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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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Schmutz M, Chartier S, Leblanc T, Mussini C, Gardin A, Gonzales E, Roque-Afonso AM, Le Cam S, Hery G, Neven B, Charbel R, Vartanian JP, Jacquemin E, Morelle G, Almes M. Increased incidence of seronegative autoimmune hepatitis in children during SARS-CoV-2 pandemia period. Front Immunol 2024; 15:1445610. [PMID: 39328418 PMCID: PMC11425678 DOI: 10.3389/fimmu.2024.1445610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Accepted: 08/12/2024] [Indexed: 09/28/2024] Open
Abstract
Background Seronegative autoimmune hepatitis in children is a rare but potentially severe disease, sometimes requiring liver transplantation. This type of hepatitis may be associated with various immunological and hematological disorders, ranging from isolated lymphopenia to aplastic anemia. Precise pathophysiological mechanisms are still unknown, but the role of viruses cannot be excluded, either as directly pathogenic or as triggers, responsible for an inappropriate immune stimulation. Having the impression of an increasing number of seronegative autoimmune hepatitis since the beginning of SARS-CoV-2 pandemia period, we hypothesized that SARS-CoV-2 virus could be an infectious trigger. Methods We conducted a retrospective, observational, descriptive study about children with seronegative autoimmune hepatitis, in a tertiary care center, between 2010 and 2022. Results Thirty-two patients were included. The overall incidence of seronegative autoimmune hepatitis increased 3.3-fold in 2020-2022, during the SARS-CoV-2 pandemia period (16 patients in 2.8 years) compared with 2010-2019 the pre pandemia period (16 patients in 9 years). Patients' clinical and biochemical liver characteristics did not differ between the two periods. Hematological damages were less severe during the pandemia period. Immunological studies revealed a dysregulated immune response. The initiation of immunosuppressive therapy (corticosteroids ± cyclosporine) was earlier during the pandemia period than before. Conclusion In cases of undetermined acute hepatitis, an immune-mediated origin should be considered, prompting a liver biopsy. If the histological aspect points to an immune origin, immunosuppressive treatment should be instituted even though autoimmune hepatitis antibodies are negative. Close hematological monitoring must be performed in all cases. The 3.3-fold increase of cases during the SARS-CoV-2 pandemia will need to be further analyzed to better understand the underlying immunological mechanisms, and to prove its potential involvement.
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Affiliation(s)
- Muriel Schmutz
- Pediatric Hepatology and Pediatric Liver Transplant Department, Reference Center for Biliary Atresia and Genetic Cholestasis, FSMR FILFOIE, European Reference Networks (ERN) RARE LIVER, AP-HP, Paris-Saclay University, Bicêtre Hospital, Kremlin-Bicêtre, France
| | - Suzanne Chartier
- Pathology Department, AP-HP, Paris-Saclay University, Bicêtre Hospital, Kremlin-Bicêtre, France
| | - Thierry Leblanc
- Department of Pediatric Hematology and Immunology, AP-HP, Université Paris Cité Paris, Robert Debré Hospital, Paris, France
| | - Charlotte Mussini
- Pathology Department, AP-HP, Paris-Saclay University, Bicêtre Hospital, Kremlin-Bicêtre, France
| | - Antoine Gardin
- Pediatric Hepatology and Pediatric Liver Transplant Department, Reference Center for Biliary Atresia and Genetic Cholestasis, FSMR FILFOIE, European Reference Networks (ERN) RARE LIVER, AP-HP, Paris-Saclay University, Bicêtre Hospital, Kremlin-Bicêtre, France
- INSERM Unité Mixte de Recherche (UMR)-S 1193, Paris-Saclay University, Hépatinov, Orsay, France
- European Reference Networks (ERN) Rare Liver, Hamburg, Germany
| | - Emmanuel Gonzales
- Pediatric Hepatology and Pediatric Liver Transplant Department, Reference Center for Biliary Atresia and Genetic Cholestasis, FSMR FILFOIE, European Reference Networks (ERN) RARE LIVER, AP-HP, Paris-Saclay University, Bicêtre Hospital, Kremlin-Bicêtre, France
- INSERM Unité Mixte de Recherche (UMR)-S 1193, Paris-Saclay University, Hépatinov, Orsay, France
- European Reference Networks (ERN) Rare Liver, Hamburg, Germany
| | - Anne-Marie Roque-Afonso
- INSERM Unité Mixte de Recherche (UMR)-S 1193, Paris-Saclay University, Hépatinov, Orsay, France
- Virology Department, National Reference Center for Hepatitis A virus, Paul Brousse Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Villejuif, France
| | - Solene Le Cam
- Pediatric Radiology Department, AP-HP, Paris-Saclay University, Bicêtre Hospital, Kremlin-Bicêtre, France
| | - Geraldine Hery
- Department of Paediatric Surgery, AP-HP, Paris-Saclay University, Bicêtre Hospital, Kremlin-Bicêtre, France
| | - Benedicte Neven
- Pediatric Hematology-Immunology and Rheumatology Department, AP-HP, Université Paris Cité Paris, Necker-Children’s Hospital, Paris, France
- INSERM Unité Mixte de Recherche (UMR) 1163, Imagine Institute, Paris, France
| | - Ramy Charbel
- Pediatric Intensive Care Unit, AP-HP, Paris-Saclay University, Bicêtre Hospital, Kremlin-Bicêtre, France
| | - Jean-Pierre Vartanian
- Virus and Cellular Stress Unit, Department of Virology, Institut Pasteur, Université de Paris Cité, Paris, France
| | - Emmanuel Jacquemin
- Pediatric Hepatology and Pediatric Liver Transplant Department, Reference Center for Biliary Atresia and Genetic Cholestasis, FSMR FILFOIE, European Reference Networks (ERN) RARE LIVER, AP-HP, Paris-Saclay University, Bicêtre Hospital, Kremlin-Bicêtre, France
- INSERM Unité Mixte de Recherche (UMR)-S 1193, Paris-Saclay University, Hépatinov, Orsay, France
- European Reference Networks (ERN) Rare Liver, Hamburg, Germany
| | - Guillaume Morelle
- Centre for Haemophilia and Constitutional Bleeding Disorders, AP-HP, Paris-Saclay University, Bicêtre Hospital, Kremlin-Bicêtre, France
- Department of Pediatric Emergency, AP-HP, Paris-Saclay University, Bicêtre Hospital, Kremlin-Bicêtre, France
| | - Marion Almes
- Pediatric Hepatology and Pediatric Liver Transplant Department, Reference Center for Biliary Atresia and Genetic Cholestasis, FSMR FILFOIE, European Reference Networks (ERN) RARE LIVER, AP-HP, Paris-Saclay University, Bicêtre Hospital, Kremlin-Bicêtre, France
- INSERM Unité Mixte de Recherche (UMR)-S 1193, Paris-Saclay University, Hépatinov, Orsay, France
- European Reference Networks (ERN) Rare Liver, Hamburg, Germany
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Rane SV, Jain S, Debnath P, Deshmukh R, Nair S, Chandnani S, Kamat R, Rathi P. A comparative study of uncomplicated acute non-A-E hepatitis with acute viral hepatitis and acute onset autoimmune hepatitis. Indian J Gastroenterol 2024; 43:443-451. [PMID: 38457107 DOI: 10.1007/s12664-023-01474-1] [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: 03/10/2023] [Accepted: 10/16/2023] [Indexed: 03/09/2024]
Abstract
BACKGROUND AND AIMS Non-A-E hepatitis (NAEH) not leading to acute liver failure (ALF) is poorly documented. The objective was to compare clinical and laboratory features of uncomplicated acute NAEH with acute viral (AVH) and autoimmune hepatitis (AIH) and histopathology in NAEH and AIH. METHODS Cases of hepatocellular jaundice were included. These were grouped into AVH, AIH and NAEH based on clinical, laboratory and, when indicated, liver biopsy findings. NAEH and AIH were followed up at three months. RESULTS Of 336 patients with hepatocellular jaundice, 15 (5%) were NAEH, 25 (7%) acute AIH and 45 (14%) AVH. Among NAEH patients, seven (46.7%) were males with a mean age of presentation 39 years. Jaundice (100%) was the most common presentation of NAEH. Peak bilirubin was 10.7 mg/dL. Peak aspartate and alanine aminotransferase (AST, ALT) were 512 and 670 U/L. Five (33.3%) patients had positive anti-nuclear antibody and one had anti-smooth muscle antibody. Mean immunoglobulin G (IgG) levels were 1829. On liver biopsy, all had ballooning degeneration, four (26.7%) had mild and three (20%) moderate interface hepatitis, four (26.7%) mild lymphoplasmacytic infiltrate, one (6.7%) rosette formation, bridging necrosis in none and stage 1 fibrosis in one. Comparing NAEH with AIH, AIH showed significantly older age at presentation, female predisposition, past history of jaundice, lower ALT, more autoantibodies, higher IgG, higher grade interface hepatitis, lymphoplasmacytic infiltrate, rosette formation and higher bilirubin, AST at three months. NAEH and viral hepatitis had similar features. CONCLUSION Etiology of NAEH is unlikely to be autoimmune and is probably viral, unidentified as yet. Uncomplicated NAEH likely has self-limiting course even without specific treatment.
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Affiliation(s)
- Siddhesh Vijay Rane
- Department of Gastroenterology, Topiwala National Medical College and B.Y.L. Nair Charitable Hospital, Room No.717, 7th Floor, OPD Building, Mumbai, 400 008, India.
| | - Shubham Jain
- Department of Gastroenterology, Topiwala National Medical College and B.Y.L. Nair Charitable Hospital, Room No.717, 7th Floor, OPD Building, Mumbai, 400 008, India
| | - Partha Debnath
- Department of Gastroenterology, Topiwala National Medical College and B.Y.L. Nair Charitable Hospital, Room No.717, 7th Floor, OPD Building, Mumbai, 400 008, India
| | - Rahul Deshmukh
- Department of Gastroenterology, Topiwala National Medical College and B.Y.L. Nair Charitable Hospital, Room No.717, 7th Floor, OPD Building, Mumbai, 400 008, India
| | - Sujit Nair
- Department of Gastroenterology, Topiwala National Medical College and B.Y.L. Nair Charitable Hospital, Room No.717, 7th Floor, OPD Building, Mumbai, 400 008, India
| | - Sanjay Chandnani
- Department of Gastroenterology, Topiwala National Medical College and B.Y.L. Nair Charitable Hospital, Room No.717, 7th Floor, OPD Building, Mumbai, 400 008, India
| | - Rima Kamat
- Department of Gastroenterology, Topiwala National Medical College and B.Y.L. Nair Charitable Hospital, Room No.717, 7th Floor, OPD Building, Mumbai, 400 008, India
| | - Pravin Rathi
- Department of Gastroenterology, Topiwala National Medical College and B.Y.L. Nair Charitable Hospital, Room No.717, 7th Floor, OPD Building, Mumbai, 400 008, India
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Cohen A, Alvarez F. Immunosuppression in two cases of indeterminate hepatitis. CANADIAN LIVER JOURNAL 2024; 7:64-69. [PMID: 38505788 PMCID: PMC10946185 DOI: 10.3138/canlivj-2023-0019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 09/16/2023] [Indexed: 03/21/2024]
Abstract
Background Pediatric acute liver failure (PALF) is a potentially lethal and rapidly progressive clinical syndrome, with a large proportion of cases remaining indeterminate despite extensive investigations. Patients and Results In this case report, we describe two male children with indeterminate PALF and a family history of autoimmune disease, both of whom were lymphopenic with necrosis, inflammation, and lymphocytic infiltrates on their liver biopsies. One of these patients subsequently developed hepatitis-associated aplastic anemia. Notably, in addition to receiving standard liver failure care, both patients were successfully treated off-label with anti-thymocyte globulin (ATG), as well as a more prolonged course of cyclosporine and corticosteroids. Conclusions The fact that these medications all suppress T lymphocytes further supports the theory that T-cell activation plays a prominent role in the pathophysiology of indeterminate hepatitis. Further research should examine the short-term and long-term effects of ATG in this population, as well as the necessary duration of treatment with immune-suppressing agents.
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Affiliation(s)
- Alexandra Cohen
- Pediatric Resident, Children's Hospital of Eastern Ontario (CHEO), Ottawa, Ontario, Canada
| | - Fernando Alvarez
- Department of Pediatrics, Université de Montréal, CHU Sainte-Justine, Montréal, Quebec, Canada
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Patel PV, Livingston S, Rakela JL, Stravitz RT, Reuben A, Bass NM, Tujios SR, Larson AM, Sussman NL, Rule JA, Durkalski-Mauldin VL, Lee WM, Ganger DR. Indeterminate etiology of acute liver failure in North America: Less common, still grave prognosis. Clin Transplant 2023; 37:e15128. [PMID: 37705387 PMCID: PMC11459373 DOI: 10.1111/ctr.15128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 08/22/2023] [Accepted: 09/03/2023] [Indexed: 09/15/2023]
Abstract
BACKGROUND The etiology of acute liver failure (ALF) remains one of the most important factors in determining prognosis and predicting outcomes. In a significant proportion of ALF cases, however, the etiology remains unknown and is categorized as indeterminate ALF (IND-ALF). In this study, we summarize findings from patients with IND-ALF from 32 transplant centers across the United States, and we compare laboratory, prognostic, and outcome data for patients with IND-ALF. METHODS Between 1998 and 2019, 3364 adult patients with ALF or acute liver injury (ALI) from 32 liver transplant centers were enrolled in the ALFSG registry. The primary clinical outcome of interest was 21-day transplant-free survival (TFS). RESULTS Of the 3364 patients enrolled in the ALFSG registry, 3.4 % (n = 114) were adjudicated as true indeterminate. On multivariate analysis, patients with a lower bilirubin, lower INR, lack of use of mechanical ventilation and no clinical features of coma at baseline had a higher odds ratio of transplant free survival. The number of deaths were similar between patients with true-IND ALF versus patients with indeterminable ALF (29.8% vs. 27.2%), with almost half of the patients requiring liver transplant (42.1% vs. 45.7%). CONCLUSION We illustrate the poor prognoses that true-IND-ALF and indeterminable ALF carry and the need for emergency liver transplantation in most cases.
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Affiliation(s)
- Parita V Patel
- Department of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Sherry Livingston
- Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Jorge L Rakela
- Department of Medicine, Mayo Clinic Arizona, Scottsdale, Arizona, USA
| | - R Todd Stravitz
- Department of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Adrian Reuben
- Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Nathan M Bass
- Department of Medicine, University of California, San Francisco, California, USA
| | - Shannan R Tujios
- Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Anne M Larson
- Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Norman L Sussman
- Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
| | - Jody A Rule
- Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | | | - William M Lee
- Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Daniel R Ganger
- Department of Medicine, Northwestern University, Chicago, Illinois, USA
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Mehta S, John T, Feld JJ, Shah H, Mullaithilaga N, Campigotto A, Leung K, Kamath BM, Ling SC, Science M, Ng VL. Severe acute hepatitis of unknown etiology in a large cohort of children. Hepatol Commun 2023; 7:e0272. [PMID: 37756118 PMCID: PMC10531196 DOI: 10.1097/hc9.0000000000000272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 07/18/2023] [Indexed: 09/28/2023] Open
Abstract
BACKGROUND We evaluated the proportion, clinical features, and outcomes of previously healthy children presenting to a large Canadian quaternary pediatric center with severe acute hepatitis of unknown etiology. METHODS All patients with serum alanine aminotransferase (ALT) > 500 U/L or aspartate aminotransferase (AST) > 500 U/L between June 1, 2018, and May 31, 2022, at The Hospital for Sick Children, were identified. Subjects with only AST > 500 U/L were excluded. Clinical characteristics, investigations, and outcomes for patients without clear etiology for ALT > 500 U/L (severe acute hepatitis of unknown etiology) for our study period and from October 1 to May 31 of each year 2018-2021 were reviewed. RESULTS Of 977 patients with ALT/AST> 500 U/L, 720 had only ALT > 500 U/L. We excluded age below 6 months (n = 99) or above 16 years (n = 66), known pre-existing liver conditions (n = 66), and ALT > 500 U/L in already admitted patients (n = 151). Among the remaining 338 children with ALT > 500 U/L at presentation, an etiology was identified in 303 subjects. 33 (9.8%) children [median age 6.1 y (range 0.5-15.5); 61% male] were confirmed as severe acute hepatitis of unknown etiology. Twenty patients (60.6%) were tested for blood adenovirus by PCR, and 1 (5%) was positive (serotype B7). Liver tissue specimens from 18 patients revealed no evidence of viral inclusions or adenovirus. Twelve (36.3%) presented with pediatric acute liver failure, with 8 (24.2%) requiring liver transplantation. There were no deaths. Hepatitis-associated aplastic anemia occurred in 5 (15%) patients. CONCLUSIONS Of children presenting with severe acute hepatitis to a quaternary children's hospital over a 48-month period, 9.8% had unknown etiology with no change over time. Liver transplantation remains an important treatment strategy for those presenting with pediatric acute liver failure phenotype. The frequency of cases associated with human adenovirus infection was noncontributory.
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Affiliation(s)
- Sagar Mehta
- Department of Paediatrics, Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Tomisin John
- Department of Paediatrics, Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
- Department of Paediatrics, Transplant and Regenerative Medicine Centre, Hospital for Sick Children, University of Toronto, Ontario, Canada
| | - Jordan J. Feld
- Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Hemant Shah
- Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Nisa Mullaithilaga
- Department of Paediatrics, Division of Infectious Diseases, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Aaron Campigotto
- Department of Laboratory Medicine, Division of Microbiology, University of Toronto, Toronto, Ontario, Canada
| | - Karen Leung
- Department of Paediatrics, Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
- Department of Paediatrics, Transplant and Regenerative Medicine Centre, Hospital for Sick Children, University of Toronto, Ontario, Canada
| | - Binita M. Kamath
- Department of Paediatrics, Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
- Department of Paediatrics, Transplant and Regenerative Medicine Centre, Hospital for Sick Children, University of Toronto, Ontario, Canada
| | - Simon C. Ling
- Department of Paediatrics, Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Michelle Science
- Department of Paediatrics, Division of Infectious Diseases, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Vicky L. Ng
- Department of Paediatrics, Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
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Biswas S, Shalimar. Liver Transplantation for Acute Liver Failure- Indication, Prioritization, Timing, and Referral. J Clin Exp Hepatol 2023; 13:820-834. [PMID: 37693253 PMCID: PMC10483009 DOI: 10.1016/j.jceh.2023.01.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 01/17/2023] [Indexed: 09/12/2023] Open
Abstract
Acute liver failure (ALF) is a major success story in gastroenterology, with improvements in critical care and liver transplant resulting in significant improvements in patient outcomes in the current era compared to the dismal survival rates in the pretransplant era. However, the ever-increasing list of transplant candidates and limited organ pool makes judicious patient selection and organ use mandatory to achieve good patient outcomes and prevent organ wastage. Several scoring systems exist to facilitate the identification of patients who need a liver transplant and would therefore need an early referral to a specialized liver unit. The timing of the liver transplant is also crucial as transplanting a patient too early would lead to those who would recover spontaneously receiving an organ (wastage), and a late decision might result in the patient becoming unfit for transplant (delisted) or have an advanced disease which would result in poor post-transplant outcomes. The current article reviews the indications and contraindications of liver transplant in ALF patients, the various prognostic scoring systems, etiology-specific outcomes, prioritization and timing of referral.
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Affiliation(s)
- Sagnik Biswas
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences New Delhi, India
| | - Shalimar
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences New Delhi, India
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8
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Dass L, Pacia AMM, Hamidi M. Acute hepatitis of unknown etiology in an adult female: A case report. World J Clin Cases 2023; 11:5282-5289. [DOI: 10.12998/wjcc.v11.i22.5282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 06/07/2023] [Accepted: 06/30/2023] [Indexed: 08/03/2023] Open
Abstract
BACKGROUND Acute liver injury (ALI) refers to inflammation of the hepatic parenchyma without hepatic encephalopathy that lasts less than 6 mo. When the etiology is unknown, Acute Hepatitis of Unknown Origin (AHUO) can present as a diagnostic and treatment challenge. AHUO in the adult population is unusual and poorly documented. It has an incidence between 11% and 75%. Currently, no treatment guidelines exist. With no identified cause, treatment is often blind, and the wrong treatment plan may have unintended consequences.
CASE SUMMARY We present the case of a 58-year-old woman who presented to the emergency room for elevated liver function tests (LFTs). Her symptoms started 10 d prior to admission and included nausea, vomiting, jaundice, decreased appetite, weight loss of 10 lbs, and dark urine. She denied drinking alcohol or taking any hepatotoxic agents, including acetaminophen, statins, vitamins, or supplements. She was admitted to the hospital, and an etiologic work-up was carried out. Her initial bloodwork revealed elevated liver enzymes (alanine aminotransferase 2500 U/L, aspartate aminotransferase 3159 U/L, and alkaline phosphatase 714 U/L) and elevated total bilirubin of 6.4 mg/dL. She tested negative for common infectious etiologies such as hepatotropic viruses A, B, C, and E. Further infective work-up revealed negative serology for cytomegalovirus, Epstein-Barr virus, herpes simplex virus 1 & 2, and human immunodeficiency virus. Her autoantibody test results were negative, including anti-smooth muscle antibody, anti-mitochondrial antibody, and anti-liver kidney microsome 1 antibody. Magnetic resonance cholangiopancreatography ruled out biliary causes of elevated LFTs, and her core liver biopsy proved inconclusive. Over the course of her hospital stay, the patient's LFTs improved with supportive care and without steroids.
CONCLUSION Idiopathic hepatitis makes treatment challenging. It can leave patients feeling confused and unfulfilled. Thus, educating the patient thoroughly for shared decision-making and management becomes essential.
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Affiliation(s)
- Lucinda Dass
- Department of Clinical Studies, St. George's University, True Blue 00000, Grenada
| | | | - Mahgol Hamidi
- Department of Clinical Studies, St. George's University, True Blue 00000, Grenada
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Dass L, Pacia AMM, Hamidi M. Acute hepatitis of unknown etiology in an adult female: A case report. World J Clin Cases 2023; 11:5288-5295. [PMID: 37621598 PMCID: PMC10445075 DOI: 10.12998/wjcc.v11.i22.5288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 06/07/2023] [Accepted: 06/30/2023] [Indexed: 08/04/2023] Open
Abstract
BACKGROUND Acute liver injury (ALI) refers to inflammation of the hepatic parenchyma without hepatic encephalopathy that lasts less than 6 mo. When the etiology is unknown, Acute Hepatitis of Unknown Origin (AHUO) can present as a diagnostic and treatment challenge. AHUO in the adult population is unusual and poorly documented. It has an incidence between 11% and 75%. Currently, no treatment guidelines exist. With no identified cause, treatment is often blind, and the wrong treatment plan may have unintended consequences. CASE SUMMARY We present the case of a 58-year-old woman who presented to the emergency room for elevated liver function tests (LFTs). Her symptoms started 10 d prior to admission and included nausea, vomiting, jaundice, decreased appetite, weight loss of 10 lbs, and dark urine. She denied drinking alcohol or taking any hepatotoxic agents, including acetaminophen, statins, vitamins, or supplements. She was admitted to the hospital, and an etiologic work-up was carried out. Her initial bloodwork revealed elevated liver enzymes (alanine aminotransferase 2500 U/L, aspartate aminotransferase 3159 U/L, and alkaline phosphatase 714 U/L) and elevated total bilirubin of 6.4 mg/dL. She tested negative for common infectious etiologies such as hepatotropic viruses A, B, C, and E. Further infective work-up revealed negative serology for cytomegalovirus, Epstein-Barr virus, herpes simplex virus 1 & 2, and human immunodeficiency virus. Her autoantibody test results were negative, including anti-smooth muscle antibody, anti-mitochondrial antibody, and anti-liver kidney microsome 1 antibody. Magnetic resonance cholangiopancreatography ruled out biliary causes of elevated LFTs, and her core liver biopsy proved inconclusive. Over the course of her hospital stay, the patient's LFTs improved with supportive care and without steroids. CONCLUSION Idiopathic hepatitis makes treatment challenging. It can leave patients feeling confused and unfulfilled. Thus, educating the patient thoroughly for shared decision-making and management becomes essential.
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Affiliation(s)
- Lucinda Dass
- Department of Clinical Studies, St. George's University, True Blue 00000, Grenada
| | | | - Mahgol Hamidi
- Department of Clinical Studies, St. George's University, True Blue 00000, Grenada
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10
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Shingina A, Mukhtar N, Wakim-Fleming J, Alqahtani S, Wong RJ, Limketkai BN, Larson AM, Grant L. Acute Liver Failure Guidelines. Am J Gastroenterol 2023; 118:1128-1153. [PMID: 37377263 DOI: 10.14309/ajg.0000000000002340] [Citation(s) in RCA: 64] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 04/04/2023] [Indexed: 06/29/2023]
Abstract
Acute liver failure (ALF) is a rare, acute, potentially reversible condition resulting in severe liver impairment and rapid clinical deterioration in patients without preexisting liver disease. Due to the rarity of this condition, published studies are limited by the use of retrospective or prospective cohorts and lack of randomized controlled trials. Current guidelines represent the suggested approach to the identification, treatment, and management of ALF and represent the official practice recommendations of the American College of Gastroenterology. The scientific evidence was reviewed using the Grading of Recommendations, Assessment, Development and Evaluation process to develop recommendations. When no robust evidence was available, expert opinions were summarized using Key Concepts. Considering the variety of clinical presentations of ALF, individualization of care should be applied in specific clinical scenarios.
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Affiliation(s)
- Alexandra Shingina
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Nizar Mukhtar
- Department of Gastroenterology, Kaiser Permanente, San Francisco, California, USA
| | - Jamilé Wakim-Fleming
- Department of Gastroenterology, Hepatology & Nutrition, Digestive Disease and Surgery Institute, Cleveland Clinic Foundation, Cleveland Ohio, USA
| | - Saleh Alqahtani
- Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, Maryland, USA
- Liver Transplantation Unit, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia
| | - Robert J Wong
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, California, Gastroenterology Section, Veterans Affairs Palo Alto Healthcare System, Palo Alto, California, USA
| | | | - Anne M Larson
- Division of Gastroenterology and Hepatology, University of Washington, Seattle, Washington, USA
| | - Lafaine Grant
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, Texas, USA
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11
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Hu XH, Chen L, Wu H, Tang YB, Zheng QM, Wei XY, Wei Q, Huang Q, Chen J, Xu X. Cell therapy in end-stage liver disease: replace and remodel. Stem Cell Res Ther 2023; 14:141. [PMID: 37231461 DOI: 10.1186/s13287-023-03370-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 04/26/2023] [Indexed: 05/27/2023] Open
Abstract
Liver disease is prevalent worldwide. When it reaches the end stage, mortality rises to 50% or more. Although liver transplantation has emerged as the most efficient treatment for end-stage liver disease, its application has been limited by the scarcity of donor livers. The lack of acceptable donor organs implies that patients are at high risk while waiting for suitable livers. In this scenario, cell therapy has emerged as a promising treatment approach. Most of the time, transplanted cells can replace host hepatocytes and remodel the hepatic microenvironment. For instance, hepatocytes derived from donor livers or stem cells colonize and proliferate in the liver, can replace host hepatocytes, and restore liver function. Other cellular therapy candidates, such as macrophages and mesenchymal stem cells, can remodel the hepatic microenvironment, thereby repairing the damaged liver. In recent years, cell therapy has transitioned from animal research to early human studies. In this review, we will discuss cell therapy in end-stage liver disease treatment, especially focusing on various cell types utilized for cell transplantation, and elucidate the processes involved. Furthermore, we will also summarize the practical obstacles of cell therapy and offer potential solutions.
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Affiliation(s)
- Xin-Hao Hu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Lan Chen
- Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Hao Wu
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China
| | - Yang-Bo Tang
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China
| | - Qiu-Min Zheng
- Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China
| | - Xu-Yong Wei
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Qiang Wei
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Qi Huang
- Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Jian Chen
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.
| | - Xiao Xu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.
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12
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Bhumi SA, Wu GY. Seronegative Autoimmune Hepatitis. J Clin Transl Hepatol 2023; 11:459-465. [PMID: 36643052 PMCID: PMC9817061 DOI: 10.14218/jcth.2022.00235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 08/09/2022] [Accepted: 08/22/2022] [Indexed: 01/18/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a relatively rare liver disease with varying worldwide incidence of from 0.7 to 2 per 100,000 people. It is characterized by the presence of auto-antibodies. However, an average of 10% of AIH cases have AIH symptoms and pathology but lack autoimmune serology. For such seronegative AIH (snAIH) cases, there is currently no established diagnostic algorithm for diagnosis. and improper or delayed diagnosis of snAIH can lead to no or inappropriate treatment that results in progression to fulminant hepatitis or cirrhosis. This review aims to review the current literature and to present an update of seronegative autoimmune hepatitis, including its pathophysiology, clinical presentation, methods of diagnosis, and treatment in order to increase awareness and emphasize the necessity for timely management.
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Affiliation(s)
- Sriya A. Bhumi
- Department of Medicine, University of Connecticut Health Center, Farmington, CT, USA
- Correspondence to: Sriya A. Bhumi, Department of Medicine, University of Connecticut Health Center, 263 Farmington Ave, Farmington CT 06032, USA. ORCID: https://orcid.org/0000-0002-6336-2119. Tel: +1-860-679-6296, Fax: +1-860-679-1434, E-mail:
| | - George Y. Wu
- Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
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Characteristics and outcomes of acute hepatitis of unknown etiology in Egypt: first report of adult adenovirus-associated hepatitis. Infection 2022:10.1007/s15010-022-01945-1. [DOI: 10.1007/s15010-022-01945-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 10/20/2022] [Indexed: 11/06/2022]
Abstract
Abstract
Purpose
Several outbreaks of acute hepatitis of unknown etiology (AHUE) in children were reported in 2022 in many countries, with adenovirus identified as the etiological agent in most of them. We aimed to evaluate the characteristics and outcomes of AHUE cases in Egypt.
Methodology
Hospitalized patients with acute hepatitis were included in the study. Drug-induced, alcoholic hepatitis, autoimmune hepatitis, and Wilson’s disease were identified either by medical history or by routine laboratory diagnosis. Molecular and serological approaches were used to investigate common viral causes of hepatitis, such as hepatitis A–E viruses, cytomegalovirus, Epstein–Barr virus, herpes simplex viruses (HSV1/2), adenovirus, parvovirus B19, and coxsackie virus.
Results
A total of 42 patients were recruited and divided into two groups: 24 cases of unknown hepatitis after excluding the common causes and 18 cases of known hepatitis. About two-thirds of the patients were male (61.9%), and the mean age was 34.55 ± 16.27 years. Jaundice, dark urine, abdominal pain and diarrhea were recorded at a higher incidence in group 1, while jaundice and fever were frequent in group 2. Fulminant hepatitis occurred in 28.6% of the cases, but the two groups did not differ significantly in terms of patient outcome, duration of hospitalization, ascites, and development of fulminant hepatitis. Adenovirus was detected in five cases (20.8%) in group 1, and one case co-infecting with hepatitis E virus in group 2. Herpes simplex virus 1/2, coxsackie virus, and parvovirus B19 were not detected in any case, while etiologies of 75% of the cases were still not confirmed. One out of the six adenovirus-infected patients died. The outcome significantly correlated with the severity of the liver disease.
Conclusion
This is the first report describing etiologies and characteristics of AHUE cases in Egypt, and interestingly, adenovirus was detected in adults. Further studies are required to determine the prevalence of this newly emerging viral hepatitis pathogens.
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Alexander EC, Deep A. Characterization of a Hepatitis Outbreak in Children, 2021 to 2022. JAMA Netw Open 2022; 5:e2237091. [PMID: 36255724 PMCID: PMC9579900 DOI: 10.1001/jamanetworkopen.2022.37091] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 08/31/2022] [Indexed: 12/19/2022] Open
Abstract
Importance After a cluster of pediatric cases of hepatitis of unknown etiology were identified in Scotland in March 2022, the World Health Organization published an outbreak alert, and more than 1010 probable cases were reported. Some cases progressed to acute liver failure and required liver transplant. Although many patients had positive results for adenovirus on polymerase chain reaction testing from whole blood samples and/or reported recent COVID-19 infection (with or without seropositivity), the precise pathogenesis remains unclear despite the high potential morbidity of this condition. Objective To summarize the currently available evidence regarding novel pediatric hepatitis of unknown etiology (or novel hepatitis), encompassing case numbers, testing, management, and outcomes. Evidence Review A rapid review of the literature from April 1, 2021, to August 30, 2022, aimed to identify all available published case series and case-control studies of novel hepatitis. The search included PubMed and references and citations of short-listed studies. Findings A total of 22 available case series and case-control studies describing 1643 cases were identified, with 120 children (7.3%) receiving liver transplants and 24 deaths (1.5%). Outcome reporting and testing for adenovirus and SARS-CoV-2 was incomplete. Assessment of disease severity and management was mixed and results regarding testing for adenovirus and SARS-CoV-2 were inconsistent for both serological testing and testing of explant or biopsy liver samples. More recent studies suggest a more plausible role for adenovirus and/or adeno-associated virus 2. Conclusions and Relevance This systematic review without meta-analysis describes the challenge posed by hepatitis of unknown etiology in terms of investigation and management, with many cases progressing to acute liver failure. The lack of clarity regarding pathogenesis means that these children may be missing the potential for targeted therapies to improve outcomes and avert the need for transplant. Clinicians, immunologists, and epidemiologists must collaborate to investigate the pathogenesis of this novel hepatitis.
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Affiliation(s)
- Emma C. Alexander
- Paediatric Intensive Care Unit, King’s College Hospital NHS (National Health Service) Foundation Trust, London, United Kingdom
| | - Akash Deep
- Paediatric Intensive Care Unit, King’s College Hospital NHS (National Health Service) Foundation Trust, London, United Kingdom
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15
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Lin S, Araujo C, Hall A, Kumar R, Phillips A, Hassan M, Engelmann C, Quaglia A, Jalan R. Prognostic Role of Liver Biopsy in Patients With Severe Indeterminate Acute Hepatitis. Clin Gastroenterol Hepatol 2022; 20:1130-1141.e7. [PMID: 34389485 DOI: 10.1016/j.cgh.2021.08.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 07/15/2021] [Accepted: 08/02/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Severe indeterminate acute hepatitis (sIAH) is a poorly understood rare disease with no specific therapy. This study aims to define the clinicopathological characteristics of sIAH and the role of liver biopsy in determining prognosis. METHODS Patients with sIAH admitted to a single center between 2010 and 2019 were included. Histopathological patterns of liver biopsies were reviewed by 2 histopathologists, and key findings further were specified by multiplex immunofluorescence. Patients that died or underwent liver transplantation were analyzed as nonsurvivors. RESULTS Of 294 patients with acute hepatitis, 43 with sIAH were included. Seventeen (39.5%) underwent liver transplantation and 7 (16.2%) died within 3 months. Multilobular necrosis was the predominant histopathological feature, being significantly more frequent in nonsurvivors (62.5% vs 21.1%; P = .016). Necrotic areas showed low HNF4α and Ki67 expression but high expression of CK19 and cell death markers identifying areas of severe tissue injury and inadequate regenerative response. Patients with multilobular necrosis had higher international normalized ratio, Model for End-Stage Liver Disease, and Model for End-Stage Liver Disease-Sodium scores compared with those without (P values for all markers <.05). Multivariate Cox analysis revealed that multilobular necrosis (hazard ratio, 3.675; 95% confidence interval, 1.322-10.211) and lower body mass index (hazard ratio, 0.916; 95% confidence interval, 0.848-0.991) independently predicted death or transplantation. CONCLUSIONS The results of this study provide novel insights into the important role of liver biopsy in sIAH patients, suggesting that the presence of multilobular necrosis is an early indicator of poor prognosis.
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Affiliation(s)
- Su Lin
- Liver Failure Group, Institute for Liver and Digestive Health, Division of Medicine, Royal Free Hospital, University College London Medical School, London, United Kingdom; Hepatology Research Institute, Department of Hepatology, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
| | - Catarina Araujo
- Department of Cellular Pathology, Royal Free Hospital, London, United Kingdom; Anatomical-Pathology Department, Centro Hospitalar Universitário Lisboa Central, Lisbon, Portugal
| | - Andrew Hall
- Liver Failure Group, Institute for Liver and Digestive Health, Division of Medicine, Royal Free Hospital, University College London Medical School, London, United Kingdom; Department of Cellular Pathology, Royal Free Hospital, London, United Kingdom; Sheila Sherlock Liver Center, Royal Free London NHS Foundation Trust, London, United Kingdom
| | - Rahul Kumar
- Liver Failure Group, Institute for Liver and Digestive Health, Division of Medicine, Royal Free Hospital, University College London Medical School, London, United Kingdom; Department of Gastroenterology and Hepatology, Duke-NUS Academic Medical Centre, Changi General Hospital, Singapore
| | - Alexandra Phillips
- Liver Failure Group, Institute for Liver and Digestive Health, Division of Medicine, Royal Free Hospital, University College London Medical School, London, United Kingdom
| | - Mohsin Hassan
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Cornelius Engelmann
- Liver Failure Group, Institute for Liver and Digestive Health, Division of Medicine, Royal Free Hospital, University College London Medical School, London, United Kingdom; Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany; Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany; Berlin Institute of Health, Berlin, Germany
| | - Alberto Quaglia
- Department of Cellular Pathology, UCL Cancer Institute, Royal Free Hospital, London, United Kingdom
| | - Rajiv Jalan
- Liver Failure Group, Institute for Liver and Digestive Health, Division of Medicine, Royal Free Hospital, University College London Medical School, London, United Kingdom; European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain.
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16
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Lin S, Araujo C, Hall A, Kumar R, Phillips A, Hassan M, Engelmann C, Quaglia A, Jalan R. Presence of multilobular necrosis on liver biopsy identifies corticosteroid responsiveness in acute indeterminate hepatitis. Liver Int 2022; 42:853-863. [PMID: 34936189 DOI: 10.1111/liv.15144] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 11/29/2021] [Accepted: 12/15/2021] [Indexed: 02/13/2023]
Abstract
BACKGROUND AND AIMS Treatment of patients with severe indeterminate hepatitis (IAH) is an unmet need. Corticosteroids are often used in the management of these patients but criteria for the selection of patients for this intervention are arbitrary. The aims of this study were to analyse the clinical and pathological features of patients with IAH to define predictors of corticosteroid responsiveness. METHODS This study included consecutive patients with acute indeterminate hepatitis admitted to a single hospital and underwent a liver biopsy. The clinical manifestation and histopathological features of steroid and non-steroid groups were compared and their relationship with corticosteroids response was evaluated. RESULTS Forty-eight patients were included, 24 (50%) recovered and the other half underwent liver transplantation or died within 3-months. Of the 48 cases, 24 received corticosteroids (initial dose of 45 ± 12 mg prednisolone). Corticosteroids were initiated 2.7 ± 3.8 days after admission. Liver biopsy was performed 2-days (median, IQR 1-3) after admission. Fifteen (62.5%) patients receiving corticosteroids survived without transplantation compared with 9 (37.5%) that did not receive steroids (P = .149). In those with multilobular necrosis, 50% reduction in the death/transplantation rate was observed after steroid treatment (P = .018). In patients without multilobular necrosis and with or without perivenulitis, corticosteroids did not impact the outcome. Response to corticosteroids was independent of the MELD score. CONCLUSIONS The presence of multilobular necrosis on liver biopsy helps identify a subgroup of IAH cases who may benefit from the administration of corticosteroids.
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Affiliation(s)
- Su Lin
- Liver failure Group, Institute for Liver and Digestive Health, Division of Medicine, University College London Medical School, Royal Free Hospital, London, UK.,Department of Hepatology, Hepatology Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Catarina Araujo
- Department of Cellular Pathology, Royal Free Hospital, London, UK.,Anatomical-Pathology Department, Centro Hospitalar Universitário Lisboa Central, Lisboa, Portugal
| | - Andrew Hall
- Liver failure Group, Institute for Liver and Digestive Health, Division of Medicine, University College London Medical School, Royal Free Hospital, London, UK.,Department of Cellular Pathology, Royal Free Hospital, London, UK.,Sheila Sherlock Liver Center, Royal Free London NHS Foundation Trust, London, UK
| | - Rahul Kumar
- Liver failure Group, Institute for Liver and Digestive Health, Division of Medicine, University College London Medical School, Royal Free Hospital, London, UK.,Department of Gastroenterology and Hepatology, Duke-NUS academic Medical Centre, Changi General Hospital, Singapore, Singapore
| | - Alexandra Phillips
- Liver failure Group, Institute for Liver and Digestive Health, Division of Medicine, University College London Medical School, Royal Free Hospital, London, UK
| | - Mohsin Hassan
- Department of Hepatology and Gastroenterology, Charité-Universitaetsmedizin Berlin, Berlin, Germany
| | - Cornelius Engelmann
- Liver failure Group, Institute for Liver and Digestive Health, Division of Medicine, University College London Medical School, Royal Free Hospital, London, UK.,Department of Hepatology and Gastroenterology, Charité-Universitaetsmedizin Berlin, Berlin, Germany.,Section Hepatology, Clinic for Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany.,Berlin Institute of Health (BIH), Berlin, Germany
| | - Alberto Quaglia
- Department of Cellular Pathology and UCL cancer Institute, Royal Free Hospital, London, UK
| | - Rajiv Jalan
- Liver failure Group, Institute for Liver and Digestive Health, Division of Medicine, University College London Medical School, Royal Free Hospital, London, UK.,European Foundation for the Study of Chronic Liver Failure (EFCLIF), Barcelona, Spain
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Dong Y, Kong W, An W. Downregulation of augmenter of liver regeneration impairs the therapeutic efficacy of liver epithelial progenitor cells against acute liver injury by enhancing mitochondrial fission. STEM CELLS (DAYTON, OHIO) 2021; 39:1546-1562. [PMID: 34310799 DOI: 10.1002/stem.3439] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 06/08/2021] [Accepted: 06/25/2021] [Indexed: 11/07/2022]
Abstract
Cell-based therapeutic approaches have been proven to be effective strategies for the treatment of acute liver injury (ALI). However, widespread application of these procedures is limited by several key issues, including rapid loss of stemness in vitro, aberrant differentiation into undesirable cell types, and low engraftment in vivo. In this study, liver epithelial progenitor cells (LEPCs) were characterized and transfected with augmenter of liver regeneration (ALR). The results revealed that in ALI mice with CCl4 , the transplantation of ALR-bearing LEPCs into the liver markedly protected mice against ALI by decreasing the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), thus relieving hepatic tissue injury and attenuating inflammatory infiltration. Mechanistically, the knockdown of ALR in LEPCs activated the phosphorylation of dynamin-related protein 1 (Drp1) at the S616 site and thereby enhanced mitochondrial fission. In contrast, the transfection of ALR into LEPCs significantly inhibited Drp1 phosphorylation, thereby favoring the maintenance of mitochondrial integrity and the preservation of adenosine triphosphate contents in LEPCs. Consequently, the ALR-bearing LEPCs transplanted into ALI mice exhibited substantially greater homing ability to the injured liver via the SDF-1/CXCR4 axis than that of LEPCs-lacking ALR. In conclusion, we demonstrated that the transplantation of ALR-transfected LEPCs protected mice against CCl4 -induced ALI, thus offering immense curative potential in the clinic.
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Affiliation(s)
- Yuan Dong
- Department of Cell Biology, Capital Medical University, The Municipal Key Laboratory for Liver Protection and Regulation of Regeneration, Beijing, People's Republic of China
| | - Weining Kong
- Department of Cell Biology, Capital Medical University, The Municipal Key Laboratory for Liver Protection and Regulation of Regeneration, Beijing, People's Republic of China
| | - Wei An
- Department of Cell Biology, Capital Medical University, The Municipal Key Laboratory for Liver Protection and Regulation of Regeneration, Beijing, People's Republic of China
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18
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Cell therapy for advanced liver diseases: Repair or rebuild. J Hepatol 2021; 74:185-199. [PMID: 32976865 DOI: 10.1016/j.jhep.2020.09.014] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 08/18/2020] [Accepted: 09/14/2020] [Indexed: 12/15/2022]
Abstract
Advanced liver disease presents a significant worldwide health and economic burden and accounts for 3.5% of global mortality. When liver disease progresses to organ failure the only effective treatment is liver transplantation, which necessitates lifelong immunosuppression and carries associated risks. Furthermore, the shortage of suitable donor organs means patients may die waiting for a suitable transplant organ. Cell therapies have made their way from animal studies to a small number of early clinical trials. Herein, we review the current state of cell therapies for liver disease and the mechanisms underpinning their actions (to repair liver tissue or rebuild functional parenchyma). We also discuss cellular therapies that are on the clinical horizon and challenges that must be overcome before routine clinical use is a possibility.
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19
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Rahim MN, Miquel R, Heneghan MA. Approach to the patient with acute severe autoimmune hepatitis. JHEP Rep 2020; 2:100149. [PMID: 32995712 PMCID: PMC7509236 DOI: 10.1016/j.jhepr.2020.100149] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 07/09/2020] [Accepted: 07/15/2020] [Indexed: 12/11/2022] Open
Abstract
Autoimmune hepatitis is associated with varied clinical presentations and natural history, as well as somewhat unpredictable treatment responses. Understanding how to stratify patients who require further escalation of therapy will help clinicians manage these patients. The presentation of acute severe autoimmune hepatitis (AS-AIH) is relatively uncommon, although its prevalence is potentially greater than currently perceived. Previous studies consist of small retrospective single-centre series and are not directly comparable due to the diversity of presentations, disease definitions and non-standardised treatment regimens. We define AS-AIH as those who present acutely with AIH and are icteric with an international normalised ratio ≥1.5 and no evidence of hepatic encephalopathy. Those with hepatic encephalopathy should be defined as having AS-AIH with acute liver failure. In this review, we provide a structured practical approach for diagnosing and managing this unique group of patients.
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Key Words
- ACLF, acute-on-chronic liver failure
- AIH, autoimmune hepatitis
- ALF, acute liver failure
- ALI, acute liver injury
- ALT, alanine aminotransferase
- ANA, anti-nuclear antibody
- AS-AIH, acute severe autoimmune hepatitis
- ASMA, anti-smooth muscle antibody
- AST, aspartate aminotransferase
- AUROC, analysis of area under the receiver operator characteristic curve
- Acute liver failure
- Acute severe presentation
- Autoimmune hepatitis
- CT, computed tomography
- Corticosteroids
- DILI, drug-induced liver injury
- EBV, Epstein-Barr virus
- HE, hepatic encephalopathy
- HLA, human leukocyte antigen
- IAIHG, International Autoimmune Hepatitis Group
- INR, international normalised ratio
- LT, liver transplantation
- Liver transplantation
- MELD, model for end-stage liver disease
- MELD-Na, model for end-stage liver disease-sodium
- MHN, massive hepatic necrosis
- NAC, N-acetylcysteine
- PT, prothrombin time
- UKELD, United Kingdom end-stage liver disease
- USALF, United States Acute Liver Failure
- anti-LC-1, anti-liver cytosol-1
- anti-LKM, anti-liver kidney microsomal
- anti-SLA/LP, anti-soluble liver antigen/liver pancreas
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Affiliation(s)
- Mussarat N. Rahim
- Institute of Liver Studies, King's College Hospital, London, SE5 9RS, UK
| | - Rosa Miquel
- Liver Histopathology Laboratory, King's College Hospital, London, SE5 9RS, UK
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Shalimar, Acharya SK, Kumar R, Bharath G, Rout G, Gunjan D, Nayak B. Acute Liver Failure of Non-A-E Viral Hepatitis Etiology-Profile, Prognosis, and Predictors of Outcome. J Clin Exp Hepatol 2020; 10:453-461. [PMID: 33029054 PMCID: PMC7527854 DOI: 10.1016/j.jceh.2019.12.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 12/29/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/OBJECTIVES Acute liver failure (ALF) is rare and associated with poor outcomes. The outcomes of ALF and predictors of outcome may vary as per the etiology. There are limited data on the predictors of spontaneous survival among patients with ALF of non-A-E hepatitis or cryptogenic etiology. We aimed to assess clinical course, complications, and outcome of non-A-E etiology ALF. METHODS In this prospective analysis, all consecutive ALF patients (n = 1555; January 1986-June 2018) were analyzed. Non-A-E-ALF was defined as ALF that could not be attributed to known etiologies such as drugs, viral hepatitis, autoimmune hepatitis, and Wilson's disease. Clinical course, complications, and outcomes of non-A-E-ALF patients who did not undergo liver transplantation were analyzed. Unadjusted and adjusted odds ratios (ORs) were calculated. RESULTS Non-A-E-ALF constituted 34.6% (n = 538) of all ALF patients, whereas hepatitis E virus (HEV), hepatitis B virus (HBV), and anti-tuberculosis therapy (ATT) accounted for 29.5% (n = 459), 8.6% (n = 134), and 7.4% (n = 115), respectively. Among non-A-E-ALF patients, mean age was 28.8 ± 12.0 years, 50.9% females, majority (63.1%) had hyperacute presentation, and 79.2% had advanced encephalopathy at presentation. The frequency of cerebral edema in non-A-E-ALF (53.3%) was higher than that in HEV-ALF (41.2%) and ATT-ALF (44.2%), P < 0.001. The survival rate in non-A-E-ALF (37.5%) was poorer than HEV-ALF (54.9%) and was comparable to that in HBV (35.8%) and ATT (29.6%) induced ALF. The baseline prothrombin time prolongation (odds ratio [OR] 1.041; 95% confidence intervals [CI], 1.017-1.065) and infection (OR 2.366; 95%CI, 1.107-5.055) were independent predictors of outcome in non-A-E-ALF. The 3-days acute liver failure early dynamic model had the best value in predicting the outcome. CONCLUSIONS Non-A-E-ALF accounts for one-third of all cases of ALF and is associated with poor spontaneous survival.
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Key Words
- ALF, acute liver failure
- ALFED, acute liver failure early dynamic
- ATT, anti-tuberculosis therapy
- HAV, hepatitis A virus
- HBV, hepatitis B virus
- HEV, hepatitis E virus
- INR, international normalized ratio
- KCH, King’s College Hospital criteria
- LT, liver transplant
- MELD, model for end-stage liver disease
- cerebral edema
- cryptogenic
- liver transplant
- prognosis
- viral hepatitis
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Affiliation(s)
- Shalimar
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Subrat K. Acharya
- Department of Gastroenterology, Fortis Hospital, Vasant Kunj, New Delhi, India
| | - Ramesh Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna, India
| | - Gangadhar Bharath
- Department of Medicine, All India Institute of Medical Sciences, New Delhi, India
| | - Gyanranjan Rout
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Deepak Gunjan
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Baibaswata Nayak
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
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Zhao H, Dai Y, Zhou YH. Overview of infection causing hepatitis other than non-A to E hepatitis virus during pregnancy. Best Pract Res Clin Obstet Gynaecol 2020; 68:89-102. [PMID: 32247771 DOI: 10.1016/j.bpobgyn.2020.02.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Revised: 02/27/2020] [Accepted: 02/28/2020] [Indexed: 12/20/2022]
Abstract
Abnormal liver function tests during pregnancy are common. While hepatic injury during pregnancy mostly has minimal adverse influence on maternal and fetal outcomes, severe maternal and fetal morbidities, and even death, sometimes occur. Here, we review the epidemiology, clinical features, diagnosis, and management of hepatitis during pregnancy caused by the less common pathogens, including Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes simplex viruses (HSVs), dengue fever, malaria, leptospirosis, Q fever, typhoid fever, and other occasional infections, as well as the implications on breastfeeding of the infants. Hepatitis during pregnancy with fever and systemic clinical presentations, which are not attributable to the common infectious agents, should raise the suspicion of infection with above-mentioned pathogens, and appropriate laboratory tests are required. Early recognition of severe hepatitis or acute liver failure is critical in initiating appropriate and specific therapy, together with systemic supportive care, to reduce maternal and fetal mortality and long-term sequelae.
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Affiliation(s)
- Hong Zhao
- Department of Infectious Diseases, Nanjing Second Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Yimin Dai
- Department of Obstetrics & Gynecology, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
| | - Yi-Hua Zhou
- Departments of Laboratory Medicine and Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China.
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Amoroso P, Buonocore S, Lettieri G, Pesce G, Pierri P, De Sena R, Morelli G, Matteis B, Dell'isola C, De Marino V, Ciccaglione AR, Punzi R, Esposito C, Spada E. Changing epidemiology of acute liver failure in Italy: a single-center experience over 25 years. Minerva Med 2020; 111:330-336. [PMID: 31958920 DOI: 10.23736/s0026-4806.19.06331-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
BACKGROUND Acute liver failure (ALF) is a rare but often lethal syndrome. In Italy, recent data on its incidence and causes are lacking. We report here the epidemiological analysis of ALF cases observed in Campania, a Southern Italian region, over the last 25 years. METHODS Medical records of ALF cases hospitalized from 1992 to 2018 were retrospectively analyzed. RESULTS Two hundred ten ALF cases occurred during 1992-2018: 103 (49%) hepatitis B virus (HBV)-related (including 5 cases also infected with Delta virus), 39 (19%) from undetermined cause, 36 (17%) drug-induced, 11 (5%) Wilson's disease-associated, 8 (4%) hepatitis A virus (HAV)-related and 12 (6%) from other causes. Separate time-periods analysis of data showed a significant progressive decrease in ALF incidence mainly attributable to a decline of HBV and other viruses etiology. Already before 2010, HAV or Delta virus-related cases have no longer been observed. No hepatitis C or E virus-related ALF was detected through the study period. A progressive decrease in frequency of ALF due to undetermined causes or drug was also evident. CONCLUSIONS A decrease in ALF incidence and a changing in its etiology were observed in Campania during 1992-2018. Both results were likely mainly due to 1991 introduction of HBV universal vaccination and may be considered generalizable nationwide.
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Affiliation(s)
- Pietro Amoroso
- Department of Infectious Diseases, D. Cotugno Hospital, Naples, Italy -
| | | | - Gennaro Lettieri
- Department of Infectious Diseases, D. Cotugno Hospital, Naples, Italy
| | - Gaetano Pesce
- Department of Infectious Diseases, D. Cotugno Hospital, Naples, Italy
| | - Paola Pierri
- Department of Infectious Diseases, D. Cotugno Hospital, Naples, Italy
| | - Raffaele De Sena
- Department of Infectious Diseases, D. Cotugno Hospital, Naples, Italy
| | - Giuseppe Morelli
- Department of Infectious Diseases, D. Cotugno Hospital, Naples, Italy
| | - Bianca Matteis
- Department of Infectious Diseases, D. Cotugno Hospital, Naples, Italy
| | - Chiara Dell'isola
- Department of Infectious Diseases, D. Cotugno Hospital, Naples, Italy
| | - Valeria De Marino
- Department of Infectious Diseases, D. Cotugno Hospital, Naples, Italy
| | - Anna R Ciccaglione
- Department of Infectious Diseases, National Institute of Health, Rome, Italy
| | - Rodolfo Punzi
- Department of Infectious Diseases, D. Cotugno Hospital, Naples, Italy
| | - Ciro Esposito
- Department of Transplants, A. Cardarelli Hospital, Naples, Italy
| | - Enea Spada
- Department of Infectious Diseases, National Institute of Health, Rome, Italy
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Imperatrice B, Giudici G, Marzano A. Human herpes viruses as cause of liver injury and acute liver failure. MINERVA GASTROENTERO 2020; 65:251-254. [DOI: 10.23736/s1121-421x.19.02596-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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Fujiwara K, Yasui S, Yokosuka O, Kato N. Letter: acute liver failure of indeterminate aetiology. Aliment Pharmacol Ther 2018; 48:1024-1025. [PMID: 30318678 DOI: 10.1111/apt.14931] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Affiliation(s)
- Keiichi Fujiwara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Shin Yasui
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Osamu Yokosuka
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Naoya Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
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Brennan PN, Donnelly MC, Simpson KJ. Letter: acute liver failure of indeterminate aetiology-Authors' reply. Aliment Pharmacol Ther 2018; 48:1025-1026. [PMID: 30318681 DOI: 10.1111/apt.14975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Affiliation(s)
- Paul N Brennan
- Department of Molecular and Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, DD1 9SY
| | - Mhairi C Donnelly
- Department of Hepatology and Scottish Liver Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, UK
| | - Kenneth J Simpson
- Department of Hepatology and Scottish Liver Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, UK
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