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Park S, Perumalsamy H, Kim JE, Kim HY, Jun DW, Yoon TH. The impact of G-CSF on mouse immune cells in alcoholic liver disease, focusing on variations in T cells and their subsets. Biomed Pharmacother 2024; 178:117175. [PMID: 39074426 DOI: 10.1016/j.biopha.2024.117175] [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: 04/16/2024] [Revised: 07/13/2024] [Accepted: 07/22/2024] [Indexed: 07/31/2024] Open
Abstract
Alcoholic liver disease (ALD) significantly affects immune cell function and leads to immunological dysregulation. This study explored the potential of granulocyte colony-stimulating factor (G-CSF) to mitigate the negative effects of alcohol on immune cells in a mouse model of ALD. To investigate the capacity of G-CSF, ALD was induced using a 17-day alcohol-enriched diet, followed by a single G-CSF dose prior to sampling. We focused on the dynamics of peripheral blood mononuclear cells using high-dimensional mass cytometry to detect subtle changes. Alcohol intake reduced the number of B cells, monocytes, dendritic cells, and NK cells while increasing the number of T cells. Notably, G-CSF treatment reversed the alcohol-induced increase in total CD4+ and CD8+ T cell populations. This effect was remarkable in naïve, effector CD4+ T cells and naïve CD8+ T cells. PhenoGraph and FlowSOM analysis further revealed the recovery effect of G-CSF on specific T cell subgroups, including central memory CD8+ T cells and double-negative T cells expressing Ly6chighCD44high, which are adversely affected by alcohol. These results enhance our understanding of the effect of ALD on immune function and suggest that G-CSF is a potential therapeutic agent, laying the foundation for future clinical research.
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Affiliation(s)
- Sehee Park
- Department of Chemistry, College of Natural Sciences, Hanyang University, Seoul 04763, Republic of Korea
| | - Haribalan Perumalsamy
- Center for Creative Convergence Education, Hanyang University, Seoul 04763, Republic of Korea; Research Institute for Convergence of Basic Science, Hanyang University, Seoul 04763, Republic of Korea
| | - Ji Eun Kim
- Department of Translational Medicine, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Republic of Korea
| | - Hye Young Kim
- Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul 04763, Republic of Korea
| | - Dae Won Jun
- Department of Translational Medicine, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Republic of Korea; Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul 04763, Republic of Korea; Department of Internal Medicine, College of Medicine, Hanyang University, Seoul 04763, Republic of Korea; Department of Medical and Digital Engineering, Hanyang University, Seoul 04763, Republic of Korea.
| | - Tae Hyun Yoon
- Department of Chemistry, College of Natural Sciences, Hanyang University, Seoul 04763, Republic of Korea; Research Institute for Convergence of Basic Science, Hanyang University, Seoul 04763, Republic of Korea; Department of Medical and Digital Engineering, Hanyang University, Seoul 04763, Republic of Korea; Institute for Next Generation Material Design, Hanyang University, Seoul 04763, Republic of Korea; Yoon Idea Lab. Co. Ltd., Seoul 04763, Republic of Korea.
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Rahayatri TH, Oswari H, Kekalih A, Harahap A, Hendarto A, Munasir Z, Setiabudy R, Taher A. Granulocyte Colony-stimulating Factor Improves Innate Immunity in Pediatric Pretransplant Patients. J Clin Exp Hepatol 2024; 14:101282. [PMID: 38076442 PMCID: PMC10709513 DOI: 10.1016/j.jceh.2023.09.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 09/07/2023] [Indexed: 03/03/2025] Open
Abstract
Background Children with decompensated cirrhosis (DC) awaiting LT suffer from infection linked to high pediatric end-stage liver disease (PELD) scores and mortality. Granulocyte colony-stimulating factor (G-CSF) therapy has shown promising results in adult DC. Our study investigated G-CSF as an optimizing treatment for pre-transplant DC, exploring its effect on cytokine activity. Methods An open-label, randomized controlled trial included DC patients aged 3 months-12 years. The intervention group (n=26) received 12 G-CSF courses injected subcutaneously (5 μg/kg/day) plus DC standard medical treatment (SMT). The control group (n = 24) received SMT. We obtained PELD scores, tumor necrosis factor (TNF)-α, interleukin (IL)-10, hepatocyte growth factor (HGF), CD34+ mobilization, liver function, leukocyte and neutrophil counts. Infection and side effects were documented. Results There was no significant difference in PELD scores between the groups after 3 months G-CSF treatment. Decreased TNF-α (p < 0.001) and increased IL-10 and HGF (p = 0.003 for both markers) were shown 1 month following G-CSF treatment. Alanine aminotransferase (ALT) levels improved significantly (p = 0.038). Significant increase in leucocyte and neutrophil counts (p < 0.001) and a lower incidence of sepsis (p = 0.04) were shown after intervention. There was no significant difference in survival (p = 0.372). Conclusion Following 3 months of G-CSF treatment, PELD scores did not show significant improvement. G-CSF reversed the cytokine profiles in DC, resulting in reduced TNF-α and increased IL-10. HGF significantly improved, indicating hepatic regeneration. Significantly decreased occurrence of sepsis following G-CSF treatment indicated improved clinical outcome.
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Affiliation(s)
- Tri H. Rahayatri
- Faculty of Medicine, Universitas Indonesia, Department of Pediatric Surgery, Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Hanifah Oswari
- Faculty of Medicine, Universitas Indonesia, Department of Pediatrics, Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Aria Kekalih
- Faculty of Medicine, Universitas Indonesia, Department of Community Medicine, Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Alida Harahap
- Eijkman Institute for Molecular Biology, Jakarta, Indonesia
| | - Aryono Hendarto
- Faculty of Medicine, Universitas Indonesia, Department of Pediatrics, Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Zakiudin Munasir
- Faculty of Medicine, Universitas Indonesia, Department of Pediatrics, Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Rianto Setiabudy
- Faculty of Medicine, Universitas Indonesia, Department of Pharmacology, Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Akmal Taher
- Faculty of Medicine, Universitas Indonesia, Department of Urology, Cipto Mangunkusumo Hospital, Jakarta, Indonesia
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Di Martino V, Questiaux J, Lemagoarou T, Weil D, Vendeville S, Engelmann C, Hu J, Singh V, Newsome PN, Lal SB, Sarin SK, Berg T, Thevenot T. Granulocyte colony stimulating factor in decompensated cirrhosis, acute alcoholic hepatitis, and acute-on-chronic liver failure: A comprehensive meta-analysis of randomized controlled trials. Clin Res Hepatol Gastroenterol 2023; 47:102207. [PMID: 37716522 DOI: 10.1016/j.clinre.2023.102207] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 08/08/2023] [Accepted: 09/08/2023] [Indexed: 09/18/2023]
Abstract
BACKGROUND GCSF may improve the prognosis of severe liver disease by promoting liver regeneration and immune restoration. Our Aim was to investigate its controversial efficacy in decompensated cirrhosis, acute alcoholic hepatitis (AAH), or acute-on-chronic liver failure (ACLF) through meta-analysis. METHODS Meta-analysis of proportions (random effect model) including 19 RCTs (1287 patients from 16 Asian and 3 European studies including 487 ACLF, 231 AAH and 569 cirrhotic patients) evaluating survival at day-28, day-90, 6 months, one year, and/or occurrence of sepsis as major outcomes. RESULTS In patients with decompensated cirrhosis, G-CSF administration was associated with a reduction in the weight-adjusted risk of mortality of 9% at day-90 (OR=0.33; 95%CI: 0.18-0.58; p = 0.0002), 16% at 6 months (OR=0.31; 95%CI: 0.15-0.62; p = 0.0009), 26% at one year (OR=0.21; 95%CI:0.12-0.38, p<0.0001) and a weight-adjusted 28% risk reduction for sepsis (OR=0.28; 95%CI: 0.16-0.49; p<0.0001). Only Asian studies were positive. In AAH, G-CSF was associated with an 18% reduction in weight-adjusted mortality risk at day-28 (OR=0.31; 95%CI:0.11-0.83, p = 0.021), 32% at day-90 (OR=0.20; 95%CI:0.09-0.46, p<0.0001) and a weight-adjusted 42% risk reduction for sepsis (OR=0.17; 95%CI: 0.08-0.38; p<0.0001). Only Asian studies, in which corticosteroids were not given systematically in case of severe AAH, were positive. In patients with ACLF, the results on mortality at day-28 were heterogeneous, and GCSF had no beneficial effect on sepsis or survival at day-90. CONCLUSION G-CSF may be effective in patients with decompensated cirrhosis or AAH by reducing the occurrence of sepsis and mortality. Further meta-analyses of individual data, or new, powerful and methodologically flawless therapeutic trials, are warranted to confirm these results, which harbor wide divergences between Asian and European RCTs.
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Affiliation(s)
- Vincent Di Martino
- Service d'Hépatologie, CHU Jean Minjoz, Besançon, France; Laboratoire EPILAB EA4266, Université de Franche Comté, Besançon, France.
| | | | - Tristan Lemagoarou
- Département d'information Médicale et de Santé Publique, GHPSO CREIL, Creil, France
| | - Delphine Weil
- Service d'Hépatologie, CHU Jean Minjoz, Besançon, France; Laboratoire EPILAB EA4266, Université de Franche Comté, Besançon, France
| | | | - Cornelius Engelmann
- Department of Hepatology and Gastroenterology, Universitätsmedizin Berlin, Berlin, Germany; Berlin Institute of Health, Berlin, Germany; Institute for Liver and Digestive Health, University College London, London, United Kingdom
| | - Jinhua Hu
- Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Virendra Singh
- Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Philip N Newsome
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Sadhna B Lal
- Division of Paediatric Gastroenterology and Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Shiv K Sarin
- Institute of Liver and Biliary Sciences (ILBS), New Delhi, India
| | - Thomas Berg
- Division of Hepatology Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
| | - Thierry Thevenot
- Service d'Hépatologie, CHU Jean Minjoz, Besançon, France; Laboratoire EPILAB EA4266, Université de Franche Comté, Besançon, France
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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.
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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
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Butt MF, Jalan R. Review article: Emerging and current management of acute-on-chronic liver failure. Aliment Pharmacol Ther 2023; 58:774-794. [PMID: 37589507 DOI: 10.1111/apt.17659] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 05/02/2023] [Accepted: 07/24/2023] [Indexed: 08/18/2023]
Abstract
BACKGROUND Acute-on-chronic liver failure (ACLF) is a clinically and pathophysiologically distinct condition from acutely decompensated cirrhosis and is characterised by systemic inflammation, extrahepatic organ failure, and high short-term mortality. AIMS To provide a narrative review of the diagnostic criteria, prognosis, epidemiology, and general management principles of ACLF. Four specific interventions that are explored in detail are intravenous albumin, extracorporeal liver assist devices, granulocyte-colony stimulating factor, and liver transplantation. METHODS We searched PubMed and Cochrane databases for articles published up to July 2023. RESULTS Approximately 35% of hospital inpatients with decompensated cirrhosis have ACLF. There is significant heterogeneity in the criteria used to diagnose ACLF; different definitions identify different phenotypes with varying mortality. Criteria established by the European Association for the Study of the Liver were developed in prospective patient cohorts and are, to-date, the most well validated internationally. Systemic haemodynamic instability, renal dysfunction, coagulopathy, neurological dysfunction, and respiratory failure are key considerations when managing ACLF in the intensive care unit. Apart from liver transplantation, there are no accepted evidence-based treatments for ACLF, but several different approaches are under investigation. CONCLUSION The recognition of ACLF as a distinct entity from acutely decompensated cirrhosis has allowed for better patient stratification in clinical settings, facilitating earlier engagement with the intensive care unit and liver transplantation teams. Research priorities over the next decade should focus on exploring novel treatment strategies with a particular focus on which, when, and how patients with ACLF should be treated.
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Affiliation(s)
- Mohsin F Butt
- Centre for Neuroscience, Trauma and Surgery, Wingate Institute of Neurogastroenterology, The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- Liver Failure Group, University College London Medical School, Royal Free Hospital Campus, London, UK
- National Institute for Health Research, Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, University of Nottingham, Nottinghamshire, UK
| | - Rajiv Jalan
- Liver Failure Group, University College London Medical School, Royal Free Hospital Campus, London, UK
- European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) Consortium, Barcelona, Spain
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Liu BC, Cheng MR, Lang L, Li L, Si YH, Li AJ, Xu Q, Zhang H. Autologous bone marrow infusion via portal vein combined with splenectomy for decompensated liver cirrhosis: A retrospective study. World J Gastrointest Surg 2023; 15:1919-1931. [PMID: 37901728 PMCID: PMC10600764 DOI: 10.4240/wjgs.v15.i9.1919] [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: 04/06/2023] [Revised: 06/08/2023] [Accepted: 07/11/2023] [Indexed: 09/21/2023] Open
Abstract
BACKGROUND In a previous study, autologous bone marrow infusion (ABMI) was performed in patients with decompensated liver cirrhosis (DLC) and acquired immunodeficiency syndrome and achieved good results, but whether splenectomy affected outcome was unclear. AIM To investigate the efficacy of ABMI combined with splenectomy for treatment of DLC. METHODS Eighty-three patients with DLC were divided into an intervention group (43 cases) and control group (40 cases) according to whether splenectomy was performed. The control group was treated with ABMI through the right omental vein, and the intervention group was additionally treated with splenectomy. RESULTS After ABMI, the prothrombin time, serum total bilirubin levels, ascites volume and model for end-stage liver disease score in both groups were significantly lower, while the albumin levels were significantly higher than before ABMI (P < 0.01), but there were no significant differences between the groups (P > 0.05). After ABMI, the white blood cell and platelets counts in both groups were significantly higher than before ABMI (P < 0.01), and the counts in the intervention group were significantly higher than in the control group (P < 0.01). After ABMI the CD4+ and CD8+ T cell counts in both groups were significantly higher than before ABMI (P < 0.01). The CD8+ T cell counts in the intervention group increased continuously and the increase had a shorter duration compared with control group. CONCLUSION ABMI through the portal vein in patients with DLC can significantly improve liver synthetic and secretory functions, and splenectomy promotes improvement of bone marrow hematopoietic and cellular immune functions.
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Affiliation(s)
- Bao-Chi Liu
- Department of Surgery, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
- He Nuo Medical Clinic, Shanghai New Hongqiao International Medical Center, Shanghai 201100, China
| | - Ming-Rong Cheng
- Department of Anorectal Surgery, The Third Affiliated Hospital of Guizhou Medical University, Duyun 558000, Guizhou Province, China
| | - Lin Lang
- He Nuo Medical Clinic, Shanghai New Hongqiao International Medical Center, Shanghai 201100, China
| | - Lei Li
- Department of Surgery, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Yan-Hui Si
- Department of Surgery, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Ai-Jun Li
- Department of Hepatobiliary Surgery, Oriental Hepatobiliary Surgery Hospital, Shanghai 200433, China
| | - Qing Xu
- Department of Hepatobiliary Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Hui Zhang
- Department of Hepatobiliary Surgery, Shanghai Oriental Hospital Affiliated to Tongji University, Shanghai 200120, China
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Colli A, Fraquelli M, Prati D, Casazza G. Granulocyte colony-stimulating factor with or without stem or progenitor cell or growth factors infusion for people with compensated or decompensated advanced chronic liver disease. Cochrane Database Syst Rev 2023; 6:CD013532. [PMID: 37278488 PMCID: PMC10243114 DOI: 10.1002/14651858.cd013532.pub2] [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: 06/07/2023]
Abstract
BACKGROUND Advanced chronic liver disease is characterised by a long compensated phase followed by a rapidly progressive 'decompensated' phase, which is marked by the development of complications of portal hypertension and liver dysfunction. Advanced chronic liver disease is considered responsible for more than one million deaths annually worldwide. No treatment is available to specifically target fibrosis and cirrhosis; liver transplantation remains the only curative option. Researchers are investigating strategies to restore liver functionality to avoid or slow progression towards end-stage liver disease. Cytokine mobilisation of stem cells from the bone marrow to the liver could improve liver function. Granulocyte colony-stimulating factor (G-CSF) is a 175-amino-acid protein currently available for mobilisation of haematopoietic stem cells from the bone marrow. Multiple courses of G-CSF, with or without stem or progenitor cell or growth factors (erythropoietin or growth hormone) infusion, might be associated with accelerated hepatic regeneration, improved liver function, and survival. OBJECTIVES To evaluate the benefits and harms of G-CSF with or without stem or progenitor cell or growth factors (erythropoietin or growth hormone) infusion, compared with no intervention or placebo in people with compensated or decompensated advanced chronic liver disease. SEARCH METHODS We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, three other databases, and two trial registers (October 2022) together with reference-checking and web-searching to identify additional studies. We applied no restrictions on language and document type. SELECTION CRITERIA We only included randomised clinical trials comparing G-CSF, independent of the schedule of administration, as a single treatment or combined with stem or progenitor cell infusion, or with other medical co-interventions, with no intervention or placebo, in adults with chronic compensated or decompensated advanced chronic liver disease or acute-on-chronic liver failure. We included trials irrespective of publication type, publication status, outcomes reported, or language. DATA COLLECTION AND ANALYSIS We followed standard Cochrane procedures. All-cause mortality, serious adverse events, and health-related quality of life were our primary outcomes, and liver disease-related morbidity, non-serious adverse events, and no improvement of liver function scores were our secondary outcomes. We undertook meta-analyses, based on intention-to-treat, and presented results using risk ratios (RR) for dichotomous outcomes and the mean difference (MD) for continuous outcomes, with 95% confidence intervals (CI) and I2 statistic values as a marker of heterogeneity. We assessed all outcomes at maximum follow-up. We determined the certainty of evidence using GRADE, evaluated the risk of small-study effects in regression analyses, and conducted subgroup and sensitivity analyses. MAIN RESULTS We included 20 trials (1419 participants; sample size ranged from 28 to 259), which lasted between 11 and 57 months. Nineteen trials included only participants with decompensated cirrhosis; in one trial, 30% had compensated cirrhosis. The included trials were conducted in Asia (15), Europe (four), and the USA (one). Not all trials provided data for our outcomes. All trials reported data allowing intention-to-treat analyses. The experimental intervention consisted of G-CSF alone or G-CSF plus any of the following: growth hormone, erythropoietin, N-acetyl cysteine, infusion of CD133-positive haemopoietic stem cells, or infusion of autologous bone marrow mononuclear cells. The control group consisted of no intervention in 15 trials and placebo (normal saline) in five trials. Standard medical therapy (antivirals, alcohol abstinence, nutrition, diuretics, β-blockers, selective intestinal decontamination, pentoxifylline, prednisolone, and other supportive measures depending on the clinical status and requirement) was administered equally to the trial groups. Very low-certainty evidence suggested a decrease in mortality with G-CSF, administered alone or in combination with any of the above, versus placebo (RR 0.53, 95% CI 0.38 to 0.72; I2 = 75%; 1419 participants; 20 trials). Very low-certainty evidence suggested no difference in serious adverse events (G-CSF alone or in combination versus placebo: RR 1.03, 95% CI 0.66 to 1.61; I2 = 66%; 315 participants; three trials). Eight trials, with 518 participants, reported no serious adverse events. Two trials, with 165 participants, used two components of the quality of life score for assessment, with ranges from 0 to 100, where higher scores indicate better quality of life, with a mean increase from baseline of the physical component summary of 20.7 (95% CI 17.4 to 24.0; very low-certainty evidence) and a mean increase from baseline of the mental component summary of 27.8 (95% CI 12.3 to 43.3; very low-certainty evidence). G-CSF, alone or in combination, suggested a beneficial effect on the proportion of participants who developed one or more liver disease-related complications (RR 0.40, 95% CI 0.17 to 0.92; I2 = 62%; 195 participants; four trials; very low-certainty evidence). When we analysed the occurrences of single complications, there was no suggestion of a difference between G-CSF, alone or in combination, versus control, in participants in need of liver transplantation (RR 0.85, 95% CI 0.39 to 1.85; 692 participants; five trials), in the development of hepatorenal syndrome (RR 0.65, 95% CI 0.33 to 1.30; 520 participants; six trials), in the occurrence of variceal bleeding (RR 0.68, 95% CI 0.37 to 1.23; 614 participants; eight trials), and in the development of encephalopathy (RR 0.56, 95% CI 0.31 to 1.01; 605 participants; seven trials) (very low-certainty evidence). The same comparison suggested that G-CSF reduces the development of infections (including sepsis) (RR 0.50, 95% CI 0.29 to 0.84; 583 participants; eight trials) and does not improve liver function scores (RR 0.67, 95% CI 0.53 to 0.86; 319 participants; two trials) (very low-certainty evidence). AUTHORS' CONCLUSIONS G-CSF, alone or in combination, seems to decrease mortality in people with decompensated advanced chronic liver disease of whatever aetiology and with or without acute-on-chronic liver failure, but the certainty of evidence is very low because of high risk of bias, inconsistency, and imprecision. The results of trials conducted in Asia and Europe were discrepant; this could not be explained by differences in participant selection, intervention, and outcome measurement. Data on serious adverse events and health-related quality of life were few and inconsistently reported. The evidence is also very uncertain regarding the occurrence of one or more liver disease-related complications. We lack high-quality, global randomised clinical trials assessing the effect of G-CSF on clinically relevant outcomes.
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Affiliation(s)
- Agostino Colli
- Department of Transfusion Medicine and Haematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Mirella Fraquelli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Daniele Prati
- Department of Transfusion Medicine and Haematology, Ospedale Alessandro Manzoni, Lecco, Italy
| | - Giovanni Casazza
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
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Ballester MP, Sittner R, Jalan R. Alcohol and Acute-on-Chronic Liver Failure. J Clin Exp Hepatol 2022; 12:1360-1370. [PMID: 36157143 PMCID: PMC9499845 DOI: 10.1016/j.jceh.2021.12.010] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Accepted: 12/15/2021] [Indexed: 12/12/2022] Open
Abstract
Acute-on-chronic liver failure (ACLF) is a clinical syndrome that occurs in patients with cirrhosis and is characterised by acute deterioration, organ failure and high short-term mortality. Alcohol is one of the leading causes of ACLF and the most frequently reported aetiology of underlying chronic liver disease. Among patients with alcoholic hepatitis (AH), ACLF is a frequent and severe complication. It is characterised by both immune dysfunction associated to an increased risk of infection and high-grade systemic inflammation that ultimately induce organ failure. Diagnosis and severity of ACLF determine AH prognosis, and therefore, ACLF prognostic scores should be used in severe AH with organ failure. Corticosteroids remain the first-line treatment for severe AH but they seem insufficient when ACLF is associated. Novel therapeutic targets to contain the excessive inflammatory response and reduce infection have been identified and are under investigation. With liver transplantation remaining one of the most effective therapies for severe AH and ACLF, adequate organ allocation represents a growing challenge. Hence, a clear understanding of the pathophysiology, clinical implications and management strategies of ACLF in AH is essential for hepatologists, which is narrated briefly in this review.
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Key Words
- ACLF, Acute-on-chronic liver failure
- AH, alcoholic hepatitis
- ALT, alanine aminotransferase
- APASL, Asian Pacific Association for the Study of the Liver
- AST, aspartate aminotransferase
- DAMPs, damage-associated molecular patterns
- EASL-CLIF, European Association for the Study of the Liver – Chronic Liver Failure Consortium
- GAHS, Glasgow alcoholic hepatitis score
- IL, interleukin
- INR, international normalised ratio
- MELD, model for end-stage liver disease
- NAC, N-acetylcysteine
- NACSELD, North American Consortium for the Study of End-Stage Liver Disease
- PAMPs, pathogen-associated molecular patterns
- TNF, tumour necrosis factor
- WGO, World Gastroenterology Organization
- acute-on-chronic liver failure
- alcoholic hepatitis
- cirrhosis
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Affiliation(s)
- Maria Pilar Ballester
- Digestive Disease Department, University Clinic Hospital of Valencia, Blasco Ibañez Av, 17, Valencia, 46010, Spain
- INCLIVA Biomedical Research Institute, Menéndez y Pelayo St., 4, Valencia, 46010, Spain
| | - Richard Sittner
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum, Charitéplatz 1 Berlin, 10117, Germany
| | - Rajiv Jalan
- Liver Failure Group, Institute for Liver and Disease Health, University College London, Royal Free Campus, Rowland Hill Street, London, NW3 2PF, United Kingdom
- European Foundation for the Study of Chronic Liver Failure (EF Clif) and the European Association for the Study of the Liver–Chronic Liver Failure (EASL-CLIF) Consortium, Travessera de Gràcia St., 11, Barcelona, 08021, Spain
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9
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Nevens F, van der Merwe S. Mesenchymal Stem Cell Transplantation in Liver Diseases. Semin Liver Dis 2022; 42:283-292. [PMID: 36049782 DOI: 10.1055/s-0042-1755328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Promising preclinical data suggested that bone marrow-derived mesenchymal stem cells (BM-MSC) can reduce hepatic fibrosis and stimulate liver regeneration. Preclinical studies moreover suggested that the immunomodulatory and anti-inflammatory functions of MSCs may reduce hepatic inflammation, improve liver function, and decrease infection incidences which are deemed especially important in the case of acute-on-chronic liver failure (ACLF). Studies in patients with decompensated cirrhosis demonstrated that injection of BM-MSC resulted in an improvement of biochemical tests and led to a survival benefit in ACLF. Most of these studies were performed in hepatitis B virus infected patients. However, two adequately powered studies performed in Europe could not confirm these data. A possible alternative to mobilize BM-MSC into the liver is the use of granulocyte colony-stimulating factor (G-CSF) which has proregenerative and immunomodulatory effects. In Indian studies, the use of G-CSF was associated with improvement of survival, although this finding could not be confirmed in European studies. Human allogeneic liver-derived progenitor cell therapy represents a potential treatment for ACLF, of which the main action is paracrine. These human liver-derived MSC can perform various functions, including the downregulation of proinflammatory responses. The clinical beneficial effect of these cells is further explored in patients with alcoholic cirrhosis and ACLF in Europe.
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Affiliation(s)
- Frederik Nevens
- Department of Chronic Diseases, Laboratory of Hepatology, Metabolism and Aging (CHROMETA), University of Leuven, Leuven, Belgium.,Division of Hepatology, Department of Gastroenterology and Hepatology, University Hospital KU Leuven, Belgium
| | - Schalk van der Merwe
- Department of Chronic Diseases, Laboratory of Hepatology, Metabolism and Aging (CHROMETA), University of Leuven, Leuven, Belgium.,Division of Hepatology, Department of Gastroenterology and Hepatology, University Hospital KU Leuven, Belgium
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10
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Kulkarni AV, Premkumar M, Arab JP, Kumar K, Sharma M, Reddy ND, Padaki NR, Reddy RK. Early Diagnosis and Prevention of Infections in Cirrhosis. Semin Liver Dis 2022; 42:293-312. [PMID: 35672014 DOI: 10.1055/a-1869-7607] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Strategies to prevent infection and improve outcomes in patients with cirrhosis. HAV, hepatitis A virus; HBV, hepatitis B virus; COVID-19, novel coronavirus disease 2019; NSBB, nonselective β-blocker; PPI, proton pump inhibitors.Cirrhosis is a risk factor for infections. Majority of hospital admissions in patients with cirrhosis are due to infections. Sepsis is an immunological response to an infectious process that leads to end-organ dysfunction and death. Preventing infections may avoid the downstream complications, and early diagnosis of infections may improve the outcomes. In this review, we discuss the pathogenesis, diagnosis, and biomarkers of infection; the incremental preventive strategies for infections and sepsi; and the consequent organ failures in cirrhosis. Strategies for primary prevention include reducing gut translocation by selective intestinal decontamination, avoiding unnecessary proton pump inhibitors' use, appropriate use of β-blockers, and vaccinations for viral diseases including novel coronavirus disease 2019. Secondary prevention includes early diagnosis and a timely and judicious use of antibiotics to prevent organ dysfunction. Organ failure support constitutes tertiary intervention in cirrhosis. In conclusion, infections in cirrhosis are potentially preventable with appropriate care strategies to then enable improved outcomes.
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Affiliation(s)
- Anand V Kulkarni
- Department of Hepatology, Asian Institute of Gastroenterology, Hyderabad, Telangana, India
| | - Madhumita Premkumar
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Juan P Arab
- Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Karan Kumar
- Department of Hepatology, Mahatma Gandhi Medical College and Hospital, Jaipur, Rajasthan, India
| | - Mithun Sharma
- Department of Hepatology, Asian Institute of Gastroenterology, Hyderabad, Telangana, India
| | - Nageshwar D Reddy
- Department of Hepatology, Asian Institute of Gastroenterology, Hyderabad, Telangana, India
| | - Nagaraja R Padaki
- Department of Hepatology, Asian Institute of Gastroenterology, Hyderabad, Telangana, India
| | - Rajender K Reddy
- Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, Pennsylvania
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11
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Study protocol of Phase 2 open-label multicenter randomized controlled trial for granulocyte-colony stimulating factor (GCSF) in post-Kasai Type 3 biliary atresia. Pediatr Surg Int 2022; 38:1019-1030. [PMID: 35391541 DOI: 10.1007/s00383-022-05115-0] [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] [Accepted: 03/17/2022] [Indexed: 12/07/2022]
Abstract
Animal studies support RCT findings of improved liver function and short-term benefits using repurposed Granulocyte Colonic Stimulating Factor GCSF in adults with decompensated cirrhosis. We describe the protocol for phase 2 RCT of sequential Kasai-GCSF under an FDA-approved IND to test that GCSF improves early bile flow and post-Kasai biliary atresia BA clinical outcome. Immediate post-Kasai neonates, age 15-180 days, with biopsy-confirmed type 3 BA, without access to early liver transplantation, will be randomized 1:1 to standard of care SOC + GCSF at 10 ug/kg in 3 daily doses within 4 days of Kasai vs SOC + NO-GCSF (ClinicalTrials.gov NCT0437391). They will be recruited from children's hospitals in Vietnam, Pakistan and one US center. The primary objective is to demonstrate that GCSF decreases the proportion of subjects with a 3-month post-Kasai serum Total Bilirubin ≥ 34 umol/L by 20%, (for a = 0.05, b = 0.80, i.e., calculated sample size of 218 subjects). The secondary objectives are to demonstrate that the frequency of post-Kasai cholangitis at 6-month and 24-month transplant-free survival are improved. The benefits are that GCSF is an affordable BA adjunct therapy, especially in developing countries, to improve biliary complications, enhance quality of liver and survival while diminishing costly liver transplantation.Clinical trial registration: A phase 1 for GCSF dose and safety determination under ClinicalTrials.gov identifier NCT03395028 was completed in 2019. The current Phase 2 trial was registered under NCT04373941.
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12
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Tranah TH, Kronsten VT, Shawcross DL. Implications and Management of Cirrhosis-Associated Immune Dysfunction Before and After Liver Transplantation. Liver Transpl 2022; 28:700-716. [PMID: 34738724 DOI: 10.1002/lt.26353] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/18/2021] [Accepted: 10/27/2021] [Indexed: 12/28/2022]
Abstract
Cirrhosis-associated immune dysfunction (CAID) describes a panacea of innate and adaptive deficits that result from the sequelae of cirrhotic portal hypertension that is similar in its manifestations regardless of etiology of chronic liver injury. CAID is associated with synchronous observations of dysregulated priming of innate immune effector cells that demonstrate a proinflammatory phenotype but are functionally impaired and unable to adequately prevent invading pathogens. CAID is mainly driven by gut-barrier dysfunction and is associated with deficits of microbial compartmentalization and homeostasis that lead to tonic activation, systemic inflammation, and exhaustion of innate-immune cells. CAID leads to a high frequency of bacterial and fungal infections in patients with cirrhosis that are often associated with acute decompensation of chronic liver disease and acute-on-chronic liver failure and carry a high mortality rate. Understanding the deficits of mucosal and systemic immunity in the context of chronic liver disease is essential to improving care for patients with cirrhosis, preventing precipitants of acute decompensation of cirrhosis, and improving morbidity and survival. In this review, we summarize the detailed dynamic immunological perturbations associated with advanced chronic liver disease and highlight the importance of recognizing immune dysregulation as a sequela of cirrhosis. Furthermore, we address the role of screening, prevention, and early treatment of infections in cirrhosis in improving patient outcomes in transplant and nontransplant settings.
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Affiliation(s)
- Thomas H Tranah
- Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK.,Institute of Liver Studies, King's College Hospital National Health Service Foundation Trust, London, UK
| | - Victoria T Kronsten
- Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK.,Institute of Liver Studies, King's College Hospital National Health Service Foundation Trust, London, UK
| | - Debbie L Shawcross
- Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK.,Institute of Liver Studies, King's College Hospital National Health Service Foundation Trust, London, UK
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13
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Jindal A, Jagdish RK, Kumar A. Hepatic Regeneration in Cirrhosis. J Clin Exp Hepatol 2022; 12:603-616. [PMID: 35535091 PMCID: PMC9077225 DOI: 10.1016/j.jceh.2021.08.029] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 08/31/2021] [Indexed: 01/03/2023] Open
Abstract
End-stage liver disease is characterized by massive hepatocyte death resulting in clinical decompensation and organ failures. Clinical consequences in cirrhosis are the results of the loss of functional hepatocytes and excessive scarring. The only curative therapy in advanced cirrhosis is orthotropic liver transplantation, but the clinical demand outweighs the availability of acceptable donor organs. Moreover, this also necessitates lifelong immunosuppression and carries associated risks. The liver has a huge capability for regeneration. Self-replication of quiescent differentiated hepatocytes and cholangiocytes occurs in patients with acute liver injury. Due to limited hepatocyte self-renewal capacity in advanced cirrhosis, great interest has therefore been shown in characterizing the possible role of hepatic progenitor cells and bone marrow-derived stem cells to therapeutically aid this process. Transplantation of cells from various sources that can be properly differentiated into functional liver cells or use of growth factors for ex-vivo expansion of progenitor cells is needed at utmost priority. Multiple researches over the last two decades have aided researchers in refining proliferation, differentiation, and storage techniques and understand the functionality of these cells for use in clinical practice. However, these cell-based therapies are still experimental and have to be used in trial settings.
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Key Words
- Ang2, angiopoietin 2
- BM, Bone marrow
- BM-MNCs, bone marrow mononuclear cells
- BMSC, bone marrow stem cells
- DAMPs, Damage associated molecular patterns
- EPCs, endothelial progenitor cells
- ESRP2, epithelial splicing regulatory protein 2
- GCSF
- HGF, hepatocyte growth factor
- HPC, Hepatocyte progenitor cells
- HSCs, hematopoietic stem cells
- Hh, Hedgehog
- HybHP, hybrid periportal hepatocytes
- MMP, matrix metalloprotease
- MSCs, mesenchymal stromal cells
- OLT, Orthotropic liver transplantation
- PAMPs, Pathogen associated molecular patterns
- SAH, severe alcoholic hepatitis
- SDF1, stromal-derived factor 1
- TNFSF12, tumor necrosis factor ligand superfamily member 12
- Terthigh, high Telomerase reverse transcriptase
- [Hnf4a], Hepatocyte Nuclear Factor 4 Alpha
- [Mfsd2a], Major Facilitator Superfamily Domain containing 2A
- acute liver failure
- chronic liver diseases
- hepatocyte transplant
- liver regeneration
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Affiliation(s)
- Ankur Jindal
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi 110070, India
| | | | - Anupam Kumar
- Department of Research, Institute of Liver and Biliary Sciences, New Delhi 110070, India
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14
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Lamatsch S, Sittner R, Tacke F, Engelmann C. Novel drug discovery strategies for the treatment of decompensated cirrhosis. Expert Opin Drug Discov 2021; 17:273-282. [PMID: 34971342 DOI: 10.1080/17460441.2022.2020755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
INTRODUCTION Disease progression in cirrhosis leads to decompensation and acute-on-chronic liver failure (ACLF), which is characterized by organ failure and high mortality. Portal hypertension and cardiovascular dysfunction trigger the development of cirrhosis-related complications whilst tissue injury and cellular metabolic dysfunction lead to organ failure. System inflammation is the overarching mechanism mediating both the transition from compensation to decompensation as well as progression to ACLF. Treatment of precipitating events and intensive organ support is the only established therapeutic strategies. Liver transplantationrepresents the only curative therapy but contraindications and organ scarcity limit its availability to only a minority of patients with end-stage liver disease. Therefore, the discovery and development of novel interventions modifying the disease course and improving patients' outcome are of utmost importance. AREAS COVERED This review highlights and discusses therapeutic novelties in the field of end-stage liver disease. EXPERT OPINION Despite decades of research, there are still no established therapies to improve the devastating prognosis of patients with end-stage liver disease. The clinical heterogeneity and complex pathogenesis will put high demands on drug discovery. Combinatorial therapies tailored to the patients' individual pattern of pathomechanisms may be the most efficient way to modify disease course.
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Affiliation(s)
- Sven Lamatsch
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
| | - Richard Sittner
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
| | - Cornelius Engelmann
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany.,Berlin Institute of Health at Charité (BIH) - BIH Biomedical Innovation Academy, Berlin, Germany.,Institute for Liver and Digestive Health, University College London, London, UK
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15
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Zaccherini G, Tufoni M, Bernardi M, Caraceni P. Prevention of Cirrhosis Complications: Looking for Potential Disease Modifying Agents. J Clin Med 2021; 10:4590. [PMID: 34640608 PMCID: PMC8509683 DOI: 10.3390/jcm10194590] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 09/29/2021] [Accepted: 10/04/2021] [Indexed: 02/07/2023] Open
Abstract
The current therapeutic strategies for the management of patients with cirrhosis rely on the prevention or treatment of specific complications. The removal of the causative agents (i.e., viruses or alcohol) prevents decompensation in the vast majority of patients with compensated cirrhosis. In contrast, even when etiological treatment has been effective, a significant proportion of patients with decompensated cirrhosis remains at risk of further disease progression. Therefore, therapies targeting specific key points in the complex pathophysiological cascade of decompensated cirrhosis could represent a new approach for the management of these severely ill patients. Some of the interventions currently employed for treating or preventing specific complications of cirrhosis or used in other diseases (i.e., poorly absorbable oral antibiotics, statins, albumin) have been proposed as potential disease-modifying agents in cirrhosis (DMAC) since clinical studies have shown their capacity of improving survival. Additional multicenter, large randomized clinical trials are awaited to confirm these promising results. Finally, new drugs able to antagonize key pathophysiological mechanisms are under pre-clinical development or at the initial stages of clinical assessment.
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Affiliation(s)
- Giacomo Zaccherini
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy; (G.Z.); (M.B.)
| | - Manuel Tufoni
- IRCCS AOU di Bologna—Policlinico di S. Orsola, 40138 Bologna, Italy;
| | - Mauro Bernardi
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy; (G.Z.); (M.B.)
| | - Paolo Caraceni
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy; (G.Z.); (M.B.)
- IRCCS AOU di Bologna—Policlinico di S. Orsola, 40138 Bologna, Italy;
- Center for Biomedical Applied Research, University of Bologna, 40138 Bologna, Italy
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16
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Abstract
Alcohol-associated hepatitis is associated with poor outcomes, especially when severe. Despite extensive study with a plethora of potential therapeutic agents, treatment options remain limited, with the current standard of therapy being corticosteroids. Granulocyte colony-stimulating factor is an alternate agent that seems promising, although further study in a more heterogenous patient population is needed before implementation. Adjuncts to therapy that are often overlooked are alcohol abstinence and adequate optimization of nutrition to improve outcomes. In select patients, early liver transplantation may be an option or enrollment in clinical trials.
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Affiliation(s)
- Haripriya Maddur
- Department of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, 676 North Street Clair, Suite 1900, Chicago, IL 60611, USA.
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17
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Engelmann C, Martino VD, Kerbert AJC, Weil-Verhoeven D, Aehling NF, Herber A, Thévenot T, Berg T. The Current Status of Granulocyte-Colony Stimulating Factor to Treat Acute-on-Chronic Liver Failure. Semin Liver Dis 2021; 41:298-307. [PMID: 33992029 DOI: 10.1055/s-0041-1723034] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Patients with acute-on-chronic liver failure (ACLF) have a devastating prognosis and therapeutic options are limited. Granulocyte-colony stimulating factor (G-CSF) mobilizes immune and stem cells and possess immune-modulatory and proregenerative capacities. In this review, we aim to define the current evidence for the treatment with G-CSF in end-stage liver disease. Several smaller clinical trials in patients with different severity grades of end-stage liver disease have shown that G-CSF improves survival and reduces the rate of complications. Adequately powered multicenter European trials could not confirm these beneficial effects. In mouse models of ACLF, G-CSF increased the toll-like receptor (TLR)-mediated inflammatory response which led to an increase in mortality. Adding a TLR4 signaling inhibitor allowed G-CSF to unfold its proregenerative properties in these ACLF models. These data suggest that G-CSF requires a noninflammatory environment to exert its protective properties.
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Affiliation(s)
- Cornelius Engelmann
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom.,Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany.,Division of Hepatology and Gastroenterology, Department of Medical, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Vincent Di Martino
- Service d'Hépatologie et de Soins Intensifs Digestifs, Hôpital Jean Minjoz, 25000 Besançon, France
| | - Annarein J C Kerbert
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom
| | - Delphine Weil-Verhoeven
- Service d'Hépatologie et de Soins Intensifs Digestifs, Hôpital Jean Minjoz, 25000 Besançon, France
| | - Niklas Friedemann Aehling
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
| | - Adam Herber
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
| | - Thierry Thévenot
- Service d'Hépatologie et de Soins Intensifs Digestifs, Hôpital Jean Minjoz, 25000 Besançon, France
| | - Thomas Berg
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
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18
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Holterman A, Nguyen HPA, Nadler E, Vu GH, Mohan P, Vu M, Trinh TT, Bui HTT, Nguyen BT, Quynh AT, Pham HD. Granulocyte-colony stimulating factor GCSF mobilizes hematopoietic stem cells in Kasai patients with biliary atresia in a phase 1 study and improves short term outcome. J Pediatr Surg 2021; 56:1179-1185. [PMID: 33965236 DOI: 10.1016/j.jpedsurg.2021.03.038] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 03/12/2021] [Indexed: 02/07/2023]
Abstract
AIMS In RCT of adults with decompensated cirrhosis, GCSF mobilizes hematopoietic stem cells HSC and improves short-term outcome. An FDA-IND for sequential Kasai-GCSF treatment in biliary atresia BA was approved. This phase 1 study examines GCSF safety in Kasai subjects. Preliminary short-term outcome was evaluated. METHODS GCSF (Neupogen) at 5 or 10 μg/kg (n = 3/group) was given in 3 daily doses starting on day 3 of Kasai surgery (NCT03395028). Serum CD34+ HSC cell counts, and 1-month of GCSF-related adverse events were monitored. The 6-months Phase 1 clinical outcome was compared against 10 subsequent post Phase 1 Kasai patients who did not receive GCSF. RESULTS With GCSF, WBC and platelet count transiently increased, LFT and serum creatinine remained stable. Reversible splenic enlargement (by 8.5-20%) occurred in 5/6 subjects. HSC count increased 12-fold and 17.5-fold for the 5 μg/kg and10 ug/kg dose respectively; with respective median total bilirubin levels for GCSF vs no-GCSF groups of 55 vs 91 μM at 1 month, p = 0.05; 15 vs 37 μM at 3 months, p = 0.24); and the 6-months cholangitis frequency of 40% vs 90%, p = 0.077. CONCLUSIONS GCSF safely mobilizes HSC in Kasai infants and may improve short-term biliary drainage and cholangitis. Phase 2 efficacy outcome of GCSF adjunct therapy for sequential Kasai and GCSF is pending.
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Affiliation(s)
- AiXuan Holterman
- Department of Surgery and Pediatrics, University of Illinois College of Medicine, Chicago, IL, United States.
| | | | - Evan Nadler
- Children's National Hospital, Washington, D.C, United States
| | - Giap H Vu
- University of Rochester School of Medicine and Dentistry, Rochester, NY, United States
| | - Parvathi Mohan
- Children's National Hospital, Washington, D.C, United States
| | - Megan Vu
- Baylor College of Medicine Department of Surgery, Houston, TX, United States
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19
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Caraceni P, Abraldes JG, Ginès P, Newsome PN, Sarin SK. The search for disease-modifying agents in decompensated cirrhosis: From drug repurposing to drug discovery. J Hepatol 2021; 75 Suppl 1:S118-S134. [PMID: 34039483 DOI: 10.1016/j.jhep.2021.01.024] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 01/14/2021] [Accepted: 01/15/2021] [Indexed: 02/06/2023]
Abstract
Patients with decompensated cirrhosis are currently managed through targeted strategies aimed at preventing or treating specific complications. In contrast, a disease-modifying agent should, by definition, be aimed at globally addressing 'decompensated cirrhosis'. To be defined as a disease-modifying agent in decompensated cirrhosis, interventions need to demonstrate an unequivocal benefit on the course of disease in well-designed and adequately powered randomised clinical trials with hard endpoints (i.e. patient survival). These trials also need to define the target population, dosage and timing of administration, factors guiding treatment, temporary or permanent stopping rules, transferability to daily clinical practice, cost-effectiveness, and global treatment access. By eliminating the underlying cause of cirrhosis, aetiologic treatments can still influence the course of decompensated disease by halting or slowing down disease progression or even inducing reversion to the compensated state. In contrast, there remains an unmet clinical need for disease-modifying agents which can antagonise key pathophysiological mechanisms of decompensated cirrhosis, such as portal hypertension, gut translocation, circulatory dysfunction, systemic inflammation, and immunological dysfunction. However, in the last few years, the repurposing of "old drugs" that have already been prescribed for more limited indications in hepatology or for other diseases has provided a few candidates, including human albumin, statins, and poorly absorbable oral antibiotics, which are under further evaluation in large-scale randomised clinical trials. New disease-modifying agents are also expected to be identified in the next decade through the systematic repurposing of existing drugs and the development of novel molecules which are currently undergoing pre-clinical or early clinical testing.
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Affiliation(s)
- Paolo Caraceni
- Division of Medical Semeiotics, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy; Department of Medical and Surgical Sciences and Center for Biomedical Applied Research, Alma Mater Studiorum University of Bologna, Italy.
| | - Juan G Abraldes
- Liver Unit, Division of Gastroenterology, University of Alberta, Canada
| | - Pere Ginès
- Hospital Clinic of Barcelona, University of Barcelona, IDIBAPS, CIBEReHD, Barcelona, Catalonia, Spain
| | - Phil N Newsome
- National Institute for Health Research Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, UK; Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, UK; Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Shiv K Sarin
- Hepatology, Institute of Liver and Biliary Sciences (ILBS), New Delhi, India
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20
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Knooihuizen SAI, Alexander NJ, Hopke A, Barros N, Viens A, Scherer A, Atallah NJ, Dagher Z, Irimia D, Chung RT, Mansour MK. Loss of Coordinated Neutrophil Responses to the Human Fungal Pathogen, Candida albicans, in Patients With Cirrhosis. Hepatol Commun 2021; 5:502-515. [PMID: 33681682 PMCID: PMC7917271 DOI: 10.1002/hep4.1645] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 10/02/2020] [Accepted: 10/26/2020] [Indexed: 12/31/2022] Open
Abstract
Neutrophils are the most abundant white blood cell in the body and are key participants in the defense against fungal infections. Fungal infections occur often in patients with cirrhosis and are associated with increased 30-day and 90-day mortality. Previous studies have shown that specific neutrophil functions are abnormal in patients with cirrhosis, although the extent of neutrophil dysfunction is not well understood. We tested the ability of neutrophils from 21 hospitalized patients with cirrhosis and 23 healthy control patients to kill Candida albicans, a common fungal pathogen in patients with cirrhosis. Using an assay, we also measured the ability of neutrophils to coordinate multicellular, synchronized control of C. albicans hyphae through a process known as swarming. We found that neutrophils from patients with cirrhosis have significantly decreased fungicidal capacity compared with healthy control neutrophils (53% vs. 74%, P < 0.0001) and diminished ability to control hyphal growth normalized as a ratio to healthy control (0.22 vs. 0.65, P < 0.0001). Moreover, serum from patients with cirrhosis decreases the ability of healthy control neutrophils to kill C. albicans (from 60% to 41%, P < 0.003). Circulating concentration of the inflammatory cytokines tumor necrosis factor α, interleukin-6, and interleukin-8 were found to be significantly elevated in patients with cirrhosis compared to healthy controls. Following pretreatment with granulocyte-colony stimulating factor and granulocyte-macrophage colony-stimulating factor, neutrophil function was restored to almost that of healthy controls. Conclusion: Our data establish profound neutrophil dysfunction against, and altered swarming to, C. albicans in patients with cirrhosis. This dysfunction can be partially reversed with cytokine augmentation ex vivo.
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Affiliation(s)
- Sally A I Knooihuizen
- Department of MedicineMassachusetts General HospitalBostonMAUSA.,Harvard Medical SchoolBostonMAUSA
| | | | - Alex Hopke
- Harvard Medical SchoolBostonMAUSA.,Department of SurgeryCenter for Engineering in MedicineMassachusetts General HospitalBostonMAUSA.,Shriners Burns HospitalBostonMAUSA
| | - Nicolas Barros
- Department of MedicineMassachusetts General HospitalBostonMAUSA.,Harvard Medical SchoolBostonMAUSA.,Division of Infectious DiseasesMassachusetts General HospitalBostonMAUSA
| | - Adam Viens
- Division of Infectious DiseasesMassachusetts General HospitalBostonMAUSA
| | - Allison Scherer
- Department of MedicineMassachusetts General HospitalBostonMAUSA.,Harvard Medical SchoolBostonMAUSA.,Division of Infectious DiseasesMassachusetts General HospitalBostonMAUSA
| | - Natalie J Atallah
- Department of MedicineMassachusetts General HospitalBostonMAUSA.,Harvard Medical SchoolBostonMAUSA.,Division of Infectious DiseasesMassachusetts General HospitalBostonMAUSA
| | - Zeina Dagher
- Department of MedicineMassachusetts General HospitalBostonMAUSA.,Harvard Medical SchoolBostonMAUSA.,Division of Infectious DiseasesMassachusetts General HospitalBostonMAUSA
| | - Daniel Irimia
- Harvard Medical SchoolBostonMAUSA.,Department of SurgeryCenter for Engineering in MedicineMassachusetts General HospitalBostonMAUSA.,Shriners Burns HospitalBostonMAUSA
| | - Raymond T Chung
- Department of MedicineMassachusetts General HospitalBostonMAUSA.,Harvard Medical SchoolBostonMAUSA.,Liver Center and Gastrointestinal DivisionMassachusetts General HospitalBostonMAUSA
| | - Michael K Mansour
- Department of MedicineMassachusetts General HospitalBostonMAUSA.,Harvard Medical SchoolBostonMAUSA.,Division of Infectious DiseasesMassachusetts General HospitalBostonMAUSA
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Variceal Bleed and Portal Hypertensive Gastropathy in a Noncirrhotic Patient with Isolated Splenomegaly. Case Reports Hepatol 2021; 2020:8893713. [PMID: 33381333 PMCID: PMC7762672 DOI: 10.1155/2020/8893713] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Revised: 11/06/2020] [Accepted: 12/04/2020] [Indexed: 12/12/2022] Open
Abstract
Portal hypertension caused by cirrhosis is the most common etiology of esophageal varices. However, abnormalities of the splenoportal axis in the absence of liver disease may also cause portal hypertension resulting in varices. We report a rare case of esophageal variceal bleed in a noncirrhotic patient with isolated splenomegaly secondary to chronic granulocyte colony stimulating factor (G-CSF) therapy. The patient is a 26-year-old male with Cohen syndrome who required long-term G-CSF treatment for chronic neutropenia. He presented with large volume hematemesis and pancytopenia in the setting of known splenomegaly with no evidence of cirrhosis. An urgent EGD revealed active variceal bleeding and portal hypertensive gastropathy. The patient was appropriately resuscitated and underwent a successful transjugular intrahepatic portosystemic shunt and CT-guided coil placement for the bleeding varices. We are the first to report variceal bleed as a complication of long-term G-CSF use, a life-threatening consequence that requires urgent intervention.
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Philips CA, Augustine P. Still 'dwelling in the possibility' - critical update on stem cell therapy for acute on chronic liver failure. World J Stem Cells 2020; 12:1124-1132. [PMID: 33178396 PMCID: PMC7596449 DOI: 10.4252/wjsc.v12.i10.1124] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 08/29/2020] [Accepted: 09/22/2020] [Indexed: 02/06/2023] Open
Abstract
Stem cells therapy could improve survival in patients with liver failure. Studies on stem cell therapy and related growth factors in decompensated cirrhosis has been on the forefront but has shown heterogenous results. Recent high-quality studies have shown a lack of efficacy and safety. Patients with acute-on-chronic liver failure (ACLF) are a unique group with high mortality in the short-term associated with rapid onset extrahepatic organ failures. In these patients, there is an urgent need to identify treatments that can improve liver cell function and mass, prevent sepsis/organ failure, ameliorate systemic inflammation, and increase transplant-free survival. Stem cells are a novel treatment in ACLF but with unclear efficacy and safety. In this narrative review, we discuss the basics of liver regeneration in patients with ACLF and update current clinical status of stem cell use in patients with ACLF for improving our understanding of future directions.
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Affiliation(s)
- Cyriac Abby Philips
- The Liver Unit and Monarch Liver Lab, Cochin Gastroenterology Group, Ernakulam Medical Center, Kochi 682025, Kerala, India.
| | - Philip Augustine
- Department of Gastroenterology and Advanced GI Endoscopy, Cochin Gastroenterology Group, Ernakulam Medical Center, Kochi 682025, Kerala, India
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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.
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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
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Philips CA, Augustine P, Ahamed R, Rajesh S, George T, Valiathan GC, John SK. Role of Granulocyte Colony-stimulating Factor Therapy in Cirrhosis, 'Inside Any Deep Asking Is the Answering'. J Clin Transl Hepatol 2019; 7:371-383. [PMID: 31915607 PMCID: PMC6943215 DOI: 10.14218/jcth.2019.00034] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Revised: 09/20/2019] [Accepted: 10/05/2019] [Indexed: 12/13/2022] Open
Abstract
Liver cirrhosis progresses through multiple clinical stages which culminate in either death or liver transplantation. Availability of organs, timely listing and prompt receipt of donor-livers pose difficulties in improving transplant-listed and transplant outcomes. In this regard, regenerative therapies, particularly with granulocyte colony-stimulating factor (GCSF), has become a lucrative option for improving transplant-free survival. However, the literature is confusing with regards to patient selection and real outcomes. In this exhaustive review, we describe the basics of liver fibrosis and cirrhosis through novel insights from a therapeutic point of view, discuss preclinical studies on GCSF in advanced liver disease to improve on clinical utility, shed light on the pertinent literature of GCSF in advanced cirrhosis, and provide astute inputs on growth factor therapy in decompensated cirrhosis.
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Affiliation(s)
- Cyriac Abby Philips
- The Liver Unit and Monarch Liver Lab, Cochin Gastroenterology Group, Ernakulam Medical Centre, Kochi, Kerala, India
| | - Philip Augustine
- Department of Gastroenterology, Cochin Gastroenterology Group, Ernakulam Medical Centre, Kochi, Kerala, India
| | - Rizwan Ahamed
- Department of Gastroenterology, Cochin Gastroenterology Group, Ernakulam Medical Centre, Kochi, Kerala, India
| | - Sasidharan Rajesh
- Interventional Radiology, Hepatobiliary Division, Cochin Gastroenterology Group, Ernakulam Medical Centre, Kochi, Kerala, India
| | - Tom George
- Interventional Radiology, Hepatobiliary Division, Cochin Gastroenterology Group, Ernakulam Medical Centre, Kochi, Kerala, India
| | - Gopakumar C. Valiathan
- Department of Hepatobiliary and Transplant Surgery, Cochin Gastroenterology Group, Ernakulam Medical Centre, Kochi, Kerala, India
| | - Solomon K. John
- Department of Hepatobiliary and Transplant Surgery, Cochin Gastroenterology Group, Ernakulam Medical Centre, Kochi, Kerala, India
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