|
1
|
Maiwall R, Singh SP, Angeli P, Moreau R, Krag A, Singh V, Singal AK, Tan SS, Puri P, Mahtab M, Lau G, Ning Q, Sharma MK, Rao PN, Kapoor D, Gupta S, Duseja A, Wadhawan M, Jothimani D, Saigal S, Taneja S, Shukla A, Puri P, Govil D, Pandey G, Madan K, Eapen CE, Benjamin J, Chowdhury A, Singh S, Salao V, Yang JM, Hamid S, Shalimar, Jasuja S, Kulkarni AV, Niriella MA, Tevethia HV, Arora V, Mathur RP, Roy A, Jindal A, Saraf N, Verma N, De A, Choudhary NS, Mehtani R, Chand P, Rudra O, Sarin SK. APASL clinical practice guidelines on the management of acute kidney injury in acute-on-chronic liver failure. Hepatol Int 2024; 18:833-869. [PMID: 38578541 DOI: 10.1007/s12072-024-10650-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Accepted: 01/20/2024] [Indexed: 04/06/2024]
Abstract
Acute-on-chronic liver failure (ACLF) is a syndrome that is characterized by the rapid development of organ failures predisposing these patients to a high risk of short-term early death. The main causes of organ failure in these patients are bacterial infections and systemic inflammation, both of which can be severe. For the majority of these patients, a prompt liver transplant is still the only effective course of treatment. Kidneys are one of the most frequent extrahepatic organs that are affected in patients with ACLF, since acute kidney injury (AKI) is reported in 22.8-34% of patients with ACLF. Approach and management of kidney injury could improve overall outcomes in these patients. Importantly, patients with ACLF more frequently have stage 3 AKI with a low rate of response to the current treatment modalities. The objective of the present position paper is to critically review and analyze the published data on AKI in ACLF, evolve a consensus, and provide recommendations for early diagnosis, pathophysiology, prevention, and management of AKI in patients with ACLF. In the absence of direct evidence, we propose expert opinions for guidance in managing AKI in this very challenging group of patients and focus on areas of future research. This consensus will be of major importance to all hepatologists, liver transplant surgeons, and intensivists across the globe.
Collapse
Affiliation(s)
- Rakhi Maiwall
- Department of Hepatology, Institute of Liver and Biliary Sciences, D1 Vasant Kunj, New Delhi, 110070, India
| | - Satender Pal Singh
- Department of Hepatology, Institute of Liver and Biliary Sciences, D1 Vasant Kunj, New Delhi, 110070, India
| | - Paolo Angeli
- Department of Internal Medicine and Hepatology, University of Padova, Padua, Italy
| | - Richard Moreau
- European Foundation for the Study of Chronic Liver Failure (EF CLIF), European Association for the Study of the Liver (EASL)-CLIF Consortium, and Grifols Chair, Barcelona, Spain
- Centre de Recherche sur l'Inflammation (CRI), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Cité, Paris, France
- Service d'Hépatologie, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Beaujon, Clichy, France
| | - Aleksander Krag
- Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
| | - Virender Singh
- Punjab Institute of Liver and Biliary Sciences, Mohali, Punjab, India
| | - Ashwani K Singal
- Department of Medicine, University of Louisville School of Medicine, Trager Transplant Center and Jewish Hospital, Louisville, USA
| | - S S Tan
- Department of Medicine, Hospital Selayang, Bata Caves, Selangor, Malaysia
| | - Puneet Puri
- Department of Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Mamun Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - George Lau
- Humanity and Health Medical Group, Humanity and Health Clinical Trial Center, Hong Kong SAR, China
- The Fifth Medical Center of Chinese, PLA General Hospital, Beijing, 100039, China
| | - Qin Ning
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- State Key Laboratory for Zoonotic Diseases, Wuhan, China
- Department of Pediatrics, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Manoj Kumar Sharma
- Department of Hepatology, Institute of Liver and Biliary Sciences, D1 Vasant Kunj, New Delhi, 110070, India
| | - P N Rao
- Department of Hepatology and Nutrition, Asian Institute of Gastroenterology, Hyderabad, India
| | - Dharmesh Kapoor
- Department of Hepatology, Gleneagles Global Hospitals, Hyderabad, Telangana, India
| | - Subhash Gupta
- Department of Surgery, Center for Liver and Biliary Sciences, Max Healthcare, Saket, New Delhi, India
| | - Ajay Duseja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Manav Wadhawan
- Institute of Digestive & Liver Diseases, BLK Superspeciality Hospital Delhi, New Delhi, India
| | - Dinesh Jothimani
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Centre, Bharat Institute of Higher Education and Research, Chennai, India
| | - Sanjiv Saigal
- Department of Gastroenterology and Hepatology, Centre for Liver and Biliary Sciences, Max Super Speciality Hospital, Saket, New Delhi, India
| | - Sunil Taneja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Akash Shukla
- Department of Gastroenterology, Seth GS Medical College and KEM Hospital, Mumbai, India
| | - Pankaj Puri
- Fortis Escorts Liver & Digestive Diseases Institute, New Delhi, India
| | - Deepak Govil
- Department of Critical Care and Anaesthesia, Medanta-The Medicity, Gurugram, Haryana, India
| | - Gaurav Pandey
- Gastroenterology and Hepatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Kaushal Madan
- Department of Gastroenterology and Hepatology, Centre for Liver and Biliary Sciences, Max Super Speciality Hospital, Saket, New Delhi, India
| | - C E Eapen
- Department of Hepatology, Christian Medical College, Vellore, Tamil Nadu, India
| | - Jaya Benjamin
- Department of Clinical Nutrition, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Ashok Chowdhury
- Department of Hepatology, Institute of Liver and Biliary Sciences, D1 Vasant Kunj, New Delhi, 110070, India
| | - Shweta Singh
- Centre for Liver and Biliary Sciences, Max Super Speciality Hospital, Saket, New Delhi, India
| | - Vaishali Salao
- Department of Critical Care, Fortis Hospital, Mulund, Mumbai, India
| | - Jin Mo Yang
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Saeed Hamid
- Department of Hepatology, Aga Khan University, Karachi, Pakistan
| | - Shalimar
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Sanjiv Jasuja
- Department of Nephrology, Indraprastha Apollo Hospitals, New Delhi, India
| | | | - Madund A Niriella
- Department of Medicine, Faculty of Medicine, University of Kelaniya, Colombo, Sri Lanka
| | - Harsh Vardhan Tevethia
- Department of Hepatology, Institute of Liver and Biliary Sciences, D1 Vasant Kunj, New Delhi, 110070, India
| | - Vinod Arora
- Department of Hepatology, Institute of Liver and Biliary Sciences, D1 Vasant Kunj, New Delhi, 110070, India
| | - R P Mathur
- Department of Nephrology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Akash Roy
- Department of Gastroenterology, Institute of Gastrosciences and Liver Transplantation, Apollo Hospitals, Kolkata, India
| | - Ankur Jindal
- Department of Hepatology, Institute of Liver and Biliary Sciences, D1 Vasant Kunj, New Delhi, 110070, India
| | - Neeraj Saraf
- Institute of Liver Transplantation and Regenerative Medicine, Medanta-The Medicity, Gurgaon, Delhi (NCR), India
| | - Nipun Verma
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Arka De
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Narendra S Choudhary
- Department of Hepatology and Liver Transplantation, Medanta-The Medicity Hospital, Gurugram, Haryana, India
| | - Rohit Mehtani
- Department of Gastroenterology, Seth GS Medical College and KEM Hospital, Mumbai, India
| | - Phool Chand
- Department of Hepatology, Institute of Liver and Biliary Sciences, D1 Vasant Kunj, New Delhi, 110070, India
| | - Omkar Rudra
- Department of Hepatology, Institute of Liver and Biliary Sciences, D1 Vasant Kunj, New Delhi, 110070, India
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, D1 Vasant Kunj, New Delhi, 110070, India.
| |
Collapse
|
|
2
|
Díaz LA, Arab JP, Leggio L. Granulocyte-colony stimulating factor use in alcohol-associated hepatitis: is it time to promote liver regeneration? THE AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE 2024; 50:128-131. [PMID: 38593134 DOI: 10.1080/00952990.2024.2308789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Revised: 01/16/2024] [Accepted: 01/18/2024] [Indexed: 04/11/2024]
Affiliation(s)
- Luis Antonio Díaz
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Juan Pablo Arab
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
- Division of Gastroenterology, Department of Medicine, Schulich School of Medicine, Western University & London Health Sciences Centre, London, ON, Canada
- Department of Epidemiology and Biostatistics, Schulich School of Medicine, Western University, London, ON, Canada
| | - Lorenzo Leggio
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Baltimore, MD, USA
- Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, School of Public Health, Brown University, Providence, RI, USA
- Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
- Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA
| |
Collapse
|
|
3
|
Rajpurohit S, Musunuri B, Basthi Mohan P, Bhat G, Shetty S. Role of granulocyte colony stimulating factor in the treatment of cirrhosis of liver: a systematic review. J Int Med Res 2023; 51:3000605231207064. [PMID: 37946367 PMCID: PMC10637184 DOI: 10.1177/03000605231207064] [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: 04/24/2023] [Accepted: 09/21/2023] [Indexed: 11/12/2023] Open
Abstract
OBJECTIVE We performed a systematic review to analyze the benefits of and risk factors associated with granulocyte colony stimulating factor (GCSF) in patients with liver cirrhosis. METHODS PubMed, Scopus, and Embase were searched for randomized controlled trials and case-control studies that compared the use of GCSF with another treatment or control group. The Jadad and Newcastle-Ottawa scales were used to assess the risk of bias in the included studies. The primary outcome studied was mortality; and the secondary outcomes were the disease severity score, liver transplantation criteria, complications, CD34+ cell count, adverse events, and health-related quality of life (HRQOL). PROSPERO registration number CRD42023416014. RESULTS The initial search yielded 2,235 studies, of which seven studies of 670 patients with liver cirrhosis were included. Multiple cycles of GCSF significantly improved the survival rate, disease severity score, CD34+ cell count, and HRQOL; and significantly reduced the incidences of liver transplantation, ascites, infection, and hepatic encephalopathy. Fatigue and backache were the most commonly reported adverse events. CONCLUSION GCSF significantly improves the survival rate and disease severity scores, and reduces the incidence of complications in patients with liver cirrhosis. The administration of GCSF is likely to be effective in patients awaiting liver transplantation.
Collapse
Affiliation(s)
- Siddheesh Rajpurohit
- Department of Gastroenterology & Hepatology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India
| | - Balaji Musunuri
- Department of Gastroenterology & Hepatology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India
| | - Pooja Basthi Mohan
- Department of Gastroenterology & Hepatology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India
| | - Ganesh Bhat
- Department of Gastroenterology & Hepatology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India
| | - Shiran Shetty
- Department of Gastroenterology & Hepatology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India
| |
Collapse
|
|
4
|
Tayek JA, Stolz AA, Nguyen DV, Fleischman MW, Donovan JA, Alcorn JM, Chao DCK, Asghar A, Morgan TR. A phase II, multicenter, open-label, randomized trial of pegfilgrastim for patients with alcohol-associated hepatitis. EClinicalMedicine 2022; 54:101689. [PMID: 36267499 PMCID: PMC9576807 DOI: 10.1016/j.eclinm.2022.101689] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 09/15/2022] [Accepted: 09/16/2022] [Indexed: 11/20/2022] Open
Abstract
Background In trials conducted in India, recombinant granulocyte colony stimulating factor (GCSF) improved survival in alcohol-associated hepatitis (AH). The aim of this trial was to determine the safety and efficacy of pegfilgrastim, a long-acting recombinant GCSF, in patients with AH in the United States. Methods This prospective, randomized, open label trial conducted between March 2017 and March 2020 randomized patients with a clinical diagnosis of AH and a Maddrey discriminant function score ≥32 to standard of care (SOC) or SOC+pegfilgrastim (0.6 mg subcutaneously) on Day 1 and Day 8 (clinicaltrials.gov NCT02776059). SOC was 28 days of either pentoxifylline or prednisolone, as determined by the patient's primary physician. The second injection of pegfilgrastim was not administered if the white blood cell count exceeded 30,000/mm3 on Day 8. Primary outcome was survival at Day 90. Secondary outcomes included the incidence of acute kidney injury (AKI), hepatorenal syndrome (HRS), hepatic encephalopathy, or infections. Findings The study was terminated early due to COVID19 pandemic. Eighteen patients were randomized to SOC and 16 to SOC+pegfilgrastim. All patients received prednisolone as SOC. Nine patients failed to receive a second dose of pegfilgrastin due to WBC > 30,000/mm3 on Day 8. Survival at 90 days was similar in both groups (SOC: 0.83 [95% confidence interval [CI]: 0.57-0.94] vs. pegfilgrastim: 0.73 [95% CI: 0.44-0.89]; p > 0.05; CI for difference: -0.18-0.38). The incidences of AKI, HRS, hepatic encephalopathy, and infections were similar in both treatment arms and there were no serious adverse events attributed to pegfilgrastim. Interpretation This phase II trial found no survival benefit at 90 days among subjects with AH who received pegfilgrastim+prednisolone compared with subjects receiving prednisolone alone. Funding was provided by the United States National Institutes of Health and National Institute on Alcohol Abuse and Alcoholism U01-AA021886 and U01-AA021884.
Collapse
Key Words
- ACLF, acute on chronic liver failure
- AH, alcohol-related hepatitis
- AKI, acute kidney injury
- Alcoholic hepatitis
- CTCAE, common terminology criteria for adverse events
- DF, discriminant function
- DSMB, data safety monitoring board
- FDA, food and drug administration
- FU, follow-up
- GCSF, granulocyte colony stimulating factor
- HIV, human immunodeficiency virus
- HRS, hepatorenal syndrome
- INR, international normalized ratio
- NIAAA, national institute on alcohol abuse and alcoholism
- Pegfilgrastim
- Phase II
- Randomized clinical trial
- SD, standard deviation
- SOC, standard of care
- WBC, white blood cell count
Collapse
Affiliation(s)
- John A. Tayek
- Department of Medicine, Harbor-UCLA Medical Center and Lundquist Institute, Torrance, CA, United States
| | - Andrew A. Stolz
- LAC-USC Medical Center, Los Angeles, CA and the Hepatology Section, Division of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Danh V. Nguyen
- Division of General Internal Medicine, Department of Medicine, University of California, Irvine, CA, United States
| | - M. Wayne Fleischman
- Department of Medicine, Harbor-UCLA Medical Center and Lundquist Institute, Torrance, CA, United States
| | - John A. Donovan
- LAC-USC Medical Center, Los Angeles, CA and the Hepatology Section, Division of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Joseph M. Alcorn
- Division of Gastroenterology, Department of Medicine University of New Mexico, Albuquerque, New Mexico and Medical Service, Raymond G. Murphy VA Medical Center, Albuquerque, NM, United States
| | - Daniel C-K. Chao
- Gastroenterology Section, Medical Service, VA Healthcare System, Loma Linda, CA, United States
| | - Aliya Asghar
- Research Service, VA Healthcare System, Long Beach, CA, United States
| | - Timothy R. Morgan
- Gastroenterology Section, Medical Service, VA Healthcare System, Long Beach, CA, United States
- Division of Gastroenterology, Department of Medicine, University of California, Irvine, CA, United States
| |
Collapse
|
|
5
|
Kaur B, Rosenblatt R, Sundaram V. Infections in Alcoholic Hepatitis. J Clin Transl Hepatol 2022; 10:718-725. [PMID: 36062291 PMCID: PMC9396323 DOI: 10.14218/jcth.2022.00024] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 04/11/2022] [Accepted: 04/21/2022] [Indexed: 12/04/2022] Open
Abstract
Severe alcoholic hepatitis (sAH) is defined by a modified discriminant function ≥32 or model for end-stage liver disease (MELD) >20. Patients with sAH are in an immunocompromised state attributed to cirrhosis-related immunoparesis and corticosteroid use. Individuals with sAH often develop severe infections that adversely impact short-term prognosis. Currently, the corticosteroid prednisolone is the only treatment with proven efficacy in sAH; however, the combination of corticosteroid treatment and altered host defense in sAH has been thought to increase the risk of acquiring of bacterial, opportunistic fungal, and viral infections. Newer studies have shown that corticosteroids do not increase occurrence of infections in those with sAH; unfortunately, the lack of response to corticosteroids may instead predispose to infection development. Prompt and appropriate antibiotic treatment is therefore essential to improving patient outcomes. This review highlights common infections and risk factors in patients with sAH. Additionally, current diagnostic, therapeutic, and prophylactic strategies in these patients are discussed.
Collapse
Affiliation(s)
- Bhupinder Kaur
- Internal Medicine Department, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Russell Rosenblatt
- Department of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY, USA
| | - Vinay Sundaram
- Department of Gastroenterology and Hepatology and Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Correspondence to: Vinay Sundaram, Department of Gastroenterology and Hepatology and Comprehensive Transplant Center, Cedars-Sinai Medical Center, 8635W. Third Street, Suite 1060W, Los Angeles, CA 90048, USA. ORCID: https://orcid.org/0000-0002-1450-7756. Tel: +1-310-423-6000, Fax: +1-310-423-6086, E-mail:
| |
Collapse
|
|
6
|
Tong J, Wang H, Xu X, Wan Z, Fang H, Chen J, Mu X, Liu Z, Chen J, Su H, Liu X, Li C, Huang X, Hu J. Granulocyte Colony-Stimulating Factor Accelerates the Recovery of Hepatitis B Virus-Related Acute-on-Chronic Liver Failure by Promoting M2-Like Transition of Monocytes. Front Immunol 2022; 13:885829. [PMID: 35651610 PMCID: PMC9148949 DOI: 10.3389/fimmu.2022.885829] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 04/20/2022] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND AND AIM Acute-on-chronic liver failure (ACLF) has a high mortality rate. The role of granulocyte colony-stimulating factor (G-CSF) in ACLF remains controversial. Monocytes/macrophages are core immune cells, which are involved in the initiation and progression of liver failure; however, the effect of G-CSF on monocytes/macrophages is unclear. The study aimed to verify the clinical efficacy of G-CSF and explore the effect of it on monocytes in hepatitis B virus (HBV)-related ACLF (HBV-ACLF) paitents. METHODS We performed a large randomized controlled clinical trial for the treatment of HBV-ACLF using G-CSF. A total of 111 patients with HBV-ACLF were prospectively randomized into the G-CSF group (5 μg/kg G-CSF every day for 6 days, then every other day until day 18) or the control group (standard therapy). All participants were followed up for at least 180 days. The relationship between monocyte count and mortality risk was analyzed. The effect of G-CSF on the phenotype and function of monocytes from patients with HBV-ACLF was evaluated using flow cytometry in vivo and in vitro experiments. RESULTS The survival probability of the G-CSF group at 180 days was higher than that of the control group (72.2% vs. 53.8%, P = 0.0142). In the G-CSF-treated group, the monocyte counts on days 0 and 7 were independently associated with an evaluated mortality risk in the fully adjusted model (Model 3) [at day 0: hazard ratio (HR) 95% confidence interval (CI): 15.48 (3.60, 66.66), P = 0.0002; at day 7: HR (95% CI): 1.10 (0.50, 2.43), P=0.8080]. Further analysis showed that after treatment with G-CSF in HBV-ACLF patients, the expression of M1-like markers (HLA-DR and CD86) in monocytes decreased (HLA-DR: P = 0.0148; CD86: P = 0.0764). The expression of MerTK (M2-like marker) increased (P = 0.0002). The secretion of TNF-α, IL-6, and IL-10 from monocytes decreased without lipopolysaccharide (LPS) stimulation (TNF-α: P < 0.0001; IL-6: P= 0.0025; IL-10: P = 0.0004) or with LPS stimulation (TNF-α: P = 0.0439; P = 0.0611; IL-10: P = 0.0099). Similar effects were observed in vitro experiments. CONCLUSION G-CSF therapy confers a survival benefit to patients with HBV-ACLF. G-CSF can promote the anti-inflammatory/pro-restorative phenotype (M2-like) transition of monocytes, which may contribute to the recovery of ACLF.Clinical Trial Registration Number: ClinicalTrials.gov, identifier (NCT02331745).
Collapse
Affiliation(s)
- Jingjing Tong
- Chinese PLA Medical School, Beijing, China
- Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China
- Department of Infectious Diseases, Beijing Jishuitan Hospital, Beijing, China
| | - Hongmin Wang
- Peking University 302 Clinical Medical School, Beijing, China
| | - Xiang Xu
- Laboratory of Translational Medicine, Medical Innovation Research Division of Chinese PLA General Hospital, Beijing, China
| | - Zhihong Wan
- Center for Drug Evaluation, National Medical Products Administration, Beijing, China
| | - Hongbin Fang
- Department of Biostatistics, Bioinformatics and Biomathematics, Georgetown University Medical Center, Washington, DC, United States
| | - Jing Chen
- Chinese PLA Medical School, Beijing, China
- Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Xiuying Mu
- Peking University 302 Clinical Medical School, Beijing, China
| | - Zifeng Liu
- Chinese PLA Medical School, Beijing, China
| | - Jing Chen
- Chinese PLA Medical School, Beijing, China
| | - Haibin Su
- Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Xiaoyan Liu
- Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Chen Li
- Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | | | - Jinhua Hu
- Chinese PLA Medical School, Beijing, China
- Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China
- Peking University 302 Clinical Medical School, Beijing, China
| |
Collapse
|
|
7
|
Asgharpour A, Dinani A, Friedman SL. Basic science to clinical trials in non-alcoholic fatty liver disease and alcohol-related liver disease: collaboration with industry. Transl Gastroenterol Hepatol 2021; 6:5. [PMID: 33409399 PMCID: PMC7724182 DOI: 10.21037/tgh.2020.01.04] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 01/17/2020] [Indexed: 12/19/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ALD) are highly prevalent forms of chronic liver diseases globally, associated with rising all-cause morbidity and mortality. While distinct diseases, NAFLD and ALD share several similarities; both can result in fatty liver disease, steatohepatitis, associated hepatic fibrosis and cirrhosis-related complications, including hepatocellular carcinoma (HCC). Our understanding of the pathophysiology and manifestations of these diseases has advanced significantly, which has established a new foundation to identify therapeutic targets and test new treatments. This review underscores emerging pathogenic pathways that establish a template for target identification and clinical trials. Success is critically dependent upon productive interactions between academic investigators and industry to address unmet therapeutic needs in NAFLD and ALD.
Collapse
Affiliation(s)
- Amon Asgharpour
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Amreen Dinani
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Scott L Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| |
Collapse
|
|
8
|
Abstract
Cirrhosis is a multisystemic disease wherein inflammatory responses originating from advanced liver disease and its sequelae affect distant compartments. Patients with cirrhosis are susceptible to bacterial infections, which may precipitate acute decompensation and acute-on-chronic liver failure, both of which are associated with high short-term mortality. Innate immune cells are an essential first line of defence against pathogens. Activation of liver macrophages (Kupffer cells) and resident mastocytes generate proinflammatory and vaso-permeating mediators that induce accumulation of neutrophils, lymphocytes, eosinophils and monocytes in the liver, and promote tissue damage. During cirrhosis progression, damage- and pathogen-associated molecular patterns activate immune cells and promote development of systemic inflammatory responses which may involve different tissues and compartments. The antibacterial function of circulating neutrophils and monocytes is gradually and severely impaired as cirrhosis worsens, contributing to disease progression. The mechanisms underlying impaired antimicrobial responses are complex and incompletely understood. This review focuses on the continuous and distinct perturbations arising in innate immune cells during cirrhosis, including their impact on disease progression, as well as reviewing potential therapeutic targets.
Collapse
|
|
9
|
Marot A, Singal AK, Moreno C, Deltenre P. Granulocyte colony-stimulating factor for alcoholic hepatitis: A systematic review and meta-analysis of randomised controlled trials. JHEP Rep 2020; 2:100139. [PMID: 32775975 PMCID: PMC7396826 DOI: 10.1016/j.jhepr.2020.100139] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 06/06/2020] [Accepted: 06/08/2020] [Indexed: 12/11/2022] Open
Abstract
Background & Aims Granulocyte colony-stimulating factor (G-CSF) treatment has been proposed as a therapeutic option for patients with severe alcoholic hepatitis (AH). The aim of this study was to synthesise available evidence on the efficacy of G-CSF in AH. Methods This is a meta-analysis of randomised controlled trials evaluating the risk of death at 90 days and the risk of infection. Results Seven studies were included. Of a total of 396 patients, 336 had AH, 197 patients were treated with G-CSF, and 199 received placebo or pentoxifylline. In overall meta-analysis, G-CSF therapy was associated with a reduced risk of death at 90 days (odds ratio [OR] 0.28; 95% CI 0.09–0.88; p = 0.03). There was high heterogeneity between studies (p <0.001; I2 = 80%). Five studies were performed in Asia and 2 in Europe. In the subgroup analysis of studies performed in Asia, G-CSF was associated with a reduced risk of death (OR 0.15; 95% CI 0.08–0.28; p <0.001; heterogeneity: p = 0.5, I2 = 0%). In European studies, G-CSF tended to increase mortality compared with controls, although the difference was not significant (OR 1.89; 95% CI 0.90–3.98; p = 0.09; heterogeneity: p = 0.8, I2 = 0%). In Asian studies, occurrence of infection was less frequent in G-CSF patients than in controls (OR 0.12; 95% CI 0.06–0.23; p <0.001; heterogeneity: p = 0.7, I2 = 0%), whilst in European studies, this occurrence was not statistically different (OR 0.92; 95% CI 0.50–1.68; p = 0.78; heterogeneity: p = 0.5, I2 = 0%). In sensitivity analyses, excluding studies that included patients with acute-on-chronic liver failure (ACLF) other than AH, patients with less severe AH, or patients with non-response to corticosteroids, results were similar to those of overall analyses, both for mortality and occurrence of infection. Conclusions Granulocyte colony-stimulating factor therapy may improve the prognosis of patients with severe AH. However, owing to the high heterogeneity observed in the overall analysis caused by conflicting results between the Asian and European studies, G-CSF cannot currently be recommended for AH, particularly in Europe. Whether these differences can be explained by ethnic differences or disparities in patient selection and disease severity remains unclear. Lay summary The main finding of this meta-analysis is that the use of granulocyte colony-stimulating factor (G-CSF) is associated with a mortality reduction of more than 70% at 3 months amongst patients with alcoholic hepatitis (AH) compared with controls who did not receive this therapy. However, owing to the high heterogeneity observed in the overall analysis caused by conflicting results between the Asian and European studies, G-CSF cannot currently be recommended for patients with AH, particularly in Europe. Whether these differences can be explained by ethnic differences or disparities in patient selection and disease severity remains unclear.
This meta-analysis reports pooled data from 7 studies on the use of G-CSF in patients with alcoholic hepatitis. The favourable effect of G-CSF was only encountered in Asian not European studies. Additional data are needed to clarify the usefulness of G-CSF in severe alcoholic hepatitis, particularly in Europe.
Collapse
Affiliation(s)
- Astrid Marot
- Department of Gastroenterology and Hepatology, CHU UCL Namur, Université Catholique de Louvain, Yvoir, Belgium
- Corresponding author. Address: Department of Gastroenterology and Hepatology, CHU UCL Namur, Université Catholique de Louvain, avenue Gaston Thérasse, 1, 5530 Yvoir, Belgium. Tel.: +32 81 42 32 72; fax: +32 81 42 32 54.
| | - Ashwani K. Singal
- Division of Transplant Hepatology, Avera Transplant Institute and Department of Medicine, University of South Dakota Sanford School of Medicine, Sioux Falls, SD, USA
| | - Christophe Moreno
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
| | - Pierre Deltenre
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
- Department of Gastroenterology and Hepatology, Clinique St Luc, Bouge, Belgium
| |
Collapse
|
|
10
|
Chauhan A, Sheriff L, Hussain MT, Webb GJ, Patten DA, Shepherd EL, Shaw R, Weston CJ, Haldar D, Bourke S, Bhandari R, Watson S, Adams DH, Watson SP, Lalor PF. The platelet receptor CLEC-2 blocks neutrophil mediated hepatic recovery in acetaminophen induced acute liver failure. Nat Commun 2020; 11:1939. [PMID: 32321925 PMCID: PMC7176690 DOI: 10.1038/s41467-020-15584-3] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 03/17/2020] [Indexed: 02/07/2023] Open
Abstract
Acetaminophen (APAP) is the main cause of acute liver failure in the West. Specific efficacious therapies for acute liver failure (ALF) are limited and time-dependent. The mechanisms that drive irreversible acute liver failure remain poorly characterized. Here we report that the recently discovered platelet receptor CLEC-2 (C-type lectin-like receptor) perpetuates and worsens liver damage after toxic liver injury. Our data demonstrate that blocking platelet CLEC-2 signalling enhances liver recovery from acute toxic liver injuries (APAP and carbon tetrachloride) by increasing tumour necrosis factor-α (TNF-α) production which then enhances reparative hepatic neutrophil recruitment. We provide data from humans and mice demonstrating that platelet CLEC-2 influences the hepatic sterile inflammatory response and that this can be manipulated for therapeutic benefit in acute liver injury. Since CLEC-2 mediated platelet activation is independent of major haemostatic pathways, blocking this pathway represents a coagulopathy-sparing, specific and novel therapy in acute liver failure.
Collapse
Affiliation(s)
- Abhishek Chauhan
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Inflammation, and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, The Medical School, University of Birmingham, Birmingham, B15 2TT, UK.
| | - Lozan Sheriff
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Inflammation, and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, The Medical School, University of Birmingham, Birmingham, B15 2TT, UK
| | - Mohammed T Hussain
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Inflammation, and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, The Medical School, University of Birmingham, Birmingham, B15 2TT, UK
| | - Gwilym J Webb
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Inflammation, and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, The Medical School, University of Birmingham, Birmingham, B15 2TT, UK
| | - Daniel A Patten
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Inflammation, and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, The Medical School, University of Birmingham, Birmingham, B15 2TT, UK
| | - Emma L Shepherd
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Inflammation, and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, The Medical School, University of Birmingham, Birmingham, B15 2TT, UK
| | - Robert Shaw
- Technology Hub, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK
| | - Christopher J Weston
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Inflammation, and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, The Medical School, University of Birmingham, Birmingham, B15 2TT, UK
| | - Debashis Haldar
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Inflammation, and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, The Medical School, University of Birmingham, Birmingham, B15 2TT, UK
| | - Samuel Bourke
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Inflammation, and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, The Medical School, University of Birmingham, Birmingham, B15 2TT, UK
| | - Rajan Bhandari
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Inflammation, and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, The Medical School, University of Birmingham, Birmingham, B15 2TT, UK
| | - Stephanie Watson
- Institute of Cardiovascular Sciences, The Medical School, University of Birmingham, Birmingham, B15 2TT, UK
| | - David H Adams
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Inflammation, and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, The Medical School, University of Birmingham, Birmingham, B15 2TT, UK
| | - Steve P Watson
- Institute of Cardiovascular Sciences, The Medical School, University of Birmingham, Birmingham, B15 2TT, UK
- Centre of Membrane Proteins and Receptors (COMPARE), Universities of Birmingham and Nottingham, The Midlands, Nottingham, UK
| | - Patricia F Lalor
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Inflammation, and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, The Medical School, University of Birmingham, Birmingham, B15 2TT, UK
| |
Collapse
|
|
11
|
Abstract
Alcoholic liver diseases (ALD) are a wide spectrum of liver diseases caused by excessive alcohol consumption, from steatosis to cirrhosis. The pathogenesis of ALD is insufficiently understood, but mainly involves oxidative stress, inflammation, bacterial translocation, cell death, and impaired regeneration. Despite numerous attempts to improve patient prognosis, the treatment of advanced ALD is still based on abstinence, brief exposure to corticosteroids, or liver transplantation. However, poor response to corticosteroids and the shortage of liver donors leaves patients helpless towards the end stages. Advances in basic research have contributed to a better understanding of ALD pathophysiology, which offers new options for treatment. In recent years, several therapies related to liver regeneration have been tested with promising prospects, including molecule-induced liver regeneration, stem cell transplantation, and full-function 3D artificial liver assembly. This review discusses mechanisms underlying ALD that can be considered therapeutic targets for regeneration-based treatments.
Collapse
Affiliation(s)
- Yi Lv
- Laboratory of Neuroendocrinology, Fujian Key Laboratory of Developmental and Neurobiology, College of Life Sciences, Fujian Normal University, Fuzhou 350108, China
| | - Kwok Fai So
- Laboratory of Neuroendocrinology, Fujian Key Laboratory of Developmental and Neurobiology, College of Life Sciences, Fujian Normal University, Fuzhou 350108, China
| | - Jia Xiao
- Laboratory of Neuroendocrinology, Fujian Key Laboratory of Developmental and Neurobiology, College of Life Sciences, Fujian Normal University, Fuzhou 350108, China.,Institute of Clinical Medicine, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China
| |
Collapse
|
|
12
|
Crabb DW, Im GY, Szabo G, Mellinger JL, Lucey MR. Diagnosis and Treatment of Alcohol-Associated Liver Diseases: 2019 Practice Guidance From the American Association for the Study of Liver Diseases. Hepatology 2020; 71:306-333. [PMID: 31314133 DOI: 10.1002/hep.30866] [Citation(s) in RCA: 552] [Impact Index Per Article: 110.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 05/31/2019] [Indexed: 12/12/2022]
Affiliation(s)
- David W Crabb
- Indiana University School of Medicine, Indianapolis, IN
| | - Gene Y Im
- Icahn School of Medicine at Mount Sinai, New York, NY
| | - Gyongyi Szabo
- University of Massachusetts Medical School, Worcester, MA
| | | | | |
Collapse
|
|
13
|
Shasthry SM, Sharma MK, Shasthry V, Pande A, Sarin SK. Efficacy of Granulocyte Colony-stimulating Factor in the Management of Steroid-Nonresponsive Severe Alcoholic Hepatitis: A Double-Blind Randomized Controlled Trial. Hepatology 2019; 70:802-811. [PMID: 30664267 DOI: 10.1002/hep.30516] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Accepted: 01/15/2019] [Indexed: 12/17/2022]
Abstract
Severe alcoholic hepatitis (SAH) is often a progressive disease with high mortality and limited steroid responsiveness. Management options of steroid nonresponsive SAH (day 7 Lille score > 0.45) are limited. We assessed the efficacy and safety of granulocyte colony-stimulating factor (G-CSF) in steroid nonresponders. A randomized, double-blind, single-center trial (NCT01820208) was conducted between March 2013 and June 2016 in patients with histologically proven SAH, nonresponsive to 40 mg/day of prednisolone were randomized to G-CSF (12 doses, 300 μg each in 28 days) or placebo. Responders were continued with prednisolone. Of the 430 patients with SAH, 132 received steroid therapy. Of these, 33 (25%) were nonresponders and were randomized to G-CSF or placebo (14 in each group after exclusions). The baseline characteristics of both groups were comparable. The 28-day mortality was comparable between the groups (21.4%, G-CSF; 28.6%, placebo; P = 0.69). At 90 days, in the G-CSF but not in the placebo group, the Model for End-Stage Liver Disease reduced from 24.6 ± 3.9 to 19.4 ± 3.7 (P = 0.002) and Maddrey's discriminant function from 74.8 ± 22.8 to 57.4 ± 31 (P = 0.26). Infections were less common (28% versus 71%; P < 0.001) with lower 90-day mortality (35.7% versus 71.4%; P = 0.04) in the G-CSF than in the placebo group. On Cox regression analysis, receiving G-CSF (hazard ratio, 0.37; SD, 0.14-0.98; P = 0.04), and high baseline serum creatinine (hazard ratio, 4.12; SD, 1.7-10.3; P = 0.002) predicted day-90 outcomes in steroid nonresponsive SAH. Patients tolerated G-CSF without any major adverse events. Conclusion: Approximately one-quarter of patients with SAH do not respond to corticosteroid therapy. Administration of G-CSF is safe and helps to reduce the disease severity and 90-day mortality in these patients.
Collapse
Affiliation(s)
| | - Manoj Kumar Sharma
- Department of Hepatology, Institute of Liver & Biliary Sciences, New Delhi, India
| | - Varsha Shasthry
- Department of Hepatology, Institute of Liver & Biliary Sciences, New Delhi, India
| | - Apurva Pande
- Department of Hepatology, Institute of Liver & Biliary Sciences, New Delhi, India
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver & Biliary Sciences, New Delhi, India
| |
Collapse
|
|
14
|
Abstract
Granulocytes are the major type of phagocytes constituting the front line of innate immune defense against bacterial infection. In adults, granulocytes are derived from hematopoietic stem cells in the bone marrow. Alcohol is the most frequently abused substance in human society. Excessive alcohol consumption injures hematopoietic tissue, impairing bone marrow production of granulocytes through disrupting homeostasis of granulopoiesis and the granulopoietic response. Because of the compromised immune defense function, alcohol abusers are susceptible to infectious diseases, particularly septic infection. Alcoholic patients with septic infection and granulocytopenia have an exceedingly high mortality rate. Treatment of serious infection in alcoholic patients with bone marrow inhibition continues to be a major challenge. Excessive alcohol consumption also causes diseases in other organ systems, particularly severe alcoholic hepatitis which is life threatening. Corticosteroids are the only therapeutic option for improving short-term survival in patients with severe alcoholic hepatitis. The existence of advanced alcoholic liver diseases and administration of corticosteroids make it more difficult to treat serious infection in alcoholic patients with the disorder of granulopoieis. This article reviews the recent development in understanding alcohol-induced disruption of marrow granulopoiesis and the granulopoietic response with the focus on progress in delineating cell signaling mechanisms underlying the alcohol-induced injury to hematopoietic tissue. Efforts in exploring effective therapy to improve patient care in this field will also be discussed.
Collapse
|
|
15
|
Wang W, Xu Y, Jiang C, Gao Y. Advances in the treatment of severe alcoholic hepatitis. Curr Med Res Opin 2019; 35:261-273. [PMID: 29781336 DOI: 10.1080/03007995.2018.1479247] [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] [Indexed: 10/16/2022]
Abstract
Severe alcoholic hepatitis (SAH) is a costly and worldwide public health issue with high morbidity and mortality. Specific effective treatments for SAH have yet to be established. The aim of the present article is to review the current knowledge of the pathogenesis, assessment and treatment options in patients with SAH. To date, alcohol abstinence and enteral nutrition are the recommended first-line treatments. Although corticosteroids remain the preferred therapy for certain patients with a modified Maddrey discriminant function level greater than 54, they only improve short-term survival rates. New research focuses on liver inflammation, liver regeneration, the gut-liver axis, human induced pluripotent stem cells and extracorporeal albumin dialysis. Liver transplantation is considered the last medical option for patients with SAH who are nonresponsive to other medical treatments.
Collapse
Affiliation(s)
- Wenjun Wang
- a Department of Hepatology , First Hospital of Jilin University, Jilin University , Jilin , China
| | - Ying Xu
- a Department of Hepatology , First Hospital of Jilin University, Jilin University , Jilin , China
| | - Chang Jiang
- a Department of Hepatology , First Hospital of Jilin University, Jilin University , Jilin , China
| | - Yanhang Gao
- a Department of Hepatology , First Hospital of Jilin University, Jilin University , Jilin , China
| |
Collapse
|
|
16
|
Rolas L, Boussif A, Weiss E, Lettéron P, Haddad O, El-Benna J, Rautou PE, Moreau R, Périanin A. NADPH oxidase depletion in neutrophils from patients with cirrhosis and restoration via toll-like receptor 7/8 activation. Gut 2018; 67:1505-1516. [PMID: 28601846 DOI: 10.1136/gutjnl-2016-313443] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Revised: 04/27/2017] [Accepted: 05/01/2017] [Indexed: 12/20/2022]
Abstract
OBJECTIVE Cirrhosis downregulates phagocyte oxidant production via their antibacterial superoxide-generating system, NADPH oxidase (NOX2) and increases patients' susceptibility to infection and mortality rate. To explore novel biochemical parameters that explain susceptibility to infections, we investigated the expression of NOX2 and partners in neutrophils of patients with severe alcoholic cirrhosis and have provided a novel approach to restore superoxide production capacity in patients' neutrophils and blood. DESIGN Neutrophils were isolated from patients with decompensated alcoholic cirrhosis. NOX2 activity was assessed after stimulation of purified neutrophils or whole blood with the bacterial-derived peptide fMet-Leu-Phe. The expression of NOX2 and partners was studied by western blot analysis, flow cytometry and reverse transcription-PCR. RESULTS The impaired superoxide production by patients' neutrophils was associated with a severe deficient expression of the NADPH oxidase catalytic core flavocytochrome-b558 (gp91 phox /NOX2 and p22 phox ), its cytosolic partner p47 phox but not p67 phox . NOX2 expression decreased rapidly by protein degradation involving elastase released during degranulation of healthy neutrophils stimulated with fMet-Leu-Phe, or highly present in patients' plasma. Interestingly, the deficient superoxide production was reversed by treatment of patients' neutrophils and whole blood with toll-like receptor 7/8 (TLR7/8) agonists. This treatment stimulated a rapid NOX2 transcription and translation through a process involving mammalian target of rapamycin (mTOR) whose expression was also deficient in patients' neutrophils. NOX2 expression was also increased by the TLR4 agonist lipopolysaccharide but with only a modest improvement of reactive oxygen species production. CONCLUSION Impairment of neutrophil oxidants production in alcoholic cirrhosis is associated with NOX2 degradation and deficient mTOR-dependent translational machinery. The NOX2 depletion can be reversed via TRL7/8 activation and might be used to restore antimicrobial responses of immunocompromised patients.
Collapse
Affiliation(s)
- Loïc Rolas
- INSERM UMRS-1149, Faculté de Médecine Xavier Bichat, Paris, France.,CNRS ERL-8252, Centre de Recherche sur l'Inflammation, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence INFLAMEX, Paris, France
| | - Abdelali Boussif
- INSERM UMRS-1149, Faculté de Médecine Xavier Bichat, Paris, France.,CNRS ERL-8252, Centre de Recherche sur l'Inflammation, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence INFLAMEX, Paris, France.,Département de Biochimie, Université de Batna, Faculté de Biologie, Batna, Algérie
| | - Emmanuel Weiss
- INSERM UMRS-1149, Faculté de Médecine Xavier Bichat, Paris, France.,CNRS ERL-8252, Centre de Recherche sur l'Inflammation, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence INFLAMEX, Paris, France.,Département d'Anesthésie Réanimation, Hôpital Beaujon, APHP, Clichy, France
| | - Philippe Lettéron
- INSERM UMRS-1149, Faculté de Médecine Xavier Bichat, Paris, France.,CNRS ERL-8252, Centre de Recherche sur l'Inflammation, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence INFLAMEX, Paris, France
| | - Oualid Haddad
- UFR SMBH, Université Paris 13, Sorbonne Paris Cité, Bobigny, France
| | - Jamel El-Benna
- INSERM UMRS-1149, Faculté de Médecine Xavier Bichat, Paris, France.,CNRS ERL-8252, Centre de Recherche sur l'Inflammation, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence INFLAMEX, Paris, France
| | - Pierre-Emmanuel Rautou
- Département Hospitalo-Universitaire (DHU) Unity, Service d'Hépatologie, Hôpital Beaujon, APHP, Clichy, France.,INSERM U970, Paris Cardiovascular Research Center-PARCC, Paris, France
| | - Richard Moreau
- INSERM UMRS-1149, Faculté de Médecine Xavier Bichat, Paris, France.,CNRS ERL-8252, Centre de Recherche sur l'Inflammation, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence INFLAMEX, Paris, France.,Département Hospitalo-Universitaire (DHU) Unity, Service d'Hépatologie, Hôpital Beaujon, APHP, Clichy, France
| | - Axel Périanin
- INSERM UMRS-1149, Faculté de Médecine Xavier Bichat, Paris, France.,CNRS ERL-8252, Centre de Recherche sur l'Inflammation, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence INFLAMEX, Paris, France
| |
Collapse
|
|
17
|
Philips CA, Augustine P, Mathew S, Valiathan GC, John SK. Growth factor therapy for decompensated cirrhosis: Much ado about nothing? Hepatology 2018; 68:387-388. [PMID: 29500913 DOI: 10.1002/hep.29866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 01/29/2018] [Accepted: 01/31/2018] [Indexed: 12/07/2022]
Affiliation(s)
- Cyriac Abby Philips
- The Liver Unit, Cochin Gastroenterology Group, Ernakulam Medical Centre, Cochin, India
| | - Philip Augustine
- The Liver Unit, Cochin Gastroenterology Group, Ernakulam Medical Centre, Cochin, India
| | - Sunil Mathew
- The Liver Unit, Cochin Gastroenterology Group, Ernakulam Medical Centre, Cochin, India
| | - Gopakumar C Valiathan
- Hepatobiliary Surgery and Liver Transplant, Cochin Gastroenterology Group, Ernakulam Medical Centre, Cochin, India
| | - Solomon K John
- Hepatobiliary Surgery and Liver Transplant, Cochin Gastroenterology Group, Ernakulam Medical Centre, Cochin, India
| |
Collapse
|
|
18
|
Zhou Z, Xu MJ, Cai Y, Wang W, Jiang JX, Varga ZV, Feng D, Pacher P, Kunos G, Torok NJ, Gao B. Neutrophil-Hepatic Stellate Cell Interactions Promote Fibrosis in Experimental Steatohepatitis. Cell Mol Gastroenterol Hepatol 2018; 5:399-413. [PMID: 29552626 PMCID: PMC5852390 DOI: 10.1016/j.jcmgh.2018.01.003] [Citation(s) in RCA: 129] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Accepted: 01/04/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Hepatic infiltration of neutrophils is a hallmark of steatohepatitis; however, the role of neutrophils in the progression of steatohepatitis remains unknown. METHODS A clinically relevant mouse model of steatohepatitis induced by high-fat diet (HFD) plus binge ethanol feeding was used. Liver fibrosis was examined. In vitro cell culture was used to analyze the interaction of hepatic stellate cells (HSCs) and neutrophils. RESULTS HFD plus one binge ethanol (HFD+1B) feeding induced significant hepatic neutrophil infiltration, liver injury, and fibrosis. HFD plus multiple binges of ethanol (HFD+mB) caused more pronounced liver fibrosis. Microarray analyses showed that the most highly activated signaling pathway in this HFD+1B model was related to liver fibrosis and HSC activation. Blockade of chemokine (C-X-C motif) ligand 1 or intercellular adhesion molecule-1 expression reduced hepatic neutrophil infiltration and ameliorated liver injury and fibrosis. Disruption of the p47phox gene (also called neutrophil cytosolic factor 1), a critical component of reactive oxygen species producing nicotinamide adenine dinucleotide phosphate-oxidase in neutrophils, diminished HFD+1B-induced liver injury and fibrosis. Co-culture of HSCs with neutrophils, but not with neutrophil apoptotic bodies, induced HSC activation and prolonged neutrophil survival. Mechanistic studies showed that activated HSCs produce granulocyte-macrophage colony-stimulating factor and interleukin-15 to prolong the survival of neutrophils, which may serve as a positive forward loop to promote liver damage and fibrosis. CONCLUSIONS The current data from a mouse model of HFD plus binge ethanol feeding suggest that obesity and binge drinking synergize to promote liver fibrosis, which is partially mediated via the interaction of neutrophils and HSCs. Microarray data in this article have been uploaded to NCBI's Gene Expression Omnibus (GEO accession number: GSE98153).
Collapse
Key Words
- 4-HNE, 4-hydroxynonenal
- ALT, alanine aminotransferase
- AST, aspartate aminotransferase
- Alcohol
- CXCL1, chemokine (C-X-C motif) ligand 1
- Csf, colony-stimulating factor gene
- FBS, fetal bovine serum
- Fatty Liver
- G-CSF, granulocyte colony-stimulating factor
- GM-CSF, granulocyte-macrophage colony-stimulating factor
- HFD+1B, high-fat diet feeding plus 1 binge of ethanol
- HFD+mB, high-fat diet plus multiple binges
- HFD, high-fat diet
- HSC, hepatic stellate cell
- High-Fat Diet
- ICAM-1, intercellular adhesion molecule-1
- IL, interleukin
- Inflammation
- KO, knockout
- MPO, myeloperoxidase
- PCR, polymerase chain reaction
- ROS, reactive oxygen species
- RT-PCR, reverse-transcription polymerase chain reaction
- Reactive Oxygen Species
- TUNEL, terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling
- WT, wild-type
- cDNA, complementary DNA
- mRNA, messenger RNA
Collapse
Affiliation(s)
- Zhou Zhou
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Ming-Jiang Xu
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Yan Cai
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Wei Wang
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Joy X. Jiang
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California Davis Medical Center, Davis, California
| | - Zoltan V. Varga
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Dechun Feng
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Pal Pacher
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - George Kunos
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Natalie J. Torok
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California Davis Medical Center, Davis, California
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| |
Collapse
|
|
19
|
Sidhu SS, Goyal O, Kishore H, Sidhu S. New paradigms in management of alcoholic hepatitis: a review. Hepatol Int 2017; 11:255-267. [PMID: 28247264 DOI: 10.1007/s12072-017-9790-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Accepted: 02/08/2017] [Indexed: 12/12/2022]
Abstract
Severe alcoholic hepatitis (SAH) is defined by modified Maddrey discriminant function ≥32 or Model for End-Stage Liver Disease (MELD) >21 and/or hepatic encephalopathy. It has a 3-month mortality rate ≥30-70 %. Patients with severe alcoholic hepatitis need combined, i.e., static (MELD score) and dynamic (Lille's score), prognostication. Systemic inflammation and poor regeneration are hallmarks of SAH, rather than intrahepatic inflammation. SAH is characterized by dysregulated and uncontrolled systemic inflammatory response followed by weak compensatory antiinflammatory response that leads to increased susceptibility to infection and multiple organ failure. Massive necrosis of hepatocytes exceeds the proliferative capacity of hepatocytes. Liver progenitor cells proliferate to form narrow ductules which radiate out into the damaged liver parenchyma. Corticosteroids have been the standard-of-care therapy, albeit controversial. However, the recent Steroids or Pentoxifylline for Alcoholic Hepatitis (STOPAH) trial revealed that prednisolone was not associated with a significant reduction in 28-day mortality, with no improvement in outcomes at 90 days or 1 year. A paradigm shift from antiinflammatory therapy such as corticosteroids to liver regeneration treatment, e.g., granulocyte-colony stimulating factor, molecular targeted treatments, and fecal microbiota transplantation, for severe alcoholic hepatitis is taking place. Liver transplantation should be offered to select patients with severe alcoholic hepatitis who are nonresponsive to medical treatment.
Collapse
Affiliation(s)
- Sandeep Singh Sidhu
- Department of Gastroenterology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India.
| | - Omesh Goyal
- Department of Gastroenterology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India
| | - Harsh Kishore
- Department of Gastroenterology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India
| | - Simran Sidhu
- Himalayan Institute of Medical Sciences, Dehradun, Uttarakhand, India
| |
Collapse
|
|
20
|
Yang SS. Alcoholic Liver Disease in the Asian–Pacific Region with High Prevalence of Chronic Viral Hepatitis. J Med Ultrasound 2016. [DOI: 10.1016/j.jmu.2016.08.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
|
|
21
|
Nikou T, Ioannidis A, Zoga M, Tzavellas E, Paparrigopoulos T, Magana M, Pliatsika P, Nikolaou C, Chatzipanagiotou S. Alteration in the concentrations of Interleukin-7 (IL-7), Interleukin-10 (IL-10) and Granulocyte Colony Stimulating Factor (G-CSF) in alcohol-dependent individuals without liver disease, during detoxification therapy. Drug Alcohol Depend 2016; 163:77-83. [PMID: 27068251 DOI: 10.1016/j.drugalcdep.2016.03.022] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2015] [Revised: 03/17/2016] [Accepted: 03/28/2016] [Indexed: 12/23/2022]
Abstract
BACKGROUND The course of Interleukin-7 (IL-7), Interleukin-10 (IL-10) and Granulocyte Colony Stimulating Factor (G-CSF) was investigated in alcohol-dependent individuals without liver disease in order to ascertain the use of these cytokines as markers for the follow-up testing and the outcome of the detoxification treatment. METHODS Forty-eight alcohol-dependent individuals were admitted for alcohol detoxification. Blood was obtained upon admission, two weeks later and after the completion of the detoxification period (4-5 weeks). Serum IL-7, IL-10 and G-CSF were measured with a commercially available sandwich enzyme immunoassay. RESULTS IL-7 concentration was steadily high from admission up to two weeks later and then showed a fall, yet still remaining significantly higher than in the control group at the end of the detoxification treatment. IL-10 concentration was significantly low on admission, presenting a linear increase during therapy and remained insignificantly low at the end. G-CSF was significantly elevated on admission and presented a linear fall ending up in almost normal values at the end of the detoxification therapy. CONCLUSIONS The alterations in the concentration of IL-7, IL-10 and G-CSF and their trend to normalization during the detoxification therapy are indicative of the generalized immune system disorder, caused by alcohol abuse. Further studies will help in further elucidating the pathophysiology of the immune system function in alcohol abuse, while immunological parameters might serve as biological markers and diagnostic tools for the assessment of the course and the outcome of the detoxification therapy.
Collapse
Affiliation(s)
- Thomas Nikou
- Athens Medical School, Aeginition Hospital, Department of Psychiatry, National and Kapodistrian University of Athens, Greece
| | - Anastasios Ioannidis
- Department of Nursing, Faculty of Human Movement and Quality of Life Sciences, University of Peloponnese, Sparta, Greece; Athens Medical School, Aeginition Hospital, Department of Biopathology and Clinical Microbiology, National and Kapodistrian University of Athens, Greece
| | - Margarita Zoga
- Athens Medical School, Aeginition Hospital, Department of Biopathology and Clinical Microbiology, National and Kapodistrian University of Athens, Greece
| | - Elias Tzavellas
- Athens Medical School, Aeginition Hospital, Department of Psychiatry, National and Kapodistrian University of Athens, Greece
| | - Thomas Paparrigopoulos
- Athens Medical School, Aeginition Hospital, Department of Psychiatry, National and Kapodistrian University of Athens, Greece
| | - Maria Magana
- Athens Medical School, Aeginition Hospital, Department of Biopathology and Clinical Microbiology, National and Kapodistrian University of Athens, Greece
| | - Paraskevi Pliatsika
- Athens Medical School, Aeginition Hospital, Department of Biopathology and Clinical Microbiology, National and Kapodistrian University of Athens, Greece
| | - Chryssoula Nikolaou
- Athens Medical School, Aeginition Hospital, Department of Biopathology and Clinical Microbiology, National and Kapodistrian University of Athens, Greece
| | - Stylianos Chatzipanagiotou
- Athens Medical School, Aeginition Hospital, Department of Biopathology and Clinical Microbiology, National and Kapodistrian University of Athens, Greece.
| |
Collapse
|
|
22
|
Boussif A, Rolas L, Weiss E, Bouriche H, Moreau R, Périanin A. Impaired intracellular signaling, myeloperoxidase release and bactericidal activity of neutrophils from patients with alcoholic cirrhosis. J Hepatol 2016; 64:1041-1048. [PMID: 26719020 DOI: 10.1016/j.jhep.2015.12.005] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2015] [Revised: 11/13/2015] [Accepted: 12/08/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Myeloperoxidase exocytosis and production of hydrogen peroxide via the neutrophil superoxide-generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase contribute to efficient elimination of bacteria. Cirrhosis impairs immune functions and increases susceptibility to bacterial infection. We recently showed that neutrophils from patients with decompensated alcoholic cirrhosis exhibit a severe impairment of formylpeptide receptor (fPR)-mediated intracellular signaling and superoxide production. Here, we performed ex vivo studies with these patients' neutrophils to further investigate myeloperoxidase release, bactericidal capacity and signaling events following fPR stimulation by the formylpeptide formyl-met-leu-phe (fMLP). METHODS Myeloperoxidase release was studied by measuring extracellular myeloperoxidase activity. Activation of signaling effectors was studied by Western blot and their respective contribution to myeloperoxidase release studied using pharmacological antagonists. RESULTS fMLP-induced myeloperoxidase release was strongly impaired in patients' neutrophils whereas the intracellular myeloperoxidase stock was unaltered. The fMLP-induced phosphorylation of major signaling effectors, AKT, ERK1/2 and p38-MAP-Kinases, was also strongly deficient despite a similar expression of signaling effectors or fPR. However, based on effector inhibition in healthy neutrophils, AKT and p38-MAPK but not ERK1/2 upregulated fMLP-induced myeloperoxidase exocytosis. Interestingly, patients' neutrophils exhibited a defective bactericidal capacity that was reversed ex vivo by the TLR7/8 agonist CL097, through potentiation of the fMLP-induced AKT/p38-MAPK signaling axis and myeloperoxidase release. CONCLUSIONS We provide first evidence that neutrophils from patients with decompensated alcoholic cirrhosis exhibit a deficient AKT/p38-MAPK signaling, myeloperoxidase release and bactericidal activity, which can be reversed via TLR7/8 activation. These defects, together with the previously described severe deficient superoxide production, may increase cirrhotic patients' susceptibility to bacterial infections.
Collapse
Affiliation(s)
- Abdelali Boussif
- INSERM UMRS-1149, Faculté de Médécine X. Bichat, 75018 Paris, France; CNRS ERL 8252, Centre de Recherche sur l'Inflammation, 75018 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'excellence INFLAMEX, 75018 Paris, France; Université de Batna, Faculté des Sciences, Département de Biologie, Algeria
| | - Loïc Rolas
- INSERM UMRS-1149, Faculté de Médécine X. Bichat, 75018 Paris, France; CNRS ERL 8252, Centre de Recherche sur l'Inflammation, 75018 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'excellence INFLAMEX, 75018 Paris, France
| | - Emmanuel Weiss
- INSERM UMRS-1149, Faculté de Médécine X. Bichat, 75018 Paris, France; CNRS ERL 8252, Centre de Recherche sur l'Inflammation, 75018 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'excellence INFLAMEX, 75018 Paris, France; Département d'Anesthésie Réanimation, Hôpital Beaujon, APHP, 92118 Clichy, France
| | - Hamama Bouriche
- Laboratoire de Biochimie Appliquée, Département de Biochimie, Faculté des Sciences de la Nature et de Vie, Université Ferhat Abbas, Sétif 1, Algeria
| | - Richard Moreau
- INSERM UMRS-1149, Faculté de Médécine X. Bichat, 75018 Paris, France; CNRS ERL 8252, Centre de Recherche sur l'Inflammation, 75018 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'excellence INFLAMEX, 75018 Paris, France; Département Hospitalo-Universitaire (DHU) Unity, Service d'Hépatologie, Hôpital Beaujon, APHP, 92118 Clichy, France
| | - Axel Périanin
- INSERM UMRS-1149, Faculté de Médécine X. Bichat, 75018 Paris, France; CNRS ERL 8252, Centre de Recherche sur l'Inflammation, 75018 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'excellence INFLAMEX, 75018 Paris, France.
| |
Collapse
|
|
23
|
Shasthry SM, Sarin SK. New treatment options for alcoholic hepatitis. World J Gastroenterol 2016; 22:3892-3906. [PMID: 27099434 PMCID: PMC4823241 DOI: 10.3748/wjg.v22.i15.3892] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Revised: 03/07/2016] [Accepted: 03/18/2016] [Indexed: 02/06/2023] Open
Abstract
The burden of alcoholic liver disease has rapidly grown in the past two decades and is expected to increase further in the coming years. Alcoholic hepatitis, the most florid presentation of alcoholic liver disease, continues to have high morbidity and mortality, with significant financial and healthcare burden with limited treatment options. Steroids remain the current standard of care in severe alcoholic hepatitis in carefully selected patients. No specific treatments are available for those patients who are steroid ineligible, intolerant or unresponsive. Liver transplant has shown good short-term outcome; however, feasibility, ethical and economic concerns remain. Modification of gut microbiota composition and their products, such as lipopolysaccharide, nutritional interventions, immune modulation, increasing steroid sensitivity, genetic polymorphism and epigenetic modification of alcohol induced liver damage, augmenting hepatic regeneration using GCSF are potential therapeutic avenues in steroid non-responsive/ineligible patients. With better understanding of the pathophysiology, using “Omics” platforms, newer options for patients with alcoholic hepatitis are expected soon.
Collapse
|