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Wang D, Wang X, Mu J, Kuang Z, Zhang J, Lu X, Wang X, Lin F. Prognostic indicators and outcome in patients with acute liver failure, sepsis and with and without shock: a retrospective cohort study. Ann Med 2025; 57:2438833. [PMID: 39661398 PMCID: PMC11636143 DOI: 10.1080/07853890.2024.2438833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 09/14/2024] [Accepted: 11/16/2024] [Indexed: 12/12/2024] Open
Abstract
BACKGROUND Sepsis or septic shock is associated with severe morbidity and mortality in patients with acute liver failure (ALF). This study aimed to explore the potential prognostic value of common clinical indicators in patients with ALF, sepsis and with and without shock. PATIENTS AND METHODS The clinical, laboratory, and microbiological data of patients with ALF and sepsis or septic shock who were admitted to the intensive care unit from January 2014 to December 2019 were collected retrospectively. Clinical indicators, outcomes and the associations among them were analyzed and defined. RESULTS Of 150 patients, 64 (42.7%) and 86 (57.3%) were divided into the shock and non-shock groups, respectively. Plasma procalcitonin (PCT), C-reactive protein (CRP), and creatinine (Cre) levels, aspartate aminotransferase to alanine aminotransferase (AST/ALT) ratio, and prothrombin time (PT) in the shock group and plasma PCT and Cre levels in the non-shock group were positively correlated with 30-day, 60-day, and 90-day mortality. Furthermore, plasma ALT levels were positively correlated with 60-day and 90-day mortality, and PTA showed negative correlations with 30-day, 60-day, and 90-day mortality in both groups. Multivariate logistic regression analysis revealed that the combination of plasma PCT and CRP levels, the combination of plasma PCT and ALT levels, and the combination of plasma ALT levels and PTA were found to be associated with 90-day mortality. CONCLUSIONS Clinical indicators, especially plasma PCT, CRP, and ALT levels, PTA, and their combinations were associated with poor outcomes in patients with ALF, sepsis and with and without shock.
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Affiliation(s)
- Dan Wang
- Department of Critical Care Medicine, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Xin Wang
- Department of Critical Care Medicine, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Jinsong Mu
- Department of Critical Care Medicine, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Zhidan Kuang
- Department of Critical Care Medicine, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Junchang Zhang
- Department of Critical Care Medicine, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Xianghong Lu
- Department of Critical Care Medicine, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Xuemei Wang
- Department of Critical Care Medicine, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Fang Lin
- Department of Critical Care Medicine, The Fifth Medical Center of PLA General Hospital, Beijing, China
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2
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Impey ORE, Baker JD, Smyth RS, Potts SG. Death after psychiatric contraindications to urgent liver transplant for paracetamol overdose. World J Transplant 2025; 15:101865. [DOI: 10.5500/wjt.v15.i3.101865] [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: 09/28/2024] [Revised: 02/20/2025] [Accepted: 02/25/2025] [Indexed: 04/18/2025] Open
Abstract
BACKGROUND Paracetamol overdose (POD) is the most common cause of acute hepatic failure (AHF) in the United Kingdom. Without urgent orthotopic liver transplant (OLT), mortality is high. Psychiatric assessment for transplant is time-pressured and often undertaken by psychiatrists without transplant experience. Assessors may identify absolute psychiatric contraindications (APCIs) precluding transplant in otherwise medically suitable patients. It is unknown how often this occurs. The combination of high but unknown mortality, time pressure, and relative inexperience is likely to provoke anxiety in assessors. This study hypothesised that the proportion of POD patients assessed for OLT who die because psychiatric contraindications preclude transplant would be small but not negligible.
AIM To determine the proportion of patients with paracetamol-induced AHF, for whom psychiatric contraindications preclude transplantation, and the consequent mortality.
METHODS This is an 18-year single-centre retrospective cohort study based in a national liver transplant centre. 524 participants were identified from a departmental database and included if they had AHF from suspected POD and received a psychiatric assessment for OLT. For those who died before discharge, records were reviewed for medical and psychiatric contraindications to transplant, alongside age, sex, and primary psychiatric diagnosis. We calculated the proportion of patients assessed for whom APCIs precluded transplant, resulting in death.
RESULTS Among 524 patients undergoing psychiatric assessment for OLT, there were 102 in-episode deaths (19.5%). APCIs were identified in 46 patients who were otherwise medically suitable for transplant and went on to die. This statistic represents 8.8% of the number of persons evaluated and 45% of the number of deaths. Within this subgroup, 27 (59%) were female, with a mean age of 44.6 years (ranging from 19-72 years). The most common primary psychiatric diagnosis was alcohol dependence syndrome, which accounted for 67% (n = 31).
CONCLUSION 8.8% of medically suitable patients with AHF following POD died with APCIs to transplant. This indicates a need for ongoing assessor training and support, and (inter) national comparisons of practice.
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Affiliation(s)
- Olivia R E Impey
- Hammersmith and Fulham Mental Health Unit, West London NHS Trust, London W6 8LN United Kingdom
| | - Jennifer D Baker
- Department of Psychological Medicine, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, United Kingdom
| | - Roger S Smyth
- Department of Psychological Medicine, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, United Kingdom
| | - Stephen G Potts
- Department of Psychological Medicine, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, United Kingdom
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3
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Haselwanter P, Fairfield S, Riedl-Wewalka M, Schmid M, Stättermayer AF, Reiberger T, Trauner M, Zauner C, Schneeweiss-Gleixner M. Acute liver failure in patients admitted to the intensive care unit-a Viennese retrospective single-center analysis. Wien Klin Wochenschr 2025:10.1007/s00508-025-02539-1. [PMID: 40419847 DOI: 10.1007/s00508-025-02539-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Accepted: 04/05/2025] [Indexed: 05/28/2025]
Abstract
BACKGROUND Acute liver failure (ALF) is characterized by a rapid deterioration of liver function and a high mortality without transplantation depending on etiology and onset. Immediate transfer to a dedicated intensive care unit (ICU) and evaluation for high-urgency liver transplantation (HU-LTx) is recommended to maximize chances of survival. Data on ALF epidemiology are limited, particularly for Central Europe. METHODS This retrospective single-center study included all ALF patients admitted to the ICU of the Department of Gastroenterology and Hepatology at the Vienna General Hospital between 2012 and 2024. RESULTS Overall, 31 patients (median age of 44 [interquartile range, IQR 32-56] years, 20 [65%] female) were included. The primary causes of ALF were viral infections (n = 8; 26%), autoimmune hepatitis (n = 5; 16%), drug-induced liver injury (DILI; n = 3; 10%), and Wilson's disease (n = 4; 13%), while in 8 patients (26%) no cause was identified. Median length of ICU stay was 12 (IQR 4-21) days, with mean sequential organ failure assessment (SOFA) and simplified acute physiology score II (SAPS II) scores of 10.55 ± 4.56 and 40.97 ± 14.84. Overall ICU survival was 61% (n = 19). Non-HU-LTx patients (n = 18) had an ICU survival of 44%. HU-LTx was performed in 13 patients (42%), with 12 patients (92%) surviving 28 days. The 6‑month overall survival of HU-LTx patients was 85%. CONCLUSION The diverse causes of ALF in Central Europe include most commonly viral infections, autoimmune hepatitis, and DILI. HU-LTx was required and performed in almost half of patients and was associated with favorable survival rates, underscoring the importance of ICU management and early transfer to liver transplantation centers in the management of ALF.
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Affiliation(s)
- Patrick Haselwanter
- Department of Medicine III, Division of Gastroenterology and Hepatology, Intensive Care Unit 13H1, Medical University of Vienna, Vienna, Austria
| | - Seanna Fairfield
- Department of Medicine III, Division of Gastroenterology and Hepatology, Intensive Care Unit 13H1, Medical University of Vienna, Vienna, Austria
| | - Marlene Riedl-Wewalka
- Department of Medicine III, Division of Gastroenterology and Hepatology, Intensive Care Unit 13H1, Medical University of Vienna, Vienna, Austria
| | - Monika Schmid
- Department of Medicine III, Division of Gastroenterology and Hepatology, Intensive Care Unit 13H1, Medical University of Vienna, Vienna, Austria
| | - Albert Friedrich Stättermayer
- Department of Medicine III, Division of Gastroenterology and Hepatology, Intensive Care Unit 13H1, Medical University of Vienna, Vienna, Austria
| | - Thomas Reiberger
- Department of Medicine III, Division of Gastroenterology and Hepatology, Intensive Care Unit 13H1, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Department of Medicine III, Division of Gastroenterology and Hepatology, Intensive Care Unit 13H1, Medical University of Vienna, Vienna, Austria
| | - Christian Zauner
- Department of Medicine III, Division of Gastroenterology and Hepatology, Intensive Care Unit 13H1, Medical University of Vienna, Vienna, Austria
| | - Mathias Schneeweiss-Gleixner
- Department of Medicine III, Division of Gastroenterology and Hepatology, Intensive Care Unit 13H1, Medical University of Vienna, Vienna, Austria.
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4
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Xie L, Huang L, Fang X, Zha J, Su Y. Assessing Liver Function in Rat Models of Acute Liver Failure Using Single-Photon Emission Computed Tomography and Cytokine Levels. PLoS One 2025; 20:e0323531. [PMID: 40333907 PMCID: PMC12057927 DOI: 10.1371/journal.pone.0323531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 04/10/2025] [Indexed: 05/09/2025] Open
Abstract
OBJECTIVE To evaluate liver function using dynamic hepatobiliary single-photon emission computed tomography (SPECT) in different rat models of acute liver failure. METHODS Twenty-four 6-8-week-old male Sprague-Dawley rats (weight 190-200 g) were evenly divided into four groups. Acute liver failure was induced by intraperitoneal injection of D-galactosamine (D-GalN, 600 mg/kg) and lipopolysaccharide (LPS, 10 µg/kg), common bile duct ligation surgery, and removing 70% of the liver mass. The fourth group served as the control without intervention. The time-activity curves for the liver and heart were generated from dynamic SPECT scans with 99mTc-ethylene hepatobiliary iminodiacetic acid (EHIDA). Image-derived functional parameters (5-minute heart/liver index [HLI5] and 15-minute receptor index [LHL15]) were calculated. Furthermore, correlations of image-derived parameters with serum interleukin-6 (IL-6) levels, liver aspartate aminotransferase (AST) and alanine transaminase (ALT) levels, and liver mRNA expression levels of tumor necrosis factor-α (TNF-α) and chemokine ligand-10 (CXCL-10) were analyzed. RESULTS All animals in the experimental groups exhibited varying degrees of liver damage. The SPECT images and indexes (HLI5 and LHL15) of the experimental groups significantly differed from those of the control group (P < 0.05). In the experimental groups, serum IL-6 levels and liver mRNA levels of TNF-α and CXCL-10 were significantly higher, while liver AST and ALT levels were significantly lower than those in the control group (P < 0.05). CONCLUSION Using SPECT with 99mTc-EHIDA, along with the calculated indexes and levels of various cytokines, presents a dependable method for assessing liver function.
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Affiliation(s)
- Long Xie
- Department of Nuclear Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Liqun Huang
- Department of Nuclear Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Xueting Fang
- Department of Pathology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Jinshun Zha
- Department of Nuclear Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Yingrui Su
- Department of Nuclear Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
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5
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Larsen FS, Saliba F. Liver support systems and liver transplantation in acute liver failure. Liver Int 2025; 45:e15633. [PMID: 37288706 PMCID: PMC11815598 DOI: 10.1111/liv.15633] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 05/15/2023] [Accepted: 05/24/2023] [Indexed: 06/09/2023]
Abstract
Acute liver failure (ALF) results in a multitude of complications that result in multi-organ failure. This review focuses on the pathophysiological processes and how to manage with these with artificial liver support and liver transplantation (LT). The pathophysiological sequence of events behind clinical deterioration in ALF comes down to two profound consequences of the failing liver. The first is the development of hyperammonemia, as the liver can no longer synthesize urea. The result is that the splanchnic system instead of removing ammonia becomes an ammonia-producing organ system that causes hepatic encephalopathy (HE) and cerebral oedema. The second complication is caused by the necrotic liver cells that release large molecules that originate from degrading proteins, that is damage associated molecular patterns (DAMPs) which causes inflammatory activation of intrahepatic macrophages and an overflow of DAMPs molecules into the systemic circulation resulting in a clinical picture that resembles septic shock. In this context the combined use of continuous renal replacement therapy (CRRT) and plasma exchange are rational and simple ways to remove ammonia and DAMPS molecules. This combination improve survival for ALF patients deemed not appropriate for LT, despite poor prognostic criteria, but also ensure a better stability of vital organs while awaiting LT. The combination of CRRT with albumin dialysis tends to have a similar effect. Currently, the selection criteria for LT for non-paracetamol cases appear robust while the criteria for paracetamol-intoxicated patients have become more unreliable and now consist of more dynamic prognostic systems. For patients that need LT for survival, a tremendous improvement in the post-LT results has been achieved during the last decade with a survival that now reach merely 90% which is mirroring the results seen after LT for chronic liver disease.
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Affiliation(s)
- Fin S. Larsen
- Department of Intestinal Failure and Liver DiseasesRigshospitalet, University Hospital CopenhagenCopenhagenDenmark
| | - Faouzi Saliba
- AP‐HP Hôpital Paul Brousse, Hepato‐Biliary Center and Liver Transplant ICUUniversity Paris Saclay, INSERM unit N°1193VillejuifFrance
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6
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Ballester MP, Elshabrawi A, Jalan R. Extracorporeal liver support and liver transplantation for acute-on-chronic liver failure. Liver Int 2025; 45:e15647. [PMID: 37312660 PMCID: PMC11815617 DOI: 10.1111/liv.15647] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 05/31/2023] [Accepted: 06/04/2023] [Indexed: 06/15/2023]
Abstract
Acute-on-chronic liver failure (ACLF) is defined by acute decompensation, organ failure and a high risk of short-term mortality. This condition is characterized by an overwhelming systemic inflammatory response. Despite treating the precipitating event, intensive monitoring and organ support, clinical deterioration can occur with very poor outcomes. During the last decades, several extracorporeal liver support systems have been developed to try to reduce ongoing liver injury and provide an improved environment for the liver to regenerate or as a bridging therapy until liver transplantation. Several clinical trials have been performed to evaluate the clinical efficacy of extracorporeal liver support systems, but no clear impact on survival has been proven. DIALIVE is a novel extracorporeal liver support device that has been built to specifically address the pathophysiological derangements responsible for the development of ACLF by replacing dysfunctional albumin and removing pathogen and damage-associated molecular patterns (PAMPs and DAMPs). In phase II clinical trial, DIALIVE appears to be safe, and it seems to be associated with a faster time to the resolution of ACLF compared with standard medical treatment. Even in patients with severe ACLF, liver transplantation saves lives and there is clear evidence of transplant benefit. Careful selection of patients is required to attain good results from liver transplantation, but many questions remain unanswered. In this review, we describe the current perspectives on the use of extracorporeal liver support and liver transplantation for ACLF patients.
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Affiliation(s)
- Maria Pilar Ballester
- Digestive Disease DepartmentHospital Clínico Universitario de ValenciaValenciaSpain
- INCLIVA Biomedical Research InstituteHospital Clínico Universitario de ValenciaValenciaSpain
| | - Ahmed Elshabrawi
- Liver Failure Group, Institute for Liver & Digestive HealthUniversity College LondonLondonUK
- Endemic Hepatology and Gastroenterology DepartmentMansoura UniversityMansouraEgypt
| | - Rajiv Jalan
- Liver Failure Group, Institute for Liver & Digestive HealthUniversity College LondonLondonUK
- European Foundation for the Study of Chronic Liver Failure (EF Clif)BarcelonaSpain
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7
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Röhlen N, Thimme R. [Acute Liver Failure]. Dtsch Med Wochenschr 2025; 150:371-384. [PMID: 40086863 DOI: 10.1055/a-2301-8259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2025]
Abstract
Acute liver failure (ALF) is a severe, potentially reversible form of liver insufficiency, which is defined by the occurrence of hepatic coagulopathy and hepatic encephalopathy in patients with no previous hepatic disease. Acute liver failure is preceded by severe acute liver injury (ALI) with an increase in transaminases, jaundice, and deterioration in general condition over a period of hours to weeks. Every year 200-500 people develop ALF in Germany, most frequently on the background of toxic liver injury (e.g. drug induced liver injury). Other potential causes include viral infections (e.g. hepatitis A and B), autoimmune hepatitis, Budd-Chiari Syndrome or Wilson's disease. Patients usually present at the stage of acute liver damage. Initial diagnostics should include a detailed medical history, clinical examination, laboratory diagnostics and abdominal sonography. The course of acute liver failure is very difficult to predict, so all patients with severe acute liver damage should be evaluated for transfer to a center. At the latest when hepatic encephalopathy occurs and thus when all the definition criteria of acute liver failure are met, the patient should be transferred to a liver transplant center immediately. While specific medical therapies may be available in the early stages of the disease, depending on the etiology, the focus in advanced stages is on preventing complications and treating associated organ dysfunctions. In progressive cases, liver transplantation is often the only life-saving measure. Overall, the mortality rate in Germany is 47%, and approximately 8% of annual liver transplants in the European Union are performed due to ALF.
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8
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Panackel C, Raja K, Fawas M, Jacob M. Prognostic models in acute liver failure-historic evolution and newer updates "prognostic models in acute liver failure". Best Pract Res Clin Gastroenterol 2024; 73:101957. [PMID: 39709212 DOI: 10.1016/j.bpg.2024.101957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Accepted: 10/22/2024] [Indexed: 12/23/2024]
Abstract
Acute liver failure (ALF) is a rare and dynamic syndrome occurring as a sequela of severe acute liver injury (ALI). Its mortality ranges from 50% to 75% based on the aetiology, patients age and severity of encephalopathy at admission. With improvement in intensive care techniques, transplant-free survival in ALF has improved over time. Timely recognition of patients who are unlikely to survive with medical intervention alone is crucial since these individuals may rapidly develop multiorgan failure and render liver transplantation futile. Various predictive models, biomarkers and AI-based models are currently used in clinical practice, each with its fallacies. The King's College Hospital criteria (KCH) were initially established in 1989 to identify patients with acute liver failure (ALF) caused by paracetamol overdose or other causes who are unlikely to improve with conventional treatment and would benefit from a liver transplant. Since then, various models have been developed and validated worldwide. Most models include age, aetiology of liver disease, encephalopathy grade, and liver injury markers like INR, lactate, factor V level, factor VIII/V ratio and serum bilirubin. But none of the currently available models are dynamic and lack accuracy in predicting transplant free survival. There is an increasing interest in developing prognostic serum biomarkers that when used alone or in combination with clinical models enhance the accuracy of predicting outcomes in ALF. Genomics, transcriptomics, proteomics, and metabolomics as well as machine learning and artificial intelligence (AI) algorithms are areas of interest for developing higher-precision predictive models. Overall, the future of prognostic models in ALF is promising, with ongoing research paving the way for more accurate, personalized, and dynamic risk assessment tools that can potentially save lives in this challenging condition. This article summarizes the history of prognostic models in ALF and future trends.
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Affiliation(s)
| | | | - Mohammed Fawas
- Aster Integrated Liver Care, Aster Medcity, Kochi, India
| | - Mathew Jacob
- Aster Integrated Liver Care, Aster Medcity, Kochi, India
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9
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Ichai P, Samuel D. Liver transplantation in acute liver failure. Best Pract Res Clin Gastroenterol 2024; 73:101968. [PMID: 39709219 DOI: 10.1016/j.bpg.2024.101968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 11/21/2024] [Indexed: 12/23/2024]
Abstract
ABO-compatible Orthotopic Liver Transplantation (OLT) is the standard treatment for patients with acute liver failure (ALF) who meet the criteria for poor prognosis. Contraindications to liver transplantation may be related to the presence of severe medical or psychiatric comorbidities, or to an unstable clinical state incompatible with transplantation. Early mortality predictive scores and factors have been developed to identify futile transplantations that exacerbate organ shortage. However, these scores are not sufficiently reliable to contraindicate transplantation. Auxiliary liver transplantation, two-stage transplantation (total hepatectomy with portal-caval anastomosis followed by delayed orthotopic liver transplantation), ABO-incompatible liver transplantation, living-donor transplantation, and living-auxiliary liver donor transplantation are alternatives to OLT. The selection of appropriate techniques must fulfill specific criteria. ABO-incompatible transplantation remains an exception, even though immunosuppressive strategies have improved prognosis. The overall survival and graft survival rates at 1 and 5 years after liver transplantation for ALF are 79 % and 72 % in Europe, and 84 % and 73 % in the United States, respectively. The survival rate has significantly improved in recent years.
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Affiliation(s)
- Philippe Ichai
- Liver Intensive Care Unit, Centre Hépato-Biliaire, AP-HP, Hôpital Paul-Brousse, Université Paris-Saclay, Inserm research unit 1193, Villejuif, F-94800, France
| | - Didier Samuel
- Liver Intensive Care Unit, Centre Hépato-Biliaire, AP-HP, Hôpital Paul-Brousse, Université Paris-Saclay, Inserm research unit 1193, Villejuif, F-94800, France.
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10
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Gurakar A, Conde Amiel I, Ozturk NB, Artru F, Selzner N, Psoter KJ, Dionne JC, Karvellas C, Rajakumar A, Saner F, Subramanian RM, Sun LY, Dhawan A, Coilly A. An international, multicenter, survey-based analysis of practice and management of acute liver failure. Liver Transpl 2024; 30:1217-1225. [PMID: 38775498 DOI: 10.1097/lvt.0000000000000402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 05/02/2024] [Indexed: 06/30/2024]
Abstract
Acute liver failure (ALF) is an acute liver dysfunction with coagulopathy and HE in a patient with no known liver disease. As ALF is rare and large clinical trials are lacking, the level of evidence regarding its management is low-moderate, favoring heterogeneous clinical practice. In this international multicenter survey study, we aimed to investigate the current practice and management of patients with ALF. An online survey targeting physicians who care for patients with ALF was developed by the International Liver Transplantation Society ALF Special-Interest Group. The survey focused on the management and liver transplantation (LT) practices of ALF. Survey questions were summarized overall and by geographic region. A total of 267 physicians completed the survey, with a survey response rate of 21.36%. Centers from all continents were represented. More than 90% of physicians specialized in either transplant hepatology/surgery or anesthesiology/critical care. Two hundred fifty-two (94.4%) respondents' institutions offered LT. A total of 76.8% of respondents' centers had a dedicated liver-intensive or transplant-intensive care unit ( p < 0.001). The median time to LT was within 48 hours in 12.7% of respondents' centers, 72 hours in 35.6%, 1 week in 37.6%, and more than 1 week in 9.6% ( p < 0.001). Deceased donor liver graft (49.6%) was the most common type of graft offered. For consideration of LT, 84.8% of physicians used King's College Criteria, and 41.6% used Clichy Criteria. Significant differences were observed between Asia, Europe, and North America for offering LT, number of LTs performed, volume of patients with ALF, admission to a dedicated intensive care unit, median time to LT, type of liver graft, monitoring HE and intracranial pressure, management of coagulopathy, and utilization of different criteria for LT. In our study, we observed significant geographic differences in the practice and management of ALF. As ALF is rare, multicenter studies are valuable for identifying global practice.
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Affiliation(s)
- Ahmet Gurakar
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Isabel Conde Amiel
- Department of Medicine, Hepatology and Liver Transplantation Unit, Hospital Universitario y Politécnico La Fe, IIS La Fe, Valencia, Spain
- Ciberehd, Instituto de Salud Carlos III, Madrid, Spain
| | - N Begum Ozturk
- Department of Internal Medicine, Beaumont Hospital, Royal Oak, Michigan, USA
| | - Florent Artru
- Liver Department, Rennes University Hospital, University of Rennes, Inserm U1241 NuMeCan, Rennes, France
| | - Nazia Selzner
- Multi-Organ Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Kevin J Psoter
- Department of Pediatrics, Division of General Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Joanna C Dionne
- Department of Medicine, Department of Health Research Medicine, Evidence and Impact, Divisions of Gastroenterology/Critical Care Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Constantine Karvellas
- Divisions of Hepatology and Critical Care Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Akila Rajakumar
- The Institute of Liver Disease & Transplantation, Dr. Rela Institute & Medical Centre, Bharath Institute of Higher Education & Research, Chennai, Tamil Nadu, India
| | - Fuat Saner
- Organ Transplant Center of Excellence, King Faisal Specialized Hospital & Research Center, Riyadh, Saudi Arabia
- Department of General, Visceral and Transplantation Surgery, University of Duisburg-Essen, Essen, Germany
| | - Ram M Subramanian
- Liver Transplantation & Liver Critical Care Services, Emory University, Atlanta, Georgia, USA
| | - Li-Ying Sun
- Critical Liver Diseases & Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Anil Dhawan
- Department of Pediatrics and Pediatric Liver GI and Nutrition Center and Mowat Labs, King's College Hospital, London, UK
| | - Audrey Coilly
- Paul-Brousse Hospital, Public Hospitals of Paris, FHU Hépatinov, Villejuif, France
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11
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Chaba A, Warrillow SJ, Fisher C, Spano S, Maeda A, Phongphithakchai A, Pattamin N, Hikasa Y, Kitisin N, Warming S, Michel C, Eastwood GM, Bellomo R. Severely Hyperammonemic Acute Liver Failure due to Paracetamol Overdose: The Impact of High-Intensity Continuous Renal Replacement Therapy. Blood Purif 2024; 54:111-121. [PMID: 39561725 DOI: 10.1159/000542556] [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: 07/15/2024] [Accepted: 11/07/2024] [Indexed: 11/21/2024]
Abstract
INTRODUCTION Paracetamol (acetaminophen)-induced acute liver failure (ALF) with severe hyperammonemia (ammonia >100 µmol⋅L-1) is a life-threatening condition. A strategy based on high-intensity continuous renal replacement therapy (CRRT) without early (up to day seven) transplantation may enable clinicians to safely identify which patients can recover and survive and which patients require transplantation. METHODS We conducted a single-center, retrospective cohort study of patients with severely hyperammonemic paracetamol-induced ALF. The primary outcome was early transplant-free survival. RESULTS We studied 84 patients (median age: 38; female sex: 79 [85%]) over a 12-year period (median ammonia level at ICU admission: 153 µmol⋅L-1; median peak aspartate aminotransferase (AST): 10,029 U⋅L-1; median lactate: 5.0 mmol⋅L-1; and median INR: 4.4) and 55 (65%) with King's College criteria for transplantation. Overall, 87% received high-intensity CRRT (92% in 2020-2023). Median CRRT intensity was 54 mL⋅kg-1⋅hr-1 within the first 48 h and increased by 1.8 mL⋅kg-1⋅hr-1 per year during the study period (p = 0.002). Transplant-free survival to day 7 was 86% in 2011-2023 and 96% in 2020-2023. Overall, only 4 patients were transplanted and only 1 (4%) in 2020-2023. On multivariable Cox analysis, factors independently associated with failure to achieve day seven transplant-free survival were higher APACHE III score (HR = 1.05, 95% CI: 1.02-1.08), higher lactate (HR = 1.27, 95% CI: 1.12-1.44), and lower platelet count at ICU admission (HR = 0.85, 95% CI: 0.78-0.93) and the median effluent dose applied within the first 48 h of ICU admission (HR = 0.67, 95% CI: 0.46-0.98). CONCLUSIONS Early transplant-free survival is achievable in most patients with paracetamol-induced ALF and severe hyperammonemia with a treatment based on high-intensity CRRT. Such transplant-free survival increased over time together with increased CRRT dose.
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Affiliation(s)
- Anis Chaba
- Department of Intensive Care, Austin Hospital, Heidelberg, Victoria, Australia,
- Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Victoria, Australia,
| | - Stephen Joseph Warrillow
- Department of Intensive Care, Austin Hospital, Heidelberg, Victoria, Australia
- Department of Critical Care, The University of Melbourne, Melbourne, Victoria, Australia
- Department of Medicine and Surgery, The University of Melbourne, Melbourne, Victoria, Australia
| | - Caleb Fisher
- Department of Intensive Care, Austin Hospital, Heidelberg, Victoria, Australia
- Department of Critical Care, The University of Melbourne, Melbourne, Victoria, Australia
| | - Sofia Spano
- Department of Intensive Care, Austin Hospital, Heidelberg, Victoria, Australia
| | - Akinori Maeda
- Department of Intensive Care, Austin Hospital, Heidelberg, Victoria, Australia
| | | | - Nuttapol Pattamin
- Department of Intensive Care, Austin Hospital, Heidelberg, Victoria, Australia
| | - Yukiko Hikasa
- Department of Intensive Care, Austin Hospital, Heidelberg, Victoria, Australia
| | - Nuanprae Kitisin
- Department of Intensive Care, Austin Hospital, Heidelberg, Victoria, Australia
| | - Scott Warming
- Department of Intensive Care, Austin Hospital, Heidelberg, Victoria, Australia
| | - Claire Michel
- Department of Intensive Care, Peninsula Health, Melbourne, Victoria, Australia
| | - Glenn M Eastwood
- Department of Intensive Care, Austin Hospital, Heidelberg, Victoria, Australia
| | - Rinaldo Bellomo
- Department of Intensive Care, Austin Hospital, Heidelberg, Victoria, Australia
- Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Victoria, Australia
- Department of Critical Care, The University of Melbourne, Melbourne, Victoria, Australia
- Department of Medicine and Surgery, The University of Melbourne, Melbourne, Victoria, Australia
- Data Analytics Research and Evaluation Centre, The University of Melbourne and Austin Hospital, Melbourne, Victoria, Australia
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12
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Amaris NR, Marenco-Flores A, Barba R, Rubio-Cruz D, Medina-Morales E, Goyes D, Saberi B, Patwardhan V, Bonder A. Acute Liver Failure Etiology Determines Long-Term Outcomes in Patients Undergoing Liver Transplantation: An Analysis of the UNOS Database. J Clin Med 2024; 13:6642. [PMID: 39597786 PMCID: PMC11594988 DOI: 10.3390/jcm13226642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 11/01/2024] [Accepted: 11/04/2024] [Indexed: 11/29/2024] Open
Abstract
Background: Acute liver failure (ALF) involves rapid liver injury, often leading to multi-organ failure. Liver transplantation (LT) has improved survival rates, with U.S. rates reaching 92%. This study analyzes UNOS data (2002-2020) to evaluate long-term survival and identify risk factors affecting waitlist and post-LT outcomes in ALF patients. Methods: A retrospective analysis was performed on adult ALF patients waitlisted for LT (Status 1/1A). ALF etiologies, including viral infections, drug-induced liver injury (DILI), acetaminophen (APAP) overdose, autoimmune hepatitis (AIH), Wilson disease (WD), and unknown causes, were assessed with patient and donor characteristics. Kaplan-Meier and Cox regression analyses identified predictors of patient and graft survival. Sensitivity analysis confirmed the model's robustness. Results: We identified 2759 ALF patients. APAP (HR 1.7; p < 0.001) and unknown etiology (HR 1.3; p = 0.037) were linked to higher waitlist removal risk, while WD (HR 0.36; p < 0.001) increased LT probability. Among 2014 LT recipients, WD showed improved survival (HR 0.53; p = 0.002). Black/African American race (HR 1.47; p < 0.001), diabetes (HR 1.81; p < 0.001), and encephalopathy (HR 1.27; p < 0.001) predicted higher mortality. AIH had the lowest 1- and 10-year survival (83% and 62%), while APAP had the lowest 5-year survival (76%). WD had the highest graft survival at 1, 5, and 10 years (93%, 88%, and 80%). Conclusions: ALF etiology significantly affects survival outcomes. AIH and APAP are associated with worse survival, while WD shows favorable outcomes. Tailored post-LT management is essential to improve survival in ALF patients.
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Affiliation(s)
- Natalia Rojas Amaris
- Division of Gastroenterology, Hepatology, and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Ana Marenco-Flores
- Division of Gastroenterology, Hepatology, and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Romelia Barba
- Department of Internal Medicine, Texas Tech University System, Lubbock, TX 79430, USA
| | - Denisse Rubio-Cruz
- Division of Gastroenterology, Hepatology, and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Esli Medina-Morales
- Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
| | - Daniela Goyes
- Division of Digestive Diseases, Yale School of Medicine, New Haven, CT 06520, USA
| | - Behnam Saberi
- Division of Gastroenterology, Hepatology, and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Vilas Patwardhan
- Division of Gastroenterology, Hepatology, and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Alan Bonder
- Division of Gastroenterology, Hepatology, and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
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13
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Kulkarni AV, Gustot T, Reddy KR. Liver transplantation for acute liver failure and acute-on-chronic liver failure. Am J Transplant 2024; 24:1950-1962. [PMID: 39094950 DOI: 10.1016/j.ajt.2024.07.012] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 07/11/2024] [Accepted: 07/11/2024] [Indexed: 08/04/2024]
Abstract
Acute liver failure (ALF) and acute-on-chronic liver (ACLF) are distinct phenotypes of liver failure and, thus, need to be compared and contrasted for appropriate management. There has been a significant improvement in the outcomes of these patients undergoing liver transplantation (LT). Survival post-LT for ALF and ACLF ranges between 90% and 95% and 80% and 90% at 1 year, futility criteria have been described in both ALF and ACLF where organ failures define survival. Plasma exchange and continuous renal replacement therapy may serve as bridging therapies. Identifying the futility of LT is as necessary as the utility of LT in patients with ALF and ACLF. The role of regenerative therapies such as granulocyte colony-stimulating factors in ACLF and hepatocyte and xenotransplantation in both conditions remains uncertain. Measures to increase the donor pool through increasing deceased donor transplants in Asian countries, living donations in Western countries, auxiliary liver transplants, and ABO-incompatible liver transplants are necessary to improve the survival of these patients. In this review, we discuss the similarities and differences in clinical characteristics and the timing and outcomes of LT for ALF and ACLF, briefly highlighting the role of bridging therapies and providing an overview of recent advances in the management of ALF and ACLF.
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Affiliation(s)
- Anand V Kulkarni
- Department of Hepatology, Asian Institute of Gastroenterology, Hyderabad, India
| | - Thierry Gustot
- Liver Transplant Unit, Department of Gastroenterology, Hepato-Pancreatology and Digestive Oncology, HUB Hôpital Erasme, Brussels, Belgium; Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium; Inserm Unité 1149, Centre de Recherche sur l'inflammation (CRI), Paris, France; UMR S_1149, Université Paris Diderot, Paris, France
| | - K Rajender Reddy
- Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, USA.
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14
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Shimata K, Yoon YI, Hibi T, Morinaga J, Narayanan AK, Toshima T, Ito T, Akamatsu N, Kotera Y, Hong SK, Hasegawa Y, Umeda Y, Reddy MS, Ong ADL, Sivaprasadan S, Varghese J, Sugawara Y, Chen CL, Nakayama N, Mochida S, Tanaka A, Suh KS, Ikegami T, Lee KW, Lee SG. A novel scoring system to predict short-term mortality after living donor liver transplantation for acute liver failure. Am J Transplant 2024; 24:1857-1867. [PMID: 38692411 DOI: 10.1016/j.ajt.2024.04.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 04/19/2024] [Accepted: 04/23/2024] [Indexed: 05/03/2024]
Abstract
Liver transplantation is often the only lifesaving option for acute liver failure (ALF); however, the predictors of short-term mortality (death within one year) after living donor liver transplantation (LDLT) for ALF have yet to be defined. We retrospectively collected patients ≥18 years old who underwent LDLT for ALF between 2010 and 2020 at 35 centers in Asia. Univariate and multivariate logistic regression analyses were conducted to identify the clinical variables related to short-term mortality and establish a novel scoring system. The Kaplan-Meier method was performed to explore the association between the score and overall survival. Of the 339 recipients, 46 (13.6%) died within 1 year after LDLT. Multivariate analyses revealed 4 independent risk factors for death: use of vasopressors or mechanical ventilation, the higher model for end-stage liver disease score, and a lower graft-to-recipient weight ratio. The internally validated c-statistic of the short-term mortality after transplant (SMT) score derived from these 4 variables was 0.80 (95% confidence interval: 0.74-0.87). The SMT score successfully stratified recipients into low-, intermediate-, and high-risk groups with 1-year overall survival rates of 96%, 80%, and 50%, respectively. In conclusion, our novel SMT score based on 4 predictors will guide ALF recipient and living donor selection.
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Affiliation(s)
- Keita Shimata
- Department of Pediatric Surgery and Transplantation, Kumamoto University Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Young-In Yoon
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Taizo Hibi
- Department of Pediatric Surgery and Transplantation, Kumamoto University Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
| | - Jun Morinaga
- Department of Clinical Investigation, Kumamoto University Hospital, Kumamoto University, Kumamoto, Japan
| | - Anila Kutty Narayanan
- Department of Gastrointestinal Surgery and Solid Organ Transplantation, Amrita Institute of Medical Sciences and Research Centre, Kochi, India
| | - Takeo Toshima
- Department of Surgery and Science, Kyusyu University Hospital, Fukuoka, Japan
| | - Takashi Ito
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Nobuhisa Akamatsu
- Hepato-Biliary-Pancreatic Surgery Division and Artificial Organ and Transplantation Division, Department of Surgery, The University of Tokyo Hospital, Tokyo, Japan
| | - Yoshihito Kotera
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University Hospital, Tokyo, Japan
| | - Suk Kyun Hong
- Department of Surgery, Seoul National University Hospital, Seoul, South Korea
| | - Yasushi Hasegawa
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Yuzo Umeda
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Mettu Srinivas Reddy
- Institute of Liver Disease & Transplantation, Gleneagles Global Hospital, Chennai, Tamil Nadu, India
| | - Aldwin De Leon Ong
- Liver Transplant Program and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, China
| | - Saraswathy Sivaprasadan
- Department of Gastrointestinal Surgery and Solid Organ Transplantation, Amrita Institute of Medical Sciences and Research Centre, Kochi, India
| | - Joy Varghese
- Institute of Liver Disease & Transplantation, Gleneagles Global Hospital, Chennai, Tamil Nadu, India
| | - Yasuhiko Sugawara
- Department of Pediatric Surgery and Transplantation, Kumamoto University Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Chao-Long Chen
- Liver Transplant Program and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, China
| | - Nobuaki Nakayama
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Satoshi Mochida
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Kyung-Suk Suh
- Department of Surgery, Seoul National University Hospital, Seoul, South Korea
| | - Toru Ikegami
- Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Kwang-Woong Lee
- Department of Surgery, Seoul National University Hospital, Seoul, South Korea
| | - Sung-Gyu Lee
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
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15
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Ozturk NB, Uskudar E, Toruner MD, Simsek C, Gurakar A. Drug-induced liver injury: Diagnosis, management and the role of liver transplantation. HEPATOLOGY FORUM 2024; 6:72-76. [PMID: 40248678 PMCID: PMC11999897 DOI: 10.14744/hf.2024.2024.0003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 03/12/2024] [Accepted: 04/04/2024] [Indexed: 04/19/2025]
Abstract
Drug-induced liver injury (DILI) is caused by various medications or herbals/nutritional supplements resulting in liver test abnormalities or hepatic dysfunction. DILI can be categorized as direct (intrinsic), idiosyncratic, or immune-mediated (indirect), and patterns of injury can be categorized as hepatocellular, cholestatic, or mixed injury. DILI is diagnosed after excluding other causes of liver injury. Cessation of the suspected drug along with supportive care is recommended for most DILI cases. In life-threatening situations, liver transplantation (LT) can be considered; however, the risks with LT and lifelong immunosuppression should be considered. In this paper, we summarize the pathophysiology, diagnosis, medical management, and LT for DILI.
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Affiliation(s)
| | - Eren Uskudar
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Merih Deniz Toruner
- Brown University Warren Alpert School of Medicine School, Providence, Rhode Island, USA
| | - Cem Simsek
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ahmet Gurakar
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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16
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Xie Y, Lin L, Sun C, Chen L, Lv W. Association between serum alkaline phosphatase and clinical prognosis in patients with acute liver failure following cardiac arrest: a retrospective cohort study. Eur J Med Res 2024; 29:453. [PMID: 39252119 PMCID: PMC11382480 DOI: 10.1186/s40001-024-02049-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Accepted: 09/02/2024] [Indexed: 09/11/2024] Open
Abstract
BACKGROUND Acute liver failure (ALF) following cardiac arrest (CA) poses a significant healthcare challenge, characterized by high morbidity and mortality rates. This study aims to assess the correlation between serum alkaline phosphatase (ALP) levels and poor outcomes in patients with ALF following CA. METHODS A retrospective analysis was conducted utilizing data from the Dryad digital repository. The primary outcomes examined were intensive care unit (ICU) mortality, hospital mortality, and unfavorable neurological outcome. Multivariable logistic regression analysis was employed to assess the relationship between serum ALP levels and clinical prognosis. The predictive value was evaluated using receiver operator characteristic (ROC) curve analysis. Two prediction models were developed, and model comparison was performed using the likelihood ratio test (LRT) and the Akaike Information Criterion (AIC). RESULTS A total of 194 patients were included in the analysis (72.2% male). Multivariate logistic regression analysis revealed that a one-standard deviation increase of ln-transformed ALP were independently associated with poorer prognosis: ICU mortality (odds ratios (OR) = 2.49, 95% confidence interval (CI) 1.31-4.74, P = 0.005), hospital mortality (OR = 2.21, 95% CI 1.18-4.16, P = 0.014), and unfavorable neurological outcome (OR = 2.40, 95% CI 1.25-4.60, P = 0.009). The area under the ROC curve for clinical prognosis was 0.644, 0.642, and 0.639, respectively. Additionally, LRT analyses indicated that the ALP-combined model exhibited better predictive efficacy than the model without ALP. CONCLUSIONS Elevated serum ALP levels upon admission were significantly associated with poorer prognosis of ALF following CA, suggesting its potential as a valuable marker for predicting prognosis in this patient population.
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Affiliation(s)
- Yuequn Xie
- Department of Emergency, The Third Affiliated to Shanghai University, Wenzhou People's Hospital, No. 299 Guan Road, Louqiao Street, Ouhai District, Wenzhou, 325000, Zhejiang, China
| | - Liangen Lin
- Department of Emergency, The Third Affiliated to Shanghai University, Wenzhou People's Hospital, No. 299 Guan Road, Louqiao Street, Ouhai District, Wenzhou, 325000, Zhejiang, China
| | - Congcong Sun
- Department of Scientific Research Center, The Third Affiliated to Shanghai University, Wenzhou People's Hospital, Wenzhou, 325000, Zhejiang, China
| | - Linglong Chen
- Department of Emergency, The Third Affiliated to Shanghai University, Wenzhou People's Hospital, No. 299 Guan Road, Louqiao Street, Ouhai District, Wenzhou, 325000, Zhejiang, China
| | - Wang Lv
- Department of Emergency, The Third Affiliated to Shanghai University, Wenzhou People's Hospital, No. 299 Guan Road, Louqiao Street, Ouhai District, Wenzhou, 325000, Zhejiang, China.
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17
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Fernández J, Bassegoda O, Toapanta D, Bernal W. Acute liver failure: A practical update. JHEP Rep 2024; 6:101131. [PMID: 39170946 PMCID: PMC11337735 DOI: 10.1016/j.jhepr.2024.101131] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 05/17/2024] [Accepted: 05/22/2024] [Indexed: 08/23/2024] Open
Abstract
Acute liver failure is a rare and dynamic condition, with a broad aetiology and an incompletely understood pathophysiology. Management of this life-threatening disease requires critical care and organ support and frequently early liver transplantation. Proper identification, prevention and treatment of complications such as intracranial hypertension and sepsis are critical to optimising outcomes. The identification of the cause of acute liver failure and the prompt initiation of the aetiological treatment can also improve prognosis. Survival has progressively improved in parallel to advances in medical treatment. Intracranial hypertension complicating hepatic encephalopathy is less frequent than in the past and intracranial pressure monitoring now relies on non-invasive techniques. Current prognostic models have good accuracy to identify patients who will die without liver transplantation but are not able to identify those in whom transplantation is futile. New prognostic markers to select patients for transplantation are still in the pipeline. Therapeutic plasma exchange and, in some centers, early renal replacement therapy are well established treatments for the disease. The use of other artificial liver devices in clinical practice is not supported by evidence. This review is intended to provide a clinical update on the management of acute liver failure, incorporating the most recent advances in the field.
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Affiliation(s)
- Javier Fernández
- Liver ICU, Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS and CIBERehd, Spain
- EF Clif, EASL-CLIF Consortium, Barcelona, Spain
| | - Octavi Bassegoda
- Liver ICU, Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS and CIBERehd, Spain
| | - David Toapanta
- Liver ICU, Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS and CIBERehd, Spain
| | - William Bernal
- Liver Intensive Therapy Unit, Institute of Liver Studies, Kings College Hospital, London, United Kingdom
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18
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Maiwall R, Kulkarni AV, Arab JP, Piano S. Acute liver failure. Lancet 2024; 404:789-802. [PMID: 39098320 DOI: 10.1016/s0140-6736(24)00693-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 03/13/2024] [Accepted: 04/03/2024] [Indexed: 08/06/2024]
Abstract
Acute liver failure (ALF) is a life-threatening disorder characterised by rapid deterioration of liver function, coagulopathy, and hepatic encephalopathy in the absence of pre-existing liver disease. The cause of ALF varies across the world. Common causes of ALF in adults include drug toxicity, hepatotropic and non-hepatotropic viruses, herbal and dietary supplements, antituberculosis drugs, and autoimmune hepatitis. The cause of liver failure affects the management and prognosis, and therefore extensive investigation for cause is strongly suggested. Sepsis with multiorgan failure and cerebral oedema remain the leading causes of death in patients with ALF and early identification and appropriate management can alter the course of ALF. Liver transplantation is the best current therapy, although the role of artificial liver support systems, particularly therapeutic plasma exchange, can be useful for patients with ALF, especially in non-transplant centres. In this Seminar, we discuss the cause, prognostic models, and management of ALF.
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Affiliation(s)
- Rakhi Maiwall
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.
| | - Anand V Kulkarni
- Department of Hepatology, Asian Institute of Gastroenterology, Hyderabad, India
| | - Juan Pablo Arab
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA; Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Salvatore Piano
- Unit of Internal Medicine and Hepatology, Department of Medicine, University and Hospital of Padova, Padova, Italy
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19
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Martínez-Martínez LM, Rosales-Sotomayor G, Jasso-Baltazar EA, Torres-Díaz JA, Aguirre-Villarreal D, Hurtado-Díaz de León I, Páez-Zayas VM, Sánchez-Cedillo A, Martínez-Vázquez SE, Tadeo-Espinoza HN, Guerrero-Cabrera JP, García-Alanis M, García-Juárez I. Acute liver failure: Management update and prognosis. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2024; 89:404-417. [PMID: 39033039 DOI: 10.1016/j.rgmxen.2024.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Accepted: 05/30/2024] [Indexed: 07/23/2024]
Abstract
Acute liver failure is a rare but serious syndrome, with an incidence of approximately 2,000 to 3,000 cases per year in North America. Its pathophysiology and clinical course vary, depending on the cause of the primary liver injury, and can lead to high morbidity and mortality or the need for liver transplantation, despite available therapies. This syndrome involves excessive activation of the immune system, with damage in other organs, contributing to its high mortality rate. The most accepted definition includes liver injury with hepatic encephalopathy and coagulopathy within the past 26 weeks in a patient with no previous liver disease. The main causes are paracetamol poisoning, viral hepatitis, and drug-induced liver injury, among others. Identifying the cause is crucial, given that it influences prognosis and treatment. Survival has improved with supportive measures, intensive therapy, complication prevention, and the use of medications, such as N-acetylcysteine. Liver transplantation is a curative option for nonresponders to medical treatment, but adequate evaluation of transplantation timing is vital for improving results. Factors such as patient age, underlying cause, and severity of organ failure influence the post-transplant outcomes and survival.
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Affiliation(s)
- L M Martínez-Martínez
- Departamento de Medicina Interna, Hospital Central Dr. Ignacio Morones Prieto, San Luis Potosí, Mexico
| | - G Rosales-Sotomayor
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - E A Jasso-Baltazar
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - J A Torres-Díaz
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - D Aguirre-Villarreal
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - I Hurtado-Díaz de León
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - V M Páez-Zayas
- Departamento de Trasplante de Órganos, Hospital General de México Dr. Eduardo Liceaga, Mexico City, Mexico
| | - A Sánchez-Cedillo
- Departamento de Trasplante de Órganos, Hospital General de México Dr. Eduardo Liceaga, Mexico City, Mexico
| | - S E Martínez-Vázquez
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - H N Tadeo-Espinoza
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - J P Guerrero-Cabrera
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - M García-Alanis
- Departamento de Neurología y Psiquiatría, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - I García-Juárez
- Departamento de Gastroenterología, Clínica de Hígado y Trasplante Hepático, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
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20
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Chung E, Wen X, Jia X, Ciallella HL, Aleksunes LM, Zhu H. Hybrid non-animal modeling: A mechanistic approach to predict chemical hepatotoxicity. JOURNAL OF HAZARDOUS MATERIALS 2024; 471:134297. [PMID: 38677119 PMCID: PMC11519847 DOI: 10.1016/j.jhazmat.2024.134297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 04/10/2024] [Accepted: 04/11/2024] [Indexed: 04/29/2024]
Abstract
Developing mechanistic non-animal testing methods based on the adverse outcome pathway (AOP) framework must incorporate molecular and cellular key events associated with target toxicity. Using data from an in vitro assay and chemical structures, we aimed to create a hybrid model to predict hepatotoxicants. We first curated a reference dataset of 869 compounds for hepatotoxicity modeling. Then, we profiled them against PubChem for existing in vitro toxicity data. Of the 2560 resulting assays, we selected the mitochondrial membrane potential (MMP) assay, a high-throughput screening (HTS) tool that can test chemical disruptors for mitochondrial function. Machine learning was applied to develop quantitative structure-activity relationship (QSAR) models with 2536 compounds tested in the MMP assay for screening new compounds. The MMP assay results, including QSAR model outputs, yielded hepatotoxicity predictions for reference set compounds with a Correct Classification Ratio (CCR) of 0.59. The predictivity improved by including 37 structural alerts (CCR = 0.8). We validated our model by testing 37 reference set compounds in human HepG2 hepatoma cells, and reliably predicting them for hepatotoxicity (CCR = 0.79). This study introduces a novel AOP modeling strategy that combines public HTS data, computational modeling, and experimental testing to predict chemical hepatotoxicity.
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Affiliation(s)
- Elena Chung
- Department of Chemistry and Biochemistry, Rowan University, NJ, USA; Center for Biomedical Informatics and Genomics, Tulane University, New Orleans, LA, USA
| | - Xia Wen
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ, USA
| | - Xuelian Jia
- Department of Chemistry and Biochemistry, Rowan University, NJ, USA; Center for Biomedical Informatics and Genomics, Tulane University, New Orleans, LA, USA
| | - Heather L Ciallella
- Department of Toxicology, Cuyahoga County Medical Examiner's Office, Cleveland, OH, USA
| | - Lauren M Aleksunes
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ, USA
| | - Hao Zhu
- Department of Chemistry and Biochemistry, Rowan University, NJ, USA; Center for Biomedical Informatics and Genomics, Tulane University, New Orleans, LA, USA.
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21
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Orozco G, Gupta M, Ancheta A, Shah MB, Warriner Z, Marti F, Mei X, Desai S, Bernard A, Gedaly R. Liver transplantation for severe hepatic trauma: A multicenter analysis from the UNOS data set. J Trauma Acute Care Surg 2024; 96:763-768. [PMID: 37994467 DOI: 10.1097/ta.0000000000004220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2023]
Abstract
BACKGROUND Orthotopic liver transplantation (OLT) is rarely indicated after hepatic trauma but it can be the only therapeutic option in some patients. There are scarce data analyzing the surgical outcomes of OLT after trauma. METHODS We used the UNOS data set to identify patients who underwent OLT for trauma from 1987 to 2022 and compared them to a cohort of patients transplanted for other indications. Cox proportional hazard and multivariable logistic regression analyses were performed to assess predictors of graft and patient survival. RESULTS Seventy-two patients underwent OLT for trauma during the study period. Patients with trauma were more frequently on mechanical ventilation at the time of transplantation (26.4% vs. 7.6%, p < 0.001) and had a greater incidence of pretransplant portal vein thrombosis (12.5% vs. 4%, p = 0.002). Our 4:1 matched analysis showed that trauma patients had significantly shorter wait times, higher incidence of pretransplant portal vein thrombosis and prolonged length of stay. Trauma was associated with decreased overall graft survival (hazards ratio, 1.42; 95% confidence interval, 1.01-1.98), and increased length of stay ( p = 0.048). There were no significant differences in long-term patient survival. CONCLUSION Unique physiological and vascular challenges after severe hepatic trauma might be associated with decreased graft survival in patients requiring liver transplantation. LEVEL OF EVIDENCE Prognostic and Epidemiological; Level III.
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Affiliation(s)
- Gabriel Orozco
- From the Division of Transplantation, Department of Surgery (G.O., M.G., A.A., M.B.S., F.M., X.M., S.D., R.G.), and Division of Acute Care Surgery, Trauma & Surgical Critical Care, Department of Surgery (Z.W., A.B.), University of Kentucky, Lexington, Kentucky
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22
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Azoulay D, Desterke C, Bhangui P, Serrablo A, De Martin E, Cauchy F, Salloum C, Allard MA, Golse N, Vibert E, Sa Cunha A, Cherqui D, Adam R, Saliba F, Ichai P, Feray C, Scatton O, Lim C. Rescue Liver Transplantation for Posthepatectomy Liver Failure: A Systematic Review and Survey of an International Experience. Transplantation 2024; 108:947-957. [PMID: 37749790 DOI: 10.1097/tp.0000000000004813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/27/2023]
Abstract
BACKGROUND Rescue liver transplantation (LT) is the only life-saving option for posthepatectomy liver failure (PHLF) whenever it is deemed as irreversible and likely to be fatal. The goals were to perform a qualitative systematic review of rescue LT for PHLF and a survey among various international LT experts. METHODS A literature search was performed from 2000 to 2022 using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Population, Intervention, Comparison, Outcome framework, and to this, the authors' experience was added. The international online open survey included 6 cases of PHLF extracted from the literature and submitted to 976 LT experts. The primary outcome was whether experts would consider rescue LT for each case. Interrater agreement among experts was calculated using the free-marginal multirater kappa methodology. RESULTS The review included 40 patients. Post-LT mortality occurred in 8 (20%) cases (7/28 with proven cancer and 1/12 with benign disease). In the long term, 6 of 21 (28.6%) survivors with cancer died of recurrence (median = 38 mo) and 15 (71.4%) were alive with no recurrence (median = 111 mo). All 11 survivors with benign disease were alive and well (median = 39 mo). In the international survey among experts in LT, the percentage agreement to consider rescue LT was 28%-98%, higher for benign than for malignant disease ( P = 0.011). Interrater agreement for the primary endpoint was low, expected 5-y survival >50% being the strongest independent predictor to consider LT. CONCLUSIONS Rescue LT for PHLF may achieve good results in selected patients. Considerable inconsistencies of decision-making exist among LT experts when considering LT for PHLF.
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Affiliation(s)
- Daniel Azoulay
- Centre Hépato-Biliaire, Hôpital Universitaire Paul Brousse, Université Paris-Saclay, Villejuif, France
| | - Christophe Desterke
- University of Medicine Paris Saclay, Le Kremlin-Bicêtre, France
- INSERM Unit UMR1310, Villejuif, France
| | - Prashant Bhangui
- Institute of Liver Transplantation and Regenerative Medicine, Medanta-The Medicity, Delhi NCR, India
| | - Alejandro Serrablo
- Department of Surgery, Miguel Servet University Hospital, Zaragoza, Spain
| | - Eleonora De Martin
- Centre Hépato-Biliaire, Hôpital Universitaire Paul Brousse, Université Paris-Saclay, Villejuif, France
| | - François Cauchy
- Department of Hepato-biliary and Pancreatic Surgery and Liver Transplantation, University of Geneva, Geneva, Switzerland
| | - Chady Salloum
- Centre Hépato-Biliaire, Hôpital Universitaire Paul Brousse, Université Paris-Saclay, Villejuif, France
| | - Marc Antoine Allard
- Centre Hépato-Biliaire, Hôpital Universitaire Paul Brousse, Université Paris-Saclay, Villejuif, France
| | - Nicolas Golse
- Centre Hépato-Biliaire, Hôpital Universitaire Paul Brousse, Université Paris-Saclay, Villejuif, France
| | - Eric Vibert
- Centre Hépato-Biliaire, Hôpital Universitaire Paul Brousse, Université Paris-Saclay, Villejuif, France
| | - Antonio Sa Cunha
- Centre Hépato-Biliaire, Hôpital Universitaire Paul Brousse, Université Paris-Saclay, Villejuif, France
| | - Daniel Cherqui
- Centre Hépato-Biliaire, Hôpital Universitaire Paul Brousse, Université Paris-Saclay, Villejuif, France
| | - René Adam
- Centre Hépato-Biliaire, Hôpital Universitaire Paul Brousse, Université Paris-Saclay, Villejuif, France
| | - Faouzi Saliba
- Centre Hépato-Biliaire, Hôpital Universitaire Paul Brousse, Université Paris-Saclay, Villejuif, France
| | - Philippe Ichai
- Centre Hépato-Biliaire, Hôpital Universitaire Paul Brousse, Université Paris-Saclay, Villejuif, France
| | - Cyrille Feray
- Centre Hépato-Biliaire, Hôpital Universitaire Paul Brousse, Université Paris-Saclay, Villejuif, France
| | - Olivier Scatton
- Département de Chirurgie et Transplantation Hépatique, Hôpital Universitaire Pitié-Salpêtrière, Sorbonne Université, Paris, France
- Centre de Recherche de Saint-Antoine (CRSA), INSERM, UMRS-938, Paris, France
| | - Chetana Lim
- Département de Chirurgie et Transplantation Hépatique, Hôpital Universitaire Pitié-Salpêtrière, Sorbonne Université, Paris, France
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23
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Singh SA, Jadaun S, Gain A, Saigal S, Gupta S. Difficult transplant decisions in acute liver failure -Benefit versus futility, where to draw a line. Indian J Gastroenterol 2024; 43:522-526. [PMID: 38664346 DOI: 10.1007/s12664-024-01579-1] [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] [Indexed: 05/28/2024]
Affiliation(s)
- Shweta A Singh
- Department of Anaesthesia and Critical Care, Center for Liver and Biliary Sciences, Max Super Speciality Hospital, Saket, New Delhi, 110 017, India.
| | - Shekhar Jadaun
- Department of Hepatology, Center for Liver and Biliary Sciences, Max Super Speciality Hospital, Saket, New Delhi, 110 017, India
| | - Avijit Gain
- Department of Anaesthesia and Critical Care, Center for Liver and Biliary Sciences, Max Super Speciality Hospital, Saket, New Delhi, 110 017, India
| | - Sanjiv Saigal
- Department of Hepatology, Center for Liver and Biliary Sciences, Max Super Speciality Hospital, Saket, New Delhi, 110 017, India
| | - Subhash Gupta
- Department of Liver Transplant and HPB Surgery, Center for Liver and Biliary Sciences, Max Super Speciality Hospital, Saket, New Delhi, 110 017, India
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24
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Wang Z, Xing C, van der Laan LJW, Verstegen MMA, Spee B, Masereeuw R. Cholangiocyte organoids to study drug-induced injury. Stem Cell Res Ther 2024; 15:78. [PMID: 38475870 DOI: 10.1186/s13287-024-03692-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Accepted: 03/07/2024] [Indexed: 03/14/2024] Open
Abstract
BACKGROUND Drug induced bile duct injury is a frequently observed clinical problem leading to a wide range of pathological features. During the past decades, several agents have been identified with various postulated mechanisms of bile duct damage, however, mostly still poorly understood. METHODS Here, we investigated the mechanisms of chlorpromazine (CPZ) induced bile duct injury using advanced in vitro cholangiocyte cultures. Intrahepatic cholangiocyte organoids (ICOs) were driven into mature cholangiocyte like cells (CLCs), which were exposed to CPZ under cholestatic or non-cholestatic conditions through the addition of a bile acid cocktail. RESULTS CPZ caused loss of monolayer integrity by reducing expression levels of tight junction protein 1 (TJP1), E-cadherin 1 (CDH1) and lysyl oxidase homolog 2 (LOXL2). Loss of zonula occuludens-1 (ZO-1) and E-cadherin was confirmed by immunostaining after exposure to CPZ and rhodamine-123 leakage further confirmed disruption of the cholangiocyte barrier function. Furthermore, oxidative stress seemed to play a major role in the early damage response by CPZ. The drug also decreased expression of three main basolateral bile acid transporters, ABCC3 (ATP binding cassette subfamily C member 3), SLC51A/B (solute carrier family 51 subunit alpha/beta) and multidrug resistance transporter ABCB1 (ATP binding cassette subfamily B member 1), thereby contributing to bile acid accumulation. CPZ did not induce an inflammatory response by itself, but addition of TNFα revealed a synergistic effect. CONCLUSION These results show that ICOs present a model to identify toxic drugs affecting the bile ducts while providing mechanistic insights into hepatotoxicity.
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Affiliation(s)
- Zhenguo Wang
- Division of Pharmacology, Faculty of Sciences, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Chen Xing
- Division of Pharmacology, Faculty of Sciences, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Luc J W van der Laan
- Department of Surgery, Erasmus MC Transplant Institute, University Medical Center, Rotterdam, The Netherlands
| | - Monique M A Verstegen
- Department of Surgery, Erasmus MC Transplant Institute, University Medical Center, Rotterdam, The Netherlands
| | - Bart Spee
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Rosalinde Masereeuw
- Division of Pharmacology, Faculty of Sciences, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
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25
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Li D, Chen Y, Wan M, Mei F, Wang F, Gu P, Zhang X, Wei R, Zeng Y, Zheng H, Chen B, Xiong Q, Xue T, Guan T, Guo J, Tian Y, Zeng LY, Liu Z, Yuan H, Yang L, Liu H, Dai L, Yu Y, Qiu Y, Wu P, Win S, Than TA, Wei R, Schnabl B, Kaplowitz N, Jiang Y, Ma Q, Chen P. Oral magnesium prevents acetaminophen-induced acute liver injury by modulating microbial metabolism. Cell Host Microbe 2024; 32:48-62.e9. [PMID: 38056458 DOI: 10.1016/j.chom.2023.11.006] [Citation(s) in RCA: 26] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 10/10/2023] [Accepted: 11/08/2023] [Indexed: 12/08/2023]
Abstract
Acetaminophen overuse is a common cause of acute liver failure (ALF). During ALF, toxins are metabolized by enzymes such as CYP2E1 and transformed into reactive species, leading to oxidative damage and liver failure. Here, we found that oral magnesium (Mg) alleviated acetaminophen-induced ALF through metabolic changes in gut microbiota that inhibit CYP2E1. The gut microbiota from Mg-supplemented humans prevented acetaminophen-induced ALF in mice. Mg exposure modulated Bifidobacterium metabolism and enriched indole-3-carboxylic acid (I3C) levels. Formate C-acetyltransferase (pflB) was identified as a key Bifidobacterium enzyme involved in I3C generation. Accordingly, a Bifidobacterium pflB knockout showed diminished I3C generation and reduced the beneficial effects of Mg. Conversely, treatment with I3C or an engineered bacteria overexpressing Bifidobacterium pflB protected against ALF. Mechanistically, I3C bound and inactivated CYP2E1, thus suppressing formation of harmful reactive intermediates and diminishing hepatocyte oxidative damage. These findings highlight how interactions between Mg and gut microbiota may help combat ALF.
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Affiliation(s)
- Dongping Li
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Yu Chen
- Department of Gastroenterology, The Seventh Affiliated Hospital of Southern Medical University, Foshan 528244, China
| | - Meijuan Wan
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Fengyi Mei
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Fangzhao Wang
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Peng Gu
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Xianglong Zhang
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Rongjuan Wei
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Yunong Zeng
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Hanzhao Zheng
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Bangguo Chen
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Qingquan Xiong
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Tao Xue
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Tianshan Guan
- Department of Gastroenterology, The Seventh Affiliated Hospital of Southern Medical University, Foshan 528244, China
| | - Jiayin Guo
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Yuanxin Tian
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Li-Yan Zeng
- School of Chemistry and Chemical Engineering, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China
| | - Zhanguo Liu
- Department of Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Hang Yuan
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Ling Yang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Hongbin Liu
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Lei Dai
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Yao Yu
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yifeng Qiu
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Peng Wu
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Sanda Win
- Research Center for Liver Disease, Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Tin Aung Than
- Research Center for Liver Disease, Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Riqing Wei
- Department of Biopharmaceutics, Guangdong Provincial Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Bernd Schnabl
- Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA MC0063, USA
| | - Neil Kaplowitz
- Research Center for Liver Disease, Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Yong Jiang
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
| | - Qiang Ma
- Department of Biopharmaceutics, Guangdong Provincial Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China.
| | - Peng Chen
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; Department of Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.
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26
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Ma J, Slaven JE, Nephew L, Patidar KR, Desai AP, Orman E, Kubal C, Chalasani N, Ghabril M. Severe hepatic encephalopathy with mechanical ventilation may inform waitlist priority in acute liver failure: A UNOS database analysis. Clin Transplant 2024; 38:e15215. [PMID: 38041474 DOI: 10.1111/ctr.15215] [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: 06/21/2023] [Accepted: 11/19/2023] [Indexed: 12/03/2023]
Abstract
BACKGROUND & AIMS Patients with acute liver failure (ALF) awaiting liver transplantation (LT) may develop multiorgan failure, but organ failure does not impact waitlist prioritization. The aim of this study was to examine the impact of organ failure on waitlist mortality risk and post LT outcomes in patients with ALF. METHODS We studied adults waitlisted for ALF in the United Network for Organ Sharing (UNOS) database (2002-2019). Organ failures were defined using a previously described Chronic Liver Failure modified sequential organ failure score assessment adapted to UNOS data. Regression analyses of the primary endpoints, 30-day waitlist mortality (Competing risk), and post-LT mortality (Cox-proportional hazards), were performed. Latent class analysis (LCA) was used to determine the organ failures most closely associated with 30-day waitlist mortality. RESULTS About 3212 adults with ALF were waitlisted, for hepatotoxicity (41%), viral (12%) and unspecified (36%) etiologies. The median number of organ failures was three (interquartile range 1-3). Having ≥3 organ failures (vs. ≤2) was associated with a sub hazard ratio (HR) of 2.7 (95%CI 2.2-3.4)) and a HR of 1.5 (95%CI 1.1-2.5)) for waitlist and post-LT mortality, respectively. LCA identified neurologic and respiratory failure as most impactful on 30-day waitlist mortality. The odds ratios for both organ failures (vs. neither) were higher for mortality 4.5 (95% CI 3.4-5.9) and lower for delisting for spontaneous survival .5 (95%CI .4-.7) and LT .6 (95%CI .5-.7). CONCLUSION Cumulative organ failure, especially neurologic and respiratory failure, significantly impacts waitlist and post-LT mortality in patients with ALF and may inform risk-prioritized allocation of organs.
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Affiliation(s)
- Jiayi Ma
- Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - James E Slaven
- Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Lauren Nephew
- Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Kavish R Patidar
- Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Archita P Desai
- Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Eric Orman
- Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Chandrashekhar Kubal
- Transplant Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Naga Chalasani
- Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Marwan Ghabril
- Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
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27
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Ozturk NB, Herdan E, Saner FH, Gurakar A. A Comprehensive Review of the Diagnosis and Management of Acute Liver Failure. J Clin Med 2023; 12:7451. [PMID: 38068503 PMCID: PMC10707329 DOI: 10.3390/jcm12237451] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Revised: 11/27/2023] [Accepted: 11/28/2023] [Indexed: 04/27/2025] Open
Abstract
Acute liver failure (ALF) is a rare and specific form of severe hepatic dysfunction characterized by coagulopathy and hepatic encephalopathy in a patient with no known liver disease. ALF carries a high morbidity and mortality. Careful attention should be given to hemodynamics and metabolic parameters along with the active surveillance of infections. Timely transfer and supportive management are important in an intensive care unit in a liver transplant center. Identifying patients who will and will not improve with medical management and may need emergent liver transplantation is critical. In this review, we provide a comprehensive update on the etiology, diagnosis, and management of ALF.
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Affiliation(s)
- Nazli Begum Ozturk
- Department of Internal Medicine, Beaumont Hospital, Royal Oak, MI 48073, USA
| | - Emre Herdan
- Division of Gastroenterology and Hepatology, Johns Hopkins University Hospital, Baltimore, MD 21287, USA
| | - Fuat H. Saner
- Department of General, Visceral and Transplantation Surgery, University of Duisburg-Essen, 45147 Essen, Germany
- Organ Transplant Center of Excellence, King Faisal Specialized Hospital & Research Center, Riyadh 11211, Saudi Arabia
| | - Ahmet Gurakar
- Division of Gastroenterology and Hepatology, Johns Hopkins University Hospital, Baltimore, MD 21287, USA
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28
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Jin D, Kang K, Yan BZ, Zhang JN, Zheng JB, Wang ZH, Wu D, Tang YJ, Wang XT, Lai QQ, Cao Y, Wang HL, Gao Y. Combined Age with Mean Decrease Rates of Total Bilirubin and MELD Score as a Novel and Simple Clinical Predictor on 90-Day Transplant-Free Mortality in Adult Patients with Acute Liver Failure Undergoing Plasma Exchange: A Single-Center Retrospective Study. Can J Gastroenterol Hepatol 2023; 2023:6115499. [PMID: 38021269 PMCID: PMC10645502 DOI: 10.1155/2023/6115499] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 10/13/2023] [Accepted: 10/27/2023] [Indexed: 12/01/2023] Open
Abstract
Background Acute liver failure (ALF), previously known as fulminant hepatic failure, has become a common, rapidly progressive, and life-threatening catastrophic hepatic disease in intensive care unit (ICU) due to the continuous increase in drug abuse, viral infection, metabolic insult, and auto-immune cause. At present, plasma exchange (PE) is the main effective alternative treatment for ALF in ICU clinical practice, and high-volume plasma exchange (HVP) has been listed as a grade I recommendation for ALF management in the American Society for Apheresis (ASFA) guidelines. However, no existing models can provide a satisfactory performance for clinical prediction on 90-day transplant-free mortality in adult patients with ALF undergoing PE. Our study aims to identify a novel and simple clinical predictor of 90-day transplant-free mortality in adult patients with ALF undergoing PE. Methods This retrospective study contained adult patients with ALF undergoing PE from the Medical ICU (MICU) in the Second Affiliated Hospital of Harbin Medical University between January 2017 and December 2020. Baseline and clinical data were collected and calculated on admission to ICU before PE, including gender, age, height, weight, body mass index (BMI), etiology, total bilirubin, direct bilirubin, indirect bilirubin, prothrombin activity, model for end-stage liver disease (MELD) score, and sequential organ failure assessment (SOFA) score. Enrolled adult patients with ALF undergoing PE were divided into a survival group and a death group at discharge and 90 days on account of medical records and telephone follow-up. After each PE, decreased rates of total bilirubin and MELD score and increased rates of prothrombin activity were calculated according to the clinical parameters. In clinical practice, different patients underwent different times of PE, and thus, mean decrease rates of total bilirubin and MELD score and mean increase rate of prothrombin activity were obtained for further statistical analysis. Results A total of 73 adult patients with ALF undergoing 204 PE were included in our retrospective study, and their transplant-free mortality at discharge and 90 days was 6.85% (5/73) and 31.51% (23/73), respectively. All deaths could be attributed to ALF-induced severe and life-threatening complications or even multiple organ dysfunction syndrome (MODS). Most of the enrolled adult patients with ALF were men (76.71%, 56/73), with a median age of 48.77 years. Various hepatitis virus infections, unknown etiology, auto-immune liver disease, drug-induced liver injury, and acute pancreatitis (AP) accounted for 75.34%, 12.33%, 6.85%, 4.11%, and 1.37% of the etiologies in adult patients with ALF, respectively. Univariate analysis showed a significant difference in age, mean decrease rates of total bilirubin and MELD score mean increase rate of prothrombin activity, decrease rates of total bilirubin and MELD score, and increase rate of prothrombin activity after the first PE between the death group and survival group. Multivariate analysis showed that age and mean decrease rates of total bilirubin and MELD score were closely associated with 90-day transplant-free mortality in adult patients with ALF undergoing PE. The 90-day transplant-free mortality was 1.081, 0.908, and 0.893 times of the original value with each one-unit increase in age and mean decrease rates of total bilirubin and MELD score, respectively. The areas under the receiver operatingcharacteristic (ROC) curve of age, mean decrease rates of total bilirubin and MELD score, and the three combined were 0.689, 0.225, 0.123, and 0.912, respectively. The cut-off values of age, mean decrease rates of total bilirubin and MELD score, and the three combined were 61.50, 3.12, 1.21, and 0.33, respectively. The specificity and sensitivity of combined age with mean decrease rates of total bilirubin and MELD score for predicting 90-day transplant-free mortality in adult patients with ALF undergoing PE were 87% and 14%. Conclusion Combined age with mean decrease rates of total bilirubin and MELD score as a novel and simple clinical predictor can accurately predict 90-day transplant-free mortality in adult patients with ALF undergoing PE, which is worthy of application and promotion in clinical practice, especially in the identification of potential transplant candidates.
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Affiliation(s)
- Di Jin
- Department of Anesthesiology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, Heilongjiang Province, China
| | - Kai Kang
- Department of Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Bing-zhu Yan
- Department of Infectious Diseases, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, Heilongjiang Province, China
| | - Jian-nan Zhang
- Department of Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Jun-bo Zheng
- Department of Critical Care Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, Heilongjiang Province, China
| | - Zhi-hui Wang
- Department of Critical Care Medicine, The Sixth Affiliated Hospital of Harbin Medical University, Harbin 150027, Heilongjiang Province, China
| | - Di Wu
- Department of Critical Care Medicine, The Sixth Affiliated Hospital of Harbin Medical University, Harbin 150027, Heilongjiang Province, China
| | - Yu-jia Tang
- Department of Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Xin-tong Wang
- Department of Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Qi-qi Lai
- Department of Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Yang Cao
- Department of Critical Care Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, Heilongjiang Province, China
| | - Hong-liang Wang
- Department of Critical Care Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, Heilongjiang Province, China
| | - Yang Gao
- Department of Critical Care Medicine, The Sixth Affiliated Hospital of Harbin Medical University, Harbin 150027, Heilongjiang Province, China
- Institute of Critical Care Medicine, The Sino Russian Medical Research Center of Harbin Medical University, Harbin 150081, Heilongjiang Province, China
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Pravisani R, Cocchi L, Cesaretti M, Dondero F, Sepulveda A, Farges O, Weiss E, Vilgrain V, Francoz C, Roux O, Belghiti J, Durand F, Lesurtel M, Dokmak S. Refining Auxiliary Orthotopic Liver Transplantation (AOLT) Improves Outcomes in Adult Patients With Acute Liver Failure. Ann Surg 2023; 278:790-797. [PMID: 37470188 DOI: 10.1097/sla.0000000000006019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/21/2023]
Abstract
OBJECTIVE To investigate whether and how experience accumulation and technical refinements simultaneously implemented in auxiliary orthotopic liver transplantation (AOLT) may impact on outcomes. BACKGROUND AOLT for acute liver failure (ALF) provides the unique chance of complete immunosuppression withdrawal after adequate native liver remnant regeneration but is a technically demanding procedure. Our department is a reference center for ALF and an early adopter of AOLT. METHODS This is a single-center retrospective before/after study of a prospectively maintained cohort of 48 patients with ALF who underwent AOLT between 1993 and 2019. In 2012, technical refinements were implemented to improve outcomes: (i) favoring the volume of the graft rather than that of the native liver, (ii) direct anastomosis of graft hepatic artery with recipient right hepatic artery instead of the use of large size vessels, (iii) end-to-side hepaticocholedocostomy instead of bilioenteric anastomosis. Early experience (1993-2011) group (n=26) and recent experience (2012-2019) group (n=22) were compared. Primary endpoint was 90-day severe morbidity rate (Clavien-Dindo≥IIIa) and secondary endpoints were overall patient survival and complete immunosuppression withdrawal rates. RESULTS Compared with the earlier experience group, the recent experience group was associated with a lower severe complication rate (27% vs 65%, P <0.001), as well as less biliary (18% vs 54%, P =0.017) and arterial (0% vs 15%, P =0.115) complications. The 1-, 3-, and 5-year patient survival was significantly improved (91%, 91%, 91% vs 76%, 61%, 60%, P =0.045). The rate of complete immunosuppression withdrawal increased to 94% vs 70%, ( P =0.091) with no need of long-term graft explant. CONCLUSION These technical refinements favoring the liver graft and reducing morbidity may promote AOLT implementation among LT centers.
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Affiliation(s)
- Riccardo Pravisani
- Liver-Kidney Transplant Unit, Department of Medicine, University of Udine, Udine, Italy
- Department of HPB Surgery and Liver Transplantation, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, University of Paris Cité, Clichy, France
| | - Lorenzo Cocchi
- Department of HPB Surgery and Liver Transplantation, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, University of Paris Cité, Clichy, France
| | - Manuela Cesaretti
- Department of HPB Surgery and Liver Transplantation, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, University of Paris Cité, Clichy, France
| | - Federica Dondero
- Department of HPB Surgery and Liver Transplantation, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, University of Paris Cité, Clichy, France
| | - Ailton Sepulveda
- Department of HPB Surgery and Liver Transplantation, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, University of Paris Cité, Clichy, France
| | - Olivier Farges
- Department of HPB Surgery and Liver Transplantation, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, University of Paris Cité, Clichy, France
| | - Emmanuel Weiss
- Department of Anesthesiology and Critical Care, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, University of Paris Cité, Clichy, France
| | - Valérie Vilgrain
- Department of Radiology, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, University of Paris Cité, Clichy, France
| | - Claire Francoz
- Hepatology and Liver Intensive Care, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, University of Paris Cité, Clichy, France
| | - Olivier Roux
- Hepatology and Liver Intensive Care, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, University of Paris Cité, Clichy, France
| | - Jacques Belghiti
- Department of HPB Surgery and Liver Transplantation, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, University of Paris Cité, Clichy, France
| | - Francois Durand
- Hepatology and Liver Intensive Care, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, University of Paris Cité, Clichy, France
| | - Mickaël Lesurtel
- Department of HPB Surgery and Liver Transplantation, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, University of Paris Cité, Clichy, France
| | - Safi Dokmak
- Department of HPB Surgery and Liver Transplantation, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, University of Paris Cité, Clichy, France
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Stravitz RT, Fontana RJ, Karvellas C, Durkalski V, McGuire B, Rule JA, Tujios S, Lee WM. Future directions in acute liver failure. Hepatology 2023; 78:1266-1289. [PMID: 37183883 PMCID: PMC10521792 DOI: 10.1097/hep.0000000000000458] [Citation(s) in RCA: 54] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 04/20/2023] [Indexed: 05/16/2023]
Abstract
Acute liver failure (ALF) describes a clinical syndrome of rapid hepatocyte injury leading to liver failure manifested by coagulopathy and encephalopathy in the absence of pre-existing cirrhosis. The hallmark diagnostic features are a prolonged prothrombin time (ie, an international normalized ratio of prothrombin time of ≥1.5) and any degree of mental status alteration (HE). As a rare, orphan disease, it seemed an obvious target for a multicenter network. The Acute Liver Failure Study Group (ALFSG) began in 1997 to more thoroughly study and understand the causes, natural history, and management of ALF. Over the course of 22 years, 3364 adult patients were enrolled in the study registry (2614 ALF and 857 acute liver injury-international normalized ratio 2.0 but no encephalopathy-ALI) and >150,000 biosamples collected, including serum, plasma, urine, DNA, and liver tissue. Within the Registry study sites, 4 prospective substudies were conducted and published, 2 interventional ( N -acetylcysteine and ornithine phenylacetate), 1 prognostic [ 13 C-methacetin breath test (MBT)], and 1 mechanistic (rotational thromboelastometry). To review ALFSG's accomplishments and consider next steps, a 2-day in-person conference was held at UT Southwestern Medical Center, Dallas, TX, entitled "Acute Liver Failure: Science and Practice," in May 2022. To summarize the important findings in the field, this review highlights the current state of understanding of ALF and, more importantly, asks what further studies are needed to improve our understanding of the pathogenesis, natural history, and management of this unique and dramatic condition.
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Affiliation(s)
| | | | | | - Valerie Durkalski
- Medical University of South Carolina, Charleston, South Carolina, USA
| | | | - Jody A. Rule
- University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
| | - Shannan Tujios
- University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
| | - William M. Lee
- University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
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Benítez C, Arnold J, Cambindo V, Schoenfeldt F, Cancino A, Ibáñez S, Grandy C, Hunfan P, González J, Guerra C, Godoy E, Araneda V, Mollo C, Poniachik J, Urzúa A, Cattaneo M, Roblero JP, Oppenheimer I, Pizarro V. Effect of acute on chronic liver failure over post-transplant survival. Ann Hepatol 2023; 28:101128. [PMID: 37331597 DOI: 10.1016/j.aohep.2023.101128] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 05/06/2023] [Accepted: 05/26/2023] [Indexed: 06/20/2023]
Abstract
INTRODUCTION AND OBJECTIVES Acute-on-chronic liver failure (ACLF) is associated with reduced short-term survival, and liver transplantation is frequently the only therapeutic option. Nonetheless, the post-transplantation prognosis seems to be worse in ACLF patients. MATERIALS AND METHODS The databases of two university centers were retrospectively evaluated, and adult patients with cirrhosis who underwent transplantation between 2013 and 2020 were included. One-year survival of patients with ACLF was compared to that of patients without ACLF. Variables associated with mortality were identified. RESULTS A total of 428 patients were evaluated, and 303 met the inclusion criteria; 57.1% were male, the mean age was 57.1 ± 10.2 years, 75 patients had ACLF, and 228 did not. The main etiologies of ACLF were NASH (36.6%), alcoholic liver disease (13.9%), primary biliary cholangitis (8.6%) and autoimmune hepatitis (7.9%). Mechanical ventilation, renal replacement therapy, the use of vasopressors and the requirement of blood product transfusion during liver transplantation were significantly more frequent in ACLF patients. Among those recipients without and with ACLF, survival at 1, 3 and 5 years was 91.2% vs. 74.7%, 89.1% vs. 72.6% and 88.3% vs. 72.6%, respectively (p=0.001). Among pre-transplantation variables, only the presence of ACLF was independently associated with survival (HR 3.2, 95% CI: 1.46-7.11). Post-transplantation variables independently associated with survival were renal replacement therapy (HR 2.8, 95% CI: 1.1-6.8) and fungal infections (HR 3.26, 95% CI: 1.07-9.9). CONCLUSIONS ACLF is an independent predictor of one-year post-transplantation survival. Importantly, transplant recipients with ACLF require the use of more resources than patients without ACLF.
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Affiliation(s)
- Carlos Benítez
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Marcoleta 367, Santiago, Chile.
| | - Jorge Arnold
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Marcoleta 367, Santiago, Chile
| | - Verónica Cambindo
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Marcoleta 367, Santiago, Chile
| | | | - Alejandra Cancino
- Instituto de Trasplante, Hospital Clínico UC Christus, Lira 40, Santiago, Chile
| | - Samuel Ibáñez
- Escuela de Medicina, Pontificia Universidad Católica de Chile, Marcoleta 367, Santiago, Chile
| | - Catalina Grandy
- Escuela de Medicina, Pontificia Universidad Católica de Chile, Marcoleta 367, Santiago, Chile
| | - Paola Hunfan
- Escuela de Medicina, Pontificia Universidad Católica de Chile, Marcoleta 367, Santiago, Chile
| | - Jorge González
- Escuela de Medicina, Pontificia Universidad Católica de Chile, Marcoleta 367, Santiago, Chile
| | - Catalina Guerra
- Escuela de Medicina, Pontificia Universidad Católica de Chile, Marcoleta 367, Santiago, Chile
| | - Esteban Godoy
- Escuela de Medicina, Pontificia Universidad Católica de Chile, Marcoleta 367, Santiago, Chile
| | - Verónica Araneda
- Escuela de Medicina, Pontificia Universidad Católica de Chile, Marcoleta 367, Santiago, Chile
| | - Constanza Mollo
- Escuela de Medicina, Pontificia Universidad Católica de Chile, Marcoleta 367, Santiago, Chile
| | - Jaime Poniachik
- Departamento de Medicina. Sección Gastroenterología. Hospital Clínico Universidad de Chile, Dr. Carlos Lorca Tobar, Independencia, Chile
| | - Alvaro Urzúa
- Departamento de Medicina. Sección Gastroenterología. Hospital Clínico Universidad de Chile, Dr. Carlos Lorca Tobar, Independencia, Chile
| | - Máximo Cattaneo
- Departamento de Medicina. Sección Gastroenterología. Hospital Clínico Universidad de Chile, Dr. Carlos Lorca Tobar, Independencia, Chile
| | - Juan Pablo Roblero
- Departamento de Medicina. Sección Gastroenterología. Hospital Clínico Universidad de Chile, Dr. Carlos Lorca Tobar, Independencia, Chile
| | - Ilan Oppenheimer
- Escuela de Medicina Universidad de Chile, Avenida Independencia 1077, Independencia, Chile
| | - Vicente Pizarro
- Escuela de Medicina Universidad de Chile, Avenida Independencia 1077, Independencia, Chile
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Harrison SP, Siller R, Tanaka Y, Chollet ME, de la Morena-Barrio ME, Xiang Y, Patterson B, Andersen E, Bravo-Pérez C, Kempf H, Åsrud KS, Lunov O, Dejneka A, Mowinckel MC, Stavik B, Sandset PM, Melum E, Baumgarten S, Bonanini F, Kurek D, Mathapati S, Almaas R, Sharma K, Wilson SR, Skottvoll FS, Boger IC, Bogen IL, Nyman TA, Wu JJ, Bezrouk A, Cizkova D, Corral J, Mokry J, Zweigerdt R, Park IH, Sullivan GJ. Scalable production of tissue-like vascularized liver organoids from human PSCs. Exp Mol Med 2023; 55:2005-2024. [PMID: 37653039 PMCID: PMC10545717 DOI: 10.1038/s12276-023-01074-1] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 04/18/2023] [Accepted: 06/02/2023] [Indexed: 09/02/2023] Open
Abstract
The lack of physiological parity between 2D cell culture and in vivo culture has led to the development of more organotypic models, such as organoids. Organoid models have been developed for a number of tissues, including the liver. Current organoid protocols are characterized by a reliance on extracellular matrices (ECMs), patterning in 2D culture, costly growth factors and a lack of cellular diversity, structure, and organization. Current hepatic organoid models are generally simplistic and composed of hepatocytes or cholangiocytes, rendering them less physiologically relevant compared to native tissue. We have developed an approach that does not require 2D patterning, is ECM independent, and employs small molecules to mimic embryonic liver development that produces large quantities of liver-like organoids. Using single-cell RNA sequencing and immunofluorescence, we demonstrate a liver-like cellular repertoire, a higher order cellular complexity, presenting with vascular luminal structures, and a population of resident macrophages: Kupffer cells. The organoids exhibit key liver functions, including drug metabolism, serum protein production, urea synthesis and coagulation factor production, with preserved post-translational modifications such as N-glycosylation and functionality. The organoids can be transplanted and maintained long term in mice producing human albumin. The organoids exhibit a complex cellular repertoire reflective of the organ and have de novo vascularization and liver-like function. These characteristics are a prerequisite for many applications from cellular therapy, tissue engineering, drug toxicity assessment, and disease modeling to basic developmental biology.
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Affiliation(s)
- Sean P Harrison
- Hybrid Technology Hub-Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
- Department of Pediatric Research, Oslo University Hospital, Oslo, Norway
| | - Richard Siller
- Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Yoshiaki Tanaka
- Department of Genetics, Yale Stem Cell Center, Child Study Center, Yale School of Medicine, New Haven, USA
- Department of Medicine, Faculty of Medicine, Maisonneuve-Rosemont Hospital Research Center (CRHMR), University of Montreal, Montreal, Canada
| | - Maria Eugenia Chollet
- Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
- Department of Haematology, Oslo University Hospital, Oslo, Norway
| | - María Eugenia de la Morena-Barrio
- Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB, CIBERER, Murcia, Spain
| | - Yangfei Xiang
- Department of Genetics, Yale Stem Cell Center, Child Study Center, Yale School of Medicine, New Haven, USA
| | - Benjamin Patterson
- Department of Genetics, Yale Stem Cell Center, Child Study Center, Yale School of Medicine, New Haven, USA
| | - Elisabeth Andersen
- Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
- Department of Haematology, Oslo University Hospital, Oslo, Norway
| | - Carlos Bravo-Pérez
- Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB, CIBERER, Murcia, Spain
| | - Henning Kempf
- Department: Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Hannover Medical School, Hannover, Germany
| | - Kathrine S Åsrud
- Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Oleg Lunov
- Department of Optical and Biophysical Systems, Institute of Physics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Alexandr Dejneka
- Department of Optical and Biophysical Systems, Institute of Physics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Marie-Christine Mowinckel
- Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
- Department of Haematology, Oslo University Hospital, Oslo, Norway
| | - Benedicte Stavik
- Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
- Department of Haematology, Oslo University Hospital, Oslo, Norway
| | - Per Morten Sandset
- Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
- Department of Haematology, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Espen Melum
- Hybrid Technology Hub-Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
- Department of Haematology, Oslo University Hospital, Oslo, Norway
- Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Section for Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
- European Reference Network RARE-LIVER, Hamburg, Germany
| | - Saphira Baumgarten
- Hybrid Technology Hub-Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
- Department of Pediatric Research, Oslo University Hospital, Oslo, Norway
| | | | | | - Santosh Mathapati
- Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Runar Almaas
- Department of Pediatric Research, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- European Reference Network RARE-LIVER, Hamburg, Germany
| | - Kulbhushan Sharma
- Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Steven R Wilson
- Hybrid Technology Hub-Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
- Department of Chemistry, University of Oslo, P.O. Box 1033, Blindern, NO-0315, Oslo, Norway
| | - Frøydis S Skottvoll
- Hybrid Technology Hub-Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
- Department of Chemistry, University of Oslo, P.O. Box 1033, Blindern, NO-0315, Oslo, Norway
| | - Ida C Boger
- Department of Chemistry, University of Oslo, P.O. Box 1033, Blindern, NO-0315, Oslo, Norway
| | - Inger Lise Bogen
- Department of Forensic Sciences, Oslo University Hospital, Oslo, Norway
| | - Tuula A Nyman
- Department of Immunology, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Jun Jie Wu
- Department of Engineering, Faculty of Science, Durham University, Durham, DH1 3LE, United Kingdom
| | - Ales Bezrouk
- Department of Medical Biophysics, Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic
| | - Dana Cizkova
- Department of Histology and Embryology, Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic
| | - Javier Corral
- Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB, CIBERER, Murcia, Spain
| | - Jaroslav Mokry
- Department of Histology and Embryology, Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic
| | - Robert Zweigerdt
- Department: Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Hannover Medical School, Hannover, Germany
| | - In-Hyun Park
- Department of Genetics, Yale Stem Cell Center, Child Study Center, Yale School of Medicine, New Haven, USA
| | - Gareth J Sullivan
- Hybrid Technology Hub-Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
- Department of Pediatric Research, Oslo University Hospital, Oslo, Norway.
- Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
- Department of Immunology, University of Oslo and Oslo University Hospital, Oslo, Norway.
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Biswas S, Shalimar. Liver Transplantation for Acute Liver Failure- Indication, Prioritization, Timing, and Referral. J Clin Exp Hepatol 2023; 13:820-834. [PMID: 37693253 PMCID: PMC10483009 DOI: 10.1016/j.jceh.2023.01.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 01/17/2023] [Indexed: 09/12/2023] Open
Abstract
Acute liver failure (ALF) is a major success story in gastroenterology, with improvements in critical care and liver transplant resulting in significant improvements in patient outcomes in the current era compared to the dismal survival rates in the pretransplant era. However, the ever-increasing list of transplant candidates and limited organ pool makes judicious patient selection and organ use mandatory to achieve good patient outcomes and prevent organ wastage. Several scoring systems exist to facilitate the identification of patients who need a liver transplant and would therefore need an early referral to a specialized liver unit. The timing of the liver transplant is also crucial as transplanting a patient too early would lead to those who would recover spontaneously receiving an organ (wastage), and a late decision might result in the patient becoming unfit for transplant (delisted) or have an advanced disease which would result in poor post-transplant outcomes. The current article reviews the indications and contraindications of liver transplant in ALF patients, the various prognostic scoring systems, etiology-specific outcomes, prioritization and timing of referral.
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Affiliation(s)
- Sagnik Biswas
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences New Delhi, India
| | - Shalimar
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences New Delhi, India
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Shingina A, Mukhtar N, Wakim-Fleming J, Alqahtani S, Wong RJ, Limketkai BN, Larson AM, Grant L. Acute Liver Failure Guidelines. Am J Gastroenterol 2023; 118:1128-1153. [PMID: 37377263 DOI: 10.14309/ajg.0000000000002340] [Citation(s) in RCA: 73] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 04/04/2023] [Indexed: 06/29/2023]
Abstract
Acute liver failure (ALF) is a rare, acute, potentially reversible condition resulting in severe liver impairment and rapid clinical deterioration in patients without preexisting liver disease. Due to the rarity of this condition, published studies are limited by the use of retrospective or prospective cohorts and lack of randomized controlled trials. Current guidelines represent the suggested approach to the identification, treatment, and management of ALF and represent the official practice recommendations of the American College of Gastroenterology. The scientific evidence was reviewed using the Grading of Recommendations, Assessment, Development and Evaluation process to develop recommendations. When no robust evidence was available, expert opinions were summarized using Key Concepts. Considering the variety of clinical presentations of ALF, individualization of care should be applied in specific clinical scenarios.
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Affiliation(s)
- Alexandra Shingina
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Nizar Mukhtar
- Department of Gastroenterology, Kaiser Permanente, San Francisco, California, USA
| | - Jamilé Wakim-Fleming
- Department of Gastroenterology, Hepatology & Nutrition, Digestive Disease and Surgery Institute, Cleveland Clinic Foundation, Cleveland Ohio, USA
| | - Saleh Alqahtani
- Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, Maryland, USA
- Liver Transplantation Unit, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia
| | - Robert J Wong
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, California, Gastroenterology Section, Veterans Affairs Palo Alto Healthcare System, Palo Alto, California, USA
| | | | - Anne M Larson
- Division of Gastroenterology and Hepatology, University of Washington, Seattle, Washington, USA
| | - Lafaine Grant
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, Texas, USA
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Lenz D, Hørby Jørgensen M, Kelly D, Cardinale V, Geerts A, Gonçalves Costa I, Fichtner A, Garbade SF, Hegen B, Hilberath J, de Kleine R, Kupčinskas L, McLin V, Niesert M, Prado Gonzalez V, Sturm E, Staufner C, Tjwa E, Willemse J, Zecher BF, Larsen FS, Sebode M, Ytting H. Etiology and Outcome of Adult and Pediatric Acute Liver Failure in Europe. J Pediatr Gastroenterol Nutr 2023; 77:115-120. [PMID: 36930963 DOI: 10.1097/mpg.0000000000003777] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/19/2023]
Abstract
Acute liver failure (ALF) is rare but life-threatening. Common causes include intoxications, infections, and metabolic disorders. Indeterminate etiology is still frequent. No systematic data on incidence, causes, and outcome of ALF across Europe are available. Via an online survey we reached out to European Reference Network Centers on rare liver diseases. Numbers and etiology of ALF cases during 2020 were retrieved and diagnostic and treatment availabilities assessed. In total, 455 cases (306 adult, 149 pediatric) were reported from 36 centers from 20 countries. Intoxication was the most common cause in adult and pediatric care. The number of cases with indeterminate etiology is low. Diagnostic tools and specific treatment options are broadly available within this network. This is the first approach to report on etiology and outcome of ALF in the pediatric and adult population in Europe. High diagnostic yield and standard of care reflects the expert status of involved centers.
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Affiliation(s)
- Dominic Lenz
- From the Department of Pediatrics I, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Marianne Hørby Jørgensen
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
- the Department of Pediatrics and Adolescent Medicine, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark
| | - Deirdre Kelly
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
- the Liver Unit, Birmingham Women's and Children's Hospital, University of Birmingham, Birmingham, United Kingdom
| | - Vincenzo Cardinale
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
- the Medical-Surgical and Biotechnologies Sciences, Polo Pontino, Sapienza University of Rome, Latina, Italy
| | - Anja Geerts
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
- the Hepatology Research Unit, Department of Internal Medicine and Paediatrics, Liver Research Center Ghent, Ghent University, Ghent, Belgium
| | - Isabel Gonçalves Costa
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
- the Unidade de Hepatologia e Transplantação Hepática Pediátrica, Hospital Pediátrico de Coimbra, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Alexander Fichtner
- From the Department of Pediatrics I, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Sven F Garbade
- From the Department of Pediatrics I, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Bianca Hegen
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
- University Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Johannes Hilberath
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
- Paediatric Gastroenterology/Hepatology, University Hospital Tuebingen, Tuebingen, Germany
| | - Ruben de Kleine
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
- the Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Limas Kupčinskas
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
- Institute for Digestive Research and Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Valérie McLin
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
- the Swiss Pediatric Liver Center, Division of Pediatric Specialties, Department of Pediatrics, Gynecology and Obstetrics, University Hospitals Geneva and University of Geneva, Geneva, Switzerland
| | - Moritz Niesert
- From the Department of Pediatrics I, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Veronica Prado Gonzalez
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
- Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg
| | - Ekkehard Sturm
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
- Paediatric Gastroenterology/Hepatology, University Hospital Tuebingen, Tuebingen, Germany
| | - Christian Staufner
- From the Department of Pediatrics I, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Eric Tjwa
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
- the Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - José Willemse
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
- Dutch Liver Patient Association (NLV), Hoogland, The Netherlands
| | - Britta F Zecher
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
- the I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Fin Stolze Larsen
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
- the Department of Gastroenterology and Hepatology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Marcial Sebode
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
- the I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Henriette Ytting
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
- the Gastro Unit, Medical Division, Hvidovre University Hospital, Copenhagen, Denmark
- the Department of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
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Özbilgin M, Egeli T, Ağalar C, Özkardeşler S, Oğuz VA, Akarsu M, Sağol Ö, Ünek T, Karademir S, Astarcıoğlu I. Complications and Long-Term Outcomes in Adult Patients Undergoing Living Donor Liver Transplantation Because of Fulminant Hepatitis. Transplant Proc 2023; 55:1186-1192. [PMID: 37137763 DOI: 10.1016/j.transproceed.2023.01.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 01/05/2023] [Indexed: 05/05/2023]
Abstract
BACKGROUND The present study investigates the complications that may occur during long-term follow-up in patients aged 18 years and older undergoing living donor liver transplantation (LDLT) in our clinic because of fulminant hepatitis. METHODS The study included patients aged 18 years and older with a minimum survival of 6 months who underwent an LDLT between June 2000 and June 2017. The demographic data of the patients were evaluated in terms of late-term complications. RESULTS Of the 240 patients who met the study criteria, 8 (3.3%) underwent LDLT for fulminant hepatitis. The indication for transplantation in patients with fulminant hepatitis was cryptogenic liver hepatitis in 4 patients, acute hepatitis B infection in 2 patients, hemochromatosis in 1 patient, and toxic hepatitis in 1 patient. Of the 240 patients, 65 (27%) undergoing LDLT underwent a liver biopsy for suspected rejection because of an elevation in liver function test results during follow-up. Histopathologic scoring was carried out according to the Banff scoring system. A diagnosis of late acute rejection was made in only 1 of the 8 patients (12.5%) who underwent LDLT for fulminant hepatitis. CONCLUSION Patients with fulminant hepatitis must be prepared for an LDLT, if available, while waiting for a cadaveric donor. The results of the present study suggest that LDLTs in patients with fulminant hepatitis are safe, and the outcomes are acceptable in terms of survival and complications.
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Affiliation(s)
- Mücahit Özbilgin
- Department of General Surgery, Dokuz Eylül University Hospital, Hepatobiliary Surgery and Liver Transplantation Unit, Izmir, Turkey.
| | - Tufan Egeli
- Department of General Surgery, Dokuz Eylül University Hospital, Hepatobiliary Surgery and Liver Transplantation Unit, Izmir, Turkey
| | - Cihan Ağalar
- Department of General Surgery, Dokuz Eylül University Hospital, Hepatobiliary Surgery and Liver Transplantation Unit, Izmir, Turkey
| | - Sevda Özkardeşler
- Department of Anesthesiology and Reanimation, Dokuz Eylül University Hospital, Izmir, Turkey
| | - Vildan Avkan Oğuz
- Department of Infectious Diseases, Dokuz Eylül University Hospital, Izmir, Turkey
| | - Mesut Akarsu
- Department of Gastroenterology, Dokuz Eylül University Hospital, Izmir, Turkey
| | - Özgül Sağol
- Department of Pathology, Dokuz Eylül University Hospital, Izmir, Turkey
| | - Tarkan Ünek
- Department of General Surgery, Dokuz Eylül University Hospital, Hepatobiliary Surgery and Liver Transplantation Unit, Izmir, Turkey
| | - Sedat Karademir
- Department of General Surgery, Güven Hospital, Ankara, Turkey
| | - Ibrahim Astarcıoğlu
- Department of General Surgery, Memorial Bahçelievler Hospital, Istanbul, Turkey
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Belicard F, Pinceaux K, Le Pabic E, Coirier V, Delamaire F, Painvin B, Lesouhaitier M, Maamar A, Guillot P, Quelven Q, Houssel P, Boudjema K, Reizine F, Camus C. Bacterial and fungal infections: a frequent and deadly complication among critically ill acute liver failure patients. Infect Dis (Lond) 2023:1-10. [PMID: 37211670 DOI: 10.1080/23744235.2023.2213326] [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: 03/31/2023] [Revised: 05/03/2023] [Accepted: 05/07/2023] [Indexed: 05/23/2023] Open
Abstract
BACKGROUND Acute liver failure (ALF) is a rare but life-threatening condition mostly requiring intensive care unit (ICU) admission. ALF induces immune disorders and may promote infection acquisition. However, the clinical spectrum and impact on patients' prognosis remain poorly explored. METHODS We conducted a retrospective single-centre study on patients admitted for ALF to the ICU of a referral University Hospital from 2000 to 2021. Baseline characteristics and outcomes according to the presence of infection until day 28 were analysed. Risk factors for infection were determined using logistic regression. The impact of infection on 28-day survival was assessed using the proportional hazard Cox model. RESULTS Of the 194 patients enrolled, 79 (40.7%) underwent infection: community-acquired, hospital-acquired before ICU and ICU-acquired before/without and after transplant in 26, 23, 23 and 14 patients, respectively. Most infections were pneumonia (41.4%) and bloodstream infection (38.8%). Of a total of 130 microorganisms identified, 55 were Gram-negative bacilli (42.3%), 48 Gram-positive cocci (36.9%) and 21 were fungi (16.2%). Obesity (OR 3.77 [95% CI 1.18-14.40]; p = .03) and initial mechanical ventilation (OR 2.26 [95% CI 1.25-4.12]; p = .007) were independent factors associated with overall infection. SAPSII > 37 (OR 3.67 [95% CI 1.82-7.76], p < .001) and paracetamol aetiology (OR 2.10 [95% CI 1.06-4.22], p = .03) were independently associated with infection at admission to ICU. On the opposite, paracetamol aetiology was associated with lower risk of ICU-acquired infection (OR 0.37 [95% CI 0.16-0.81], p = .02). Patients with any type of infection had lower day 28 survival rates (57% versus 73%; HR 1.65 [1.01-2.68], p = .04). The presence of infection at ICU admission (p = .04), but not ICU-acquired infection, was associated with decreased survival. CONCLUSIONS The prevalence of infection is high in ALF patients which is associated with a higher risk of death. Further studies assessing the use of early antimicrobial therapy are needed.
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Affiliation(s)
- Félicie Belicard
- CHU Rennes, Maladies Infectieuses et Réanimation Médicale, Rennes, France
| | - Kieran Pinceaux
- CHU Rennes, Maladies Infectieuses et Réanimation Médicale, Rennes, France
| | | | - Valentin Coirier
- CHU Rennes, Maladies Infectieuses et Réanimation Médicale, Rennes, France
| | - Flora Delamaire
- CHU Rennes, Maladies Infectieuses et Réanimation Médicale, Rennes, France
| | - Benoît Painvin
- CHU Rennes, Maladies Infectieuses et Réanimation Médicale, Rennes, France
| | | | - Adel Maamar
- CHU Rennes, Maladies Infectieuses et Réanimation Médicale, Rennes, France
| | - Pauline Guillot
- CHU Rennes, Maladies Infectieuses et Réanimation Médicale, Rennes, France
| | - Quentin Quelven
- CHU Rennes, Maladies Infectieuses et Réanimation Médicale, Rennes, France
| | | | - Karim Boudjema
- CHU Rennes, Service de Chirurgie Hépatobiliaire et Digestive, Rennes, France
| | - Florian Reizine
- CHU Rennes, Maladies Infectieuses et Réanimation Médicale, Rennes, France
- CH Vannes, Service de Réanimation Polyvalente, Vannes, France
| | - Christophe Camus
- CHU Rennes, Maladies Infectieuses et Réanimation Médicale, Rennes, France
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Hosack T, Damry D, Biswas S. Drug-induced liver injury: a comprehensive review. Therap Adv Gastroenterol 2023; 16:17562848231163410. [PMID: 36968618 PMCID: PMC10031606 DOI: 10.1177/17562848231163410] [Citation(s) in RCA: 67] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 02/24/2023] [Indexed: 03/24/2023] Open
Abstract
Drug-induced liver injury (DILI) remains a challenge in clinical practice and is
still a diagnosis of exclusion. Although it has a low incidence amongst the
general population, DILI accounts for most cases of acute liver failure with a
fatality rate of up to 50%. While multiple mechanisms of DILI have been
postulated, there is no clear causal relationship between drugs, risk factors
and mechanisms of DILI. Current best practice relies on a combination of high
clinical suspicion, thorough clinical history of risk factors and timeline, and
extensive hepatological investigations as supported by the international Roussel
Uclaf Causality Assessment Method criteria, the latter considered a key
diagnostic algorithm for DILI. This review focuses on DILI classification, risk
factors, clinical evaluation, future biomarkers and management, with the aim of
facilitating physicians to correctly identify DILI early in presentation.
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Affiliation(s)
| | - Djamil Damry
- Department of Gastroenterology &
Hepatology, Stoke Mandeville Hospital, Buckinghamshire Health NHS Trust,
Aylesbury, Buckinghamshire, UK
| | - Sujata Biswas
- Department of Gastroenterology &
Hepatology, Stoke Mandeville Hospital, Buckinghamshire Health NHS Trust,
Aylesbury, Buckinghamshire, UK
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Karvellas CJ, Leventhal TM, Rakela JL, Zhang J, Durkalski V, Reddy KR, Fontana RJ, Stravitz RT, Lake JR, Lee WM, Parekh JR. Outcomes of patients with acute liver failure listed for liver transplantation: A multicenter prospective cohort analysis. Liver Transpl 2023; 29:318-330. [PMID: 35980605 PMCID: PMC10662679 DOI: 10.1002/lt.26563] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 07/10/2022] [Accepted: 07/27/2022] [Indexed: 01/12/2023]
Abstract
Liver transplantation (LT) is a life-saving treatment for patients with acute liver failure (ALF). Currently, there are few detailed data regarding long-term outcomes after LT for ALF. We combined prospective data from the Acute Liver Failure Study Group (ALFSG) Registry with those of the Scientific Registry of Transplant Recipients (SRTR) to assess outcomes among consecutive patients with ALF listed for LT. Cohort analysis of detailed pretransplantation data for patients listed for LT for ALF in the ALFSG Registry between January 1998 and October 2018 matched with transplantation-related data from the SRTR. Primary outcomes were 1- and 3-year post-LT patient survival. Secondary outcome was receipt of LT; independent associations with successful receipt of LT were determined using multivariable logistic regression. Of 624 patients with ALF listed for LT, 398 (64%) underwent LT, 100 (16%) died without LT, and 126 (20%) recovered spontaneously. Among LT recipients, etiologies included seronegative/indeterminate (22%), drug-induced liver injury (18%), acetaminophen overdose (APAP; 16%), and viral hepatitis (15%). The 1- and 3-year post-LT patient survival rates were 91% and 90%, respectively. Comparing those dying on the waiting list versus with those who received LT, the former had more severe multiorgan failure, reflected by increased vasopressor use (65% vs. 22%), mechanical ventilation (84% vs. 57%), and renal replacement therapy (57% vs. 30%; p < 0.0001 for all). After adjusting for relevant covariates, age (adjusted odds ratio [aOR] 1.02, 95% confidence interval [CI] 1.00-1.04), APAP etiology (aOR 2.72, 95% CI 1.42-5.23), requirement for vasopressors (aOR 4.19, 95% CI 2.44-7.20), Grade III/IV hepatic encephalopathy (aOR 2.47, 95% CI 1.29-4.72), and Model for End-Stage Liver Disease (MELD) scores (aOR 1.05, 95% CI 1.02-1.09; p < 0.05 for all) were independently associated with death without receipt of LT. Post-LT outcomes for ALF are excellent in this cohort of very ill patients. The development of multiorgan failure while on the transplantation list and APAP ALF etiology were associated with a lower likelihood of successful receipt of LT.
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Affiliation(s)
- Constantine J Karvellas
- Division of Gastroenterology (Liver Unit), Department of Critical Care Medicine , University of Alberta , Edmonton , Alberta , Canada
| | - Thomas M Leventhal
- Division of Gastroenterology, Hepatology, and Nutrition , University of Minnesota , Minneapolis , Minnesota , USA
| | - Jorge L Rakela
- Division of Gastroenterology and Hepatology , Mayo Clinic Arizona , Phoenix , Arizona , USA
| | - Jingwen Zhang
- Department of Public Health Sciences , Medical University of South Carolina , Charleston , South Carolina , USA
| | - Valerie Durkalski
- Department of Public Health Sciences , Medical University of South Carolina , Charleston , South Carolina , USA
| | - K Rajender Reddy
- Division of Gastroenterology and Hepatology , University of Pennsylvania , Philadelphia , Pennsylvania , USA
| | - Robert J Fontana
- Division of Gastroenterology, Department of Internal Medicine , University of Michigan Medical Center , Ann Arbor , Michigan , USA
| | - R Todd Stravitz
- Hume-Lee Transplant Center , Virginia Commonwealth University , Richmond , Virginia , USA
| | - John R Lake
- Division of Gastroenterology, Hepatology, and Nutrition , University of Minnesota , Minneapolis , Minnesota , USA
- Scientific Registry of Transplant Recipients , Minneapolis , Minnesota , USA
| | - William M Lee
- Division of Digestive and Liver Diseases , University of Texas Southwestern Medical Center at Dallas , Dallas , Texas , USA
| | - Justin R Parekh
- Department of Surgery , University of California, San Diego , San Diego , California , USA
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Rao A, Rule JA, Cerro-Chiang G, Stravitz RT, McGuire BM, Lee G, Fontana RJ, Lee WM. Role of Hepatitis C Infection in Acute Liver Injury/Acute Liver Failure in North America. Dig Dis Sci 2023; 68:304-311. [PMID: 35546205 PMCID: PMC9094131 DOI: 10.1007/s10620-022-07524-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 04/18/2022] [Indexed: 02/01/2023]
Abstract
BACKGROUND While hepatitis A and B are well-known causes of acute liver failure (ALF), few well-documented cases of hepatitis C virus (HCV) infection (absent preexisting liver disease or other liver insults) have been described that result in ALF. We reviewed the Acute Liver Failure Study Group registry for evidence of HCV as a primary or contributing cause to ALF. METHODS From January 1998 to January 2017, 2,332 patients with ALF (INR ≥ 1.5, any degree of hepatic encephalopathy) and 667 with acute liver injury (ALI; INR ≥ 2.0, no hepatic encephalopathy) were enrolled. Anti-HCV testing was done routinely, with confirmatory RT-PCR testing for HCV RNA where necessary. RESULTS A total of 136 patients were anti-HCV-antibody positive, as follows: 56 HCV RNA negative, 65 HCV RNA positive, and 8 with no result nor sera available for testing. Only three subjects with ALI/ALF were determined to represent acute HCV infection. Case 1: 47-year-old female with morbid obesity (BMI 52.4) developed ALF and recovered, experiencing anti-HCV seroconversion. Case 2: 37-year-old female using cocaine presented with ALI and fully recovered. Case 3: 54-year-old female developed ALF requiring transplantation and was anti-HCV negative but viremic prior to transplant experiencing anti-HCV seroconversion thereafter. Among 1636 APAP overdose patients, the 52 with concomitant chronic HCV had higher 3-week mortality than the 1584 without HCV (31% vs 17%, p = 0.01). CONCLUSIONS ALI/ALF solely related to acute hepatitis C infection is very rare. Chronic HCV infection, found in at least 65 (2.2%) of ALI/ALF patients studied, contributed to more severe outcomes in APAP ALI/ALF; ClinicalTrials.gov number, NCT000518440. Trial Registration ClinicalTrials.gov number NCT000518440.
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Affiliation(s)
- Ashwin Rao
- Division of Digestive and Liver Diseases, Department of Internal Medicine, UT Southwestern Medical Center at Dallas, 5959 Harry Hines Blvd. Ste. 420, Dallas, TX, 75390-8887, USA
| | - Jody A Rule
- Division of Digestive and Liver Diseases, Department of Internal Medicine, UT Southwestern Medical Center at Dallas, 5959 Harry Hines Blvd. Ste. 420, Dallas, TX, 75390-8887, USA
| | - Giuliana Cerro-Chiang
- Division of Pulmonary Critical Care, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Richard T Stravitz
- Lee-Hume Transplant Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Brendan M McGuire
- Division of Gastroenterology, University of Alabama, Birmingham, AL, USA
| | - Goo Lee
- Division of Anatomic Pathology, University of Alabama, Birmingham, AL, USA
| | - Robert J Fontana
- Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - William M Lee
- Division of Digestive and Liver Diseases, Department of Internal Medicine, UT Southwestern Medical Center at Dallas, 5959 Harry Hines Blvd. Ste. 420, Dallas, TX, 75390-8887, USA.
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Bittermann T, Lewis JD, Goldberg DS. Recipient and Center Factors Associated With Immunosuppression Practice Beyond the First Year After Liver Transplantation and Impact on Outcomes. Transplantation 2022; 106:2182-2192. [PMID: 35706103 PMCID: PMC9613480 DOI: 10.1097/tp.0000000000004209] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Immunosuppression is a critical aspect of post-transplant management, yet practices at intermediate and late time points after liver transplantation (LT) are poorly characterized. METHODS A retrospective cohort of 11 326 adult first LT alone recipients between 2007 and 2016 was identified by linking United Network for Organ Sharing transplant data to Medicare administrative claims. The immunosuppression regimen was obtained from Medicare billing claims. Factors associated with calcineurin inhibitor (CNI) monotherapy at 1-, 3-, and 5-y post-LT were investigated using mixed-effects logistic regression. Center practice heterogeneity was evaluated. The association of immunosuppression regimen (time-updating) with patient and graft survival was studied. RESULTS CNI monotherapy was used in 51.9% at 1-y post-LT and 68.6% at 5-y post-LT. Center-specific rates ranged from 20.0%-79.9% to 15.4%-95.2%, respectively. CNI monotherapy at 1- and 3-y post-LT was less likely among Black recipients ( P = 0.027 and P = 0.015 versus White, respectively). CNI plus antimetabolite was associated with improved adjusted patient (hazard ratio, 0.59; P < 0.001) and graft (hazard ratio, 0.62; P < 0.001) survival versus CNI monotherapy. The benefit of CNI plus antimetabolite on patient and graft survival increased with older age. CONCLUSIONS In this first longitudinal analysis of LT immunosuppression practices among Medicare beneficiaries, a CNI plus antimetabolite approach led to improved outcomes. Significant center heterogeneity in practice was observed.
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Affiliation(s)
- Therese Bittermann
- Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
- Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - James D Lewis
- Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
- Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - David S Goldberg
- Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, Miami, FL
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Luo L, Wang S, Chen B, Zhong M, Du R, Wei C, Huang F, Kou X, Xing Y, Tong G. Inhibition of inflammatory liver injury by the HMGB1-A box through HMGB1/TLR-4/NF-κB signaling in an acute liver failure mouse model. Front Pharmacol 2022; 13:990087. [PMID: 36313316 PMCID: PMC9614247 DOI: 10.3389/fphar.2022.990087] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Accepted: 09/29/2022] [Indexed: 11/17/2022] Open
Abstract
We aimed to investigate the preventive effect of high mobility group box 1 (HMGB1)-A box and the mechanism by which it alleviates inflammatory injury in acute liver failure (ALF) by inhibiting the extracellular release of HMGB1. BALB/c mice were intraperitoneally (i.p.) administered LPS/D-GalN to establish an ALF mouse model. HMGB1-A box was administered (i.p.) 1 h before establishing the ALF mouse model. The levels of extracellularly released HMGB1, TLR-4/NF-κB signaling molecules, the proinflammatory cytokines TNF-α, IL-1β, and IL-6 and COX-2 were measured in the liver tissue and/or serum by Immunohistochemistry, Western blotting and Enzyme-linked immunosorbent assay (ELISA). The levels of extracellularly released HMGB1, TLR-4/NF-κB signaling molecules and proinflammatory cytokines were measured in Huh7 cells as well as LPS- and/or HMGB1-A box treatment by confocal microscopy, Western blotting and ELISA. In the ALF mouse model, the levels of HMGB1 were significantly increased both in the liver and serum, TLR-4/NF-κB signaling molecules and proinflammatory cytokines also was upregulated. Notably, HMGB1-A box could reverse these changes. HMGB1-A box could also cause these changes in LPS-induced Huh7 cells. HMGB1-A box played a protective role by inhibiting inflammatory liver injury via the regulation of HMGB1/TLR-4/NF-κB signaling in the LPS/D-GaIN-induced ALF mouse model, which may be related to inhibiting the extracellular release of HMGB1.
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Affiliation(s)
- Lidan Luo
- Department of Hepatology, The Fourth Clinical Medical College of Guangzhou University of Traditional Chinese Medicine, Shenzhen, China
| | - Shuai Wang
- Department of Hepatology, The Fourth Clinical Medical College of Guangzhou University of Traditional Chinese Medicine, Shenzhen, China
| | - Bohao Chen
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital Affiliated to Nanjing University of Chinese Medicine, Shenzhen, China
| | - Mei Zhong
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital Affiliated to Nanjing University of Chinese Medicine, Shenzhen, China
| | - Ruili Du
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital Affiliated to Nanjing University of Chinese Medicine, Shenzhen, China
| | - ChunShan Wei
- Department of Hepatology, The Fourth Clinical Medical College of Guangzhou University of Traditional Chinese Medicine, Shenzhen, China
| | - Furong Huang
- Department of Hepatology, The Fourth Clinical Medical College of Guangzhou University of Traditional Chinese Medicine, Shenzhen, China
- Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao, China
| | - Xinhui Kou
- Department of Hepatology, The Fourth Clinical Medical College of Guangzhou University of Traditional Chinese Medicine, Shenzhen, China
| | - Yufeng Xing
- Department of Hepatology, The Fourth Clinical Medical College of Guangzhou University of Traditional Chinese Medicine, Shenzhen, China
| | - Guangdong Tong
- Department of Hepatology, The Fourth Clinical Medical College of Guangzhou University of Traditional Chinese Medicine, Shenzhen, China
- Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao, China
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Nie YZ, Zheng YW, Taniguchi H. Improving the repopulation capacity of elderly human hepatocytes by decoding aging-associated hepatocyte plasticity. Hepatology 2022; 76:1030-1045. [PMID: 35243665 DOI: 10.1002/hep.32443] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 02/15/2022] [Accepted: 03/01/2022] [Indexed: 12/08/2022]
Abstract
BACKGROUND AND AIMS The loss of liver regenerative capacity is the most dramatic age-associated alteration. Because of an incomplete mechanistic understanding of the liver aging process, a successful therapeutic strategy to improve liver regeneration in the elderly has not been developed so far. Hepatocyte plasticity is a principal mechanism for producing new hepatocytes and cholangiocytes during regeneration. This study aims to promote the repopulation capacity of elderly hepatocytes by decoding the underlying mechanism about the regulation of aging on human hepatocyte plasticity. APPROACH AND RESULTS To understand the age-related mechanisms, we established a hepatocyte aging model from human-induced pluripotent stem cells and developed a method for ex vivo characterization of hepatocyte plasticity. We found that hepatocyte plasticity was gradually diminished with aging, and the impaired plasticity was caused by age-induced histone hypoacetylation. Notably, selective inhibition of histone deacetylases could markedly restore aging-impaired plasticity. Based on these findings, we successfully improved the plasticity of elderly primary human hepatocytes that enhanced their repopulation capacity in the liver injury model. CONCLUSIONS This study suggests that age-induced histone hypoacetylation impairs hepatocyte plasticity, and hepatocyte plasticity might be a therapeutic target for promoting the regenerative capacity of the elderly liver.
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Affiliation(s)
- Yun-Zhong Nie
- Department of Regenerative MedicineYokohama City University Graduate School of MedicineYokohamaKanagawaJapan
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical ScienceThe University of TokyoMinato-ku, TokyoJapan
| | - Yun-Wen Zheng
- Department of Regenerative MedicineYokohama City University Graduate School of MedicineYokohamaKanagawaJapan
- Guangdong Provincial Key Laboratory of Large Animal Models for BiomedicineSchool of Biotechnology and Heath SciencesWuyi UniversityJiangmenGuangdongChina
- Department of Medicinal and Life Sciences, Faculty of Pharmaceutical SciencesTokyo University of ScienceNodaChibaJapan
- Institute of Regenerative MedicineAffiliated Hospital of Jiangsu UniversityJiangsu UniversityZhenjiangJiangsuChina
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Faculty of MedicineUniversity of TsukubaTsukubaIbarakiJapan
| | - Hideki Taniguchi
- Department of Regenerative MedicineYokohama City University Graduate School of MedicineYokohamaKanagawaJapan
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical ScienceThe University of TokyoMinato-ku, TokyoJapan
- Advanced Medical Research CenterYokohama City University Graduate School of MedicineYokohamaKanagawaJapan
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Perez Ruiz de Garibay A, Kortgen A, Leonhardt J, Zipprich A, Bauer M. Critical care hepatology: definitions, incidence, prognosis and role of liver failure in critically ill patients. Crit Care 2022; 26:289. [PMID: 36163253 PMCID: PMC9511746 DOI: 10.1186/s13054-022-04163-1] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 09/10/2022] [Indexed: 01/11/2023] Open
Abstract
AbstractOrgan dysfunction or overt failure is a commonplace event in the critically ill affecting up to 70% of patients during their stay in the ICU. The outcome depends on the resolution of impaired organ function, while a domino-like deterioration of organs other than the primarily affected ones paves the way for increased mortality. “Acute Liver Failure” was defined in the 1970s as a rare and potentially reversible severe liver injury in the absence of prior liver disease with hepatic encephalopathy occurring within 8 weeks. Dysfunction of the liver in general reflects a critical event in “Multiple Organ Dysfunction Syndrome” due to immunologic, regulatory and metabolic functions of liver parenchymal and non-parenchymal cells. Dysregulation of the inflammatory response, persistent microcirculatory (hypoxic) impairment or drug-induced liver injury are leading problems that result in “secondary liver failure,” i.e., acquired liver injury without underlying liver disease or deterioration of preexisting (chronic) liver disease (“Acute-on-Chronic Liver Failure”). Conventional laboratory markers, such as transaminases or bilirubin, are limited to provide insight into the complex facets of metabolic and immunologic liver dysfunction. Furthermore, inhomogeneous definitions of these entities lead to widely ranging estimates of incidence. In the present work, we review the different definitions to improve the understanding of liver dysfunction as a perpetrator (and therapeutic target) of multiple organ dysfunction syndrome in critical care.
Graphic Abstract
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Abstract
Abbreviated pathogenesis and clinical course of the acute liver failure syndrome. The pathogenesis and clinical course of the syndrome of acute liver failure (ALF) differs depending upon the etiology of the primary liver injury. In turn, the severity of the liver injury and resulting synthetic failure is often the primary determinant of whether a patient is referred for emergency liver transplantation. Injuries by viral etiologies trigger the innate immune system via pathogen-associated molecular patterns (PAMPs), while toxin-induced (and presumably ischemia-induced) injuries do so via damage-associated molecular patterns (DAMPs). The course of the clinical syndrome further depends upon the relative intensity and composition of cytokine release, resulting in an early proinflammatory phenotype (SIRS) and later compensatory anti-inflammatory response phenotype (CARS). The outcomes of overwhelming immune activation are the systemic (extrahepatic) features of ALF (cardiovascular collapse, cerebral edema, acute kidney injury, respiratory failure, sepsis) which ultimately determine the likelihood of death.Acute liver failure (ALF) continues to carry a high risk of mortality or the need for transplantation despite recent improvements in overall outcomes over the past two decades. Optimal management begins with identifying that liver failure is indeed present and its etiology, since outcomes and the need for transplantation vary widely across the different etiologies. Most causes of ALF can be divided into hyperacute (ischemia and acetaminophen) and subacute types (other etiologies), based on time of evolution of signs and symptoms of liver failure; the former evolve in 3 to 4 days and the latter typically in 2 to 4 weeks. Both involve intense release of cytokines and hepatocellular contents into the circulation with multiorgan effects/consequences.Management involves optimizing fluid balance and cardiovascular support, including the use of continuous renal replacement therapy, vasopressors, and pulmonary ventilation. Early evaluation for liver transplantation is advised particularly for acetaminophen toxicity, which evolves so rapidly that delay is likely to lead to death.Vasopressor support, high-grade hepatic encephalopathy, and unfavorable (subacute) etiologies heighten the need for urgent listing for liver transplantation. Prognostic scores such as Kings Criteria, Model for End-Stage Liver Disease, and the Acute Liver Failure Group prognostic index take these features into account and provide reasonable but imperfect predictive accuracy. Future treatments may include liver support devices and/or agents that improve hepatocyte regeneration.
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Affiliation(s)
- Shannan Tujios
- Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas
| | - R. Todd Stravitz
- Section of Hepatology, Department of Internal Medicine, Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, Virginia
| | - William M. Lee
- Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas
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Keeling SS, McDonald MF, Anand A, Handing GE, Prather LL, Christmann CR, Jalal PK, Kanwal F, Cholankeril G, Goss JA, Rana A. Significant improvements, but consistent disparities in survival for African Americans after liver transplantation. Clin Transplant 2022; 36:e14646. [PMID: 35304775 PMCID: PMC9310351 DOI: 10.1111/ctr.14646] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 02/20/2022] [Accepted: 03/06/2022] [Indexed: 11/28/2022]
Abstract
Despite improvements in survival across races in the past 20 years, African Americans have worse liver transplant outcomes after orthotopic liver transplantation (OLT). This study aims at quantifying the change in disparities between African Americans and other races in survival after OLT. We retrospectively analyzed the United Network for Organ Sharing (UNOS) database for patient data for candidates who received a liver transplant between January 1, 2007 and December 31, 2017. Multivariate Cox proportional hazards regression indicated similar decreases in mortality over time for each race with a decrease in mortality for African Americans: 2010-2012 (HR = .930), 2012-2015 (HR = .882), and 2015-2017 (HR = .883) when compared to 2007-2010. Risk of mortality for African Americans compared to Caucasians varied across the 4 eras: 2007-2010 (HR = 1.083), 2010-2012 (HR = 1.090), 2012-2015 (HR = 1.070), and 2015-2017 (HR = 1.125). While African Americans have seen increases in survival in the past decade, a similar increase in survival for other races leaves a significant survival disparity in African Americans.
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Affiliation(s)
| | - Malcolm F. McDonald
- Department of Student Affairs, Baylor College of Medicine, Houston, Texas, USA
| | - Adrish Anand
- Department of Student Affairs, Baylor College of Medicine, Houston, Texas, USA
| | - Greta E. Handing
- Department of Student Affairs, Baylor College of Medicine, Houston, Texas, USA
| | - Lyndsey L. Prather
- Department of Student Affairs, Baylor College of Medicine, Houston, Texas, USA
| | | | - Prasun K. Jalal
- Division of Abdominal Transplant, Michael E DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, USA
| | - Fasiha Kanwal
- Division of Abdominal Transplant, Michael E DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, USA
| | - George Cholankeril
- Division of Abdominal Transplant, Michael E DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, USA
| | - John A. Goss
- Division of Abdominal Transplant, Michael E DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, USA
| | - Abbas Rana
- Division of Abdominal Transplant, Michael E DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, USA
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Wong NZ, Reddy KR, Bittermann T. Acute Liver Failure Etiology Is an Independent Predictor of Waitlist Outcome but Not Posttransplantation Survival in a National Cohort. Liver Transpl 2022; 28:39-50. [PMID: 34081838 PMCID: PMC8639833 DOI: 10.1002/lt.26187] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 05/22/2021] [Accepted: 05/26/2021] [Indexed: 01/03/2023]
Abstract
The impact of acute liver failure (ALF) etiology on waitlist (WL) and posttransplantation outcomes, independent of severity of illness, is incompletely characterized. All adults (n = 1691) listed for primary liver transplantation (LT) between 2002 and 2019 with ALF due to acetaminophen toxicity (APAP), drug-induced liver injury (DILI), autoimmune hepatitis (AIH), and hepatitis B virus (HBV) were identified in the United Network for Organ Sharing database. ALF etiology was evaluated as an independent predictor of WL mortality and spontaneous survival (SS; versus outcome of LT), as well as post-LT overall survival, graft survival, and in-hospital mortality using multivariable models accounting for differences in clinical parameters at listing. Accounting for severity of illness at listing, WL mortality and SS for DILI, AIH, and HBV were each lower than those for APAP toxicity (adjusted relative risk ratio <1 in all analyses with P < 0.001 for both outcomes). ALF etiology was not associated with adjusted overall survival after LT (P = 0.09) or graft survival (P = 0.13). Inpatient mortality rate after LT was high at 9.0%. While ALF etiology was also not associated with adjusted inpatient mortality (P = 0.42), cause of death (COD) was different. For example, the rate of post-LT brain death was 5.3% for APAP toxicity, 3.0% for other DILI, 1.1% for AIH, and 3.0% for HBV (P = 0.02). ALF etiology is an independent predictor of WL outcome, even after adjusting for severity of illness, but is not associated with post-LT outcomes with the exception of COD. The majority of post-LT deaths for all ALF etiologies studied occurred during the index hospital stay, suggesting a continued need for enhanced prognostic tools to ensure efficient organ utilization and ALF- and etiology-specific post-LT care to prevent brain death.
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Affiliation(s)
- Natalie Z. Wong
- Department of Internal Medicine, University of Pennsylvania, Philadelphia, PA
| | - K. Rajender Reddy
- Division of Gastroenterology / Transplant Hepatology, University of Pennsylvania, Philadelphia, PA
| | - Therese Bittermann
- Division of Gastroenterology / Transplant Hepatology, University of Pennsylvania, Philadelphia, PA,Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA
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Cardoso FS, Mcphail MJ, Karvellas CJ, Fuhrmann V, Germano N, Auzinger G. Variation in the Care of Acute Liver Failure: A Survey of Intensive Care Professionals. GE PORTUGUESE JOURNAL OF GASTROENTEROLOGY 2022; 29:22-30. [PMID: 35111961 PMCID: PMC8787500 DOI: 10.1159/000516672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 03/20/2021] [Indexed: 08/30/2023]
Abstract
INTRODUCTION Acute liver failure (ALF) is a rare disease with potentially high mortality. We sought to assess the individual approach to ALF by intensive care unit (ICU) professionals. METHODS Cross-sectional survey of ICU professionals. Web-based survey capturing data on respondents' demographics, characteristics of patients with ALF admitted to ICU, and their management. RESULTS Among 204 participants from 50 countries, 140 (68.6%) worked in Europe, 146 (71.6%) were intensivists, 142 (69.6%) admitted <25 patients with ALF per year, and 166 (81.8%) reported <25% of patients had paracetamol-related ALF. On patients' outcomes, 126 (75.0%) reported an emergency liver transplantation (ELT) rate <25% and 140 (73.3%) a hospital mortality rate <50%. The approach to ALF in the ICU varied with age, region, level of training, type of hospital, and etiology (prescribing N-acetylcysteine for paracetamol toxicity, triggers for endotracheal intubation, measurement of and strategies for lowering serum ammonia, extracorporeal device deployment, and prophylactic antibiotics). CONCLUSIONS The management of patients with ALF by ICU professionals differed substantially concerning the relevant clinical measures taken. Further education and high-quality research are warranted.
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Affiliation(s)
| | - Mark J. Mcphail
- Liver Intensive Therapy Unit, King's College Hospital, London, United Kingdom
| | | | - Valentin Fuhrmann
- Department of Medicine B, Gastroenterology and Hepatology, University of Münster, Münster, Germany
| | - Nuno Germano
- Intensive Care Unit, Curry Cabral Hospital, Lisbon, Portugal
| | - Georg Auzinger
- Liver Intensive Therapy Unit, King's College Hospital, London, United Kingdom
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Bernal W. Acute Liver Failure on the Transplant Waiting List: Acetaminophen Both Better and Worse? Liver Transpl 2022; 28:11-12. [PMID: 34407297 DOI: 10.1002/lt.26274] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 08/10/2021] [Indexed: 12/06/2022]
Affiliation(s)
- William Bernal
- Liver Intensive Therapy Unit, Institute of Liver Studies, Kings College Hospital, London, United Kingdom
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50
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MacDonald AJ, Speiser JL, Ganger DR, Nilles KM, Orandi BJ, Larson AM, Lee WM, Karvellas CJ. Clinical and Neurologic Outcomes in Acetaminophen-Induced Acute Liver Failure: A 21-Year Multicenter Cohort Study. Clin Gastroenterol Hepatol 2021; 19:2615-2625.e3. [PMID: 32920216 PMCID: PMC10656032 DOI: 10.1016/j.cgh.2020.09.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 08/25/2020] [Accepted: 09/04/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND & AIMS Acetaminophen (APAP)-induced acute liver failure (ALF) is a rare disease associated with high mortality rates. This study aimed to evaluate changes in interventions, psychosocial profile, and clinical outcomes over a 21-year period using data from the ALF Study Group registry. METHODS A retrospective review of this prospective, multicenter cohort study of all APAP-ALF patients enrolled during the study period (1998-2018) was completed. Primary outcomes evaluated were the 21-day transplant-free survival (TFS) and neurologic complications. Covariates evaluated included enrollment cohort (early, 1998-2007; recent, 2008-2018), intentionality, psychiatric comorbidity, and use of organ support including continuous renal replacement therapy (CRRT). RESULTS Of 1190 APAP-ALF patients, recent cohort patients (n = 608) had significantly improved TFS (recent, 69.8% vs early, 61.7%; P = .005). Recent cohort patients were more likely to receive CRRT (22.2% vs 7.6%; P < .001), and less likely to develop intracranial hypertension (29.9% vs 51.5%; P < .001) or die by day 21 from cerebral edema (4.5% vs 11.6%; P < .001). Grouped by TFS status (non-TFS, n = 365 vs TFS, n = 704), there were no differences in psychiatric comorbidity (51.5% vs 55.0%; P = .28) or intentionality (intentional, 39.7% vs 41.6%; P = .58). On multivariable logistic regression adjusting for vasopressor support, development of grade 3/4 hepatic encephalopathy, King's College criteria, and MELD score, the use of CRRT (odds ratio, 1.62; P = .023) was associated with significantly increased TFS (c-statistic, 0.86). In a second model adjusting for the same covariates, recent enrollment was associated significantly with TFS (odds ratio, 1.42; P = .034; c-statistic, 0.86). CONCLUSIONS TFS in APAP-ALF has improved in recent years and rates of intracranial hypertension/cerebral edema have decreased, possibly related to increased CRRT use.
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Affiliation(s)
- Andrew J MacDonald
- Department of Surgery, Division of General Surgery, Edmonton, Alberta, Canada
| | - Jaime L Speiser
- Department of Biostatistics and Data Science, Wake Forest School of Medicine, Winston-Salem, North Carolina
| | - Daniel R Ganger
- Department of Gastroenterology and Hepatology, Northwestern University, Chicago, Illinois
| | - Kathleen M Nilles
- MedStar Georgetown Transplant Institute, Division of Gastroenterology and Hepatology, Georgetown University School of Medicine, Washington, District of Columbia
| | - Babak J Orandi
- Division of Transplantation, Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama
| | - Anne M Larson
- Department of Internal Medicine, Division of Gastroenterology, University of Washington Medical Center, Seattle, Washington
| | - William M Lee
- Department of Internal Medicine, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Constantine J Karvellas
- Liver Unit, Division of Gastroenterology, Department of Critical Care Medicine, University of Alberta, Edmonton, Alberta, Canada.
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