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Ocak I, Colak M, Bilici BN. Comparative Analysis of Plasmapheresis Versus Plasmapheresis Combined With Continuous Renal Replacement Therapy in Adult Liver Failure: A Retrospective Observational Study. Transplant Proc 2025; 57:598-605. [PMID: 40102129 DOI: 10.1016/j.transproceed.2025.02.051] [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: 10/06/2024] [Revised: 10/09/2024] [Accepted: 02/26/2025] [Indexed: 03/20/2025]
Abstract
BACKGROUND Liver failure constitutes a critical medical condition marked by the rapid decline in hepatic functions. Novel therapeutic approaches, including therapeutic plasma exchange (TPE) and continuous venovenous hemodiafiltration (CVVHDF), have emerged as promising modalities for mitigating the effects of this condition by facilitating detoxification and enhancing liver function. The efficacy of these interventions, whether administered individually or in combination, is a prominent area of investigation in the management of liver failure among adult populations. This study aims to evaluate the role and effectiveness of TPE, both as a standalone treatment and in conjunction with CVVHDF, in the management of liver failure in adult patients. METHODS This retrospective study was conducted in a Liver Transplant Intensive Care Unit (LTICU), focusing on the medical records of adult patients aged 35 to 62 years. The patient cohort consisted of individuals admitted between January 1, 2021, and June 1, 2024, due to acute liver failure or acute-on-chronic liver failure. The analysis specifically included patients who underwent therapeutic plasma exchange (TPE) or those who received continuous renal replacement therapy in conjunction with TPE. For the statistical analysis, a P-value of less than .05 was deemed indicative of statistical significance. The study encompassed a total of 47 patients with liver failure, comprising 23 males and 24 females. Among these patients, 25 (53.2%) received only TPE, while 22 (46.8%) were treated with a combination of TPE and continuous venovenous hemodiafiltration (CVVHDF). RESULTS In the cohort of patients who received only therapeutic plasma exchange (TPE), the median International Normalized Ratio (INR) improved significantly, decreasing from 2 (1.6-2.6) to 1.3 (1.1-1.7). Similarly, alanine aminotransferase levels reduced from 351 (66-1482) to 166 (71-367), while aspartate aminotransferase levels decreased from 259 (132-1392) to 86 (35-160). In the group receiving a combination of TPE and continuous venovenous hemodiafiltration (CVVHDF), notable reductions were also observed: INR decreased from 3 (2.4-4.7) to 1.5 (1.3-2.4), alanine aminotransferase levels dropped from 691 (59-2397) to 162 (70-1060), and aspartate aminotransferase levels fell from 916 (134-1828) to 69 (45-503). These changes were statistically significant, with P-values of less than .05 for each parameter in both treatment groups. Overall, 21 patients achieved survival without requiring a liver transplant, while 7 patients underwent liver transplantation, resulting in a transplant-free survival rate of 44.7%. CONCLUSION The findings from our study on the management of liver failure in adults demonstrate that both therapeutic plasma exchange (TPE) administered alone and in conjunction with continuous venovenous hemodiafiltration (CVVHDF) are effective treatment modalities, particularly as a bridging strategy to liver transplantation. The observed transplant-free survival rate of 44.7% underscores the significant clinical advantages of these therapies. However, to enhance the validity of these results and their applicability in broader clinical contexts, additional multicenter studies are essential for further exploration of these treatment approaches in liver failure management.
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Affiliation(s)
- Ilhan Ocak
- Liver Transplant Intensive Care Unit, Istanbul Basaksehir Cam and Sakura City Hospital, Istanbul, Turkey.
| | - Mustafa Colak
- Liver Transplant Intensive Care Unit, Istanbul Basaksehir Cam and Sakura City Hospital, Istanbul, Turkey
| | - Bilge Nur Bilici
- Liver Transplant Intensive Care Unit, Istanbul Basaksehir Cam and Sakura City Hospital, Istanbul, Turkey
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Clouston AD, Gouw ASH, Tiniakos D, Bedossa P, Brunt EM, Callea F, Dienes HP, Goodman ZD, Hubscher SG, Kakar S, Kleiner DE, Lackner C, Park YN, Roberts EA, Schirmacher P, Terracciano L, Torbenson M, Wanless IR, Zen Y, Burt AD. Severe acute liver disease in adults: Contemporary role of histopathology. Histopathology 2024; 85:549-561. [PMID: 38773813 DOI: 10.1111/his.15212] [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: 03/08/2024] [Revised: 04/11/2024] [Accepted: 05/02/2024] [Indexed: 05/24/2024]
Abstract
Liver biopsies have consistently contributed to our understanding of the pathogenesis and aetiologies of acute liver disease. As other diagnostic modalities have been developed and refined, the role of biopsy in the management of patients with acute liver failure (ALF), acute-on-chronic liver failure (ACLF) and acute hepatitis, including acute liver injury (ALI), has changed. Liver biopsy remains particularly valuable when first-line diagnostic algorithms fail to determine aetiology. Despite not being identified as a mandatory diagnostic tool in recent clinical guidelines for the management of ALF or ACLF, many centres continue to undertake biopsies given the relative safety of transjugular biopsy in this setting. Several studies have demonstrated that liver biopsy can provide prognostic information, particularly in the context of so-called indeterminate hepatitis, and is extremely useful in excluding conditions such as metastatic tumours that would preclude transplantation. In addition, its widespread use of percutaneous biopsies in cases of less severe acute liver injury, for example in the establishment of a diagnosis of acute presentation of autoimmune hepatitis or confirmation of a probable or definite drug-induced liver injury (DILI), has meant that many centres have seen a shift in the ratio of specimens they are receiving from patients with chronic to acute liver disease. Histopathologists therefore need to be equipped to deal with these challenging specimens. This overview provides an insight into the contemporary role of biopsies (as well as explant and autopsy material) in diagnosing acute liver disease. It outlines up-to-date clinical definitions of liver injury and considers recent recommendations for the diagnosis of AIH and drug-induced, autoimmune-like hepatitis (DI-AIH).
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Affiliation(s)
- Andrew D Clouston
- Centre for Liver Disease Research, School of Medicine (Southern), University of Queensland, Princess Alexandra Hospital, Ipswich, Australia
| | - Annette S H Gouw
- Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, the Netherlands
| | - Dina Tiniakos
- Department of Pathology, Aretaieion Hospital, Medical School, National & Kapodistrian University of Athens, Athens, Greece
- Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | | | - Elizabeth M Brunt
- Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA
| | | | - Hans-Peter Dienes
- Institute of Pathology, Meduniwien, Medical University of Vienn, Wien, Austria
| | - Zachary D Goodman
- Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, VA, USA
| | - Stefan G Hubscher
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Sanjay Kakar
- Department of Pathology, University of California, San Francisco, CA, USA
| | - David E Kleiner
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, USA
| | - Carolin Lackner
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Young N Park
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
| | - Eve A Roberts
- Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, ON, Canada
| | | | - Luigi Terracciano
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- IRCCS Humanitas Research Hospital, Milan, Italy
| | - Michael Torbenson
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Ian R Wanless
- Department of Pathology, Dalhousie University, Queen Elizabeth II Health Sciences Centre, Halifax, NS, Canada
| | - Yoh Zen
- Institute of Liver Studies, King's College Hospital, London, UK
| | - Alastair D Burt
- Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
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Xu W, Tang W, Yang W, Sun L, Li W, Wang S, Zang X. Acute liver failure as initial presentation in a Chinese patient with Budd-Chiari syndrome due to protein C deficiency: A case report and literature review. Heliyon 2024; 10:e29776. [PMID: 38707271 PMCID: PMC11068517 DOI: 10.1016/j.heliyon.2024.e29776] [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: 12/15/2023] [Revised: 04/15/2024] [Accepted: 04/15/2024] [Indexed: 05/07/2024] Open
Abstract
Acute liver failure is an uncommon presentation in the clinic. Common causes for acute liver failure include viral hepatitis and drug-related hepatotoxicity. However, acute liver failure due to Budd-Chiari syndrome is rare. This case highlights the importance of necessary constrast-enhanced imaging studies to rule out vascular etiologies of acute liver failure, in addition to common causes like viral or drug-induced hepatic failure. We present a case of a male Chinese patient who presented with nausea, vomiting, fatigue, and fever after eating a large amount of fatty food. Six days after hospitalization, the patient developed acute liver failure and hepatic encephalopathy. Contrast-enhanced computerized tomography and ultrasound examinations revealed thromboses in the hepatic veins and inferior vena cava. Further testing also showed decreased protein C activity. Therefore, a diagnosis of Budd-Chiari syndrome secondary to protein C deficiency was made. He received supportive care and a transjugular intrahepatic portal shunt. Hepatic function, coagulation panel results, and clinical presentations gradually returned to normal. Budd-Chiari syndrome from protein C deficiency could be a rare but valid cause of acute liver failure in Chinese patients.
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Affiliation(s)
- Wanling Xu
- Department of Emergency Medicine, The First Hospital of Jilin University, Changchun, Jilin, PR China
| | - Wenjing Tang
- Department of Emergency Medicine, The First Hospital of Jilin University, Changchun, Jilin, PR China
| | - Weiying Yang
- Department of Emergency Medicine, The First Hospital of Jilin University, Changchun, Jilin, PR China
| | - Lichao Sun
- Department of Emergency Medicine, The First Hospital of Jilin University, Changchun, Jilin, PR China
| | - Wei Li
- Department of Emergency Medicine, The First Hospital of Jilin University, Changchun, Jilin, PR China
| | - Shouqing Wang
- Department of Ultrasound, The First Hospital of Jilin University, Changchun, Jilin, PR China
| | - Xiuxian Zang
- Department of Emergency Medicine, The First Hospital of Jilin University, Changchun, Jilin, PR China
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Seth S, Maharshi S, Sharma KK, Pokharna R, Nijhawan S, Sharma SS. Changing etiological spectrum of acute liver failure. Indian J Gastroenterol 2024; 43:452-458. [PMID: 38676907 DOI: 10.1007/s12664-024-01578-2] [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: 01/15/2024] [Accepted: 03/19/2024] [Indexed: 04/29/2024]
Abstract
BACKGROUND AND OBJECTIVES Acute liver failure (ALF) is an uncommon but potentially dramatic syndrome characterized by massive hepatic necrosis and has a very high mortality rate of 50% to 75% without liver transplantation. This study is aimed at analyzing the etiological spectrum of ALF patients and compare these with ALF mimics such as malaria, dengue fever and other tropical infectious diseases. METHODS The study population included patients who presented with ALF and ALF mimics in a tertiary care center over two years. We retrospectively analyzed the patient case files and a comparison was made concerning the baseline demographic details, clinical profile, laboratory values and outcomes. RESULTS Sixty-three patients were assessed, with 32 in ALF and 31 in ALF mimics group. The most common cause for ALF was hepatitis A virus (25%), followed by hepatitis B virus (18.7%), drug-induced liver injury (12.7%), autoimmune hepatitis (12.5%), hepatitis E virus (9.3%) and Wilson's disease (6.25%). In the ALF mimics group, malaria (58.06%) was the most common cause, followed by dengue fever (16.1%), leptospirosis (12.9%) and scrub typhus (12.9%). Patients in the ALF mimics group had significantly higher incidence of fever (p = 0.001), hepatosplenomegaly (p = 0.01), anemia (p = 0.02) and shorter jaundice to encephalopathy duration (p = 0.032) as compared to the ALF group, while higher transaminase levels (p = 0.03), bilirubin (p = 0.01), prothrombin time (p = 0.01), serum ammonia (p = 0.02) and mortality (p = 0.02) were observed in ALF patients. CONCLUSIONS The most common cause for ALF was hepatitis A virus, followed by hepatitis B virus, while in ALF mimics it was malaria followed by dengue fever, in our study. Patients of ALF mimics can have similar presentation, but a high index of suspicion and awareness is required to identify the common infectious ALF mimics for early diagnosis.
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Affiliation(s)
- Saksham Seth
- Department of Gastroenterology, SMS Medical College and Hospitals, Room No. 218, Superspeciality Block, Jaipur, 302 004, India
| | - Sudhir Maharshi
- Department of Gastroenterology, SMS Medical College and Hospitals, Room No. 218, Superspeciality Block, Jaipur, 302 004, India.
| | - Kamlesh Kumar Sharma
- Department of Gastroenterology, SMS Medical College and Hospitals, Room No. 218, Superspeciality Block, Jaipur, 302 004, India
| | - Rupesh Pokharna
- Department of Gastroenterology, SMS Medical College and Hospitals, Room No. 218, Superspeciality Block, Jaipur, 302 004, India
| | - Sandeep Nijhawan
- Department of Gastroenterology, SMS Medical College and Hospitals, Room No. 218, Superspeciality Block, Jaipur, 302 004, India
| | - Shyam Sunder Sharma
- Department of Gastroenterology, SMS Medical College and Hospitals, Room No. 218, Superspeciality Block, Jaipur, 302 004, India
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Abstract
Acute liver failure is a rare but important clinical syndrome, with a high mortality rate. Prompt recognition, appropriate management and early referral to a liver transplant centre can lead to good outcomes in these critically unwell patients. This article gives an overview of the key clinical challenges and optimal management of patients with acute liver failure. Acute liver failure is defined and a comprehensive list of aetiologies and suggested investigations is provided. The clinical challenges of sepsis, renal impairment, coagulopathy, hypoglycaemia, haemodynamic instability and cerebral oedema are discussed. Quadruple H therapy, a combination of therapies aimed to reduce cerebral oedema in acute liver failure, is described. A systemic guide to managing patients with acute liver failure is provided, as are indications for referral to a liver transplant centre.
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Affiliation(s)
| | - Stephen Warrillow
- Department of Intensive Care and Medicine, Austin Health, Melbourne, Australia
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6
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Jindal A, Sarin SK. Epidemiology of liver failure in Asia-Pacific region. Liver Int 2022; 42:2093-2109. [PMID: 35635298 DOI: 10.1111/liv.15328] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 05/26/2022] [Accepted: 05/27/2022] [Indexed: 02/13/2023]
Abstract
The global burden of deaths caused by liver failure is substantial. The Asia-Pacific region is home to more than half of the global population and accounted for 62.6% of global deaths because of liver diseases in 2015. The aetiology of liver failure varies in different countries at different times. Viruses (Hepatitis A, B and E), drugs (herbs and anti-tuberculous drugs), toxins (alcohol use) and autoimmune flares are mainly responsible of majority of liver failure in individuals with normal liver (acute liver failure; ALF); else these may precipitate liver failure in those with chronic liver disease (acute-on-chronic liver failure; ACLF). Concomitant increases in alcohol misuse and metabolic syndrome in recent years are concerning. Ongoing efforts to address liver failure-related morbidity and mortality require accurate contemporary estimates of epidemiology and outcomes. In light of the ever-changing nature of liver disease epidemiology, accurate estimates for the burden of liver failure across the countries are vital for setting clinical, research and policy priorities. In this review, we aimed to describe the current as well as changing epidemiological trends of common liver failure syndromes, ALF and ACLF in the Asia-Pacific region.
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Affiliation(s)
- Ankur Jindal
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shiv K Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
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7
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Liao TJ, Pan B, Hong H, Hayashi P, Rule JA, Ganger D, Lee WM, Rakela J, Chen M. Whole Exome Sequencing Reveals Genetic Variants in HLA Class II Genes Associated With Transplant-free Survival of Indeterminate Acute Liver Failure. Clin Transl Gastroenterol 2022; 13:e00502. [PMID: 35905417 PMCID: PMC10476814 DOI: 10.14309/ctg.0000000000000502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 05/17/2022] [Indexed: 09/06/2023] Open
Abstract
INTRODUCTION Indeterminate acute liver failure (IND-ALF) is a rare clinical syndrome with a high mortality rate. Lacking a known etiology makes rapid evaluation and treatment difficult, with liver transplantation often considered as the only therapeutic option. Our aim was to identify genetic variants from whole exome sequencing data that might be associated with IND-ALF clinical outcomes. METHODS Bioinformatics analysis was performed on whole exome sequencing data for 22 patients with IND-ALF. A 2-tier approach was used to identify significant single-nucleotide polymorphisms (SNPs) associated with IND-ALF clinical outcomes. Tier 1 identified the SNPs with a higher relative risk in the IND-ALF population compared with those identified in control populations. Tier 2 determined the SNPs connected to transplant-free survival and associated with model for end-stage liver disease serum sodium and Acute Liver Failure Study Group prognostic scores. RESULTS Thirty-one SNPs were found associated with a higher relative risk in the IND-ALF population compared with those in controls, of which 11 belong to the human leukocyte antigen (HLA) class II genes but none for the class I. Further analysis showed that 5 SNPs: rs796202376, rs139189937, and rs113473719 of HLA-DRB5; rs9272712 of HLA-DQA1; and rs747397929 of IDO1 were associated with a higher probability of IND-ALF transplant-free survival. Using 3 selected SNPs, a model for the polygenic risk score was developed to predict IND-ALF prognoses, which are comparable with those by model for end-stage liver disease serum sodium and Acute Liver Failure Study Group prognostic scores. DISCUSSION Certain gene variants in HLA-DRB5, HLA-DQA1, and IDO1 were found associated with IND-ALF transplant-free survival. Once validated, these identified SNPs may help elucidate the mechanism of IND-ALF and assist in its diagnosis and management.
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Affiliation(s)
- Tsung-Jen Liao
- Division of Bioinformatics and Biostatistics, U.S. Food and Drug Administration (FDA) National Center for Toxicological Research, Jefferson, Arkansas, USA;
| | - Bohu Pan
- Division of Bioinformatics and Biostatistics, U.S. Food and Drug Administration (FDA) National Center for Toxicological Research, Jefferson, Arkansas, USA;
| | - Huixiao Hong
- Division of Bioinformatics and Biostatistics, U.S. Food and Drug Administration (FDA) National Center for Toxicological Research, Jefferson, Arkansas, USA;
| | - Paul Hayashi
- Division of Hepatology and Nutrition, Office of New Drugs, FDA Center for Drug Evaluation and Research, Silver Spring, Maryland, USA;
| | - Jody A. Rule
- Division of Gastroenterology and Hepatology, University of Texas Southwestern, Dallas, Texas, USA;
| | - Daniel Ganger
- Division of Gastroenterology and Hepatology, Northwestern University, Chicago, Illinois, USA;
| | - William M. Lee
- Division of Gastroenterology and Hepatology, University of Texas Southwestern, Dallas, Texas, USA;
| | - Jorge Rakela
- Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, Arizona, USA.
| | - Minjun Chen
- Division of Bioinformatics and Biostatistics, U.S. Food and Drug Administration (FDA) National Center for Toxicological Research, Jefferson, Arkansas, USA;
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Gavriilidis P, Marangoni G, Ahmad J, Azoulay D. State of the Art, Current Perspectives, and Controversies of Budd-Chiari Syndrome: A Review. J Clin Med Res 2022; 14:147-157. [PMID: 35573933 PMCID: PMC9076137 DOI: 10.14740/jocmr4724] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 04/25/2022] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND Budd-Chiari syndrome (BCS) is an eponym that includes a group of conditions characterized by partial or complete hepatic venous tract outflow obstruction, and the site of obstruction may involve one or more hepatic veins, inferior vena cava, or the right atrium. The classification of BCS is based on etiology, site of obstruction, and duration. Its etiology is very heterogeneous; in particular, hepatic vein thrombosis is the most common type of obstruction and myeloproliferative disorder, the most common thrombophilic disorder, in the West. In Asian countries, the type of obstruction, thrombophilic disorders, clinical features, and treatment strategies vary widely from region to region. Although the cause can be identified in 90% of patients with the help of gene mutation testing, BCS remains under-recognized in many countries. A higher prevalence of acute cases has been reported in the West than in the East. This global and regional heterogeneity raises several challenges regarding the evaluation, management strategy, and individualized approach of BCS. This study aimed to conduct a systematic review of BCS to elucidate treatment strategy options. METHODS PubMed, Embase, Cochrane Library, and Google Scholar databases were searched systematically. RESULTS Sixty-nine pertinent articles were retrieved and included in the present study. CONCLUSIONS Further research on the following three topics would help define individualized treatment strategies. The first is a better understanding of the molecular pathways underlying the thrombophilic conditions implicated in the pathogenesis of BCS. The second is the role of the genotype and gene mutations in the determination of coagulation status of patients with BCS. The third is the definition of clear criteria and development of a common prognostic index to risk stratify the patients at presentation and consequently detect candidates for invasive therapies.
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Affiliation(s)
- Paschalis Gavriilidis
- Department of HBP Surgery, University Hospitals of Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry CV2 2DX, UK
| | - Gabriele Marangoni
- Department of HBP Surgery, University Hospitals of Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry CV2 2DX, UK
| | - Jawad Ahmad
- Department of HBP Surgery, University Hospitals of Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry CV2 2DX, UK
| | - Daniel Azoulay
- Department of Hepato-Biliary and Liver Transplantation Surgery, Paul Brousse University Hospital, Paris-Saclay University, 94800 Villejuif, France
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Goel R, Eapen CE. Recognizing Dysfunctional Innate and Adaptive Immune Responses Contributing to Liver Damage in Patients With Cirrhosis. J Clin Exp Hepatol 2022; 12:993-1002. [PMID: 34744379 PMCID: PMC8560502 DOI: 10.1016/j.jceh.2021.10.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 10/02/2021] [Indexed: 02/07/2023] Open
Abstract
The human host immune system wards off attacks by enemies such as viruses by mounting an inflammatory response which may sometimes injure self-tissues. Dysfunctional immune/inflammatory response by the host may affect the functioning of vital organs. The largest number of innate immune cells in the body resides in the liver. On encountering a new insult or injury to the liver, the innate immune system responds quickly to counter it. Acute liver insults may trigger acute liver failure or acute on chronic liver failure; these disorders are associated with a predominant innate immune response. Activation of the reticuloendothelial system (part of the innate immune response) predicts short-term and medium-term survival in patients with acute on chronic liver failure. Liver diseases associated with an aberrant adaptive immune response like autoimmune hepatitis respond well to treatment with steroids and other immunosuppressants, while those associated with innate immune dysfunction like acute on chronic liver failure do not respond well to steroids; recent reports suggest that the latter disorders may respond to therapeutic plasma exchange. How does the immune system in a patient with liver disease respond to SARS CoV2 infection? While commonly used tests in routine clinical practice provide clues to activation of different arms of immune response in patients with cirrhosis, specialized tests may help characterize this further. This review discusses the tests which reflect aberrant immune responses and treatment of patients with cirrhosis.
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Key Words
- ACLF, acute on chronic liver failure
- AIH, autoimmune hepatitis
- ANCA, anti-neutrophil cytoplasmic antibodies
- APASL, Asia Pacific Association for Study of Liver
- COVID-19, coronavirus disease of 2019
- CRP, C-reactive protein
- DAMPs, damage-associated molecular patterns
- EASL, European Association for Study of Liver
- HLA, human leukocyte antigen
- IgG, immunoglobulin G
- IgG4 RD, IgG4 related disease
- MELD, Model for End-Stage Liver Disease
- NK cells, natural killer cells
- PAMPs, pathogen-associated molecular patterns
- PBC, primary biliary cholangitis
- PSC, primary sclerosing cholangitis
- SARS CoV2, severe acute respiratory syndrome coronavirus 2
- TLR, toll-like receptor
- VWF, von Willebrand factor
- cirrhosis
- immune dysfunction
- investigations
- reticuloendothelial activation
- sMR, soluble mannose receptor
- treatment
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Affiliation(s)
- Ruchika Goel
- Clinical Immunology and Rheumatology Department, Christian Medical College, Vellore, Tamil Nadu, India
| | - Chundamannil Eapen Eapen
- Hepatology Department, Christian Medical College, Vellore, Tamil Nadu, India,Address for correspondence: Dr CE Eapen, Hepatology Department, Christian Medical College, Vellore, Tamil Nadu, 632004, India.
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Govindarajan R, Ramamoorthy G, Shanmugam RM, Bavanandam S, Murugesan M, Shanmugam C, Arumugam A, Chellamuthu VP, Venkatraj RK, Sampathkumar K, Rejoice P, Kumar KA, Adamali S, Mariappan K, Rathnavel R, Manivasagam VSC, Velusamy A, Arumugam S, Elikkottil TT, Dev AV, Sen M, Palaniappan A, Dorairaj AJ, Kedarisetty CK, Venkataraman J, Karthikeyan M, Somasundaram A, Ramakrishnan A, Madesh VP, Varghese J, Anupa DK, Leelakrishnan V, Swaminathan M, Kantamaneni R, Dhus JU, Murugan N, Natarajan K, Selvi C, Saithanyamurthi HV, Nadaraj A, Jeyaseelan L, Eapen CE. Rodenticide ingestion is an important cause of acute hepatotoxicity in Tamil Nadu, southern India. Indian J Gastroenterol 2021; 40:373-379. [PMID: 34189713 DOI: 10.1007/s12664-021-01178-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 03/29/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIM Though rodenticidal hepatotoxicity is reported from India, there is no systematic study to assess its magnitude. This study aimed to assess exposure to rodenticide as a risk factor for acute hepatotoxicity in Tamil Nadu, India. METHODS We retrospectively analyzed acute hepatotoxicity caused by ingestion of hepatotoxin or potentially hepatotoxic drug overdose across 15 hospitals in 6 districts of Tamil Nadu from 1 January 2019 to 30 June 2019. Study exclusion criteria were idiosyncratic drug-induced liver injury and chronic liver diseases. RESULTS Of the 702 patients, 685 gave history of consuming rodenticide; hepatotoxicity in the other patients resulted from paracetamol overdose (n=10) and due to other drugs (n=7); 97% patients had a suicidal intent. Of 671 patients with complete data, ratio of number of patients with hepatotoxicity due to rodenticide to paracetamol overdose was 450:6 (i.e. 75:1). The 451 rodenticidal hepatotoxicity patients (255 males, 75% were 15-34 years old) underwent conservative management (n=396), plasma exchange (n=54) and plasma exchange followed by liver transplant (n=1); 159 patients (35%) had poor outcome (131 died, 28 discharged in moribund state). Based on our observations, we estimate a case burden of 1584 rodenticidal hepatotoxicity patients (95% CI: 265-6119) with poor outcome in 554 patients in Tamil Nadu from January 2019 to June 2019. Population attributable risk for rodenticide as cause of hepatotoxicity was 22.7%. CONCLUSION Rodenticide ingestion was an important cause of acute hepatotoxicity in Tamil Nadu. Most patients were young and one-third had poor outcome. Public health interventions are needed to address this.
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Affiliation(s)
- Ramkumar Govindarajan
- Department of Medical Gastroenterology, Thanjavur Medical College, Thanjavur, 613 004, India
| | - Ganesan Ramamoorthy
- Department of Medical Gastroenterology, Thanjavur Medical College, Thanjavur, 613 004, India
| | | | - Sumathi Bavanandam
- Department of Medical Gastroenterology, Stanley Medical College, Chennai, 600 001, India
| | - Manimaran Murugesan
- Department of Medical Gastroenterology, Stanley Medical College, Chennai, 600 001, India
| | - Chitra Shanmugam
- Department of Medical Gastroenterology, Stanley Medical College, Chennai, 600 001, India
| | - Aravind Arumugam
- Department of Medical Gastroenterology, Government Kilpauk Medical College, Chennai, 600 010, India.,Department of Digestive Health and Diseases, Government Kilpauk Medical College, Chennai, 600 010, India
| | - Vaishnavi Priyaa Chellamuthu
- Department of Medical Gastroenterology, Government Kilpauk Medical College, Chennai, 600 010, India.,Department of Digestive Health and Diseases, Government Kilpauk Medical College, Chennai, 600 010, India
| | | | - Kavitha Sampathkumar
- Department of Medical Gastroenterology, Government Kilpauk Medical College, Chennai, 600 010, India.,Department of Digestive Health and Diseases, Government Kilpauk Medical College, Chennai, 600 010, India
| | - Poppy Rejoice
- Department of Medical Gastroenterology, Tirunelveli Medical College, Tirunelveli, 627 011, India
| | - Kandasamy Alias Kumar
- Department of Medical Gastroenterology, Tirunelveli Medical College, Tirunelveli, 627 011, India
| | - Shafique Adamali
- Department of Medical Gastroenterology, Tirunelveli Medical College, Tirunelveli, 627 011, India
| | - Kannan Mariappan
- Department of Medical Gastroenterology, Government Rajaji Hospital, Madurai Medical College, Madurai, 625 020, India
| | - Ramani Rathnavel
- Department of Medical Gastroenterology, Government Rajaji Hospital, Madurai Medical College, Madurai, 625 020, India
| | | | - Arulselvan Velusamy
- Department of Medical Gastroenterology, Government Medical College, Coimbatore, 641 018, India
| | - Senthilvadivu Arumugam
- Department of Medical Gastroenterology, Government Medical College, Coimbatore, 641 018, India
| | - Thasneem Taj Elikkottil
- Department of Medical Gastroenterology, Government Medical College, Coimbatore, 641 018, India
| | - Anand Vimal Dev
- Department of Hepatology, Christian Medical College, Vellore, 632 004, India
| | - Mousumi Sen
- Department of Forensic Medicine, Christian Medical College, Vellore, 632 004, India
| | - Alagammai Palaniappan
- Department of Gastroenterology, Meenakshi Mission Hospital and Research Centre, Madurai, 625 107, India
| | - Allwin James Dorairaj
- Department of Gastroenterology, Meenakshi Mission Hospital and Research Centre, Madurai, 625 107, India
| | - Chandan Kumar Kedarisetty
- Department of Hepatology, Sri Ramachandra Institute of Higher Education and Research, Chennai, 600 116, India
| | - Jayanthi Venkataraman
- Department of Hepatology, Sri Ramachandra Institute of Higher Education and Research, Chennai, 600 116, India
| | - Mugilan Karthikeyan
- Department of Hepatology, Sri Ramachandra Institute of Higher Education and Research, Chennai, 600 116, India
| | - Aravindh Somasundaram
- Department of Gastroenterology, Kovai Medical Center Hospital, Coimbatore, 641 014, India
| | - Arulraj Ramakrishnan
- Department of Gastroenterology, Kovai Medical Center Hospital, Coimbatore, 641 014, India
| | - Vijaya Prakash Madesh
- Department of Gastroenterology, Kovai Medical Center Hospital, Coimbatore, 641 014, India
| | - Joy Varghese
- Department of Hepatology and Transplant Hepatology, Gleneagles Global Health City Hospital, Chennai, 600 100, India
| | - Dheeraj Kumar Anupa
- Department of Hepatology and Transplant Hepatology, Gleneagles Global Health City Hospital, Chennai, 600 100, India
| | - Venkatakrishnan Leelakrishnan
- Department of Gastroenterology and Hepatology, PSG Institute of Medical Sciences and Research, Coimbatore, 641 004, India
| | - Mukundan Swaminathan
- Department of Gastroenterology and Hepatology, PSG Institute of Medical Sciences and Research, Coimbatore, 641 004, India
| | - Ravindra Kantamaneni
- Department of Gastroenterology and Hepatology, PSG Institute of Medical Sciences and Research, Coimbatore, 641 004, India
| | - Jeyaraj Ubal Dhus
- Department of Medical Gastroenterology and Hepatology, Apollo Hospitals, Chennai, 600 006, India
| | - Natarajan Murugan
- Department of Medical Gastroenterology and Hepatology, Apollo Hospitals, Chennai, 600 006, India
| | - Kartik Natarajan
- Department of Medical Gastroenterology and Hepatology, Apollo Hospitals, Chennai, 600 006, India
| | - Caroline Selvi
- Department of Medical Gastroenterology, Government Royapettah Hospital, Kilpauk Medical College, Chennai, 600 010, India
| | | | - Ambily Nadaraj
- Clinical Epidemiology Unit, Christian Medical College, Vellore, 632 004, India
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11
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Neupane R, Taweesedt PT, Anjum H, Surani S. Current state of medical tourism involving liver transplantation-the risk of infections and potential complications. World J Hepatol 2021; 13:717-722. [PMID: 34367493 PMCID: PMC8326159 DOI: 10.4254/wjh.v13.i7.717] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Revised: 03/29/2021] [Accepted: 07/02/2021] [Indexed: 02/06/2023] Open
Abstract
Liver transplant has been shown to significantly improve mortality and quality of life in various liver diseases such as acute liver failure, end-stage liver disease, and liver cancer. While the organ transplant demand is continuing to rise, the organ donation supply remains unmatched. The organ shortage, high cost, and long waiting lists have stimulated a desire for routes that may be unethical. This process which is named transplant tourism is the term used to describe traveling to another country to purchase an organ for transplant. Liver transplant tourism has been associated with post-transplant complications and higher mortality compared to a domestic liver transplant. Improper pre-and post-transplant infectious screening, inadequate opportunistic infection prophylaxis, and loss to follow-up were noted in patients who travel abroad for a liver transplant. It is crucial to understand the risk of transplant tourism to prevent morbidity and mortality.
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Affiliation(s)
- Ritesh Neupane
- Department of Medicine, Penn State Health Milton S Hershey Medical Center, Hershey, PA 17033, United States
| | - Pahnwat Tonya Taweesedt
- Department of Medicine, Corpus Christi Medical Center, Corpus Christi, TX 78412, United States
| | - Humayun Anjum
- Department of Medicine, University of North Texas, Corpus Christi, TX 78412, United States
| | - Salim Surani
- Department of Medicine, Texas A&M University, College Station, TX 77843, United States.
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12
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Shukla A, Shreshtha A, Mukund A, Bihari C, Eapen CE, Han G, Deshmukh H, Cua IHY, Lesmana CRA, Al Meshtab M, Kage M, Chaiteeraki R, Treeprasertsuk S, Giri S, Punamiya S, Paradis V, Qi X, Sugawara Y, Abbas Z, Sarin SK. Budd-Chiari syndrome: consensus guidance of the Asian Pacific Association for the study of the liver (APASL). Hepatol Int 2021; 15:531-567. [PMID: 34240318 DOI: 10.1007/s12072-021-10189-4] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Accepted: 04/11/2021] [Indexed: 02/07/2023]
Abstract
Budd Chiari syndrome (BCS) is a diverse disease with regard to the site of obstruction, the predisposing thrombophilic disorders and clinical presentation across the Asia-Pacific region. The hepatic vein ostial stenosis and short segment thrombosis are common in some parts of Asia-Pacific region, while membranous obstruction of the vena cava is common in some and complete thrombosis of hepatic veins in others. Prevalence of myeloproliferative neoplasms and other thrombophilic disorders in BCS varies from region to region and with different sites of obstruction. This heterogeneity also raises several issues and dilemmas in evaluation and approach to management of a patient with BCS. The opportunity to recanalize hepatic vein in patients with hepatic vein ostial stenosis or inferior vena cava stenting or pasty among those membranous obstruction of the vena cava is a unique opportunity in the Asia-Pacific region to restore hepatic outflow closely mimicking physiology. In order to address these issues arising out of the diversity as well as the unique features in the region, the Asia Pacific Association for Study of Liver has formulated these guidelines for clinicians.
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Affiliation(s)
- Akash Shukla
- Department of Gastroenterology, King Edward Memorial Hospital and Seth Gordhandas Sunderdas Medical College, Mumbai, India.
| | | | - Amar Mukund
- Institute of Liver and Biliary Sciences, New Delhi, India
| | - Chhagan Bihari
- Institute of Liver and Biliary Sciences, New Delhi, India
| | - C E Eapen
- Christian Medical College, Vellore, India
| | - Guohong Han
- Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xian, China
| | - Hemant Deshmukh
- Dean and Head of Radiology, King Edward Memorial Hospital and Seth Gordhandas Sunderdas Medical College, Mumbai, India
| | - Ian Homer Y Cua
- Institute of Digestive and Liver Diseases, St Lukes Medical Center, Global City, Philippines
| | - Cosmas Rinaldi Adithya Lesmana
- Dr. Cipto Mangunkusumo National General Hospital, Universitas Indonesia, Jakarta, Indonesia
- Digestive Disease & GI Oncology Center, Medistra Hospital, Jakarta, Indonesia
| | - Mamun Al Meshtab
- Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
- Center for Innovative Cancer Therapy, Kurume University Research, 67 Asahi-machi, Kurume, 830-0011, Japan
| | - Masayoshi Kage
- Department of Gastroenterology, King Edward Memorial Hospital and Seth Gordhandas Sunderdas Medical College, Mumbai, India
| | - Roongruedee Chaiteeraki
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Sombat Treeprasertsuk
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Suprabhat Giri
- Department of Gastroenterology, King Edward Memorial Hospital and Seth Gordhandas Sunderdas Medical College, Mumbai, India
| | - Sundeep Punamiya
- Vascular and Interventional Radiology, Tan Tock Seng Hospital, Singapore, Singapore
| | - Valerie Paradis
- Dpt dAnatomie Pathologique, Hôpital Beaujon, 100 bd du Gal Leclerc, Clichy, 92110, France
| | - Xingshun Qi
- General Hospital of Northern Theater Command (formerly General Hospital of Shenyang Military Area), No. 83 Wenhua Road, Shenyang, China
| | - Yasuhiko Sugawara
- Department of Transplantation and Pediatric Surgery, Kumamoto University, Kumamoto, Japan
| | - Zaigham Abbas
- Department of Hepatogastroenterology, Dr. Ziauddin University Hospital Clifton, Karachi, Pakistan
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13
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Krishnamoorthy S, Gayathri P, Chandra S, K Pillai MG, Menon R, Iyer S. Prognostic markers in acute liver failure - Alpha feto protein. ARCHIVES OF MEDICINE AND HEALTH SCIENCES 2021. [DOI: 10.4103/amhs.amhs_14_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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14
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Steiner-Temnykh L, Dakhoul L, Slaven J, Nephew L, Patidar KR, Orman E, Desai AP, Vilar-Gomez E, Kubal C, Ekser B, Chalasani N, Ghabril M. Comorbidity Burden May Be Associated with Increased Mortality in Patients with Severe Acute Liver Injury Referred for Liver Transplantation. Ann Transplant 2020; 25:e926453. [PMID: 33139688 PMCID: PMC7648405 DOI: 10.12659/aot.926453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Severe acute liver injury (S-ALI) can lead to acute liver and multisystem failure, with high mortality and need for liver transplantation (LT); however, the burden and impact of liver disease and comorbid conditions are unknown. MATERIAL AND METHODS We assessed liver disease and Charlson Comorbidity Index (CCI) in adults without cirrhosis evaluated for LT at our center for S-ALI between 2004 and 2017. The study endpoints were 30-day death or LT and 90-day mortality (with LT as a competing risk). RESULTS A total of 136 patients with S-ALI were included; 13% had underlying liver disease and a higher Model for End-stage Liver Disease score than those without liver disease. Sixty patients (41%) died or underwent LT within 30 days. They were older and more frequently female and had disease of autoimmune, viral, or indeterminate etiology. Transplant-free survival was associated with acetaminophen injury. The mean CCI was higher in patients with 30-day mortality or LT (1.5±2.4) vs. LT-free survivors (0.8±1.2), (P=0.03). Beyond severity of illness, CCI was associated with increased 90-day mortality (subhazard ratio 1.17, 95% confidence interval, 1.01-1.35) but not 30-day mortality or LT in the risk-adjusted analyses. CONCLUSIONS Comorbidity burden may be an important modifier of transplant-free survival in patients with S-ALI, but further studies are needed to validate these findings.
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Affiliation(s)
| | - Lara Dakhoul
- Departmental of Gastroenterology and Hepatology, Indiana University, Indianapolis, IN, USA
| | - James Slaven
- Departmental of Biostatistics, Indiana University, Indianapolis, IN, USA
| | - Lauren Nephew
- Departmental of Gastroenterology and Hepatology, Indiana University, Indianapolis, IN, USA
| | - Kavish R Patidar
- Departmental of Gastroenterology and Hepatology, Indiana University, Indianapolis, IN, USA
| | - Eric Orman
- Departmental of Gastroenterology and Hepatology, Indiana University, Indianapolis, IN, USA
| | - Archita P Desai
- Departmental of Gastroenterology and Hepatology, Indiana University, Indianapolis, IN, USA
| | - Eduardo Vilar-Gomez
- Departmental of Gastroenterology and Hepatology, Indiana University, Indianapolis, IN, USA
| | | | - Burcin Ekser
- Departmental of Transplant Surgery, Indiana University, Indianapolis, IN, USA
| | - Naga Chalasani
- Departmental of Gastroenterology and Hepatology, Indiana University, Indianapolis, IN, USA
| | - Marwan Ghabril
- Departmental of Gastroenterology and Hepatology, Indiana University, Indianapolis, IN, USA
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15
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Inchingolo R, Posa A, Mariappan M, Tibana TK, Nunes TF, Spiliopoulos S, Brountzos E. Transjugular intrahepatic portosystemic shunt for Budd-Chiari syndrome: A comprehensive review. World J Gastroenterol 2020; 26:5060-5073. [PMID: 32982109 PMCID: PMC7495032 DOI: 10.3748/wjg.v26.i34.5060] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Revised: 06/06/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023] Open
Abstract
Budd-Chiari syndrome (BCS) is a relatively rare clinical condition with a wide range of symptomatology, caused by the obstruction of the hepatic venous outflow. If left untreated, it has got an high mortality rate. Its management is based on a step-wise approach, depending on the clinical presentation, and includes different treatment from anticoagulation therapy up to Interventional Radiology techniques, such as transjugular intrahepatic portosystemic shunt (TIPS). TIPS is today considered a safe and highly effective treatment and should be recommended for BCS patients, including those awaiting orthotopic liver transplantation. In this review the pathophysiology, diagnosis and treatment options of BCS are presented, with a special focus on published data regarding the techniques and outcomes of TIPS for the treatment of BCS. Moreover, unresolved issues and future research will be discussed.
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Affiliation(s)
- Riccardo Inchingolo
- Interventional Radiology Unit, "F. Miulli" Regional Hospital, Acquaviva delle Fonti 70021, Italy
- Department of Radiology, King´s College Hospital, London SE5 9RS, United Kingdom
| | - Alessandro Posa
- Department of Radiology, Gemelli Hospital, Roma 00135, Italy
| | - Martin Mariappan
- Interventional Radiology Department, Aberdeen Royal Infirmary Hospital, Aberdeen AB25 2ZN, United Kingdom
| | - Tiago Kojun Tibana
- Interventional Radiology Department, Universidade Federal de Mato Grosso do Sul, Campo Grande 79070-900, Brazil
| | - Thiago Franchi Nunes
- Interventional Radiology Department, Universidade Federal de Mato Grosso do Sul, Campo Grande 79070-900, Brazil
| | - Stavros Spiliopoulos
- 2nd Department of Radiology, School of Medicine, National and Kapodistrian University of Athens, Chaidari Athens GR 12461, Greece
| | - Elias Brountzos
- 2nd Department of Radiology, School of Medicine, National and Kapodistrian University of Athens, Chaidari Athens GR 12461, Greece
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16
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Anand AC, Nandi B, Acharya SK, Arora A, Babu S, Batra Y, Chawla YK, Chowdhury A, Chaoudhuri A, Eapen EC, Devarbhavi H, Dhiman R, Datta Gupta S, Duseja A, Jothimani D, Kapoor D, Kar P, Khuroo MS, Kumar A, Madan K, Mallick B, Maiwall R, Mohan N, Nagral A, Nath P, Panigrahi SC, Pawar A, Philips CA, Prahraj D, Puri P, Rastogi A, Saraswat VA, Saigal S, Shalimar, Shukla A, Singh SP, Verghese T, Wadhawan M, The INASL Task-Force on Acute Liver Failure. Indian National Association for the Study of the Liver Consensus Statement on Acute Liver Failure (Part 1): Epidemiology, Pathogenesis, Presentation and Prognosis. J Clin Exp Hepatol 2020; 10:339-376. [PMID: 32655238 PMCID: PMC7335721 DOI: 10.1016/j.jceh.2020.04.012] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Accepted: 04/12/2020] [Indexed: 12/12/2022] Open
Abstract
Acute liver failure (ALF) is an infrequent, unpredictable, potentially fatal complication of acute liver injury (ALI) consequent to varied etiologies. Etiologies of ALF as reported in the literature have regional differences, which affects the clinical presentation and natural course. In this part of the consensus article designed to reflect the clinical practices in India, disease burden, epidemiology, clinical presentation, monitoring, and prognostication have been discussed. In India, viral hepatitis is the most frequent cause of ALF, with drug-induced hepatitis due to antituberculosis drugs being the second most frequent cause. The clinical presentation of ALF is characterized by jaundice, coagulopathy, and encephalopathy. It is important to differentiate ALF from other causes of liver failure, including acute on chronic liver failure, subacute liver failure, as well as certain tropical infections which can mimic this presentation. The disease often has a fulminant clinical course with high short-term mortality. Death is usually attributable to cerebral complications, infections, and resultant multiorgan failure. Timely liver transplantation (LT) can change the outcome, and hence, it is vital to provide intensive care to patients until LT can be arranged. It is equally important to assess prognosis to select patients who are suitable for LT. Several prognostic scores have been proposed, and their comparisons show that indigenously developed dynamic scores have an edge over scores described from the Western world. Management of ALF will be described in part 2 of this document.
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Key Words
- ACLF, acute on chronic liver failure
- AFLP, acute fatty liver of pregnancy
- AKI, Acute kidney injury
- ALF, Acute liver failure
- ALFED, Acute Liver Failure Early Dynamic
- ALT, alanine transaminase
- ANA, antinuclear antibody
- AP, Alkaline phosphatase
- APTT, activated partial thromboplastin time
- ASM, alternative system of medicine
- ASMA, antismooth muscle antibody
- AST, aspartate transaminase
- ATN, Acute tubular necrosis
- ATP, adenosine triphosphate
- ATT, anti-TB therapy
- AUROC, Area under the receiver operating characteristics curve
- BCS, Budd-Chiari syndrome
- BMI, body mass index
- CBF, cerebral blood flow
- CBFV, cerebral blood flow volume
- CE, cerebral edema
- CHBV, chronic HBV
- CLD, chronic liver disease
- CNS, central nervous system
- CPI, clinical prognostic indicator
- CSF, cerebrospinal fluid
- DAMPs, Damage-associated molecular patterns
- DILI, drug-induced liver injury
- EBV, Epstein-Barr virus
- ETCO2, End tidal CO2
- GRADE, Grading of Recommendations Assessment Development and Evaluation
- HAV, hepatitis A virus
- HBV, Hepatitis B virus
- HELLP, hemolysis
- HEV, hepatitis E virus
- HLH, Hemophagocytic lymphohistiocytosis
- HSV, herpes simplex virus
- HV, hepatic vein
- HVOTO, hepatic venous outflow tract obstruction
- IAHG, International Autoimmune Hepatitis Group
- ICH, intracerebral hypertension
- ICP, intracerebral pressure
- ICU, intensive care unit
- IFN, interferon
- IL, interleukin
- IND-ALF, ALF of indeterminate etiology
- INDILI, Indian Network for DILI
- KCC, King's College Criteria
- LC, liver cirrhosis
- LDLT, living donor liver transplantation
- LT, liver transplantation
- MAP, mean arterial pressure
- MHN, massive hepatic necrosis
- MPT, mitochondrial permeability transition
- MUAC, mid-upper arm circumference
- NAPQI, n-acetyl-p-benzo-quinone-imine
- NPV, negative predictive value
- NWI, New Wilson's Index
- ONSD, optic nerve sheath diameter
- PAMPs, pathogen-associated molecular patterns
- PCR, polymerase chain reaction
- PELD, Pediatric End-Stage Liver Disease
- PPV, positive predictive value
- PT, prothrombin time
- RAAS, renin–angiotensin–aldosterone system
- SHF, subacute hepatic failure
- SIRS, systemic inflammatory response syndrome
- SNS, sympathetic nervous system
- TB, tuberculosis
- TCD, transcranial Doppler
- TGF, tumor growth factor
- TJLB, transjugular liver biopsy
- TLR, toll-like receptor
- TNF, tumor necrosis factor
- TSFT, triceps skin fold thickness
- US, ultrasound
- USALF, US Acute Liver Failure
- VZV, varicella-zoster virus
- WD, Wilson disease
- Wilson disease (WD)
- YP, yellow phosphorus
- acute liver failure
- autoimmune hepatitis (AIH)
- drug-induced liver injury
- elevated liver enzymes, low platelets
- sALI, severe acute liver injury
- viral hepatitis
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Affiliation(s)
- Anil C. Anand
- Department of Gastroenterology, Kaliga Institute of Medical Sciences, Bhubaneswar, 751024, India
| | - Bhaskar Nandi
- Department of Gastroenterology, Sarvodaya Hospital and Research Centre, Faridababd, Haryana, India
| | - Subrat K. Acharya
- Department of Gastroenterology and Hepatology, KIIT University, Patia, Bhubaneswar, Odisha, 751 024, India
| | - Anil Arora
- Institute of Liver Gastroenterology &Pancreatico Biliary Sciences, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, 110 060, India
| | - Sethu Babu
- Department of Gastroenterology, Krishna Institute of Medical Sciences, Hyderabad 500003, India
| | - Yogesh Batra
- Department of Gastroenterology, Indraprastha Apollo Hospital, SaritaVihar, New Delhi, 110 076, India
| | - Yogesh K. Chawla
- Department of Gastroenterology, Kalinga Institute of Medical Sciences (KIMS), Kushabhadra Campus (KIIT Campus-5), Patia, Bhubaneswar, Odisha, 751 024, India
| | - Abhijit Chowdhury
- Department of Hepatology, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education & Research, Kolkata, 700020, India
| | - Ashok Chaoudhuri
- Hepatology and Liver Transplant, Institute of Liver & Biliary Sciences, D-1 Vasant Kunj, New Delhi, India
| | - Eapen C. Eapen
- Department of Hepatology, Christian Medical College, Vellore, India
| | - Harshad Devarbhavi
- Department of Gastroenterology and Hepatology, St. John's Medical College Hospital, Bangalore, 560034, India
| | - RadhaKrishan Dhiman
- Department of Hepatology, Post graduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Siddhartha Datta Gupta
- Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110 029, India
| | - Ajay Duseja
- Department of Hepatology, Post graduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Dinesh Jothimani
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Centre, Chrompet, Chennai, 600044, India
| | | | - Premashish Kar
- Department of Gastroenterology and Hepatology, Max Super Speciality Hospital, Vaishali, Ghaziabad, Uttar Pradesh, 201 012, India
| | - Mohamad S. Khuroo
- Department of Gastroenterology, Dr Khuroo’ S Medical Clinic, Srinagar, Kashmir, India
| | - Ashish Kumar
- Institute of Liver Gastroenterology &Pancreatico Biliary Sciences, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, 110 060, India
| | - Kaushal Madan
- Gastroenterology and Hepatology, Max Smart Super Specialty Hospital, Saket, New Delhi, India
| | - Bipadabhanjan Mallick
- Department of Gastroenterology, Kalinga Institute of Medical Sciences, Bhubaneswar, 751024, India
| | - Rakhi Maiwall
- Hepatology Incharge Liver Intensive Care, Institute of Liver & Biliary Sciences, D-1 Vasant Kunj, New Delhi, India
| | - Neelam Mohan
- Department of Pediatric Gastroenterology, Hepatology & Liver Transplantation, Medanta – the Medicity Hospital, Sector – 38, Gurgaon, Haryana, India
| | - Aabha Nagral
- Department of Gastroenterology, Apollo and Jaslok Hospital & Research Centre, 15, Dr Deshmukh Marg, Pedder Road, Mumbai, Maharashtra, 400 026, India
| | - Preetam Nath
- Department of Gastroenterology, Kaliga Institute of Medical Sciences, Bhubaneswar, 751024, India
| | - Sarat C. Panigrahi
- Department of Gastroenterology, Kaliga Institute of Medical Sciences, Bhubaneswar, 751024, India
| | - Ankush Pawar
- Liver & Digestive Diseases Institute, Fortis Escorts Hospital, Okhla Road, New Delhi, 110 025, India
| | - Cyriac A. Philips
- The Liver Unit and Monarch Liver Lab, Cochin Gastroenterology Group, Ernakulam Medical Centre, Kochi, 682028, Kerala, India
| | - Dibyalochan Prahraj
- Department of Gastroenterology, Kaliga Institute of Medical Sciences, Bhubaneswar, 751024, India
| | - Pankaj Puri
- Department of Hepatology and Gastroenterology, Fortis Escorts Liver & Digestive Diseases Institute (FELDI), Fortis Escorts Hospital, Delhi, India
| | - Amit Rastogi
- Department of Liver Transplantation, Medanta – the MedicityHospital, Sector – 38, Gurgaon, Haryana, India
| | - Vivek A. Saraswat
- Department of Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raibareli Road, Lucknow, Uttar Pradesh, 226 014, India
| | - Sanjiv Saigal
- Department of Hepatology, Department of Liver Transplantation, India
| | - Shalimar
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 29, India
| | - Akash Shukla
- Department of Gastroenterology, LTM Medical College & Sion Hospital, India
| | - Shivaram P. Singh
- Department of Gastroenterology, SCB Medical College, Cuttack, Dock Road, Manglabag, Cuttack, Odisha, 753 007, India
| | - Thomas Verghese
- Department of Gastroenterology, Government Medical College, Kozikhode, India
| | - Manav Wadhawan
- Institute of Liver & Digestive Diseases and Head of Hepatology & Liver Transplant (Medicine), BLK Super Speciality Hospital, Delhi, India
| | - The INASL Task-Force on Acute Liver Failure
- Department of Gastroenterology, Kaliga Institute of Medical Sciences, Bhubaneswar, 751024, India
- Department of Gastroenterology, Sarvodaya Hospital and Research Centre, Faridababd, Haryana, India
- Department of Gastroenterology and Hepatology, KIIT University, Patia, Bhubaneswar, Odisha, 751 024, India
- Institute of Liver Gastroenterology &Pancreatico Biliary Sciences, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, 110 060, India
- Department of Gastroenterology, Krishna Institute of Medical Sciences, Hyderabad 500003, India
- Department of Gastroenterology, Indraprastha Apollo Hospital, SaritaVihar, New Delhi, 110 076, India
- Department of Gastroenterology, Kalinga Institute of Medical Sciences (KIMS), Kushabhadra Campus (KIIT Campus-5), Patia, Bhubaneswar, Odisha, 751 024, India
- Department of Hepatology, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education & Research, Kolkata, 700020, India
- Hepatology and Liver Transplant, Institute of Liver & Biliary Sciences, D-1 Vasant Kunj, New Delhi, India
- Department of Hepatology, Christian Medical College, Vellore, India
- Department of Gastroenterology and Hepatology, St. John's Medical College Hospital, Bangalore, 560034, India
- Department of Hepatology, Post graduate Institute of Medical Education and Research, Chandigarh, 160 012, India
- Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110 029, India
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Centre, Chrompet, Chennai, 600044, India
- Gleneagles Global Hospitals, Hyderabad, Telangana, India
- Department of Gastroenterology and Hepatology, Max Super Speciality Hospital, Vaishali, Ghaziabad, Uttar Pradesh, 201 012, India
- Department of Gastroenterology, Dr Khuroo’ S Medical Clinic, Srinagar, Kashmir, India
- Gastroenterology and Hepatology, Max Smart Super Specialty Hospital, Saket, New Delhi, India
- Department of Gastroenterology, Kalinga Institute of Medical Sciences, Bhubaneswar, 751024, India
- Hepatology Incharge Liver Intensive Care, Institute of Liver & Biliary Sciences, D-1 Vasant Kunj, New Delhi, India
- Department of Pediatric Gastroenterology, Hepatology & Liver Transplantation, Medanta – the Medicity Hospital, Sector – 38, Gurgaon, Haryana, India
- Department of Gastroenterology, Apollo and Jaslok Hospital & Research Centre, 15, Dr Deshmukh Marg, Pedder Road, Mumbai, Maharashtra, 400 026, India
- Liver & Digestive Diseases Institute, Fortis Escorts Hospital, Okhla Road, New Delhi, 110 025, India
- The Liver Unit and Monarch Liver Lab, Cochin Gastroenterology Group, Ernakulam Medical Centre, Kochi, 682028, Kerala, India
- Department of Hepatology and Gastroenterology, Fortis Escorts Liver & Digestive Diseases Institute (FELDI), Fortis Escorts Hospital, Delhi, India
- Department of Liver Transplantation, Medanta – the MedicityHospital, Sector – 38, Gurgaon, Haryana, India
- Department of Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raibareli Road, Lucknow, Uttar Pradesh, 226 014, India
- Department of Hepatology, Department of Liver Transplantation, India
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 29, India
- Department of Gastroenterology, LTM Medical College & Sion Hospital, India
- Department of Gastroenterology, SCB Medical College, Cuttack, Dock Road, Manglabag, Cuttack, Odisha, 753 007, India
- Department of Gastroenterology, Government Medical College, Kozikhode, India
- Institute of Liver & Digestive Diseases and Head of Hepatology & Liver Transplant (Medicine), BLK Super Speciality Hospital, Delhi, India
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Warrillow S, Fisher C, Tibballs H, Bailey M, McArthur C, Lawson-Smith P, Prasad B, Anstey M, Venkatesh B, Dashwood G, Walsham J, Holt A, Wiersema U, Gattas D, Zoeller M, García Álvarez M, Bellomo R. Continuous renal replacement therapy and its impact on hyperammonaemia in acute liver failure. CRIT CARE RESUSC 2020; 22:158-165. [PMID: 32389108 PMCID: PMC10692487 DOI: 10.51893/2020.2.oa6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
OBJECTIVE Hyperammonaemia contributes to complications in acute liver failure (ALF) and may be treated with continuous renal replacement therapy (CRRT), but current practice is poorly understood. DESIGN We retrospectively analysed data for baseline characteristics, ammonia concentration, CRRT use, and outcomes in a cohort of Australian and New Zealand patients with ALF. SETTING All liver transplant ICUs across Australia and New Zealand. PARTICIPANTS Sixty-two patients with ALF. MAIN OUTCOME MEASURES Impact of CRRT on hyperammonaemia and patient outcomes. RESULTS We studied 62 patients with ALF. The median initial (first 24 h) peak ammonia was 132 μmol/L (interquartile range [IQR], 91-172), median creatinine was 165 μmol/L (IQR, 92-263) and median urea was 6.9 mmol/L (IQR, 3.1-12.0). Most patients (43/62, 69%) received CRRT within a median of 6 hours (IQR, 2-12) of ICU admission. At CRRT commencement, three-quarters of such patients did not have Stage 3 acute kidney injury (AKI): ten patients (23%) had no KDIGO creatinine criteria for AKI, 12 (28%) only had Stage 1, and ten patients (23%) had Stage 2 AKI. Compared with non-CRRT patients, those treated with CRRT had higher ammonia concentrations (median, 141 μmol/L [IQR, 102-198] v 91 μmol/L [IQR, 54-115]; P = 0.02), but a nadir Day 1 pH of only 7.25 (standard deviation, 0.16). Prevention of extreme hyperammonaemia (> 140 μmol/L) after Day 1 was achieved in 36 of CRRT-treated patients (84%) and was associated with transplant-free survival (55% v 13%; P = 0.05). CONCLUSION In Australian and New Zealand patients with ALF, CRRT is typically started early, before Stage 3 AKI or severe acidaemia, and in the presence hyperammonaemia. In these more severely ill patients, CRRT use was associated with prevention of extreme hyperammonaemia, which in turn, was associated with increased transplant-free survival.
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Affiliation(s)
- Stephen Warrillow
- Department of Intensive Care, Austin Health, Melbourne, VIC, Australia.
| | - Caleb Fisher
- Department of Intensive Care, Austin Health, Melbourne, VIC, Australia
| | - Heath Tibballs
- Department of Intensive Care, Austin Health, Melbourne, VIC, Australia
| | | | - Colin McArthur
- Medical Research Institute of New Zealand, Auckland, New Zealand
| | - Pia Lawson-Smith
- Department of Critical Care Medicine, Auckland City Hospital, Auckland, New Zealand
| | | | - Matthew Anstey
- Department of Intensive Care, Sir Charles Gairdner Hospital, Perth, WA, Australia
| | - Bala Venkatesh
- Department of Intensive Care, Princess Alexandra Hospital, Brisbane, QLD, Australia
| | - Gemma Dashwood
- Department of Intensive Care, Princess Alexandra Hospital, Brisbane, QLD, Australia
| | - James Walsham
- Department of Intensive Care, Princess Alexandra Hospital, Brisbane, QLD, Australia
| | - Andrew Holt
- Department of Intensive Care, Flinders Medical Centre, Adelaide, SA, Australia
| | - Ubbo Wiersema
- Department of Intensive Care, Flinders Medical Centre, Adelaide, SA, Australia
| | - David Gattas
- Department of Intensive Care, Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - Matthew Zoeller
- Department of Intensive Care, Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - Mercedes García Álvarez
- Department of Anaesthesiology and Pain Medicine, Hospital de la Santa Creu i Sant Pau, University of Barcelona, Barcelona, Spain
| | - Rinaldo Bellomo
- Department of Intensive Care, Austin Health, Melbourne, VIC, Australia
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18
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Nephew L, Zia Z, Ghabril M, Orman E, Lammert C, Chalasani N. Black Adult Patients With Acute Liver Failure Are Sicker and More Likely to Undergo Liver Transplantation Than White Patients. Liver Transpl 2019; 25:1634-1641. [PMID: 31271697 DOI: 10.1002/lt.25594] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Accepted: 06/10/2019] [Indexed: 02/07/2023]
Abstract
Racial and ethnic differences in the presentation and outcomes of patients wait-listed with acute liver failure (ALF) have not been explored. Adult patients with ALF wait-listed for liver transplantation (LT) from 2002 to 2016 were investigated using the United Network for Organ Sharing database. Clinical characteristics and causative etiologies were compared between white, black, Hispanic, and Asian patients with ALF who were wait-listed as status 1. A competing risk analysis was used to explore differences in LT and wait-list removal rates. Kaplan-Meier survival curves were used to explore differences in 1-year posttransplant survival. There were 8208 patients wait-listed with a primary diagnosis of ALF; 4501 were wait-listed as status 1 (55.3% of whites, 64.4% of blacks, 51.6% of Hispanics, 40.7% of Asians; P < 0.001). Black patients had higher bilirubin and Model for End-Stage Liver Disease at wait-listing than other groups. White patients were the most likely to have acetaminophen toxicity as a causative etiology, whereas black patients were the most likely to have autoimmune liver disease. Black patients were significantly more likely to undergo LT than white patients (hazard ratio, 1.20; 95% confidence interval, 1.08-1.30). There was no difference in wait-list removal because of death or clinical deterioration among racial/ethnic groups. The 1-year posttransplant survival was lowest in black patients (79.6%) versus white (82.8%), Hispanic (83.9%), and Asian (89.3%) patients (P = 0.02). In conclusion, etiologies of ALF vary by race and ethnicity. Black patients with ALF were more likely to be wait-listed as status 1 and undergo LT than white patients, but they were sicker at presentation. The 1-year posttransplant survival rate was lowest among black patients.
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Affiliation(s)
- Lauren Nephew
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN
| | - Zahra Zia
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Marwan Ghabril
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN
| | - Eric Orman
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN
| | - Craig Lammert
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN
| | - Naga Chalasani
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN
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19
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Jayaraman T, Lee YY, Chan WK, Mahadeva S. Epidemiological differences of common liver conditions between Asia and the West. JGH OPEN 2019; 4:332-339. [PMID: 32514433 PMCID: PMC7273710 DOI: 10.1002/jgh3.12275] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Accepted: 10/01/2019] [Indexed: 12/19/2022]
Abstract
Liver diseases form a heterogenous group of acute and chronic disorders of varying etiologies. Not only do they result in significant morbidity and mortality, but they also lead to a marked reduction in quality of life, together with a high socioeconomic burden globally. A better understanding of their global distribution is necessary to curb the massive health-care and socioeconomic burden that they entail. Notable differences and similarities have been described between common liver disease conditions occurring in Asia and the West (Europe and North America), giving rise to the need for an updated collective appraisal of this subject. In this review, the epidemiological differences of common liver conditions, specifically acute liver failure, drug-induced liver injury, acute-on-chronic liver failure, hepatocellular carcinoma, and non-alcoholic fatty liver disease, between Asia and the West are discussed.
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Affiliation(s)
- Thevaraajan Jayaraman
- Gastroenterology Unit, Faculty of Medicine Universiti Teknologi MARA Shah Alam Malaysia
| | - Yeong-Yeh Lee
- Department of Medicine, School of Medical Sciences Universiti Sains Malaysia George Town Malaysia
| | - Wah-Kheong Chan
- Gastroenterology and Hepatology Unit, Faculty of Medicine University of Malaya Kuala Lumpur Malaysia
| | - Sanjiv Mahadeva
- Gastroenterology and Hepatology Unit, Faculty of Medicine University of Malaya Kuala Lumpur Malaysia
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20
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Warrillow S, Bailey M, Pilcher D, Kazemi A, McArthur C, Young P, Bellomo R. Characteristics and outcomes of patients with acute liver failure admitted to Australian and New Zealand intensive care units. Intern Med J 2019; 49:874-885. [PMID: 30479057 DOI: 10.1111/imj.14167] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2018] [Revised: 11/20/2018] [Accepted: 11/20/2018] [Indexed: 12/22/2022]
Abstract
BACKGROUND Knowledge about patients with acute liver failure (ALF) in Australia and New Zealand (ANZ) is lacking. AIMS To evaluate whether the pattern of ALF would be similar to previous studies and whether, despite potentially low transplantation rates, mortality would be comparable. METHODS We obtained data from the ANZ Intensive Care Society Adult Patient Database and the ANZ Liver Transplant Registry for 10 years commencing 2005 and analysed for patient outcomes. RESULTS During the study period, 1 022 698 adults were admitted to intensive care units across ANZ, of which 723 had ALF. The estimated annual incidence of ALF over this period was 3.4/million people and increased over time (P = 0.001). ALF patients had high illness severity (Acute Physiology And Chronic Health Evaluation III 79.8 vs 50.1 in non-ALF patients; P < 0.0001) and were more likely to be younger, female, pregnant and immunosuppressed. ALF was an independent predictor of mortality (odds ratio 1.5 (1.26-1.79); P < 0.0001). At less than 23%, the use of liver transplantation was low, but the mortality of 39% was similar to previous studies. CONCLUSIONS ALF is a rare but increasing diagnosis in ANZ intensive care units. Low transplantation rates in ANZ for ALF do not appear to be associated with higher mortality rates than reported in the literature.
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Affiliation(s)
- Stephen Warrillow
- Department of Intensive Care, Austin Health, Melbourne, Australia
- School of Medicine, University of Melbourne, Melbourne, Australia
| | - Michael Bailey
- Australian and New Zealand Intensive Care Research Centre, Monash University School of Public Health and Preventive Medicine, Melbourne, Australia
| | - David Pilcher
- Australian and New Zealand Intensive Care Research Centre, Monash University School of Public Health and Preventive Medicine, Melbourne, Australia
- Department of Intensive Care, Alfred Health, Melbourne, Australia
| | - Alex Kazemi
- Intensive Care Unit, Middlemore Hospital, Auckland, New Zealand
| | - Colin McArthur
- Department of Critical Care Medicine, Auckland City Hospital, Auckland, New Zealand
- Medical Research Institute of New Zealand, Auckland, New Zealand
| | - Paul Young
- Medical Research Institute of New Zealand, Auckland, New Zealand
- Intensive Care Unit, Wellington Hospital, Wellington, New Zealand
| | - Rinaldo Bellomo
- Department of Intensive Care, Austin Health, Melbourne, Australia
- School of Medicine, University of Melbourne, Melbourne, Australia
- Department of Intensive Care, Alfred Health, Melbourne, Australia
- Department of Intensive Care Royal Melbourne Hospital, Melbourne, Australia
- Data Analytics Research and Evaluation (DARE) Centre, Austin Hospital and University of Melbourne, Melbourne, Australia
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21
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Thanapirom K, Treeprasertsuk S, Soonthornworasiri N, Poovorawan K, Chaiteerakij R, Komolmit P, Phaosawasdi K, Pinzani M. The incidence, etiologies, outcomes, and predictors of mortality of acute liver failure in Thailand: a population-base study. BMC Gastroenterol 2019; 19:18. [PMID: 30691414 PMCID: PMC6348628 DOI: 10.1186/s12876-019-0935-y] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2018] [Accepted: 01/21/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Acute liver failure (ALF) is uncommon but progresses rapidly with high mortality. We investigated the incidence, etiologies, outcomes, and predictive factors for 30-day mortality in patients with ALF. METHODS We conducted a population-based study of ALF patients hospitalized between 2009 and 2013 from the Thai Nationwide Hospital Admission database, which comprises 76% of all admissions from 858 hospitals across 77 provinces in Thailand. ALF was diagnosed using ICD-10 codes K72.0 and K71.11. Patients with liver cirrhosis were excluded. RESULTS There were 20,589 patients diagnosed with ALF during the study period with 12,277 (59.6%) males and mean age of 46.6 ± 20.7 years. The incidence of ALF was 62.9 per million population per year. The most frequent causes of ALF were indeterminate (69.4%), non-acetaminophen drug-induced (26.1%), and viral hepatitis (2.5%). Acetaminophen was the presumptive cause in 1.7% of patients. There were 5502 patients (26.7%) who died within 30 days after admission. One patient (0.005%) underwent liver transplantation. The average hospital stay was 8.7 ± 13.9 days, and the total cost of management was 1075.2 ± 2718.9 USD per admission. The most prevalent complications were acute renal failure (ARF)(24.2%), septicemia (18.2%), and pneumonia (12.3%). The most influential predictive factors for 30-day mortality were ARF (HR = 3.64, 95% CI: 3.43-3.87, p < 0.001), malignant infiltration of the liver (HR = 3.37, 95% CI: 2.94-3.85, p < 0.001), and septicemia (HR = 1.96, 95%CI: 1.84-2.08, p < 0.001). CONCLUSIONS ALF patients have poor outcomes with 30-day mortality of 26.7% and high economic burden. Indeterminate etiology is the most frequent cause. ARF, malignant infiltration of the liver, and septicemia are main predictors of 30-day mortality.
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Affiliation(s)
- Kessarin Thanapirom
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai red cross society, Bangkok, 10700, Thailand
- Institute for Liver and Digestive Health, Royal Free Hospital, University College London, London, UK
| | - Sombat Treeprasertsuk
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai red cross society, Bangkok, 10700, Thailand.
| | | | - Kittiyod Poovorawan
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Roongruedee Chaiteerakij
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai red cross society, Bangkok, 10700, Thailand
| | - Piyawat Komolmit
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai red cross society, Bangkok, 10700, Thailand
| | | | - Massimo Pinzani
- Institute for Liver and Digestive Health, Royal Free Hospital, University College London, London, UK
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22
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Montrief T, Koyfman A, Long B. Acute liver failure: A review for emergency physicians. Am J Emerg Med 2018; 37:329-337. [PMID: 30414744 DOI: 10.1016/j.ajem.2018.10.032] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 10/15/2018] [Accepted: 10/17/2018] [Indexed: 02/08/2023] Open
Abstract
INTRODUCTION Acute liver failure (ALF) remains a high-risk clinical presentation, and many patients require emergency department (ED) management for complications and stabilization. OBJECTIVE This narrative review provides an evidence-based summary of the current data for the emergency medicine evaluation and management of ALF. DISCUSSION While ALF remains a rare clinical presentation, surveillance data suggest an overall incidence between 1 and 6 cases per million people every year, accounting for 6% of liver-related deaths and 7% of orthotopic liver transplants (OLT) in the U.S. The definition of ALF includes neurologic dysfunction, an international normalized ratio ≥ 1.5, no prior evidence of liver disease, and a disease course of ≤26 weeks, and can be further divided into hyperacute, acute, and subacute presentations. There are many underlying etiologies, including acetaminophen toxicity, drug induced liver injury, and hepatitis. Emergency physicians will be faced with several complications, including encephalopathy, coagulopathy, infectious processes, renal injury, and hemodynamic instability. Critical patients should be evaluated in the resuscitation bay, and consultation with the transplant team for appropriate patients improves patient outcomes. This review provides several guiding principles for management of acute complications. Using a pathophysiological-guided approach to the management of ALF associated complications is essential to optimizing patient care. CONCLUSIONS ALF remains a rare clinical presentation, but has significant morbidity and mortality. Physicians must rapidly diagnose these patients while evaluating for other diseases and complications. Early consultation with a transplantation center is imperative, as is identifying the underlying etiology and initiating symptomatic care.
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Affiliation(s)
- Tim Montrief
- University of Miami, Jackson Memorial Hospital/Miller School of Medicine, Department of Emergency Medicine, 1611 N.W. 12th Avenue, Miami, FL 33136, United States
| | - Alex Koyfman
- The University of Texas Southwestern Medical Center, Department of Emergency Medicine, 5323 Harry Hines Boulevard, Dallas, TX 75390, United States
| | - Brit Long
- Brooke Army Medical Center, Department of Emergency Medicine, 3841 Roger Brooke Dr, Fort Sam Houston, TX 78234, United States.
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23
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Abstract
Acute liver failure (ALF) is a rare but highly fatal condition. The most common causes include drug-induced and viral hepatitis, but other less common etiologies, especially autoimmune hepatitis, Budd-Chiari syndrome, and Wilson disease, need to be considered. Because diagnosis is frequently tied to potential for reversibility of ALF and prognosis, early identification in a timely manner is crucial. Other causes of ALF are more easily recognizable based on specific circumstances, such as ALF in pregnancy or ischemic hepatitis. Ultimately, maintaining a wide differential diagnosis in patients with ALF is essential to identifying the proper treatment and prognosis.
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Affiliation(s)
- Russell Rosenblatt
- Division of Gastroenterology and Hepatology, Weill Cornell Medical College, 1305 York Avenue, 4th Floor, New York, NY 10021, USA
| | - Robert S Brown
- Division of Gastroenterology and Hepatology, Weill Cornell Medical College, 1305 York Avenue, 4th Floor, New York, NY 10021, USA.
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24
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Brennan PN, Donnelly MC, Simpson KJ. Systematic review: non A-E, seronegative or indeterminate hepatitis; what is this deadly disease? Aliment Pharmacol Ther 2018; 47:1079-1091. [PMID: 29468698 DOI: 10.1111/apt.14566] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Revised: 10/20/2017] [Accepted: 01/22/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND A significant proportion of cases of acute liver failure (ALF) do not have an identifiable cause; so called "non A-E," "non A, non B, non C," "seronegative" or "indeterminate" hepatitis. However, this entity is clinically not well described. AIM To collate the known incidence and outcomes in indeterminate hepatitis. This systematic review sought to identify potential aetiologies that ought to be considered, and identify likely future objectives in classification and treatment strategies for indeterminate hepatitis. METHODS Literature review to determine aetiological factors, prevalence and outcomes relating to indeterminate hepatitis. RESULTS There is significant heterogeneity within the reported cases of indeterminate hepatitis in the literature. Some of the potential infective aetiologies which are reviewed here include: parvovirus B19 (PVB19), herpes simplex virus (HSV), Toga-Like Virus and the Annelloviridae (including SEN-V). Interestingly, this condition predominately affects middle aged women, with subacute progression of the liver failure. In addition, the prognosis of indeterminate hepatitis is poor, with reduced spontaneous survival compared with other causes of acute liver failure and increased need for emergency liver transplantation. CONCLUSIONS Whilst various pathological processes have been implicated in the development of indeterminate hepatitis, the specific cause remains elusive. There is an urgent need for general consensus on a specific definition and exclusion of confounding aetiologies with coordinated multicentre investigation of this rare condition to identify aetiology and develop therapies to reduce the significant mortality and need for emergency liver transplantation associated with this condition.
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Affiliation(s)
- P N Brennan
- Department of Hepatology and Scottish Liver Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, UK
| | - M C Donnelly
- Department of Hepatology and Scottish Liver Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, UK
| | - K J Simpson
- Department of Hepatology and Scottish Liver Transplant Unit, Royal Infirmary of Edinburgh, University of Edinburgh, Edinburgh, UK
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25
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Hessheimer AJ, Nacif L, Flores Villalba E, Fondevila C. Liver transplantation for acute liver failure. Cir Esp 2017; 95:181-189. [PMID: 28433231 DOI: 10.1016/j.ciresp.2017.01.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2016] [Revised: 01/11/2017] [Accepted: 01/19/2017] [Indexed: 12/16/2022]
Abstract
Before liver transplantation became widely applicable as a treatment option, the mortality rate for acute liver failure was as high as 85%. Today, acute liver failure is a relatively common transplant indication in some settings, but the results of liver transplantation in this context appear to be worse than those for chronic forms of liver disease. In this review, we discuss the indications and contraindications for urgent liver transplantation. In particular, we consider the roles of auxiliary, ABO-incompatible, and urgent living donor liver transplantation and address the management of a «status 1» patient with total hepatectomy and portocaval shunt for toxic liver syndrome.
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Affiliation(s)
- Amelia J Hessheimer
- Liver Transplant Unit, Department of Surgery, Hospital Clínic, CIBERehd, University of Barcelona, Barcelona, España
| | - Lucas Nacif
- Liver Transplant Unit, Department of Surgery, Hospital Clínic, CIBERehd, University of Barcelona, Barcelona, España
| | - Eduardo Flores Villalba
- Liver Transplant Unit, Department of Surgery, Hospital Clínic, CIBERehd, University of Barcelona, Barcelona, España
| | - Constantino Fondevila
- Liver Transplant Unit, Department of Surgery, Hospital Clínic, CIBERehd, University of Barcelona, Barcelona, España.
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26
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Vorrink SU, Ullah S, Schmidt S, Nandania J, Velagapudi V, Beck O, Ingelman-Sundberg M, Lauschke VM. Endogenous and xenobiotic metabolic stability of primary human hepatocytes in long-term 3D spheroid cultures revealed by a combination of targeted and untargeted metabolomics. FASEB J 2017; 31:2696-2708. [PMID: 28264975 PMCID: PMC5434660 DOI: 10.1096/fj.201601375r] [Citation(s) in RCA: 128] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Accepted: 02/21/2017] [Indexed: 12/30/2022]
Abstract
Adverse reactions or lack of response to medications are important concerns for drug
development programs. However, faithful predictions of drug metabolism and toxicity
are difficult because animal models show only limited translatability to humans.
Furthermore, current in vitro systems, such as hepatic cell lines or
primary human hepatocyte (PHH) 2-dimensional (2D) monolayer cultures, can be used
only for acute toxicity tests because of their immature phenotypes and inherent
instability. Therefore, the migration to novel phenotypically stable models is of
prime importance for the pharmaceutical industry. Novel 3-dimensional (3D) culture
systems have been shown to accurately mimic in vivo hepatic
phenotypes on transcriptomic and proteomic level, but information about their
metabolic stability is lacking. Using a combination of targeted and untargeted
high-resolution mass spectrometry, we found that PHHs in 3D spheroid cultures
remained metabolically stable for multiple weeks, whereas metabolic patterns of PHHs
from the same donors cultured as conventional 2D monolayers rapidly deteriorated.
Furthermore, pharmacokinetic differences between donors were maintained in 3D
spheroid cultures, enabling studies of interindividual variability in drug metabolism
and toxicity. We conclude that the 3D spheroid system is metabolically stable and
constitutes a suitable model for in vitro studies of long-term drug
metabolism and pharmacokinetics.—Vorrink, S. U., Ullah, S., Schmid, S.,
Nandania, J., Velagapudi, V., Beck, O., Ingelman-Sundberg, M., Lauschke, V. M.
Endogenous and xenobiotic metabolic stability of primary human hepatocytes in
long-term 3D spheroid cultures revealed by a combination of targeted and untargeted
metabolomics.
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Affiliation(s)
- Sabine U Vorrink
- Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Shahid Ullah
- Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Staffan Schmidt
- Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Jatin Nandania
- Metabolomics Unit, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Vidya Velagapudi
- Metabolomics Unit, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Olof Beck
- Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Magnus Ingelman-Sundberg
- Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Volker M Lauschke
- Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden;
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Donnelly MC, Davidson JS, Martin K, Baird A, Hayes PC, Simpson KJ. Acute liver failure in Scotland: changes in aetiology and outcomes over time (the Scottish Look-Back Study). Aliment Pharmacol Ther 2017; 45:833-843. [PMID: 28097670 DOI: 10.1111/apt.13943] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2016] [Revised: 06/07/2016] [Accepted: 12/23/2016] [Indexed: 12/13/2022]
Abstract
BACKGROUND Acute liver failure is a rare and devastating clinical condition resulting from sudden loss of hepatic parenchyma and metabolic function. The Scottish Liver Transplant Unit (SLTU) offers specialist management and emergency liver transplantation to patients with acute liver failure from across Scotland. AIM To describe temporal changes in number of admissions, aetiology of acute liver failure, severity of disease at presentation and outcomes over a 22-year period. METHODS Retrospective analysis of the SLTU database, including all patients admitted with acute liver injury or acute liver failure between November 1992 and March 2014. RESULTS There has been no change in the number of patients presenting with acute liver injury or failure secondary to paracetamol overdose, but a reduction in the number of admissions with acute liver injury or failure secondary to non paracetamol causes. Over time, disease severity at presentation has not changed in the paracetamol cohort; those with a non paracetamol aetiology have latterly presented with milder hepatic encephalopathy. Spontaneous survival rates improved significantly over time for those patients with acute liver failure due to paracetamol and non paracetamol aetiologies. The most marked improvement in survival is observed in the sickest patients meeting Kings College Hospital poor prognostic criteria. CONCLUSIONS The number of admissions to the SLTU with acute liver failure is decreasing, due to reduced numbers of non paracetamol cases. Outcomes in this condition are improving, due to improvements in intensive care management and use of liver transplantation, and the increase in survival is most marked in patients meeting Kings College Hospital poor prognostic criteria.
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Affiliation(s)
- M C Donnelly
- Department of Hepatology and Scottish Liver Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, UK
| | - J S Davidson
- Scottish Liver Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, UK
| | - K Martin
- Scottish Liver Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, UK
| | - A Baird
- Scottish Liver Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, UK
| | - P C Hayes
- University of Edinburgh and Scottish Liver Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, UK
| | - K J Simpson
- University of Edinburgh and Scottish Liver Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, UK
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Parekh J, Matei VM, Canas-Coto A, Friedman D, Lee WM, the Acute Liver Failure Study Group. Budd-chiari syndrome causing acute liver failure: A multicenter case series. Liver Transpl 2017; 23:135-142. [PMID: 27656864 PMCID: PMC5258669 DOI: 10.1002/lt.24643] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Accepted: 09/01/2016] [Indexed: 12/13/2022]
Abstract
Budd-Chiari syndrome (BCS) is a rare disease resulting from obstruction of the hepatic venous outflow tract that typically presents with abdominal pain, jaundice, and ascites without frank liver failure. However, BCS may also evolve more rapidly to acute liver failure (ALF). In this study, we describe the clinical features, treatment, and outcomes of ALF due to BCS and compare our results with those in the published literature. Twenty of the 2344 patients enrolled in the Acute Liver Failure Study Group (ALFSG) registry since 1998 presented with a clinical diagnosis of BCS. An additional 19 patients of ALF-BCS in the English language literature were reviewed and compared with the ALFSG cases. Most ALF-BCS patients were white (84%) and female (84%) in their fourth decade. A hypercoagulable state was noted in 63% of patients. BCS was diagnosed by Doppler ultrasonography or abdominal computed tomography in all patients. Liver biopsies (n = 6) all had evidence of severe pericentral necrosis. Treatments used included most commonly anticoagulation (71%), but also transjugular intrahepatic portosystemic shunt (TIPS; 37%) and orthotopic liver transplantation (37%). In-hospital mortality was approximately 60%. In conclusion, BCS is a rare cause of ALF and mandates prompt diagnosis and management for successful outcomes. Once the diagnosis is confirmed, prompt anticoagulation is recommended in conjunction with evaluation for malignancy or thrombophilic disorder. Mortality may have improved in recent years with use of TIPS and/or orthotopic liver transplantation compared with prior published reports. Liver Transplantation 23 135-142 2017 AASLD.
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Affiliation(s)
- Justin Parekh
- Department of Surgery, UT Southwestern Medical Center
| | - Vlad M Matei
- Department of Ophthalmology, UT Southwestern Medical Center
| | | | | | - William M. Lee
- Digestive and Liver Diseases Division, UT Southwestern Medical Center
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Diphenhydramine as a Cause of Drug-Induced Liver Injury. Case Reports Hepatol 2017; 2017:3864236. [PMID: 28246565 PMCID: PMC5299161 DOI: 10.1155/2017/3864236] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Accepted: 01/10/2017] [Indexed: 01/13/2023] Open
Abstract
Drug-induced liver injury (DILI) is the most common cause of acute liver failure in the Unites States and accounts for 10% of acute hepatitis cases. We report the only known case of diphenhydramine-induced acute liver injury in the absence of concomitant medications. A 28-year-old man with history of 13/14-chromosomal translocation presented with fevers, vomiting, and jaundice. Aspartate-aminotransferase and alanine-aminotransferase levels peaked above 20,000 IU/L and 5,000 IU/L, respectively. He developed coagulopathy but without altered mental status. Patient reported taking up to 400 mg diphenhydramine nightly, without concomitant acetaminophen, for insomnia. He denied taking other medications, supplements, antibiotics, and herbals. A thorough workup of liver injury ruled out viral hepatitis (including A, B, C, and E), autoimmune, toxic, ischemic, and metabolic etiologies including Wilson's disease. A liver biopsy was consistent with DILI without evidence of iron or copper deposition. Diphenhydramine was determined to be the likely culprit. This is the first reported case of diphenhydramine-induced liver injury without concomitant use of acetaminophen.
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Abstract
The diagnosis of drug-induced liver injury (DILI) is largely a diagnosis of exclusion because, with the possible exception of protein:drug adducts in paracetamol overdose, there are no laboratory, biopsy or imaging tests that alone are capable of establishing an unequivocal diagnosis of DILI. However, it is increasingly appreciated that drugs that cause DILI typically have characteristic clinical presentations or 'signatures' that can be very useful in the diagnosis of DILI. Indeed, knowing a drug's DILI signature (or sometimes signatures) and the incidence rate of DILI during treatment with that drug are perhaps the most useful pieces of historical information in arriving at the diagnosis of DILI. Components of the signature include the typical latency from the onset of treatment, whether there are extrahepatic manifestations, whether the injury is hepatocellular, cholestatic or mixed, and sometimes characteristic features on biopsy or serological testing (e.g. liver autoantibodies). A major advance has been the establishment of the LiverTox website (http://livertox.nih.gov/) which provides open access to standardized entries for over 600 different drugs, including the characteristic clinical presentations of DILI when known. LiverTox will also calculate the causality score for individual cases using the RUCAM instrument and case-specific data entered by the site user. However, the problem with standard diagnostic instruments such as the RUCAM is that DILI signatures are not incorporated into the scoring system. The person entering data must therefore subjectively weigh the RUCAM score with the characteristic DILI signature(s) of the drug to arrive at a diagnosis. In the future, it should be possible to construct improved diagnostic instruments that objectively incorporate DILI signatures, data-based estimates of the incidence rates of DILI from each implicated drug, and perhaps genetic variants associated with the risk of DILI.
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Affiliation(s)
- Paul B Watkins
- Hamner-University of North Carolina Institute for Drug Safety Sciences, University of North Carolina, Chapel Hill, N.C., USA
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Regev A, Seeff LB, Merz M, Ormarsdottir S, Aithal GP, Gallivan J, Watkins PB. Causality assessment for suspected DILI during clinical phases of drug development. Drug Saf 2015; 37 Suppl 1:S47-56. [PMID: 25352327 PMCID: PMC4212150 DOI: 10.1007/s40264-014-0185-4] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Causality assessment is a critical step in establishing the diagnosis of drug induced liver injury (DILI) during drug development. DILI may resemble almost any type of liver disease, and often presents a serious challenge to clinical investigators and drug makers. The diagnosis of DILI is largely based upon a combination of a compatible clinical course, exclusion of all other reasonable causes, resemblance of clinical and pathological features to known features of liver injury due to the drug (i.e., “drug’s signature”), and incidence of liver injury among patients treated with the drug compared to placebo or comparator. Causality assessment for suspected DILI is currently performed using either evaluation by physicians with expertise in liver disorders (i.e., expert opinion) or standardized scoring instruments such as the Roussel Uclaf Causality Assessment Method (RUCAM). Both approaches are widely used in the post marketing setting. Causality assessment based on expert opinion is considered superior to standardized instruments such as RUCAM, in the setting of drug development, and is currently the preferred approach during clinical trials. There is a need for a systematic revision of RUCAM that will render it more suitable for the setting of clinical trials and drug development. Careful monitoring and meticulous data collection during clinical trials are essential in all cases with established liver injury to allow for a proper causality assessment. A workshop was convened to discuss best practices for the assessment of drug-induced liver injury (DILI) in clinical trials. This publication is based on the conclusions of this workshop.
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Affiliation(s)
- Arie Regev
- Global Patient Safety, Eli Lilly and Company, Lilly Corporate Center, Drop Code 2121, Indianapolis, IN, 46285, USA,
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Li L, Liu YR, Gao S, Li JF, Li SS, Zhang DD, Liu S, Bai L, Zheng SJ, Duan ZP, Qi M, Chen Y. Inhibition of 5-lipoxygenase pathway attenuates acute liver failure by inhibiting macrophage activation. J Immunol Res 2014; 2014:697560. [PMID: 24987711 PMCID: PMC4058580 DOI: 10.1155/2014/697560] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2014] [Accepted: 05/12/2014] [Indexed: 12/13/2022] Open
Abstract
This study aimed to investigate the role of 5-lipoxygenase (5-LO) in acute liver failure (ALF) and changes in macrophage activation by blocking it. ALF was induced in rats by administration of D-galactosamine (D-GalN)/lipopolysaccharide (LPS). Rats were injected intraperitoneally with AA-861 (a specific 5-LO inhibitor), 24 hr before D-GalN/LPS administration. After D-GalN/LPS injection, the liver tissue was collected for assessment of histology, macrophage microstructure, macrophage counts, 5-LO mRNA formation, protein expression, and concentration of leukotrienes. Serum was collected for detecting alanine aminotransferase (ALT), aspartate transaminase (AST), total bilirubin (Tbil), and tumor necrosis factor- (TNF-) α . Twenty-four hours after injection, compared with controls, ALF rats were characterized by widespread hepatocyte necrosis and elevated ALT, AST, and Tbil, and 5-LO protein expression reached a peak. Liver leukotriene B4 was also significantly elevated. However, 5-LO mRNA reached a peak 8 hr after D-GalN/LPS injection. Simultaneously, the microstructure of macrophages was changed most significantly and macrophages counts were increased significantly. Moreover, serum TNF- α was also elevated. By contrast, AA-861 pretreatment significantly decreased liver necrosis as well as all of the parameters compared with the rats without pretreatment. Macrophages, via the 5-LO pathway, play a critical role in ALF, and 5-LO inhibitor significantly alleviates ALF, possibly related to macrophage inhibition.
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Affiliation(s)
- Lu Li
- Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Yi-Rong Liu
- Department of Toxic Hepatic Diseases, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Shan Gao
- Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Jun-Feng Li
- Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Shan-Shan Li
- Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Dan-Dan Zhang
- Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Shuang Liu
- Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Li Bai
- Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Su-Jun Zheng
- Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Zhong-Ping Duan
- Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Min Qi
- Department of General Medicine, Luoyang Central Hospital, Zhengzhou University, Luoyang 471000, China
| | - Yu Chen
- Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
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Rajput I, Prasad KR, Bellamy MC, Davies M, Attia MS, Lodge JPA. Subtotal hepatectomy and whole graft auxiliary transplantation for acetaminophen-associated acute liver failure. HPB (Oxford) 2014; 16:220-8. [PMID: 23870048 PMCID: PMC3945847 DOI: 10.1111/hpb.12124] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2012] [Accepted: 03/17/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND An acetominophen overdose (AOD) is the leading cause of acute liver failure (ALF) in the UK and USA. For patients who meet the King's College Hospital criteria, (mortality risk > 85%), an emergency orthotopic liver transplantation (OLT) is conventionally performed with subsequent life-long immunosuppression. A new technique was developed in 1998 for AOD-induced ALF where a subtotal hepatectomy (right hepatic trisectionectomy) and whole graft auxiliary liver transplant (WGALT) was performed with complete withdrawal of immunosupression during the first year post-operatively. RESULTS During 1998-2010, 68 patients were listed for an emergency transplantation for AOD ALF at our institution: 28 died waiting, 16 underwent OLT and 24 a subtotal hepatectomy with WGALT. Eight OLT (50%) and 16 WGALT remain alive (67%); actuarial survival at 5 years OLT 50%, WGALT 63%, P = 0.37. All patients who had successful WGALT are off immunosuppression. Poor prognostic factors in the WGALT group included higher donor age (40.4 versus 53.9, P = 0.043), requirements for a blood transfusion (4.3 versus 7.6, P = 0.0043) and recipient weight (63.1 versus 54 kg, P = 0.036). CONCLUSION Although OLT remains standard practice for AOD-induced ALF, life-long immunosuppression is required. A favourable survival rate using a subtotal hepatectomy and WGALT has been demonstrated, and importantly, all successful patients have undergone complete immunosuppression withdrawal. This technique is advocated for patients who have acetominophen hepatotoxicity requiring liver transplantation.
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Affiliation(s)
- Ibrahim Rajput
- HPB and Transplant Unit, St. James's University HospitalLeeds, UK
| | | | - Mark C Bellamy
- Department of Anaesthesia, St. James's University HospitalLeeds, UK
| | - Mervyn Davies
- Department of Hepatology, St. James's University HospitalLeeds, UK
| | - Magdy S Attia
- HPB and Transplant Unit, St. James's University HospitalLeeds, UK
| | - J Peter A Lodge
- HPB and Transplant Unit, St. James's University HospitalLeeds, UK
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Intrahepatic microcirculatory disorder, parenchymal hypoxia and NOX4 upregulation result in zonal differences in hepatocyte apoptosis following lipopolysaccharide- and D-galactosamine-induced acute liver failure in rats. Int J Mol Med 2013; 33:254-62. [PMID: 24317376 PMCID: PMC3896462 DOI: 10.3892/ijmm.2013.1573] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2013] [Accepted: 11/27/2013] [Indexed: 02/06/2023] Open
Abstract
Although the mechanisms responsible for acute liver failure (ALF) have not yet been fully elucidated, studies have indicated that intrahepatic macrophage activation plays an important role in the pathogenesis of ALF through intrahepatic microcirculatory disorder and consequent parenchymal cell death. Intrahepatic microcirculatory disorder has been demonstrated in animal models using intravital microscopy; however, the limitations of this method include simultaneously evaluating blood flow and the surrounding pathological changes. Therefore, in this study, we devised a novel method involving tetramethylrhodamine isothiocyanate (TRITC)-dextran administration for the pathological assessment of hepatic microcirculation. In addition, we aimed to elucidate the mechanisms through which intrahepatic microcirculatory disorder progresses with relation to activated macrophages. ALF was induced in Wistar rats by exposure to lipopolysaccharide and D-galactosamine. Intrahepatic microcirculation and microcirculatory disorder in zone 3 (pericentral zone) of the livers of rats with ALF was observed. Immunohistochemical examinations in conjunction with TRITC-dextran images revealed that the macrophages were mainly distributed in zone 2 (intermediate zone), while cleaved caspase-3-positive hepatocytes, pimonidazole and hypoxia-inducible factor 1-α were abundant in zone 3. We also found that 4-hydroxy-2-nonenal and nicotinamide adenine dinucleotide phosphate oxidase (NOX)4-positive cells were predominantly located in the zone 3 parenchyma. The majority of apoptotic hepatocytes in zone 3 were co-localized with NOX4. Our results revealed that the apoptotic cells in zone 3 were a result of hypoxic conditions induced by intrahepatic microcirculatory disorder, and were not induced by activated macrophages. The increased levels of oxidative stress in zone 3 may contribute to the progression of hepatocyte apoptosis.
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Regev A. How to avoid being surprised by hepatotoxicity at the final stages of drug development and approval. Clin Liver Dis 2013; 17:749-67, xi. [PMID: 24099029 DOI: 10.1016/j.cld.2013.07.014] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Drugs that caused severe drug-induced live injury (DILI) in humans have typically not shown clear hepatotoxic signals in preclinical assessment. However, clinical trial databases may show evidence of a drug's potential for severe DILI if clinical and laboratory data are evaluated for evidence of milder liver injury. The most specific indicator during a clinical trial for a drug's potential to cause severe DILI is occurrence of cases of drug induced hepatocellular injury accompanied by altered liver function (eg, elevated direct bilirubin). Meticulous causality assessment of hepatic cases and strict adherence to hepatic discontinuation rules are critical components of this approach.
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Affiliation(s)
- Arie Regev
- Global Patient Safety, Eli Lilly and Company, Lilly Corporate Center, Indiana University School of Medicine, Drop Code 2121, Indianapolis, IN 46285, USA.
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Pezzati D, Ghinolfi D, De Simone P, Tincani G, Fiorenza G, Filipponi F. Organ sharing in the management of acute liver failure. Transplant Proc 2013; 45:1270-2. [PMID: 23622675 DOI: 10.1016/j.transproceed.2013.02.022] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BACKGROUND Liver transplantation (OLT) for acute liver failure (ALF) is associated with high morbidity and mortality rates in the early posttransplant course. An efficient organ-sharing organization may grant favorable results. METHODS This is a retrospective analysis of prospectively collected data on patients wait listed for ALF at a single center. Patients were listed for OLT when matching King's College Criteria. Based on patients' clinical status, ABO-incompatible grafts were used. RESULTS From January 2001 to December 2010, 37 patients were wait listed for ALF. Two patients were de-listed (5.4%) for improvement of their clinical conditions; two patients (5.4%) died on the list and 33 (89.2%) underwent OLT. Among these latter, 21 (63.6%) were Italian and 12 (36.4%) were foreign citizens, with four referred from their home country on the basis of international agreements on ALF management. Donors were procured in our region in 10 cases (30.3%), nationally in 22 (66.6%), and outside Italy in 1 (3.1%). Mean time from wait listing to OLT was 1 day (range 0-6), and seven patients received an ABO-incompatible graft. Graft and patient survivals at 1 month, 1 year, and 3 years were 78.8%, 72.7%, 66.5%, and 81.8%, 75.8%, and 72.7%, respectively. Five patients underwent retransplantation: two on postoperative day (POD) 2 for primary nonfunction of the liver graft, two on POD 8 and 95 for hepatic artery thrombosis, and one at 18 months for nonanastomotic biliary stenosis. CONCLUSIONS Prompt referral to a OLT center and efficient organ-sharing system play a fundamental role in optimizing the outcome of the patient with ALF. Development of international organ exchange programs might further improve the results for this category of patients. In very selected cases, ABO-incompatible grafts may be a valuable resource.
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Affiliation(s)
- D Pezzati
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa School of Medicine, Pisa, Italy
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Al-Hourani K, Mansi R, Pettie J, Dow M, Bateman DN, Dear JW. The predictive value of hospital admission serum alanine transaminase activity in patients treated for paracetamol overdose. QJM 2013; 106:541-6. [PMID: 23550167 DOI: 10.1093/qjmed/hct062] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Paracetamol is a major cause of poisoning. Treatment decisions are predominately based on the dose ingested and a timed blood paracetamol concentration because most patients present to hospital soon after overdose, before hepatotoxicity can be confirmed/excluded using serum alanine transaminase (ALT). Nonetheless, ALT is measured at hospital presentation; we investigated its value in predicting hepatotoxicity. METHODS From March 2011 to May 2012, patients admitted to the Royal Infirmary of Edinburgh for paracetamol overdose treatment were identified. We determined the value of admission ALT (below or above our upper limit of normal-50 IU/l) at predicting three endpoints: 1-doubling of ALT; 2-peak ALT >1000 IU/l; 3-peak international normalized ratio (INR) >2. RESULTS From 500 patients, 410 met the entry criteria; 264 presented within 8 h of overdose, 54 between 8 and 24 h, 53 after 24 h and 39 were staggered ingestions. Admission ALT was increased in 71. For endpoint 1 (ALT doubling), the positive predictive value (PPV) of admission ALT was 19% [95% confidence interval (CI) 12-30] with a negative predictive value (NPV) of 98% (95% CI 96-99); endpoint 2 (ALT >1000 IU/l: PPV 23% (95% CI 14-34) and NPV 100% (95% CI 99-100) and for endpoint 3 (INR >2): PPV 14% (95% CI 7-25) and NPV of 100% (95% CI 99-100). The NPV remained high when only late presenters were included. CONCLUSION Admission ALT within the normal range has a high NPV and could be used, alone or in combination with newer biomarkers, to identify lower risk patients at hospital presentation.
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Affiliation(s)
- K Al-Hourani
- National Poisons Information Service Edinburgh, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA, UK
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Kotoh K, Kato M, Kohjima M, Nakamuta M, Enjoji M. A new treatment strategy for acute liver failure. World J Hepatol 2010; 2:395-400. [PMID: 21173907 PMCID: PMC3004032 DOI: 10.4254/wjh.v2.i11.395] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2010] [Revised: 10/18/2010] [Accepted: 10/25/2010] [Indexed: 02/06/2023] Open
Abstract
Acute liver failure (ALF) is a syndrome defined by coagulopathy and encephalopathy and no effective treatments have been established, except for liver transplantation. However, considering the limited supply of donors, we should endeavor to prevent the progression of this syndrome in its early stage to improve the prognosis of patients with ALF. Recently, several authors have reported that over-activation of intrahepatic macrophages plays an important role in the progression of ALF and we have developed a new treatment method, transcatheter arterial steroid injection therapy (TASIT), to suppress macrophage activation. We have now used TASIT for 5 years and have found that TASIT is effective for patients with over-activation of macrophages in the liver but not for those with lesser activation of macrophages. Therefore, to identify the most appropriate patients for TASIT, we tried to categorize patients with ALF or acute liver injury according to markers for the degree of intrahepatic macrophage activation. This approach was helpful to select the appropriate treatment including liver transplantation. We believe that it is essential to analyze disease progression in each patient before selecting the most appropriate treatment.
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Affiliation(s)
- Kazuhiro Kotoh
- Kazuhiro Kotoh, Masaki Kato, Department of Hepatology and Pancreatology, Kyushu University Hospital, Fukuoka 812-8582, Japan
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