and administration of different probiotics. This review analyzes the results of clinical studies that evaluated the effects of different treatments for MHE.
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Affiliation(s)
- Segundo Moran
- Laboratory of Hepatology Research, Centro Médico Nacional, Siglo XXI, Mexican Institute of Social Security, Mexico City 06720, Mexico
| | - Marlene López-Sánchez
- Laboratory of Hepatology Research, Centro Médico Nacional, Siglo XXI, Mexican Institute of Social Security, Mexico City 06720, Mexico
| | | | - Gustavo Rodríguez-Leal
- Laboratory of Hepatology Research, Centro Médico Nacional, Siglo XXI, Mexican Institute of Social Security, Mexico City 06720, Mexico
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29
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Miwa T, Hanai T, Toshihide M, Ogiso Y, Imai K, Suetsugu A, Takai K, Shiraki M, Katsumura N, Shimizu M. Zinc deficiency predicts overt hepatic encephalopathy and mortality in liver cirrhosis patients with minimal hepatic encephalopathy. Hepatol Res 2021; 51:662-673. [PMID: 33242359 DOI: 10.1111/hepr.13601] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Revised: 11/07/2020] [Accepted: 11/15/2021] [Indexed: 12/13/2022]
Abstract
AIM Minimal hepatic encephalopathy (MHE) is associated with poor outcomes and the development of overt hepatic encephalopathy (OHE) in patients with liver cirrhosis (LC). Zinc plays a key role in the detoxification of ammonia, a risk factor of hepatic encephalopathy. This study aimed to investigate whether zinc deficiency predicts OHE occurrence and mortality in LC patients with MHE. METHOD This retrospective study included 100 LC patients with MHE. MHE was diagnosed using a computer-aided neuropsychiatric test. Predictors associated with the development of OHE were analyzed using the Fine-Gray competing risk regression model. Cox proportional hazards regression analysis was carried out to evaluate the risk factors of mortality. Survival rates were analyzed using the Kaplan-Meier method and log-rank test. RESULTS Of the 100 LC patients with MHE, 41% had zinc deficiency (<60 μg/dl). Zinc deficiency was observed more frequently in the patients with reduced liver function reserve. During the median follow-up period of 9.9 months, 16% of the patients with MHE developed OHE. The patients with zinc deficiency had a higher risk of OHE than those without zinc deficiency (p = 0.03). Zinc deficiency was also associated with poor survival (p = 0.004). Multivariate analyses showed that zinc predicts the development of OHE (subdistribution hazard ratio [HR], 0.95; 95% confidence interval [CI], 0.92-0.99; p = 0.008) and mortality (HR, 0.96; 95% CI, 0.93-0.99; p = 0.02), independently of liver function reserves. CONCLUSION Zinc deficiency is likely to be a predictor of both OHE development and mortality in LC patients with MHE.
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Affiliation(s)
- Takao Miwa
- Department of Gastroenterology, Chuno Kosei Hospital, Seki, Japan.,Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Tatsunori Hanai
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.,Division for Regional Cancer Control, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Maeda Toshihide
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Yui Ogiso
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Kenji Imai
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Atsushi Suetsugu
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Koji Takai
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.,Division for Regional Cancer Control, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Makoto Shiraki
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Naoki Katsumura
- Department of Gastroenterology, Chuno Kosei Hospital, Seki, Japan
| | - Masahito Shimizu
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
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Abstract
Biliary atresia (BA) is a fibro-obliterative condition of the biliary tree, presenting in infancy. The bilioenteric conduit formed at Kasai portoenterostomy (KPE), achieves restoration of bile flow in approximately 60% of infants. Even if the operation is successful, cirrhosis and its associated complications are, however, common. BA remains the leading cause for liver transplantation (LT) in children. Antibiotic, choleretic, and steroid therapy post-KPE have not convincingly reduced LT rates. Advances in molecular technology have enabled characterisation of the encoded genes of the gut microbiota (gut microbiome). The gut microbiome plays an important role in host metabolism, nutrition, and immune function, with alterations in its diversity and/or composition, known as dysbiosis, being described in disease states, including liver disease. Liver-gut microbiome exploration in adulthood largely focuses on nonalcoholic liver disease, cirrhosis (mainly alcohol- or viral-based aetiology) and cholestatic liver diseases (eg, primary sclerosing cholangitis), with microbial signatures correlating to disease severity. Investigation of the gut microbiota in BA had been limited to culture-based methodology, but molecular studies are emerging, and although in their infancy, highlight a potential pathogenic role for Enterobacteriaceae and Streptococcus, and a potential beneficial role for Bifidobacteria. Bacterial translocation, and the production of gut microbiome-derived metabolites, are key host-microbiome-mechanistic pathways in liver disease pathogenesis. Microbiome-targeted therapeutics for liver disease are in development, with faecal microbiota transplantation showing promise in cirrhosis. Could the gut microbiome be a novel modifiable risk factor in BA, reducing the need for LT?
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31
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Chu YY, Wang X, Dai HL. Update on pharmacotherapy of hepatic encephalopathy. Shijie Huaren Xiaohua Zazhi 2021; 29:58-64. [DOI: 10.11569/wcjd.v29.i2.58] [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] [Indexed: 02/06/2023] Open
Abstract
Hepatic encephalopathy (HE) is a central nervous system disease caused by serious liver diseases or various portal vein systemic circulation abnormalities. The pathogenesis and pathophysiology of HE have not been fully elucidated yet, and among others, the most important is still the theory of ammonia intoxication proposed in the 1930s. Therefore, reducing blood ammonia is currently the main therapeutic strategy for HE, along with improving nervous system function. Thanks to the clarification of the mechanism underlying ammonia-induced brain cell injury in recent years, researchers have proposed some novel therapeutic targets and related drugs. This work will make a brief summary regarding the update of HE drugs with regard to ammonia reduction, nervous system improvement, and intervention of ammonia toxicity targets.
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Affiliation(s)
- Yu-Ying Chu
- School of Nursing, Jinzhou Medical University, Jinzhou 121001, Liaoning Province, China
| | - Xue Wang
- School of Nursing, Jinzhou Medical University, Jinzhou 121001, Liaoning Province, China
| | - Hong-Liang Dai
- School of Nursing, Jinzhou Medical University, Jinzhou 121001, Liaoning Province, China
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32
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Rackayová V, Flatt E, Braissant O, Grosse J, Capobianco D, Mastromarino P, McMillin M, DeMorrow S, McLin VA, Cudalbu C. Probiotics improve the neurometabolic profile of rats with chronic cholestatic liver disease. Sci Rep 2021; 11:2269. [PMID: 33500487 PMCID: PMC7838316 DOI: 10.1038/s41598-021-81871-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 12/23/2020] [Indexed: 02/06/2023] Open
Abstract
Chronic liver disease leads to neuropsychiatric complications called hepatic encephalopathy (HE). Current treatments have some limitations in their efficacy and tolerability, emphasizing the need for alternative therapies. Modulation of gut bacterial flora using probiotics is emerging as a therapeutic alternative. However, knowledge about how probiotics influence brain metabolite changes during HE is missing. In the present study, we combined the advantages of ultra-high field in vivo 1H MRS with behavioural tests to analyse whether a long-term treatment with a multistrain probiotic mixture (VIVOMIXX) in a rat model of type C HE had a positive effect on behaviour and neurometabolic changes. We showed that the prophylactic administration of this probiotic formulation led to an increase in gut Bifidobacteria and attenuated changes in locomotor activity and neurometabolic profile in a rat model of type C HE. Both the performance in behavioural tests and the neurometabolic profile of BDL + probiotic rats were improved compared to the BDL group at week 8 post-BDL. They displayed a significantly lesser increase in brain Gln, a milder decrease in brain mIns and a smaller decrease in neurotransmitter Glu than untreated animals. The clinical implications of these findings are potentially far-reaching given that probiotics are generally safe and well-tolerated by patients.
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Affiliation(s)
- Veronika Rackayová
- Laboratory for Functional and Metabolic Imaging, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
- Center for Biomedical Imaging, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Vaud, Switzerland
| | - Emmanuelle Flatt
- Laboratory for Functional and Metabolic Imaging, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Olivier Braissant
- Service of Clinical Chemistry, University of Lausanne and University Hospital of Lausanne, Lausanne, Switzerland
| | - Jocelyn Grosse
- Laboratory of Behavioral Genetics, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Daniela Capobianco
- Department of Public Health and Infectious Diseases, Section of Microbiology, Sapienza University of Rome, Rome, Italy
| | - Paola Mastromarino
- Department of Public Health and Infectious Diseases, Section of Microbiology, Sapienza University of Rome, Rome, Italy
| | - Matthew McMillin
- Department of Internal Medicine, Dell Medical School, The University of Texas at Austin, Austin, TX, USA
- Central Texas Veterans Health Care System, Temple, TX, USA
| | - Sharon DeMorrow
- Department of Internal Medicine, Dell Medical School, The University of Texas at Austin, Austin, TX, USA
- Central Texas Veterans Health Care System, Temple, TX, USA
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX, USA
| | - Valérie A McLin
- Swiss Pediatric Liver Center, Department of Pediatrics, Gynecology and Obstetrics, University of Geneva and University Hospitals Geneva, Geneva, Switzerland
| | - Cristina Cudalbu
- Center for Biomedical Imaging, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Vaud, Switzerland.
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Hassouneh R, Bajaj JS. Gut Microbiota Modulation and Fecal Transplantation: An Overview on Innovative Strategies for Hepatic Encephalopathy Treatment. J Clin Med 2021; 10:330. [PMID: 33477417 PMCID: PMC7830387 DOI: 10.3390/jcm10020330] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/07/2021] [Accepted: 01/09/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatic encephalopathy (HE) is a major complication of cirrhosis, which is associated with gut microbial composition and functional alterations. Current treatments largely focus on gut microbiota using lactulose, rifaximin and other agents. However, despite these treatments, patients with HE have a high rate of readmission, morbidity and cognitive impairment. Fecal microbiota transplant (FMT) involves introduction of a donor microbiota into a recipient and is currently mainly used for recurrent C. difficile infection (rCDI). The role of FMT in cirrhosis and HE is evolving. There have been two randomized clinical trials (RCT) and several case reports/series in cirrhosis. Both RCTs were safety-focused phase 1 trials. One involved pre-FMT antibiotics and FMT enema versus standard of care, while the other involved 15 FMT capsules versus placebo without pre-FMT antibiotics. There was evidence of safety in both trials and the FMT group demonstrated reduction in hospitalizations compared to the non-FMT group. Changes in microbial function centered around short-chain fatty acids, bile acids and brain function showed improvement in the FMT groups. Long-term follow-up demonstrated continued safety and reduction in the antibiotic-resistance gene carriage. However, larger trials of FMT in HE are needed that can refine the dose, duration and route of FMT administration.
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Affiliation(s)
- Ramzi Hassouneh
- Department of Internal Medicine, Virginia Commonwealth University Medical Center, Richmond, VA 23298, USA;
| | - Jasmohan S. Bajaj
- Division of Gastroenterology, Hepatology and Nutrition Virginia Commonwealth University and Central Virginia Veterans Healthcare System, 1201 Broad Rock Blvd, Richmond, VA 23249, USA
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Korotkaya Y, Conner K, Lau J, Mullin G, Harpavat S, Miloh T, Mogul D. Use of Dietary Supplements in Pediatric Liver Disease and Transplantation. J Pediatr Gastroenterol Nutr 2021; 72:e10-e14. [PMID: 32826803 DOI: 10.1097/mpg.0000000000002922] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
BACKGROUND Dietary supplements are frequently used by healthy individuals and those with chronic medical conditions but may cause damage to the liver. The aim of this study was to examine the prevalence and attitudes of dietary supplement use, and the frequency of disclosure to healthcare providers among parents/caregivers for children with chronic liver disease. METHODS We developed an anonymous survey for parents/caregivers of children (<18 years old) with chronic liver disease or liver transplant recipients and distributed the survey through social media groups organized around pediatric liver diseases. RESULTS The survey was completed by 101 parents/caregivers (48 without transplant and 53 posttransplant).Among respondents, 87% agreed they would use dietary supplements to help their child, but parents/caregivers of transplant recipients were less likely to consider use (77% vs 98%; P = 0.01). In the past 12 months, 83% reported dietary supplement use including 47% who used nonvitamin/mineral supplements. In two-thirds of parents/caregivers, use was initiated by their personal belief. Although 77% of respondents disclosed their use to their liver team, disclosure varied depending on the supplement with no individual that used cannabinoid products disclosing the use. CONCLUSIONS Dietary supplements are frequently used by children with liver disease and may exceed use in other pediatric conditions. Though most parents report use to their liver team, disclosure may vary depending on the specific supplement. Providers should take extra measures to review use of supplements with their patients and work to develop trust with their families to obtain accurate disclosure of use.
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Affiliation(s)
- Yelena Korotkaya
- Department of Pediatrics, Johns Hopkins University School of Medicine
| | - Kim Conner
- Johns Hopkins Children's Center, Baltimore, MD
| | - Jen Lau
- Patient Advocate, Chicago, IL
| | - Gerard Mullin
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Sanjiv Harpavat
- Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX
| | - Tamir Miloh
- Department of Pediatrics, University of Miami, Miami, FL
| | - Douglas Mogul
- Department of Pediatrics, Johns Hopkins University School of Medicine
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Shunt-Induced Hepatic Encephalopathy in TIPS: Current Approaches and Clinical Challenges. J Clin Med 2020; 9:jcm9113784. [PMID: 33238576 PMCID: PMC7700586 DOI: 10.3390/jcm9113784] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Revised: 11/19/2020] [Accepted: 11/20/2020] [Indexed: 12/11/2022] Open
Abstract
Transjugular intrahepatic portosystemic shunt (TIPS) is an established treatment tool in decompensated liver cirrhosis that has been shown to prolong transplant-free survival. Hepatic encephalopathy (HE) is a frequent complication of decompensated cirrhosis, eventually induced and/or aggravated by TIPS, that remains a clinical challenge especially in these patients. Therefore, patient selection for TIPS requires careful assessment of risk factors for HE. TIPS procedural parameters regarding stent size and invasive portosystemic pressure gradient measurements thereby have an important role. Endovascular shunt modification, in combination with a conservative medical approach, often results in a significant reduction of symptoms. This review summarizes HE molecular mechanisms and pathophysiology as well as diagnostic and therapeutic approaches targeting shunt-induced HE.
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An Oral Formulation of the Probiotic, Bacillus subtilis HU58, Was Safe and Well Tolerated in a Pilot Study of Patients with Hepatic Encephalopathy. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:1463108. [PMID: 32714397 PMCID: PMC7345602 DOI: 10.1155/2020/1463108] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Accepted: 05/25/2020] [Indexed: 12/14/2022]
Abstract
Background Hepatic encephalopathy often results in high blood ammonia levels because of inefficient ammonia processing by the liver. Lactulose treatment promotes the growth of urease-producing gut bacteria and a reduced colon pH, thus reducing blood ammonia absorption. It is thought that probiotics as an add-on therapy may be beneficial. Patients and Methods. Bacillus subtilis HU58 was tested for safety and tolerability in patients with hepatic encephalopathy taking lactulose in this double-bind, placebo-controlled, 4-week pilot study. Study participants received one dose of B. subtilis HU58 or placebo (orally) for the first five days and two daily doses thereafter. Participants were monitored for safety and blood ammonia levels. Results Forty patients participated (placebo, 11; probiotic, 29). Baseline characteristics were generally comparable; the mean baseline blood ammonia level was somewhat higher in the probiotic group. Mild or moderate treatment-emergent adverse events (TEAEs) were reported in 27.3% and 17.2% of patients in the placebo and probiotic groups, respectively; no severe TEAEs were reported. One patient (9.1%) taking placebo and two (6.9%) taking the probiotic experienced serious TEAEs (SAEs); none resulted in study discontinuation and all were considered to have no/unlikely relationship to the study product. There were no significant differences in the mean percent change (MPC) of blood ammonia levels between groups, though the probiotic group exhibited a trend toward a milder increase. Stratification of the probiotic group by baseline blood ammonia level (>60 μg/dL and ≤60 μg/dL) resulted in a significantly reduced MPC in the >60 μg/dL subgroup (MPC (SD); ≤60 μg/dL (n = 14), 35.3% (73.3); >60 μg/dL (n = 14), −26.5% (24.4); p = 0.0087). Conclusions Daily treatment with oral B. subtilis HU58 was safe and well tolerated over a 4-week period in patients with hepatic encephalopathy, and a significantly reduced MPC of blood ammonia level was observed in patients with a baseline level >60 µg/dL.
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Abstract
Abstract
Purpose of Review
We examine recent developments in the treatment of cirrhosis by gut microbiome manipulation specifically focusing on the phase 1 safety and feasibility trials of faecal microbiota transplantation (FMT). We interrogate the published data so far on its feasibility, safety and efficacy.
Recent Findings
A large number of trials have demonstrated the efficacy of FMT in treating recurrent Clostridium difficile infection which is now considered standard of care. In cirrhosis, FMT is still being evaluated and there are a number of clinical trials underway. There are two phase 1 pilot safety studies that have been published with promising findings. However, the importance of rigorously testing donor stool for the presence of multi-drug resistant species has been highlighted and lessons have been learned.
Summary
For those patients with cirrhosis, replacing an unhealthy gut microbiome with a healthy one offers a promising antibiotic-free treatment that may reduce bacterial translocation and endotoxemia.
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38
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Macnaughtan J, Figorilli F, García-López E, Lu H, Jones H, Sawhney R, Suzuki K, Fairclough S, Marsden J, Moratalla A, Cox IJ, Thomas L, Davies N, Williams R, Mookerjee R, Wright G, Jalan R. A Double-Blind, Randomized Placebo-Controlled Trial of Probiotic Lactobacillus casei Shirota in Stable Cirrhotic Patients. Nutrients 2020; 12:nu12061651. [PMID: 32498372 PMCID: PMC7352321 DOI: 10.3390/nu12061651] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 05/26/2020] [Accepted: 05/28/2020] [Indexed: 02/07/2023] Open
Abstract
Background: In cirrhosis, a pathological gut microbiome has been linked with immune dysfunction. A pilot study of probiotic Lactobacillus casei Shirota (LcS) in alcoholic cirrhosis demonstrated significant improvement in neutrophil function. This study aimed to evaluate the efficacy of LcS on neutrophil function and significant infection rates in patients with cirrhosis. Methods: 92 cirrhotic patients (Child-Pugh score ≤10) were randomized to receive LcS or placebo, three times daily for six months. Primary end-points were incidence of significant infection and neutrophil function. Secondary end-points were cytokine profile, endotoxin, bacterial DNA positivity, intestinal permeability and quality of life. Results: Rates of infection, decompensation or neutrophil function did not differ between placebo and probiotic groups. LcS significantly reduced plasma monocyte chemotactic protein-1 and, on subgroup analysis, plasma interleukin-1β (alcoholic cirrhosis), interleukin-17a and macrophage inflammatory protein-1β (non-alcoholic cirrhosis), compared with placebo. No significant differences in intestinal permeability, bacterial translocation or metabolomic profile were observed. Conclusion: LcS supplementation in patients with early cirrhosis is safe. Although no significant infections were observed in either group, LcS improved cytokine profile towards an anti-inflammatory phenotype, an effect which appears to be independent of bacterial translocation.
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Affiliation(s)
- Jane Macnaughtan
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, London NW3 2PF, UK; (F.F.); (H.L.); (H.J.); (R.S.); (A.M.); (N.D.); (R.M.); (G.W.); (R.J.)
- Department of Hepatology, Royal Free Hospital, London NW3 2QG, UK
- Correspondence: ; Tel.: +44-(0)20-7433-2874
| | - Francesco Figorilli
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, London NW3 2PF, UK; (F.F.); (H.L.); (H.J.); (R.S.); (A.M.); (N.D.); (R.M.); (G.W.); (R.J.)
| | - Elisabet García-López
- Data Management Centre, European Foundation for the Study of Chronic Liver Failure (EF-CLIF), 08021 Barcelona, Spain;
| | - Haw Lu
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, London NW3 2PF, UK; (F.F.); (H.L.); (H.J.); (R.S.); (A.M.); (N.D.); (R.M.); (G.W.); (R.J.)
| | - Helen Jones
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, London NW3 2PF, UK; (F.F.); (H.L.); (H.J.); (R.S.); (A.M.); (N.D.); (R.M.); (G.W.); (R.J.)
| | - Rohit Sawhney
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, London NW3 2PF, UK; (F.F.); (H.L.); (H.J.); (R.S.); (A.M.); (N.D.); (R.M.); (G.W.); (R.J.)
| | - Kaori Suzuki
- Yakult Europe B.V., 1332 EN Almere, The Netherlands; (K.S.); (L.T.)
| | - Sarah Fairclough
- Mid and South Essex NHS Foundation Trust, Basildon & Thurrock University Hospitals NHS Foundation Trust, Basildon SS16 5NL, UK;
| | - Joanne Marsden
- Department of Biochemistry, Bessemer Wing, King’s College Hospital, London SE5 9RS, UK;
| | - Alba Moratalla
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, London NW3 2PF, UK; (F.F.); (H.L.); (H.J.); (R.S.); (A.M.); (N.D.); (R.M.); (G.W.); (R.J.)
| | - I. Jane Cox
- Institute of Hepatology London, Foundation for Liver Research, London SE5 9NT, UK; (I.J.C.); (R.W.)
- Faculty of Life Sciences & Medicine, King’s College London, London SE5 9RS, UK
| | - Linda Thomas
- Yakult Europe B.V., 1332 EN Almere, The Netherlands; (K.S.); (L.T.)
| | - Nathan Davies
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, London NW3 2PF, UK; (F.F.); (H.L.); (H.J.); (R.S.); (A.M.); (N.D.); (R.M.); (G.W.); (R.J.)
| | - Roger Williams
- Institute of Hepatology London, Foundation for Liver Research, London SE5 9NT, UK; (I.J.C.); (R.W.)
- Faculty of Life Sciences & Medicine, King’s College London, London SE5 9RS, UK
| | - Raj Mookerjee
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, London NW3 2PF, UK; (F.F.); (H.L.); (H.J.); (R.S.); (A.M.); (N.D.); (R.M.); (G.W.); (R.J.)
- Department of Hepatology, Royal Free Hospital, London NW3 2QG, UK
| | - Gavin Wright
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, London NW3 2PF, UK; (F.F.); (H.L.); (H.J.); (R.S.); (A.M.); (N.D.); (R.M.); (G.W.); (R.J.)
- Department of Hepatology, Royal Free Hospital, London NW3 2QG, UK
- Mid and South Essex NHS Foundation Trust, Basildon & Thurrock University Hospitals NHS Foundation Trust, Basildon SS16 5NL, UK;
- Faculty of Life Sciences & Medicine, King’s College London, London SE5 9RS, UK
| | - Rajiv Jalan
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, London NW3 2PF, UK; (F.F.); (H.L.); (H.J.); (R.S.); (A.M.); (N.D.); (R.M.); (G.W.); (R.J.)
- Department of Hepatology, Royal Free Hospital, London NW3 2QG, UK
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Abstract
Research increasingly shows that the gut-liver-brain axis is a crucial component in the pathophysiology of hepatic encephalopathy (HE). Due to the limitations of current standard-of-care medications, non-pharmacological treatments that target gut dysbiosis, including probiotics, nutritional management, and fecal microbiota transplants, are being considered as alternative and adjunct therapies. Meta-analyses note that probiotics could offer benefits in HE treatment, but have not shown superiority over lactulose. Emerging literature suggests that fecal microbiota transplants could offer a novel strategy to treat gut dysbiosis and favorably impact HE. Finally, liver support devices and liver transplantation could offer a last-resort treatment option for persistent HE.
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Affiliation(s)
- Vanessa Weir
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, Perelman Center for Advanced Medicine, 7 South Pavilion, 3400 Civic Center Boulevard, HUP, Philadelphia, PA 19104, USA
| | - K Rajender Reddy
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, 2 Dulles, 3400 Spruce Street, HUP, Philadelphia, PA 19104, USA.
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KASL clinical practice guidelines for liver cirrhosis: Varices, hepatic encephalopathy, and related complications. Clin Mol Hepatol 2020; 26:83-127. [PMID: 31918536 PMCID: PMC7160350 DOI: 10.3350/cmh.2019.0010n] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 10/23/2019] [Indexed: 02/06/2023] Open
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Bifidobacterium sp as Probiotic Agent - Roles and Applications. JOURNAL OF PURE AND APPLIED MICROBIOLOGY 2019. [DOI: 10.22207/jpam.13.3.11] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
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Xu XY, Ding HG, Li WG, Jia JD, Wei L, Duan ZP, Liu YL, Ling-Hu EQ, Zhuang H, Hepatology CSO, Association CM. Chinese guidelines on management of hepatic encephalopathy in cirrhosis. World J Gastroenterol 2019; 25:5403-5422. [PMID: 31576089 PMCID: PMC6767982 DOI: 10.3748/wjg.v25.i36.5403] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 06/07/2019] [Accepted: 08/24/2019] [Indexed: 02/06/2023] Open
Abstract
The Chinese Society of Hepatology developed the current guidelines on the management of hepatic encephalopathy in cirrhosis based on the published evidence and the panelists' consensus. The guidelines provided recommendations for the diagnosis and management of hepatic encephalopathy (HE) including minimal hepatic encephalopathy (MHE) and overt hepatic encephalopathy, emphasizing the importance on screening MHE in patients with end-stage liver diseases. The guidelines emphasized that early identification and timely treatment are the key to improve the prognosis of HE. The principles of treatment include prompt removal of the cause, recovery of acute neuropsychiatric abnormalities to baseline status, primary prevention, and secondary prevention as soon as possible.
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Affiliation(s)
- Xiao-Yuan Xu
- Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China
| | - Hui-Guo Ding
- Hepatology and Digestion Center, Beijing You-An Hospital, Capital Medical University, Beijing 100069, China
| | - Wen-Gang Li
- Department of Liver Oncology, Cancer Radiation Therapy Center, Fifth Medical Center, PLA General Hospital, Beijing 100039, China
| | - Ji-Dong Jia
- Hepatology Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Lai Wei
- Hepatobiliary and Pancreatic Department, Beijing Tsinghua Changgeng Hospital, Beijing 102218, China
| | - Zhong-Ping Duan
- Artificial Liver Center, Beijing You-An Hospital, Capital Medical University, Beijing 100069, China
| | - Yu-Lan Liu
- Department of Gastroenterology, Peking University People's Hospital, Beijing 100044, China
| | - En-Qiang Ling-Hu
- Department of Gastroenterology, First Medical Center, PLA General Hospital, Beijing 100853, China
| | - Hui Zhuang
- Department of Pathogenic Biology, Peking University Health Science Center, Beijing 100191, China
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Shen YC, Chang YH, Fang CJ, Lin YS. Zinc supplementation in patients with cirrhosis and hepatic encephalopathy: a systematic review and meta-analysis. Nutr J 2019; 18:34. [PMID: 31279342 PMCID: PMC6612144 DOI: 10.1186/s12937-019-0461-3] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 06/25/2019] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Low serum zinc level is associated with hepatic encephalopathy (HE), but the efficacy of zinc supplementation remains uncertain. This study aimed to investigate the effects of zinc supplementation on HE treatment in patients with cirrhosis. METHODS We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (Cochrane CENTRAL) and Scopus from inception to December 2018; without publication date or language restrictions. Randomized controlled trials of zinc supplementation versus placebo or other treatment for the management of HE in adult patients with cirrhosis were selected. The primary outcome was the degree of HE as assessed by clinical signs or specialized psychometric tests. The secondary outcomes included serum ammonia levels, adverse events, or the length of hospital stay and costs. We carried out a meta-analysis with random effects model and summarized continuous outcomes using standardized mean differences (SMD) or mean differences (MD) with 95% confidence intervals (95% CI). The risk of bias was assessed using the Cochrane risk of bias tool, and the certainty of evidence for each outcome was evaluated with the Grading of Recommendations, Assessment, Development, and Evaluation approach. RESULTS Four trials with 247 patients were included. In patients with cirrhosis who had mild HE (≤ grade II), the available evidence suggested that the combination treatment of zinc supplementation and lactulose over 3 to 6 months significantly improved performance in the number connection test (SMD: -0.97; 95% CI: - 1.75 to - 0.19; P = 0.01; moderate certainty), reported in three trials (n = 227). However, compared with lactulose therapy alone, additional zinc supplementation demonstrated no significant difference in the digit symbol test (SMD: 0.44; 95% CI: - 0.12 to 1.00; P = 0.12; very low certainty) or serum ammonia levels (MD: -10.86; 95% CI: - 25.73 to 4.01; P = 0.15; very low certainty), reported in two trials (n = 137). None of the included trials reported adverse events or effects on hospitalization. CONCLUSIONS In conclusion, a combination of zinc supplementation and lactulose over 3 to 6 months may improve the number connection test in cirrhotic patients with low grade HE, compared with lactulose only. TRIAL REGISTRATION PROSPERO: CRD42017080955 . Registered 23 November 2017.
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Affiliation(s)
- Ying-Chi Shen
- Department of Medicine, MacKay Medical College, New Taipei City, Taiwan
- MacKay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan
| | - Ya-Hui Chang
- Department of Medicine, MacKay Medical College, New Taipei City, Taiwan
- MacKay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan
- Department of Pharmacy, MacKay Memorial Hospital, Taipei, Taiwan
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Ching-Ju Fang
- Medical Library, National Cheng Kung University, Tainan, Taiwan
- Department of Secretariat, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yang-Sheng Lin
- Department of Medicine, MacKay Medical College, New Taipei City, Taiwan
- MacKay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan
- Division of Gastroenterology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Evidence-Based Medicine Center, MacKay Memorial Hospital, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine and Deputy Director, Evidence-Based Medicine Center, MacKay Memorial Hospital, No. 92, Sec. 2, Zhongshan N. Rd., Zhongshan Dist., Taipei City, 104 Taiwan, Republic of China
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Luangmonkong T, Suriguga S, Mutsaers HAM, Groothuis GMM, Olinga P, Boersema M. Targeting Oxidative Stress for the Treatment of Liver Fibrosis. Rev Physiol Biochem Pharmacol 2019; 175:71-102. [PMID: 29728869 DOI: 10.1007/112_2018_10] [Citation(s) in RCA: 171] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Oxidative stress is a reflection of the imbalance between the production of reactive oxygen species (ROS) and the scavenging capacity of the antioxidant system. Excessive ROS, generated from various endogenous oxidative biochemical enzymes, interferes with the normal function of liver-specific cells and presumably plays a role in the pathogenesis of liver fibrosis. Once exposed to harmful stimuli, Kupffer cells (KC) are the main effectors responsible for the generation of ROS, which consequently affect hepatic stellate cells (HSC) and hepatocytes. ROS-activated HSC undergo a phenotypic switch and deposit an excessive amount of extracellular matrix that alters the normal liver architecture and negatively affects liver function. Additionally, ROS stimulate necrosis and apoptosis of hepatocytes, which causes liver injury and leads to the progression of end-stage liver disease. In this review, we overview the role of ROS in liver fibrosis and discuss the promising therapeutic interventions related to oxidative stress. Most importantly, novel drugs that directly target the molecular pathways responsible for ROS generation, namely, mitochondrial dysfunction inhibitors, endoplasmic reticulum stress inhibitors, NADPH oxidase (NOX) inhibitors, and Toll-like receptor (TLR)-affecting agents, are reviewed in detail. In addition, challenges for targeting oxidative stress in the management of liver fibrosis are discussed.
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Affiliation(s)
- Theerut Luangmonkong
- Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands.,Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand
| | - Su Suriguga
- Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands
| | - Henricus A M Mutsaers
- Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands.,Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Geny M M Groothuis
- Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands
| | - Peter Olinga
- Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands.
| | - Miriam Boersema
- Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands
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Abstract
PURPOSE OF REVIEW Probiotic administration to premature infants for the purpose of prevention of necrotizing enterocolitis is common in many parts of the world but uncommon in the United States. The present review will emphasize recent findings in support of routine administration of probiotics to this highly vulnerable population. RECENT FINDINGS Additional evidence from animal models describing mechanisms of protection of probiotics in the immature gut and updated meta-analyses of randomized placebo-controlled trials and observational cohorts are presented (now including more than 40 000 premature infants from countries across the globe). SUMMARY The preponderance of evidence suggests that probiotic administration to premature infants is well tolerated and decreases the risk of death, necrotizing enterocolitis, and sepsis. Further comparisons of probiotic administration to placebo are not likely to alter these conclusions. Rather, future work should focus on assurance of high-quality products with demonstrated purity and viability of probiotic microbes, and future clinical trials should focus on comparisons between high-quality products and doses.
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Ning Q. Main Complications of AECHB and Severe Hepatitis B (Liver Failure). ACUTE EXACERBATION OF CHRONIC HEPATITIS B 2019. [PMCID: PMC7498917 DOI: 10.1007/978-94-024-1603-9_2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Qin Ning
- Department of Infectious Disease, Tongji Hospital, Wuhan, China
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48
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Bernardi M, Caraceni P. Novel perspectives in the management of decompensated cirrhosis. Nat Rev Gastroenterol Hepatol 2018; 15:753-764. [PMID: 30026556 DOI: 10.1038/s41575-018-0045-2] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The current approaches to the management of patients with decompensated cirrhosis are based on targeted strategies aimed at preventing or treating specific complications of the disease. The improved knowledge of the pathophysiological background of advanced cirrhosis, represented by a sustained systemic inflammation strictly linked to a circulatory dysfunction, provides a novel paradigm for the management of these patients, with the ambitious target of modifying the course of the disease by preventing the onset of complications and multiorgan failure; these interventions will eventually improve patients' quality of life, prolong survival and reduce health-care costs. Besides aetiological treatments, these goals could be achieved by persistently antagonizing key pathophysiological events, such as portal hypertension, abnormal bacterial translocation from the gut, liver damage, systemic inflammation, circulatory dysfunction and altered immunological responses. Interestingly, in addition to strategies based on new therapeutic agents, these targets can be tackled by employing drugs that are already used in patients with cirrhosis for different indications or in other clinical settings, including non-absorbable oral antibiotics, non-selective β-blockers, human albumin and statins. The scope of the present Review includes reporting updated information on the treatments that promise to influence the course of advanced cirrhosis and thus act as disease-modifying agents.
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Affiliation(s)
- Mauro Bernardi
- Department of Medical and Surgical Sciences, Alma Mater Studiorum - University of Bologna, Bologna, Italy.
| | - Paolo Caraceni
- Department of Medical and Surgical Sciences, Alma Mater Studiorum - University of Bologna, Bologna, Italy
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Lee EW, Saab S, Kaldas F, Fletcher S, Busuttil RW, Durazo F, McWilliams JP, DiNorcia J, Padia SA, Kee ST. Coil-Assisted Retrograde Transvenous Obliteration (CARTO): An Alternative Treatment Option for Refractory Hepatic Encephalopathy. Am J Gastroenterol 2018; 113:1187-1196. [PMID: 29899437 DOI: 10.1038/s41395-018-0109-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2017] [Accepted: 04/04/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Overt hepatic encephalopathy (OHE) is a serious complication of liver dysfunction, which is associated with severe morbidity/mortality and healthcare resource utilization. OHE can be medically refractory due to spontaneous portosystemic shunts (SPSSs) and therefore a new treatment option for these SPSSs is critical. METHODS This is a retrospective study of 43 patients with medically refractory OHE, who underwent CARTO (Coil-Assisted Retrograde Transvenous Obliteration) procedures between June 2012 and October 2016. The patient demographic characteristics, technical and clinical outcomes with an emphasis on HE improvement, and complications are reviewed and analyzed. RESULTS The overall clinical success rate was 91% with a significant HE improvement. Eighty-one percent of patients had clinically significant improvement from OHE and 67% of patients had complete resolution of their HE symptoms during our follow-up period of 893 ± 585 days (range 36-1881 days, median 755.0 days). The median WH score improved from 3 (range 2-4) pre-CARTO to 1 (range 0-4) post-CARTO (p < 0.001). The median ammonia level significantly decreased from 134.5 pre-CARTO to 70.0 post-CARTO (p < 0.001) in 3 days. The overall mean survival was 1465.5 days (95% CI of 1243.0 and 1688.0 days). Only three patients had recurrent HE symptoms. There were 39.6% minor complication rate including new or worsened ascites and esophageal varices, and only 2.3% major complication rate requiring additional treatment (one patient with bleeding esophageal varices requiring treatment). No procedure-related death is noted. CONCLUSIONS CARTO appears to be a safe and effective treatment option for refractory overt hepatic encephalopathy (OHE) due to spontaneous portosystemic shunts. CARTO could be an excellent addition to currently available treatment options for these patients.
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Affiliation(s)
- Edward Wolfgang Lee
- Division of Interventional Radiology, Department of Radiology, UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. UCLA Pfleger Liver Institute, University of California at Los Angeles, Los Angeles, CA, USA. Division of Hepatology, Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA. Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California- Los Angeles, Los Angeles, CA, USA.,Division of Interventional Radiology, Department of Radiology, UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. UCLA Pfleger Liver Institute, University of California at Los Angeles, Los Angeles, CA, USA. Division of Hepatology, Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA. Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California- Los Angeles, Los Angeles, CA, USA
| | - Sammy Saab
- Division of Interventional Radiology, Department of Radiology, UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. UCLA Pfleger Liver Institute, University of California at Los Angeles, Los Angeles, CA, USA. Division of Hepatology, Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA. Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California- Los Angeles, Los Angeles, CA, USA.,Division of Interventional Radiology, Department of Radiology, UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. UCLA Pfleger Liver Institute, University of California at Los Angeles, Los Angeles, CA, USA. Division of Hepatology, Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA. Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California- Los Angeles, Los Angeles, CA, USA.,Division of Interventional Radiology, Department of Radiology, UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. UCLA Pfleger Liver Institute, University of California at Los Angeles, Los Angeles, CA, USA. Division of Hepatology, Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA. Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California- Los Angeles, Los Angeles, CA, USA
| | - Fady Kaldas
- Division of Interventional Radiology, Department of Radiology, UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. UCLA Pfleger Liver Institute, University of California at Los Angeles, Los Angeles, CA, USA. Division of Hepatology, Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA. Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California- Los Angeles, Los Angeles, CA, USA.,Division of Interventional Radiology, Department of Radiology, UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. UCLA Pfleger Liver Institute, University of California at Los Angeles, Los Angeles, CA, USA. Division of Hepatology, Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA. Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California- Los Angeles, Los Angeles, CA, USA
| | - Savannah Fletcher
- Division of Interventional Radiology, Department of Radiology, UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. UCLA Pfleger Liver Institute, University of California at Los Angeles, Los Angeles, CA, USA. Division of Hepatology, Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA. Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California- Los Angeles, Los Angeles, CA, USA
| | - Ronald W Busuttil
- Division of Interventional Radiology, Department of Radiology, UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. UCLA Pfleger Liver Institute, University of California at Los Angeles, Los Angeles, CA, USA. Division of Hepatology, Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA. Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California- Los Angeles, Los Angeles, CA, USA.,Division of Interventional Radiology, Department of Radiology, UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. UCLA Pfleger Liver Institute, University of California at Los Angeles, Los Angeles, CA, USA. Division of Hepatology, Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA. Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California- Los Angeles, Los Angeles, CA, USA
| | - Francisco Durazo
- Division of Interventional Radiology, Department of Radiology, UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. UCLA Pfleger Liver Institute, University of California at Los Angeles, Los Angeles, CA, USA. Division of Hepatology, Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA. Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California- Los Angeles, Los Angeles, CA, USA.,Division of Interventional Radiology, Department of Radiology, UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. UCLA Pfleger Liver Institute, University of California at Los Angeles, Los Angeles, CA, USA. Division of Hepatology, Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA. Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California- Los Angeles, Los Angeles, CA, USA
| | - Justin P McWilliams
- Division of Interventional Radiology, Department of Radiology, UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. UCLA Pfleger Liver Institute, University of California at Los Angeles, Los Angeles, CA, USA. Division of Hepatology, Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA. Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California- Los Angeles, Los Angeles, CA, USA
| | - Joseph DiNorcia
- Division of Interventional Radiology, Department of Radiology, UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. UCLA Pfleger Liver Institute, University of California at Los Angeles, Los Angeles, CA, USA. Division of Hepatology, Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA. Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California- Los Angeles, Los Angeles, CA, USA.,Division of Interventional Radiology, Department of Radiology, UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. UCLA Pfleger Liver Institute, University of California at Los Angeles, Los Angeles, CA, USA. Division of Hepatology, Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA. Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California- Los Angeles, Los Angeles, CA, USA
| | - Siddharth A Padia
- Division of Interventional Radiology, Department of Radiology, UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. UCLA Pfleger Liver Institute, University of California at Los Angeles, Los Angeles, CA, USA. Division of Hepatology, Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA. Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California- Los Angeles, Los Angeles, CA, USA
| | - Stephen T Kee
- Division of Interventional Radiology, Department of Radiology, UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. UCLA Pfleger Liver Institute, University of California at Los Angeles, Los Angeles, CA, USA. Division of Hepatology, Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA. Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California- Los Angeles, Los Angeles, CA, USA
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Cai X, Wang L, Hu C. Retracted
: Efficacy of different drugs in the treatment of minimal hepatic encephalopathy: A network meta‐analysis involving 826 patients based on 10 randomized controlled trials. J Cell Biochem 2018; 119:8336-8345. [PMID: 29932239 DOI: 10.1002/jcb.26886] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Accepted: 03/21/2018] [Indexed: 11/08/2022]
Affiliation(s)
- Xiao‐Jun Cai
- Heilongjiang Academy of Traditional Chinese MedicineHarbinP.R. China
| | - Lei Wang
- Heilongjiang Academy of Traditional Chinese MedicineHarbinP.R. China
| | - Chun‐Mei Hu
- The Third Hospital of Heilongjiang ProvinceBeianP.R. China
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