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Gan C, Yuan Y, Shen H, Gao J, Kong X, Che Z, Guo Y, Wang H, Dong E, Xiao J. Liver diseases: epidemiology, causes, trends and predictions. Signal Transduct Target Ther 2025; 10:33. [PMID: 39904973 PMCID: PMC11794951 DOI: 10.1038/s41392-024-02072-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 10/06/2024] [Accepted: 11/12/2024] [Indexed: 02/06/2025] Open
Abstract
As a highly complex organ with digestive, endocrine, and immune-regulatory functions, the liver is pivotal in maintaining physiological homeostasis through its roles in metabolism, detoxification, and immune response. Various factors including viruses, alcohol, metabolites, toxins, and other pathogenic agents can compromise liver function, leading to acute or chronic injury that may progress to end-stage liver diseases. While sharing common features, liver diseases exhibit distinct pathophysiological, clinical, and therapeutic profiles. Currently, liver diseases contribute to approximately 2 million deaths globally each year, imposing significant economic and social burdens worldwide. However, there is no cure for many kinds of liver diseases, partly due to a lack of thorough understanding of the development of these liver diseases. Therefore, this review provides a comprehensive examination of the epidemiology and characteristics of liver diseases, covering a spectrum from acute and chronic conditions to end-stage manifestations. We also highlight the multifaceted mechanisms underlying the initiation and progression of liver diseases, spanning molecular and cellular levels to organ networks. Additionally, this review offers updates on innovative diagnostic techniques, current treatments, and potential therapeutic targets presently under clinical evaluation. Recent advances in understanding the pathogenesis of liver diseases hold critical implications and translational value for the development of novel therapeutic strategies.
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Affiliation(s)
- Can Gan
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Yuan Yuan
- Aier Institute of Ophthalmology, Central South University, Changsha, China
| | - Haiyuan Shen
- Department of Oncology, the First Affiliated Hospital; The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China
| | - Jinhang Gao
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Xiangxin Kong
- Engineering and Translational Medicine, Medical College, Tianjin University, Tianjin, China
| | - Zhaodi Che
- Clinical Medicine Research Institute and Department of Anesthesiology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Yangkun Guo
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital; The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China.
| | - Erdan Dong
- Research Center for Cardiopulmonary Rehabilitation, University of Health and Rehabilitation Sciences Qingdao Hospital, School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, China.
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
| | - Jia Xiao
- Clinical Medicine Research Institute and Department of Anesthesiology, The First Affiliated Hospital of Jinan University, Guangzhou, China.
- Department of Gastroenterology, Qingdao Central Hospital, University of Health and Rehabilitation Sciences, Qingdao, China.
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Karnsakul W, Schwarz KB. Hepatitis. REMINGTON AND KLEIN'S INFECTIOUS DISEASES OF THE FETUS AND NEWBORN INFANT 2025:728-744.e4. [DOI: 10.1016/b978-0-323-79525-8.00036-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Berg T, Aehling NF, Bruns T, Welker MW, Weismüller T, Trebicka J, Tacke F, Strnad P, Sterneck M, Settmacher U, Seehofer D, Schott E, Schnitzbauer AA, Schmidt HH, Schlitt HJ, Pratschke J, Pascher A, Neumann U, Manekeller S, Lammert F, Klein I, Kirchner G, Guba M, Glanemann M, Engelmann C, Canbay AE, Braun F, Berg CP, Bechstein WO, Becker T, Trautwein C. [Not Available]. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2024; 62:1397-1573. [PMID: 39250961 DOI: 10.1055/a-2255-7246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/11/2024]
Affiliation(s)
- Thomas Berg
- Bereich Hepatologie, Medizinischen Klinik II, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Niklas F Aehling
- Bereich Hepatologie, Medizinischen Klinik II, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Tony Bruns
- Medizinische Klinik III, Universitätsklinikum Aachen, Aachen, Deutschland
| | - Martin-Walter Welker
- Medizinische Klinik I Gastroent., Hepat., Pneum., Endokrin. Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - Tobias Weismüller
- Klinik für Innere Medizin - Gastroenterologie und Hepatologie, Vivantes Humboldt-Klinikum, Berlin, Deutschland
| | - Jonel Trebicka
- Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster, Deutschland
| | - Frank Tacke
- Charité - Universitätsmedizin Berlin, Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Campus Virchow-Klinikum (CVK) und Campus Charité Mitte (CCM), Berlin, Deutschland
| | - Pavel Strnad
- Medizinische Klinik III, Universitätsklinikum Aachen, Aachen, Deutschland
| | - Martina Sterneck
- Medizinische Klinik und Poliklinik I, Universitätsklinikum Hamburg, Hamburg, Deutschland
| | - Utz Settmacher
- Klinik für Allgemein-, Viszeral- und Gefäßchirurgie, Universitätsklinikum Jena, Jena, Deutschland
| | - Daniel Seehofer
- Klinik für Viszeral-, Transplantations-, Thorax- und Gefäßchirurgie, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Eckart Schott
- Klinik für Innere Medizin II - Gastroenterologie, Hepatologie und Diabetolgie, Helios Klinikum Emil von Behring, Berlin, Deutschland
| | | | - Hartmut H Schmidt
- Klinik für Gastroenterologie und Hepatologie, Universitätsklinikum Essen, Essen, Deutschland
| | - Hans J Schlitt
- Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg, Regensburg, Deutschland
| | - Johann Pratschke
- Chirurgische Klinik, Charité Campus Virchow-Klinikum - Universitätsmedizin Berlin, Berlin, Deutschland
| | - Andreas Pascher
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Münster, Münster, Deutschland
| | - Ulf Neumann
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Essen, Essen, Deutschland
| | - Steffen Manekeller
- Klinik und Poliklinik für Allgemein-, Viszeral-, Thorax- und Gefäßchirurgie, Universitätsklinikum Bonn, Bonn, Deutschland
| | - Frank Lammert
- Medizinische Hochschule Hannover (MHH), Hannover, Deutschland
| | - Ingo Klein
- Chirurgische Klinik I, Universitätsklinikum Würzburg, Würzburg, Deutschland
| | - Gabriele Kirchner
- Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg und Innere Medizin I, Caritaskrankenhaus St. Josef Regensburg, Regensburg, Deutschland
| | - Markus Guba
- Klinik für Allgemeine, Viszeral-, Transplantations-, Gefäß- und Thoraxchirurgie, Universitätsklinikum München, München, Deutschland
| | - Matthias Glanemann
- Klinik für Allgemeine, Viszeral-, Gefäß- und Kinderchirurgie, Universitätsklinikum des Saarlandes, Homburg, Deutschland
| | - Cornelius Engelmann
- Charité - Universitätsmedizin Berlin, Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Campus Virchow-Klinikum (CVK) und Campus Charité Mitte (CCM), Berlin, Deutschland
| | - Ali E Canbay
- Medizinische Klinik, Universitätsklinikum Knappschaftskrankenhaus Bochum, Bochum, Deutschland
| | - Felix Braun
- Klinik für Allgemeine Chirurgie, Viszeral-, Thorax-, Transplantations- und Kinderchirurgie, Universitätsklinikum Schlewswig-Holstein, Kiel, Deutschland
| | - Christoph P Berg
- Innere Medizin I Gastroenterologie, Hepatologie, Infektiologie, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | - Wolf O Bechstein
- Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - Thomas Becker
- Klinik für Allgemeine Chirurgie, Viszeral-, Thorax-, Transplantations- und Kinderchirurgie, Universitätsklinikum Schlewswig-Holstein, Kiel, Deutschland
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Letafati A, Taghiabadi Z, Roushanzamir M, Memarpour B, Seyedi S, Farahani AV, Norouzi M, Karamian S, Zebardast A, Mehrabinia M, Ardekani OS, Fallah T, Khazry F, Daneshvar SF, Norouzi M. From discovery to treatment: tracing the path of hepatitis E virus. Virol J 2024; 21:194. [PMID: 39180020 PMCID: PMC11342613 DOI: 10.1186/s12985-024-02470-3] [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: 05/05/2024] [Accepted: 08/14/2024] [Indexed: 08/26/2024] Open
Abstract
The hepatitis E virus (HEV) is a major cause of acute viral hepatitis worldwide. HEV is classified into eight genotypes, labeled HEV-1 through HEV-8. Genotypes 1 and 2 exclusively infect humans, while genotypes 3, 4, and 7 can infect both humans and animals. In contrast, genotypes 5, 6, and 8 are restricted to infecting animals. While most individuals with a strong immune system experience a self-limiting infection, those who are immunosuppressed may develop chronic hepatitis. Pregnant women are particularly vulnerable to severe illness and mortality due to HEV infection. In addition to liver-related complications, HEV can also cause extrahepatic manifestations, including neurological disorders. The immune response is vital in determining the outcome of HEV infection. Deficiencies in T cells, NK cells, and antibody responses are linked to poor prognosis. Interestingly, HEV itself contains microRNAs that regulate its replication and modify the host's antiviral response. Diagnosis of HEV infection involves the detection of HEV RNA and anti-HEV IgM/IgG antibodies. Supportive care is the mainstay of treatment for acute infection, while chronic HEV infection may be cleared with the use of ribavirin and pegylated interferon. Prevention remains the best approach against HEV, focusing on sanitation infrastructure improvements and vaccination, with one vaccine already licensed in China. This comprehensive review provides insights into the spread, genotypes, prevalence, and clinical effects of HEV. Furthermore, it emphasizes the need for further research and attention to HEV, particularly in cases of acute hepatitis, especially among solid-organ transplant recipients.
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Affiliation(s)
- Arash Letafati
- Department of Virology, Faculty of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran.
| | - Zahra Taghiabadi
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
| | - Mahshid Roushanzamir
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
- Department of Pharmacological and Biomolecular Science, University of Milan, Milan, Italy
| | - Bahar Memarpour
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
- Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Saba Seyedi
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
| | | | - Masoomeh Norouzi
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
| | - Saeideh Karamian
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
| | - Arghavan Zebardast
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
| | - Marzieh Mehrabinia
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
| | - Omid Salahi Ardekani
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
| | - Tina Fallah
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
| | - Fatemeh Khazry
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
| | - Samin Fathi Daneshvar
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
| | - Mehdi Norouzi
- Department of Virology, Faculty of Public Health, Tehran University of Medical Sciences, Tehran, Iran
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
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Kumar A, Sahu U, Agnihotri G, Dixit A, Khare P. A novel multi-epitope peptide vaccine candidate targeting hepatitis E virus: An in silico approach. J Viral Hepat 2024; 31:446-456. [PMID: 38727597 DOI: 10.1111/jvh.13949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Revised: 04/05/2024] [Accepted: 04/29/2024] [Indexed: 07/25/2024]
Abstract
Hepatitis E virus (HEV) is a foodborne virus transmitted through the faecal-oral route that causes viral hepatitis in humans worldwide. Ever since its discovery as a zoonotic agent, HEV was isolated from several species with an expanding range of hosts. HEV possesses several features of other RNA viruses but also has certain HEV-specific traits that make its viral-host interactions inimitable. HEV leads to severe morbidity and mortality in immunocompromised people and pregnant women across the world. The situation in underdeveloped countries is even more alarming. Even after creating a menace across the world, we still lack an effective vaccine against HEV. Till date, there is only one licensed vaccine for HEV available only in China. The development of an anti-HEV vaccine that can reduce HEV-induced morbidity and mortality is required. Live attenuated and killed vaccines against HEV are not accessible due to the lack of a tolerant cell culture system, slow viral replication kinetics and varying growth conditions. Thus, the main focus for anti-HEV vaccine development is now on the molecular approaches. In the current study, we have designed a multi-epitope vaccine against HEV through a reverse vaccinology approach. For the first time, we have used viral ORF3, capsid protein and polyprotein altogether for epitope prediction. These are crucial for viral replication and persistence and are major vaccine targets against HEV. The proposed in silico vaccine construct comprises of highly immunogenic and antigenic T-cell and B-cell epitopes of HEV proteins. The construct is capable of inducing an effective and long-lasting host immune response as evident from the simulation results. In addition, the construct is stable, non-allergic and antigenic for the host. Altogether, our findings suggest that the in silico vaccine construct may be useful as a vaccine candidate for preventing HEV infections.
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Affiliation(s)
- Anoop Kumar
- National Institute of Biologicals (NIB), Noida, Uttar Pradesh, India
| | - Utkarsha Sahu
- Department of Microbiology, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
| | - Geetanjali Agnihotri
- School of Chemical Technology, Kalinga Institute of Industrial Technology (KIIT) Deemed to be University, Bhubaneswar, Odisha, India
| | | | - Prashant Khare
- Department of Microbiology, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
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Orosz L, Sárvári KP, Dernovics Á, Rosztóczy A, Megyeri K. Pathogenesis and clinical features of severe hepatitis E virus infection. World J Virol 2024; 13:91580. [PMID: 38984076 PMCID: PMC11229844 DOI: 10.5501/wjv.v13.i2.91580] [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: 12/31/2023] [Revised: 02/08/2024] [Accepted: 04/15/2024] [Indexed: 06/24/2024] Open
Abstract
The hepatitis E virus (HEV), a member of the Hepeviridae family, is a small, non-enveloped icosahedral virus divided into eight distinct genotypes (HEV-1 to HEV-8). Only genotypes 1 to 4 are known to cause diseases in humans. Genotypes 1 and 2 commonly spread via fecal-oral transmission, often through the consumption of contaminated water. Genotypes 3 and 4 are known to infect pigs, deer, and wild boars, often transferring to humans through inadequately cooked meat. Acute hepatitis caused by HEV in healthy individuals is mostly asymptomatic or associated with minor symptoms, such as jaundice. However, in immunosuppressed individuals, the disease can progress to chronic hepatitis and even escalate to cirrhosis. For pregnant women, an HEV infection can cause fulminant liver failure, with a potential mortality rate of 25%. Mortality rates also rise amongst cirrhotic patients when they contract an acute HEV infection, which can even trigger acute-on-chronic liver failure if layered onto pre-existing chronic liver disease. As the prevalence of HEV infection continues to rise worldwide, highlighting the particular risks associated with severe HEV infection is of major medical interest. This text offers a brief summary of the characteristics of hepatitis developed by patient groups at an elevated risk of severe HEV infection.
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Affiliation(s)
- László Orosz
- Department of Medical Microbiology, University of Szeged, Szeged 6720, Csongrád-Csanád, Hungary
| | - Károly Péter Sárvári
- Department of Medical Microbiology, University of Szeged, Szeged 6720, Csongrád-Csanád, Hungary
| | - Áron Dernovics
- Department of Medical Microbiology, University of Szeged, Szeged 6720, Csongrád-Csanád, Hungary
| | - András Rosztóczy
- Department of Internal Medicine, Division of Gastroenterology, University of Szeged, Szeged 6725, Csongrád-Csanád, Hungary
| | - Klára Megyeri
- Department of Medical Microbiology, University of Szeged, Szeged 6720, Csongrád-Csanád, Hungary
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Shahini E, Argentiero A, Andriano A, Losito F, Maida M, Facciorusso A, Cozzolongo R, Villa E. Hepatitis E Virus: What More Do We Need to Know? MEDICINA (KAUNAS, LITHUANIA) 2024; 60:998. [PMID: 38929615 PMCID: PMC11205503 DOI: 10.3390/medicina60060998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 06/14/2024] [Accepted: 06/17/2024] [Indexed: 06/28/2024]
Abstract
Hepatitis E virus (HEV) infection is typically a self-limiting, acute illness that spreads through the gastrointestinal tract but replicates in the liver. However, chronic infections are possible in immunocompromised individuals. The HEV virion has two shapes: exosome-like membrane-associated quasi-enveloped virions (eHEV) found in circulating blood or in the supernatant of infected cell cultures and non-enveloped virions ("naked") found in infected hosts' feces and bile to mediate inter-host transmission. Although HEV is mainly spread via enteric routes, it is unclear how it penetrates the gut wall to reach the portal bloodstream. Both virion types are infectious, but they infect cells in different ways. To develop personalized treatment/prevention strategies and reduce HEV impact on public health, it is necessary to decipher the entry mechanism for both virion types using robust cell culture and animal models. The contemporary knowledge of the cell entry mechanism for these two HEV virions as possible therapeutic target candidates is summarized in this narrative review.
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Affiliation(s)
- Endrit Shahini
- Gastroenterology Unit, National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, Castellana Grotte, 70013 Bari, Italy; (F.L.); (R.C.)
| | | | - Alessandro Andriano
- Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro Medical School, 70124 Bari, Italy;
| | - Francesco Losito
- Gastroenterology Unit, National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, Castellana Grotte, 70013 Bari, Italy; (F.L.); (R.C.)
| | - Marcello Maida
- Gastroenterology and Endoscopy Unit, S. Elia-Raimondi Hospital, 93100 Caltanissetta, Italy;
| | - Antonio Facciorusso
- Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy;
| | - Raffaele Cozzolongo
- Gastroenterology Unit, National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, Castellana Grotte, 70013 Bari, Italy; (F.L.); (R.C.)
| | - Erica Villa
- Gastroenterology Unit, CHIMOMO Department, University of Modena & Reggio Emilia, Via del Pozzo 71, 41121 Modena, Italy
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Iqbal H, Mehmood BF, Sohal A, Roytman M. Hepatitis E infection: A review. World J Virol 2023; 12:262-271. [PMID: 38187497 PMCID: PMC10768387 DOI: 10.5501/wjv.v12.i5.262] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 11/23/2023] [Accepted: 12/05/2023] [Indexed: 12/25/2023] Open
Abstract
Hepatitis E virus (HEV) is a small non-enveloped virus that is transmitted via the fecal-oral route. It is a highly common cause of acute hepatitis, particularly in low to middle income regions of Asia, Africa, and Central America. Most cases are self-limited, and symptomatic patients usually present with acute icteric hepatitis. A subset of patients including pregnant women, older men, those with pre-existing liver disease and immunocompromised patients however, may develop severe disease and hepatic failure. Immunocompromised patients are also at risk for chronic infection, and their immunosuppression should be decreased in order to facilitate viral clearance. HEV can also present with a variety of extra-intestinal manifestations including neurological, renal, hematological, and pancreatic derangements. The gold standard of diagnosis is HEV ribonucleic acid detection via nucleic acid amplification testing. Currently, there are no approved treatments for Hepatitis E, though ribavirin is the most commonly used agent to reduce viral load. Studies assessing the safety and efficacy of other antiviral agents for HEV are currently underway. HEV vaccination has been approved in China, and is currently being investigated in other regions as well. This review article aims to discuss the epidemiology, pathogenesis, presentation, diagnosis, complications, and treatment of Hepatitis E infection.
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Affiliation(s)
- Humzah Iqbal
- Department of Internal Medicine, University of California San Francisco, Fresno, CA 93701, United States
| | - Bilal Fazal Mehmood
- Department of Internal Medicine, University of California San Francisco, Fresno, CA 93701, United States
| | - Aalam Sohal
- Department of Hepatology, Liver Institute Northwest, Seattle, WA 98105, United States
| | - Marina Roytman
- Department of Gastroenterology and Hepatology, University of California San Francisco, Fresno, CA 93701, United States
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Pauly MD, Ganova-Raeva L. Point-of-Care Testing for Hepatitis Viruses: A Growing Need. Life (Basel) 2023; 13:2271. [PMID: 38137872 PMCID: PMC10744957 DOI: 10.3390/life13122271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 11/23/2023] [Accepted: 11/23/2023] [Indexed: 12/24/2023] Open
Abstract
Viral hepatitis, caused by hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), or hepatitis E virus (HEV), is a major global public health problem. These viruses cause millions of infections each year, and chronic infections with HBV, HCV, or HDV can lead to severe liver complications; however, they are underdiagnosed. Achieving the World Health Organization's viral hepatitis elimination goals by 2030 will require access to simpler, faster, and less expensive diagnostics. The development and implementation of point-of-care (POC) testing methods that can be performed outside of a laboratory for the diagnosis of viral hepatitis infections is a promising approach to facilitate and expedite WHO's elimination targets. While a few markers of viral hepatitis are already available in POC formats, tests for additional markers or using novel technologies need to be developed and validated for clinical use. Potential methods and uses for the POC testing of antibodies, antigens, and nucleic acids that relate to the diagnosis, monitoring, or surveillance of viral hepatitis infections are discussed here. Unmet needs and areas where additional research is needed are also described.
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Affiliation(s)
| | - Lilia Ganova-Raeva
- Division of Viral Hepatitis, National Center for HIV, Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, 1600 Clifton Rd., NE, Atlanta, GA 30329, USA;
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Zhang X, Cremers N, Hendrickx S, Debing Y, Roskams T, Coelmont L, Neyts J, Kaptein SJF. Establishment of a robust rat hepatitis E virus fecal-oral infection model and validation for antiviral studies. Antiviral Res 2023; 216:105670. [PMID: 37451630 DOI: 10.1016/j.antiviral.2023.105670] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 06/27/2023] [Accepted: 07/11/2023] [Indexed: 07/18/2023]
Abstract
The hepatitis E virus (HEV) is a major cause of hepatitis, with an estimated 3.3 million symptomatic cases annually. There is no HEV-specific treatment besides the off-label use of ribavirin and a vaccine is only available in China and Pakistan. To aid the development of therapeutic and preventive strategies, there is a need for convenient HEV infection models in small laboratory animals. To this end, we make use of the rat hepatitis E virus. Human infections with this virus have been reported in recent years, making it a relevant pathogen for the establishment of a small animal infection model. We here report that oral gavage of a feces suspension, containing a pre-defined viral RNA load, results in a reproducible synchronized infection in athymic nude rats. This route of administration mimics fecal-oral transmission in a standardized fashion. The suitability of the model to study the effect of antiviral drugs was assessed by using ribavirin, which significantly reduced viral loads in the feces, liver, and other tissues.
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Affiliation(s)
- Xin Zhang
- KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Virology and Chemotherapy, Leuven, Belgium
| | - Niels Cremers
- KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Virology and Chemotherapy, Leuven, Belgium
| | - Stijn Hendrickx
- KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Virology and Chemotherapy, Leuven, Belgium
| | | | - Tania Roskams
- KU Leuven, Pathology, Translational Cell and Tissue Research, Leuven, Belgium
| | - Lotte Coelmont
- KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Virology and Chemotherapy, Leuven, Belgium
| | - Johan Neyts
- KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Virology and Chemotherapy, Leuven, Belgium.
| | - Suzanne J F Kaptein
- KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Virology and Chemotherapy, Leuven, Belgium.
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11
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Marginean CM, Pirscoveanu D, Popescu M, Vasile CM, Docea AO, Mitruț R, Mărginean IC, Iacob GA, Firu DM, Mitruț P. Challenges in Diagnosis and Therapeutic Approach of Acute on Chronic Liver Failure-A Review of Current Evidence. Biomedicines 2023; 11:1840. [PMID: 37509478 PMCID: PMC10376368 DOI: 10.3390/biomedicines11071840] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 06/23/2023] [Accepted: 06/25/2023] [Indexed: 07/30/2023] Open
Abstract
Acute-on-chronic liver failure (ACLF) is a syndrome characterized by acute and severe decompensation of chronic liver disease (CLD) correlated with multiple organ failure, poor prognosis, and increased mortality. In 40-50% of ACLF cases, the trigger is not recognized; for many of these patients, bacterial translocation associated with systemic inflammation is thought to be the determining factor; in the other 50% of patients, sepsis, alcohol consumption, and reactivation of chronic viral hepatitis are the most frequently described trigger factors. Other conditions considered precipitating factors are less common, including acute alcoholic hepatitis, major surgery, TIPS insertion, or inadequate paracentesis without albumin substitution. Host response is likely the primary factor predicting ACLF severity and prognosis, the host immune response having a particular significance in this syndrome, together with the inflammatory cascade. The management of ACLF includes both the prevention of the precipitating factors that lead to acute liver decompensation and the support of vital functions, the prevention and management of complications, the estimation of prognosis, and the opportunity for liver transplantation.
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Affiliation(s)
- Cristina Maria Marginean
- Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Denisa Pirscoveanu
- Department of Neurology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Mihaela Popescu
- Department of Endocrinology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Corina Maria Vasile
- Department of Pediatric Cardiology, "Marie Curie" Emergency Children's Hospital, 041451 Bucharest, Romania
| | - Anca Oana Docea
- Department of Toxicology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Radu Mitruț
- Department of Cardiology, University and Emergency Hospital, 050098 Bucharest, Romania
| | | | - George Alexandru Iacob
- Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Dan Mihai Firu
- Ph.D. School Department, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Paul Mitruț
- Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
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12
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Azevedo Silva M, Ruge Gonçalves A, Leal C, Eliseu L. Severe hepatitis E in an immunocompetent young female treated with ribavirin. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2023; 115:269-270. [PMID: 36043559 DOI: 10.17235/reed.2022.9105/2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/13/2023]
Abstract
A healthy 24-year-old woman was admitted to the emergency department with acute hepatitis. She denied traveling, consumption of drugs, herbs, alcohol or medication other than the same oral contraceptive for years. The etiological work-up revealed positive Herpes Simplex Virus (HSV) 1+2 serology (IgG and IgM). Other viral serologies were negative, while Hepatitis E Virus (HEV) serology and viraemia were pending. Liver biopsy showed portal and lobular necroinflammatory activity without specific etiological findings. The remaining work-up was unremarkable. The patient developed jaundice. Acyclovir was started, considering a possible herpetic hepatitis, while waiting for HSV viraemia and immunohistochemistry in the liver biopsy, which later revealed to be negative. Despite therapy, hyperbilirubinemia and liver cytolysis worsened. At this point, HEV serology and viraemia came back positive. Ribavirin was started with rapid clinical and biochemical improvement. Liver enzymes were normal and HEV viraemia was negative after 12 weeks of ribavirin, remaining undetectable 3 months later.
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Affiliation(s)
| | | | - Carina Leal
- Gastroenterology, Centro Hospitalar de Leiria, Portugal
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13
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Gabrielli F, Alberti F, Russo C, Cursaro C, Seferi H, Margotti M, Andreone P. Treatment Options for Hepatitis A and E: A Non-Systematic Review. Viruses 2023; 15:1080. [PMID: 37243166 PMCID: PMC10221699 DOI: 10.3390/v15051080] [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: 03/02/2023] [Revised: 04/27/2023] [Accepted: 04/27/2023] [Indexed: 05/28/2023] Open
Abstract
Hepatitis A and hepatitis E are relatively common causes of liver disease. Both viruses are mainly transmitted through the faecal-oral route and, consequently, most outbreaks occur in countries with poor sanitation. An important role of the immune response as the driver of liver injury is also shared by the two pathogens. For both the hepatitis A (HAV) and hepatitis E (HEV) viruses, the clinical manifestations of infection mainly consist of an acute disease with mild liver injury, which results in clinical and laboratory alterations that are self-limiting in most cases. However, severe acute disease or chronic, long-lasting manifestations may occur in vulnerable patients, such as pregnant women, immunocompromised individuals or those with pre-existing liver disease. Specifically, HAV infection rarely results in fulminant hepatitis, prolonged cholestasis, relapsing hepatitis and possibly autoimmune hepatitis triggered by the viral infection. Less common manifestations of HEV include extrahepatic disease, acute liver failure and chronic HEV infection with persistent viraemia. In this paper, we conduct a non-systematic review of the available literature to provide a comprehensive understanding of the state of the art. Treatment mainly consists of supportive measures, while the available evidence for aetiological treatment and additional agents in severe disease is limited in quantity and quality. However, several therapeutic approaches have been attempted: for HAV infection, corticosteroid therapy has shown outcome improvement, and molecules, such as AZD 1480, zinc chloride and heme oxygenase-1, have demonstrated a reduction in viral replication in vitro. As for HEV infection, therapeutic options mainly rely on the use of ribavirin, and some studies utilising pegylated interferon-alpha have shown conflicting results. While a vaccine for HAV is already available and has led to a significant reduction in the prevalence of the disease, several vaccines for HEV are currently being developed, with some already available in China, showing promising results.
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Affiliation(s)
- Filippo Gabrielli
- Postgraduate School of Internal Medicine, University of Modena and Reggio Emilia, 41126 Modena, Italy
- Department of Surgical Sciences, University of Bologna, 40126 Bologna, Italy
| | - Francesco Alberti
- Postgraduate School of Internal Medicine, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Cristina Russo
- Postgraduate School of Internal Medicine, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Carmela Cursaro
- Internal and Metabolic Medicine, Department of Medical and Surgical Sciences, Maternal-Infantile and Adult, AOU di Modena, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Hajrie Seferi
- Internal and Metabolic Medicine, Department of Medical and Surgical Sciences, Maternal-Infantile and Adult, AOU di Modena, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Marzia Margotti
- Internal and Metabolic Medicine, Department of Medical and Surgical Sciences, Maternal-Infantile and Adult, AOU di Modena, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Pietro Andreone
- Internal and Metabolic Medicine, Department of Medical and Surgical Sciences, Maternal-Infantile and Adult, AOU di Modena, University of Modena and Reggio Emilia, 41126 Modena, Italy
- Division of Internal Medicine, Department of Medical and Surgical Sciences, Maternal-Infantile and Adult, University of Modena and Reggio Emilia, 41126 Modena, Italy
- Postgraduate School of Allergology and Clinical Immunology, University of Modena and Reggio Emilia, 41126 Modena, Italy
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14
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Cancela F, Rendon-Marin S, Quintero-Gil C, Houston DR, Gumbis G, Panzera Y, Pérez R, Arbiza J, Mirazo S. Modelling of Hepatitis E virus RNA-dependent RNA polymerase genotype 3 from a chronic patient and in silico interaction analysis by molecular docking with Ribavirin. J Biomol Struct Dyn 2023; 41:705-721. [PMID: 34861797 DOI: 10.1080/07391102.2021.2011416] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Hepatitis E Virus (HEV) infection is an emergent zoonotic disease, where chronic hepatitis E associated to solid organ transplant (SOT) recipients, related to genotype 3, is the clinical manifestation of major concern. In this setting, ribavirin (RBV) treatment is the only available therapy, though drug-resistant variants could emerge leading to a therapeutic failure. Crystallographic structures have not been reported for most of the HEV proteins, including the RNA-polymerase (RdRp). Therefore, the mechanism of action of RBV against HEV and the molecular interactions between this drug and RdRp are largely unknown. In this work, we aimed to model in silico the 3 D structure of a novel HEV3 RdRp (HEV_C1_Uy) from a chronically HEV infected-SOT recipient treated with RBV and to perform a molecular docking simulation between RBV triphosphate (RBVT), 7-methyl-guanosine-5'-triphosphate and the modelled protein. The models were generated using I-TASSER server and validated with multiple bioinformatics tools. The docking analysis were carried out with AutoDock Vina and LeDock software. We obtained a suitable model for HEV_C1_Uy (C-Score=-1.33, RMSD = 10.4 ± 4.6 Å). RBVT displayed a binding affinity of -7.6 ± 0.2 Kcal/mol by molecular docking, mediated by 6 hydrogen-bonds (Q195-O14, S198-O11, E257-O13, S260-O2, O3, S311-O11) between the finger's-palm-domains and a free binding energy of 31.26 ± 16.81 kcal/mol by molecular dynamics simulations. We identified the possible HEV RdRp interacting region for incoming nucleotides or analogs and provide novel insights that will contribute to better understand the molecular interactions of RBV and the enzyme and the mechanism of action of this antiviral drug.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Florencia Cancela
- Sección Virología, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
| | - Santiago Rendon-Marin
- Grupo de Investigación en Ciencias Animales - GRICA, Facultad de Medicina Veterinaria y Zootecnia, Universidad Cooperativa de Colombia, sede Bucaramanga, Bucaramanga, Colombia
| | - Carolina Quintero-Gil
- Grupo de Investigación en Ciencias Animales - GRICA, Facultad de Medicina Veterinaria y Zootecnia, Universidad Cooperativa de Colombia, sede Bucaramanga, Bucaramanga, Colombia
| | - Douglas R Houston
- Institute of Quantitative Biology, Biochemistry and Biotechnology, The University of Edinburgh, Edinburgh, UK
| | - Gediminas Gumbis
- Institute of Quantitative Biology, Biochemistry and Biotechnology, The University of Edinburgh, Edinburgh, UK
| | - Yanina Panzera
- Sección Genética Evolutiva, Instituto de Biología, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
| | - Ruben Pérez
- Sección Genética Evolutiva, Instituto de Biología, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
| | - Juan Arbiza
- Sección Virología, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
| | - Santiago Mirazo
- Sección Virología, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay.,Departamento de Bacteriología y Virología, Instituto de Higiene, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay
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15
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Hui W, Wei L. Treatment of Hepatitis E. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1417:215-226. [PMID: 37223869 DOI: 10.1007/978-981-99-1304-6_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
Hepatitis E virus (HEV) infections are the most common cause of acute hepatitis, but they can also take a chronic course. There is no specific therapy for acute hepatitis, and current treatment is supportive. Choosing ribavirin as the first-line therapy for chronic HEV is advisable, especially immunosuppressed individuals. Moreover, ribavirin therapy in the acute phase of infection provides major benefits for those at high risk of acute liver failure (ALF)/acute-on-chronic liver failure (ACLF). Pegylated interferon α has been used successfully for treatment of hepatitis E but is associated with major side effects. Cholestasis is one of the most common, but devastating, manifestations in hepatitis E. Current therapy for HEV aims to treat symptoms. Therapy generally involves several measures, such as vitamins, albumin, and plasma for supporting treatment, symptomatic treatment for cutaneous pruritus, ursodeoxycholic acid, Obeticholic acid, S-adenosylmethionine, etc. for removing jaundice. HEV infection during pregnancy and patients with underlying liver disease may develop liver failure. For these patients, active monitoring, standard care, and supportive treatment are the foundations. Ribavirin has successfully been used to prevent liver transplantation (LT). Prevention and treatment of complications are important for treatment of liver failure. Liver support devices are intended to support liver function until such time as native liver function recovers, or until LT. LT is widely considered as irreplaceable and definitive treatment for liver failure, particularly for patients who do not improve with supportive measures to sustain life.
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Affiliation(s)
- Wei Hui
- Chronic Disease Management Center, Youan Hospital, Capital Medical University, Beijing, China
| | - Linlin Wei
- The Second Department of Liver Disease Center, Youan Hospital, Capital Medical University, Beijing, China.
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16
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Wang L, Wang Y, Zhuang H. Puzzles for Hepatitis E Virus. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1417:247-256. [PMID: 37223871 DOI: 10.1007/978-981-99-1304-6_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
Hepatitis E virus (HEV) is an important but understudied virus that has been the major cause of acute viral hepatitis worldwide. In recent decades, our understanding of this neglected virus has changed greatly: novel forms of viral proteins and their functions have been discovered; HEV can transmit via blood transfusion and organ transplantation; HEV can infect many animal species and the number is still increasing; HEV can induce chronic hepatitis and extra-hepatic manifestations. However, we are short of effective treatment measures to counter the virus. In this chapter we tend to briefly introduce the puzzles and major knowledge gaps existed in the field of HEV research.
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Affiliation(s)
- Lin Wang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Youchun Wang
- Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College, Kunming, China
| | - Hui Zhuang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
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17
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Ma Z, de Man RA, Kamar N, Pan Q. Chronic hepatitis E: Advancing research and patient care. J Hepatol 2022; 77:1109-1123. [PMID: 35605741 DOI: 10.1016/j.jhep.2022.05.006] [Citation(s) in RCA: 72] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 05/08/2022] [Accepted: 05/10/2022] [Indexed: 12/15/2022]
Abstract
The hepatitis E virus (HEV) was initially thought to exclusively cause acute hepatitis. However, the first diagnosis of chronic hepatitis E in transplant recipients in 2008 profoundly changed our understanding of this pathogen. We have now begun to understand that specific HEV genotypes can cause chronic infection in certain immunocompromised populations. Over the past decade, dedicated clinical and experimental research has substantiated knowledge on the epidemiology, transmission routes, pathophysiological mechanisms, diagnosis, clinical features and treatment of chronic HEV infection. Nevertheless, many gaps and major challenges remain, particularly regarding the translation of knowledge into disease prevention and improvement of clinical outcomes. This article aims to highlight the latest developments in the understanding and management of chronic hepatitis E. More importantly, we attempt to identify major knowledge gaps and discuss strategies for further advancing both research and patient care.
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Affiliation(s)
- Zhongren Ma
- Biomedical Research Center, Northwest Minzu University, Lanzhou, China
| | - Robert A de Man
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Nassim Kamar
- Department of Nephrology, Dialysis and Organ Transplantation, CHU Rangueil, INSERM UMR 1291, Toulouse Institute for Infectious and Inflammatory Disease (Infinity), University Paul Sabatier, Toulouse, France
| | - Qiuwei Pan
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
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18
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Goetgebuer RL, Masclee GMC, van der Eijk AA, van der Woude CJ, de Man RA, de Vries AC. Hepatitis E infection with a benign course during vedolizumab treatment for Crohn's disease: A case report. Clin Res Hepatol Gastroenterol 2022; 46:101948. [PMID: 35659604 DOI: 10.1016/j.clinre.2022.101948] [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: 02/21/2022] [Revised: 04/03/2022] [Accepted: 05/09/2022] [Indexed: 02/04/2023]
Abstract
We present a 49 year old female patient with Crohn's disease (CD) in remission on vedolizumab therapy who experienced a symptomatic, though benign, course of acute hepatitis E. Routine blood tests showed substantial elevation of liver enzymes and polymerase chain reaction (PCR) testing confirmed hepatitis E virus (HEV) infection. Vedolizumab therapy was paused, liver enzymes improved three weeks after infection and normalized after six months. The patient recovered completely from mild symptoms. This case shows that hepatitis E is a potential cause of acute hepatitis during vedolizumab therapy, and in this case the infection has run a benign course.
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Affiliation(s)
- R L Goetgebuer
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Centre Rotterdam, the Netherlands.
| | - G M C Masclee
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Centre Rotterdam, the Netherlands
| | - A A van der Eijk
- Department of Viroscience, Erasmus MC, University Medical Centre Rotterdam, the Netherlands
| | - C J van der Woude
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Centre Rotterdam, the Netherlands
| | - R A de Man
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Centre Rotterdam, the Netherlands
| | - A C de Vries
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Centre Rotterdam, the Netherlands
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19
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Raji YE, Toung OP, Taib NM, Sekawi ZB. Hepatitis E Virus: An emerging enigmatic and underestimated pathogen. Saudi J Biol Sci 2022; 29:499-512. [PMID: 35002446 PMCID: PMC8716866 DOI: 10.1016/j.sjbs.2021.09.003] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 08/31/2021] [Accepted: 09/05/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatitis E virus (HEV) is an RNA virus causing hepatitis E disease. The virus is of one serotype but has diverse genotypes infecting both humans and animals. Based on evidence from seroprevalence studies, about 2 billion people are estimated to have been infected with HEV globally. HEV, therefore, poses a significant public health and economic challenge worldwide. HEV was discovered in the 1980s and was traced back to the 1955 - 1956 outbreak of hepatitis that occurred in India. Subsequently, several HEV epidemics involving thousands of individuals have occurred nearly annually in different countries in Asia and Africa. Initially, the virus was thought to be only enterically transmitted, and endemic in developing countries. Due to the environmental hygiene and sanitation challenges in those parts of the world. However, recent studies have suggested otherwise with the report of autochthonous cases in industrialised countries with no history of travel to the so-called endemic countries. Thus, suggesting that HEV has a global distribution with endemicity in both developing and industrialised nations. Studies have also revealed that HEV has multiple risk factors, and modes of transmission as well as zoonotic potentials. Additionally, recent findings have shown that HEV leads to severe disease, particularly among pregnant women. In contrast to the previous narration of a strictly mild and self-limiting infection. Studies have likewise demonstrated chronic HEV infection among immunocompromised persons. Consequent to these recent discoveries, this pathogen is considered a re - emerging virus, particularly in the developed nations. However, despite the growing public health challenges of this pathogen, the burden is still underestimated. The underestimation is often attributed to poor awareness among clinicians and a lack of routine checks for the disease in the hospitals. Thus, leading to misdiagnosis and underdiagnosis. Hence, this review provides a concise overview of epidemiology, diagnosis, and prevention of hepatitis E.
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Affiliation(s)
- Yakubu Egigogo Raji
- Department of Medical Microbiology and Parasitology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia 1, Malaysia
- Faculty of Natural and Applied Sciences Ibrahim Badamasi Babangida University, Lapai, Nigeria
| | - Ooi Peck Toung
- Department of Veterinary Clinical Studies Faculty of Veterinary Medicine, Universiti Putra Malaysia 2, Malaysia
| | - Niazlin Mohd Taib
- Department of Medical Microbiology and Parasitology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia 1, Malaysia
| | - Zamberi Bin Sekawi
- Department of Medical Microbiology and Parasitology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia 1, Malaysia
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20
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Khanam A, Kottilil S. Acute-on-Chronic Liver Failure: Pathophysiological Mechanisms and Management. Front Med (Lausanne) 2021; 8:752875. [PMID: 34820395 PMCID: PMC8606418 DOI: 10.3389/fmed.2021.752875] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 10/07/2021] [Indexed: 12/21/2022] Open
Abstract
Acute-on-chronic liver failure (ACLF) is a multifaceted condition with poor treatment options and high short-term mortality. ACLF can develop in patients with or without liver cirrhosis, where patients with decompensated cirrhosis display a higher risk of short-term mortality. Pathophysiological mechanisms include systemic inflammation due to bacterial and fungal infections and acute hepatic insult with drug, alcohol, and viral hepatitis. Cryptogenic factors also contribute to the development of ACLF. The clinical outcome of patients with ACLF gets further complicated by the occurrence of variceal hemorrhage, hepatorenal syndrome, hepatic encephalopathy, and systemic immune dysfunction. Regardless of the better understanding of pathophysiological mechanisms, no specific and definitive treatment is available except for liver transplantation. The recent approach of regenerative medicine using mesenchymal stem cells (MSCs) could be advantageous for the treatment of ACLF as these cells can downregulate inflammatory response by inducing antiinflammatory events and prevent hepatic damage and fibrosis by inhibiting hepatic stellate cell activation and collagen synthesis. Moreover, MSCs are involved in tissue repair by the process of liver regeneration. Considering the broad therapeutic potential of MSCs, it can serve as an alternative treatment to liver transplant in the near future, if promising results are achieved.
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Affiliation(s)
- Arshi Khanam
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Shyam Kottilil
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, United States
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21
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Kamani L, Padhani ZA, Das JK. Hepatitis E: Genotypes, strategies to prevent and manage, and the existing knowledge gaps. JGH Open 2021; 5:1127-1134. [PMID: 34621997 PMCID: PMC8485408 DOI: 10.1002/jgh3.12646] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Revised: 08/02/2021] [Accepted: 08/14/2021] [Indexed: 12/23/2022]
Abstract
Hepatitis E virus (HEV) is considered an emergent source of viral hepatitis worldwide, with an increasing burden of jaundice, liver failure, extrahepatic illnesses, and deaths in developed countries. With the scarcity of data from efficient animal models, there are still open-ended questions about designing new models to study pathogenesis, types, virology, and evolution of these viruses. With an emphasis on available data and updates, there is still enough information to understand the HEV life cycle, pathogen interaction with the host, and the valuation of the role of vaccine and new anti-HEV therapies. However, the World Health Organization (WHO) and the European Association for the Study of the Liver (EASL) preferred to stress prevention and control measures of HEV infections in animals, zoonotic transmission, and foodborne transmission. It is being reviewed that with current knowledge on HEV and existing prevention tools, there is an excellent room for in-depth information about the virus strains, their replication, pathogenicity, and virulence. The current knowledge set also has gaps regarding standardized and validated diagnostic tools, efficacy and safety of the vaccine, and extrahepatic manifestations specifically in pregnant females, immunocompromised patients, and others. This review highlights the areas for more research exploration, focusing on enlisted research questions based on HEV infection to endorse the need for significant improvement in the current set of knowledge for this public health problem.
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Affiliation(s)
- Lubna Kamani
- Associate Professor & Director, GI Residency Program, Department of GastroenterologyLiaquat National Hospital and Medical CollegeKarachiPakistan
- ConsultantAga Khan University HospitalKarachiPakistan
| | - Zahra Ali Padhani
- Health Policy and Management, Manager (Research)Aga Khan University HospitalKarachiPakistan
| | - Jai K Das
- Assistant Professor and Head, Section of Public Health and EpidemiologyAga Khan University HospitalKarachiPakistan
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22
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Effective treatment of acute hepatitis E by ribavirin in a patient complicated with renal impairment: a case report. JOURNAL OF PHARMACY PRACTICE AND RESEARCH 2021. [DOI: 10.1002/jppr.1719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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23
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Kamar N, Abravanel F, Behrendt P, Hofmann J, Pageaux GP, Barbet C, Moal V, Couzi L, Horvatits T, De Man RA, Cassuto E, Elsharkawy AM, Riezebos-Brilman A, Scemla A, Hillaire S, Donnelly MC, Radenne S, Sayegh J, Garrouste C, Dumortier J, Glowaki F, Matignon M, Coilly A, Figueres L, Mousson C, Minello A, Dharancy S, Rerolle JP, Lebray P, Etienne I, Perrin P, Choi M, Marion O, Izopet J, Cointault O, Del Bello A, Espostio L, Hebral AL, Lavayssière L, Lhomme S, Mansuy JM, Wedemeyer H, Nickel P, Bismuth M, Stefic K, Büchler M, D’Alteroche L, Colson P, Bufton S, Ramière C, Trimoulet P, Pischke S, Todesco E, Sberro Soussan R, Legendre C, Mallet V, Johannessen I, Simpson K. Ribavirin for Hepatitis E Virus Infection After Organ Transplantation: A Large European Retrospective Multicenter Study. Clin Infect Dis 2021; 71:1204-1211. [PMID: 31793638 DOI: 10.1093/cid/ciz953] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Accepted: 10/01/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Ribavirin is currently recommended for treating chronic hepatitis E virus (HEV) infection. This retrospective European multicenter study aimed to assess the sustained virological response (SVR) in a large cohort of solid organ transplant (SOT) recipients with chronic HEV infection treated with ribavirin monotherapy (N = 255), to identify the predictive factors for SVR, and to evaluate the impact of HEV RNA mutations on virological response. METHODS Data from 255 SOT recipients with chronic HEV infection from 30 European centers were analyzed. Ribavirin was given at the median dose of 600 (range, 29-1200) mg/day (mean, 8.6 ± 3.6 mg/kg/day) for a median duration of 3 (range, 0.25-18) months. RESULTS After a first course of ribavirin, the SVR rate was 81.2%. It increased to 89.8% when some patients were offered a second course of ribavirin. An increased lymphocyte count at the initiation of therapy was a predictive factor for SVR, while poor hematological tolerance of ribavirin requiring its dose reduction (28%) and blood transfusion (15.7%) were associated with more relapse after ribavirin cessation. Pretreatment HEV polymerase mutations and de novo mutations under ribavirin did not have a negative impact on HEV clearance. Anemia was the main adverse event. CONCLUSIONS This large-scale retrospective study confirms that ribavirin is highly efficient for treating chronic HEV infection in SOT recipients and shows that the predominant HEV RNA polymerase mutations found in this study do not affect the rate of HEV clearance.This large-scale retrospective study that included 255 solid organ transplant recipients confirms that ribavirin is highly efficient for treating chronic hepatitis E virus (HEV) infection and shows that HEV RNA polymerase mutations do not play a role in HEV clearance.
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Affiliation(s)
- Nassim Kamar
- Department of Nephrology, Dialysis and Organ Transplantation, Centre Hospitalier Universitaire (CHU) Rangueil, Institut National de la Santé et de la Recherche Médicale (INSERM) U1043, Institut Fédératif de Recherche Bio-médicale de Toulouse (IFR-BMT), University Paul Sabatier, Toulouse, France
| | - Florence Abravanel
- Department of Virology, INSERM U1043, IFR-BMT, University Paul Sabatier, Toulouse, France
| | - Patrick Behrendt
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, and Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, German Centre for Infection Research, Hannover, Germany
| | - Jörg Hofmann
- Charité Universitätsmedizin Berlin, Department of Nephrology and Intensive Care and Institute of Virology, Labor Berlin Charité-Vivantes-GmbH, Berlin, Germany
| | | | - Christelle Barbet
- Department of Nephrology and Clinical Immunology, Bretonneau Hospital, University Hospital, Tours, France
| | - Valérie Moal
- Aix Marseille Université, Asistance Publique Hôpitaux de Marseille, Institut Pour la Recherche Pour le Développement, Microbes, Evolution, Phylogénie et Infection, Institut Hospitalo-Universitaire-Méditerranée Infection, Hôpital Conception, Centre de Néphrologie et Transplantation Rénale, Marseille, France
| | - Lionel Couzi
- Department of Nephrology and Transplantation, CHU Bordeaux, Bordeaux, France
| | - Thomas Horvatits
- Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Robert A De Man
- Departments of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands
| | | | | | - Annelies Riezebos-Brilman
- Department of Medical Microbiology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Anne Scemla
- Service de néphrologie-transplantation, Hôpital Necker, Assitance publique- Hôpitaux de Paris (AP-HP), Paris et Université Paris Descartes, Paris, France
| | | | - Mhairi C Donnelly
- Department of Hepatology and Scottish Liver Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom
| | - Sylvie Radenne
- Department of Hepatology and Liver Transplantation, CHU de la Croix Rousse, Lyon, France
| | - Johnny Sayegh
- Department of Nephrology and Transplantation, CHU Angers, Angers, France
| | - Cyril Garrouste
- Department of Nephrology, CHU Clermont-Ferrand, Clermont-Ferrand, France
| | - Jérôme Dumortier
- Department of Hepatology, Edouard Herriot Hospital, CHU Lyon, Lyon, France
| | | | - Marie Matignon
- Assistance Publique-Hôpitaux de Paris, Nephrology and Renal Transplantation Department, Groupe Hospitalier Henri-Mondor/Albert-Chenevier, Université Paris-Est-Créteil, Département Hospitalo-Universitaire Virus-Immunité-Cancer, Institut Mondor de Recherche Biomédicale, Equipe 21, INSERM U 955, Créteil, France
| | - Audrey Coilly
- Centre Hépato-Biliaire, Hôpital Paul Brousse, AP-HP, INSERM U1193, Université Paris-Sud Paris-Saclay, Villejuif, France
| | - Lucile Figueres
- Department of Nephrology and Clinical Immunology, CHU Nantes, Nantes, France
| | | | - Anne Minello
- Department of Hepatogastroenterology and Digestive Oncology, CHU François Mitterrand, Dijon, France
| | - Sébastien Dharancy
- Hôpital Claude Huriez, Services Maladies de l'Appareil Digestif, INSERM Unité 995, Lille, France
| | | | - Pascal Lebray
- Department of Hepatology, Pitié Salpétrière Hospital, Paris, France
| | | | - Peggy Perrin
- Department of Nephrology, CHU Strasbourg, Strasbourg, France
| | - Mira Choi
- Charité Universitätsmedizin Berlin, Department of Nephrology and Intensive Care and Institute of Virology, Labor Berlin Charité-Vivantes-GmbH, Berlin, Germany
| | - Olivier Marion
- Department of Virology, INSERM U1043, IFR-BMT, University Paul Sabatier, Toulouse, France
| | - Jacques Izopet
- Department of Virology, INSERM U1043, IFR-BMT, University Paul Sabatier, Toulouse, France
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24
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Gorris M, van der Lecq BM, van Erpecum KJ, de Bruijne J. Treatment for chronic hepatitis E virus infection: A systematic review and meta-analysis. J Viral Hepat 2021; 28:454-463. [PMID: 33301609 PMCID: PMC7898834 DOI: 10.1111/jvh.13456] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 11/09/2020] [Accepted: 11/23/2020] [Indexed: 12/19/2022]
Abstract
Hepatitis E virus infection can cause chronic hepatitis in immunocompromised patients with significant chance of progressive fibrosis and possibly cirrhosis. The aim of this systematic review was to summarize the efficacy and safety of the various treatment options for chronic hepatitis E. We performed a systematic literature search. The primary outcome measure was a sustained virological response (SVR). Secondary end points were rapid virological response (RVR), relapse rates, side effects and adverse events. Forty-four articles were included with a total of 582 patients. Reduction of immunosuppressive medication induced viral clearance in 55/174 (32%) of the patients. Meta-analysis of 395 patients showed a pooled SVR rate of 78% (95-CI 72%-84%) after ribavirin treatment. Twenty-five per cent of the patients obtained a RVR, whereas a relapse occurred in 18% of the patients. Anaemia during treatment led to dose reduction, use of erythropoietin and/or blood transfusion in 37% of the patients. A second treatment attempt with ribavirin led to a SVR in 39/51 (76%) of the patients. Pegylated interferon-alpha was administered to 13 patients and SVR was obtained in 85%. Two patients (15%) suffered from acute transplant rejection during treatment with interferon. In conclusion, reduction of immunosuppressive medication and treatment with ribavirin is safe, generally well tolerated and induced viral clearance in 32% and 78% of patients, respectively. Therefore, ribavirin should be considered as first treatment step for chronic hepatitis E. Treatment with pegylated interferon-alpha increases the risk of transplant rejection and should therefore be administered with great caution.
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Affiliation(s)
- Myrte Gorris
- Department of Gastroenterology & HepatologyUniversity Medical Center UtrechtUtrechtThe Netherlands
| | - Bernice M. van der Lecq
- Department of Gastroenterology & HepatologyUniversity Medical Center UtrechtUtrechtThe Netherlands
| | - Karel J. van Erpecum
- Department of Gastroenterology & HepatologyUniversity Medical Center UtrechtUtrechtThe Netherlands
| | - Joep de Bruijne
- Department of Gastroenterology & HepatologyUniversity Medical Center UtrechtUtrechtThe Netherlands
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25
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Ankcorn M, Said B, Morgan D, Elsharkawy AM, Maggs J, Ryder S, Valliani T, Gordon F, Abeysekera K, Suri D, McPherson S, Galliford J, Smith B, Pelosi E, Bansal S, Bethune C, Sheridan D, Vine L, Tedder RS, Ijaz S, Zuckerman M, Dalton H, Healy B, Donati M, Bicknell K, Evans C, Poller B, Smit E, Halsema C, Williams E, Raza M, McGann H, Irving W, Douthwaite S, Ch'ng CL, McCaughey C, Irish D. Persistent Hepatitis E virus infection across England and Wales 2009-2017: Demography, virology and outcomes. J Viral Hepat 2021; 28:420-430. [PMID: 33073452 DOI: 10.1111/jvh.13424] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 09/20/2020] [Accepted: 10/02/2020] [Indexed: 01/11/2023]
Abstract
The first clinical case of persistent HEV infection in England was reported in 2009. We describe the demography, virology and outcomes of patients identified with persistent HEV infection in England and Wales between 2009 and 2017. A series of 94 patients with persistent HEV infection, defined by HEV viraemia of more than 12 weeks, was identified through routine reference laboratory testing. Virology, serology and clinical data were recorded through an approved PHE Enhanced Surveillance System. Sixty-six cases (70.2%) were transplant recipients, 16 (17.0%) had an underlying haematological malignancy without stem cell transplantation, six (6.4%) had advanced HIV infection, five (5.3%) were otherwise immunosuppressed, and one patient (1.1%) had no identified immunosuppression. Retrospective analysis of 46 patients demonstrated a median 38 weeks of viraemia before diagnostic HEV testing. At initial diagnosis, 16 patients (17.0%) had no detectable anti-HEV serological response. Of 65 patients treated with ribavirin monotherapy, 11 (16.9%) suffered virological relapse despite undetectable RNA in plasma or stool at treatment cessation. Persistent HEV infection remains a rare diagnosis, but we demonstrate that a broad range of immunocompromised patients are susceptible. Both lack of awareness and the pauci-symptomatic nature of persistent HEV infection likely contribute to significant delays in diagnosis. Diagnosis should rely on molecular testing since anti-HEV serology is insufficient to exclude persistent HEV infection. Finally, despite treatment with ribavirin, relapses occur even after cessation of detectable faecal shedding of HEV RNA, further emphasising the requirement to demonstrate sustained virological responses to treatment.
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Affiliation(s)
- Michael Ankcorn
- Blood Borne Virus Unit, Virus Reference Department, National Infection Service, Public Health England, London, UK.,Transfusion Microbiology, National Health Service Blood and Transplant, London, UK
| | - Bengü Said
- Emerging Infections and Zoonoses, National Infection Service, Public Health England, London, UK
| | - Dilys Morgan
- Emerging Infections and Zoonoses, National Infection Service, Public Health England, London, UK
| | | | - James Maggs
- Department of Gastroenterology, Buckinghamshire Healthcare NHS Trust, Buckinghamshire, UK
| | - Stephen Ryder
- Department of Hepatology, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Talal Valliani
- North Bristol Liver Unit, North Bristol NHS Trust, Southmead Hospital, Bristol, UK
| | - Fiona Gordon
- Department of Hepatology, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
| | - Kushala Abeysekera
- Department of Hepatology, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
| | - Deepak Suri
- Department of Hepatology, University College London Hospitals, London, UK
| | - Stuart McPherson
- Liver Unit, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, & Institute of Cellular Medicine, Newcastle University, Newcastle, UK
| | - Jack Galliford
- Department of Nephrology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - Belinda Smith
- Department of Hepatology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - Emanuela Pelosi
- Department of Infection, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Sanjay Bansal
- Department of Paediatric Hepatology, Gastroenterology & Nutrition Center, King's College Hospital NHS Foundation Trust, London, UK
| | - Claire Bethune
- Department of Immunology and Allergy, University Hospitals Plymouth NHS Trust, Plymouth, UK
| | - David Sheridan
- South West Liver Unit, University Hospitals Plymouth NHS Trust, Plymouth, UK
| | - Louisa Vine
- South West Liver Unit, University Hospitals Plymouth NHS Trust, Plymouth, UK
| | - Richard S Tedder
- Blood Borne Virus Unit, Virus Reference Department, National Infection Service, Public Health England, London, UK.,Transfusion Microbiology, National Health Service Blood and Transplant, London, UK.,Department of Medicine, Imperial College London, London, UK
| | - Samreen Ijaz
- Blood Borne Virus Unit, Virus Reference Department, National Infection Service, Public Health England, London, UK
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26
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Belei O, Ancusa O, Mara A, Olariu L, Amaricai E, Folescu R, Zamfir CL, Gurgus D, Motoc AG, Stânga LC, Strat L, Marginean O. Current Paradigm of Hepatitis E Virus Among Pediatric and Adult Patients. Front Pediatr 2021; 9:721918. [PMID: 34660485 PMCID: PMC8515027 DOI: 10.3389/fped.2021.721918] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 08/31/2021] [Indexed: 12/26/2022] Open
Abstract
Hepatitis E virus (HEV) infection is a polymorphic condition, present throughout the world and involving children and adults. Multiple studies over the last decade have contributed to a better understanding of the natural evolution of this infection in various population groups, several reservoirs and transmission routes being identified. To date, acute or chronic HEV-induced hepatitis has in some cases remained underdiagnosed due to the lower accuracy of serological tests and due to the evolutionary possibility with extrahepatic manifestations. Implementation of diagnostic tests based on nucleic acid analysis has increased the detection rate of this disease. The epidemiological and clinical features of HEV hepatitis differ depending on the geographical areas studied. HEV infection is usually a self-limiting condition in immunocompetent patients, but in certain categories of vulnerable patients it can induce a sudden evolution toward acute liver failure (pregnant women) or chronicity (immunosuppressed patients, post-transplant, hematological, or malignant diseases). In acute HEV infections in most cases supportive treatment is sufficient. In patients who develop chronic hepatitis with HEV, dose reduction of immunosuppressive medication should be the first therapeutic step, especially in patients with transplant. In case of unfavorable response, the initiation of antiviral therapy is recommended. In this review, the authors summarized the essential published data related to the epidemiological, clinical, paraclinical, and therapeutic aspects of HEV infection in adult and pediatric patients.
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Affiliation(s)
- Oana Belei
- First Pediatric Clinic, Disturbance of Growth and Development on Children Research Center, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
| | - Oana Ancusa
- Fifth Department of Internal Medicine, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
| | - Adelina Mara
- Department of Internal Medicine, Emergency City Hospital, Timisoara, Romania
| | - Laura Olariu
- First Pediatric Clinic, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
| | - Elena Amaricai
- Department of Rehabilitation Physical Medicine and Rheumatology, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
| | - Roxana Folescu
- Department of Balneology, Medical Recovery and Rheumatology, Family Discipline, Center for Preventive Medicine, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
| | - Carmen Lacramioara Zamfir
- Department of Morpho-Functional Sciences I, "Grigore T. Popa" University of Medicine and Pharmacy, Iasi, Romania
| | - Daniela Gurgus
- Department of Balneology, Medical Recovery and Rheumatology, Family Discipline, Center for Preventive Medicine, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
| | - Andrei G Motoc
- Department of Anatomy and Embriology, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
| | - Livia Claudia Stânga
- Department of Microbiology, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
| | - Liliana Strat
- Department of Mother and Child Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, Iasi, Romania
| | - Otilia Marginean
- First Pediatric Clinic, Disturbance of Growth and Development on Children Research Center, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
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27
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Li Y, Li P, Li Y, Zhang R, Yu P, Ma Z, Kainov DE, de Man RA, Peppelenbosch MP, Pan Q. Drug screening identified gemcitabine inhibiting hepatitis E virus by inducing interferon-like response via activation of STAT1 phosphorylation. Antiviral Res 2020; 184:104967. [PMID: 33137361 DOI: 10.1016/j.antiviral.2020.104967] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 10/23/2020] [Accepted: 10/27/2020] [Indexed: 01/01/2023]
Abstract
Exposure to hepatitis E virus (HEV) bears a high risk of developing chronic infection in immunocompromised patients, including organ transplant recipients and cancer patients. We aim to identify effective anti-HEV therapies through screening and repurposing safe-in-human broad-spectrum antiviral agents. In this study, a safe-in-human broad-spectrum antiviral drug library comprising of 94 agents was used. Upon screening, we identified gemcitabine, a widely used anti-cancer drug, as a potent inhibitor of HEV replication. The antiviral effect was confirmed in a range of cell culture models with genotype 1 and 3 HEV strains. As a cytidine analog, exogenous supplementation of pyrimidine nucleosides effectively reversed the antiviral activity of gemcitabine, but the level of pyrimidine nucleosides per se does not affect HEV replication. Surprisingly, similar to interferon-alpha (IFNα) treatment, gemcitabine activates STAT1 phosphorylation. This subsequently triggers activation of interferon-sensitive response element (ISRE) and transcription of interferon-stimulated genes (ISGs). Cytidine or uridine effectively inhibits gemcitabine-induced activation of ISRE and ISGs. As expected, JAK inhibitor 1 blocked IFNα, but not gemcitabine-induced STAT1 phosphorylation, ISRE/ISG activation, and anti-HEV activity. These effects of gemcitabine were completely lost in STAT1 knockout cells. In summary, gemcitabine potently inhibits HEV replication by triggering interferon-like response through STAT1 phosphorylation but independent of Janus kinases. This represents a non-canonical antiviral mechanism, which utilizes the innate defense machinery that is distinct from the classical interferon response. These results support repurposing gemcitabine for treating hepatitis E, especially for HEV-infected cancer patients, leading to dual anti-cancer and antiviral effects.
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Affiliation(s)
- Yunlong Li
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Pengfei Li
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Yang Li
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Ruyi Zhang
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Peifa Yu
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Zhongren Ma
- Biomedical Research Center, Northwest Minzu University, Lanzhou, China
| | - Denis E Kainov
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, 7028, Norway; Institute of Technology, University of Tartu, Tartu, 50090, Estonia
| | - Robert A de Man
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Maikel P Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Qiuwei Pan
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
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28
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Aslan AT, Balaban HY. Hepatitis E virus: Epidemiology, diagnosis, clinical manifestations, and treatment. World J Gastroenterol 2020; 26:5543-5560. [PMID: 33071523 PMCID: PMC7545399 DOI: 10.3748/wjg.v26.i37.5543] [Citation(s) in RCA: 107] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 08/11/2020] [Accepted: 09/09/2020] [Indexed: 02/06/2023] Open
Abstract
The hepatitis E virus (HEV) is the fifth known form of viral hepatitis and was first recognized as the cause of an epidemic of unexplained acute hepatitis in the early 1980s. Globally, it is one of the most frequent causes of acute viral hepatitis. The majority of HEV infections are asymptomatic and lead to the spontaneous clearance of the virus. Among the eight different genotypes identified to date, HEV genotype 1 (HEV1), HEV2, HEV3, and HEV4 are the most frequent genotypes causing infections in humans. HEV1 and HEV2 are prevalent in developing regions and able to result in large-scale outbreaks originating from contaminated water supplies. They are also responsible for severe hepatitis in pregnant patients and infants. In contrast, HEV3 and HEV4 are zoonotic, and the transmission of these genotypes to humans occurs mainly through the fecal contamination of water and consumption of contaminated meat from infected animals. Their main reservoir is the pig, and they are mostly encountered in developed countries. The major risk groups for HEV infection and its ensuing adverse consequences are pregnant women, infants, older people, immunocompromised individuals, patients with underlying chronic liver diseases, and workers that come into close contact with HEV-infected animals. In the clinical perspective, HEV infections have diverse clinical manifestations including acute and self-limiting hepatitis, acute-on-chronic liver disease, chronic hepatitis, cirrhosis, and liver failure. Although HEV mainly results in acute self-limiting infection, chronic HEV infection may occur among immunocompromised patients (e.g., solid-organ transplant recipients). Additionally, HEV-associated extrahepatic manifestations involving various organs have been reported in the last decade, although the causal link for many of them still needs to be proven. Ribavirin and interferon-alpha are the most widely used agents for the treatment of HEV infections with a certain level of success. However, ribavirin is contraindicated in pregnant patients, and interferon-alpha cannot be used in most transplant recipients. Therefore, there is an urgent need for novel antiviral compounds that are safe and effective particularly for patients having contraindications for ribavirin or interferon-alpha and infected by the ribavirin-resistant HEV. In this review article, a literature search using PubMed and MEDLINE databases was performed, up to March 2020. Only the articles published in English were reviewed.
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Affiliation(s)
| | - Hatice Yasemin Balaban
- Department of Gastroenterology, Hacettepe University Faculty of Medicine, Ankara 06100, Turkey
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29
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Thakur V, Ratho RK, Kumar S, Saxena SK, Bora I, Thakur P. Viral Hepatitis E and Chronicity: A Growing Public Health Concern. Front Microbiol 2020; 11:577339. [PMID: 33133046 PMCID: PMC7550462 DOI: 10.3389/fmicb.2020.577339] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 09/03/2020] [Indexed: 12/15/2022] Open
Abstract
Hepatitis E viral infection recently emerges as a global health concern. Over the last decade, the understanding of hepatitis E virus (HEV) had changed with the discovery of new genotypes like genotype-7 and genotype-8 with associated host and mode of infection. Diversification in the mode of hepatitis E infection transmission through blood transfusion, and organ transplants in contrast to classical feco-oral and zoonotic mode is the recent medical concern. The wide spectrum of infection ranging from self-limiting to acute liver failure is now overpowered by HEV genotype-specific chronic infection especially in transplant patients. This concern is further escalated by the extra-hepatic manifestations of HEV targeting the central nervous system (CNS), kidney, heart, and pancreas. However, with the development of advanced efficient cell culture systems and animal models simulating the infection, much clarity toward understanding the pathogenetic mechanism of HEV has been developed. Also this facilitates the development of vaccines research or therapeutics. In this review, we highlight all the novel findings in every aspect of HEV with special emphasis on recently emerging chronic mode of infection with specific diagnosis and treatment regime with an optimistic hope to help virologists and/or liver specialists working in the field of viral hepatitis.
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Affiliation(s)
- Vikram Thakur
- Department of Virology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Radha Kanta Ratho
- Department of Virology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Swatantra Kumar
- Centre for Advanced Research, Faculty of Medicine, King George's Medical University, Lucknow, India
| | - Shailendra K Saxena
- Centre for Advanced Research, Faculty of Medicine, King George's Medical University, Lucknow, India
| | - Ishani Bora
- Department of Virology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Pryanka Thakur
- Department of Virology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
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30
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Perisetti A, Laoveeravat P, Inamdar S, Tharian B, Thandassery R, Goyal H. Hepatitis E virus infection in liver transplant recipients: a descriptive literature review. Eur J Gastroenterol Hepatol 2020; 32:916-922. [PMID: 32091436 DOI: 10.1097/meg.0000000000001682] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Hepatitis E virus infection has been recognized as a rising hepatotropic viral infection in the developing countries but overlooked in the developed countries, due to its lower prevalence. However, hepatitis E virus prevalence is on rise in the liver transplant recipients due to immunosuppression, which needs prompt recognition by healthcare practitioners. Hepatitis E virus infection is commonly believed to be transmitted via an animal host; but in the post-liver transplant patients, it can also be acquired via blood and blood products transfusion and autochthonous route. Previous studies have shown the significance of hepatitis E virus infection in post-liver transplant, as the patients at a high risk of progressing to chronic hepatitis and cirrhosis. Pediatric patients are at higher risk of hepatitis E virus infection post-liver transplant. Specific hepatitis E virus genotypes have the potential for greater severity. The clinical manifestation of hepatitis E virus can also present as extrahepatic features which need high level of suspicion for early recognition and treatment. Treatment options of hepatitis E virus range from immunosuppressive drug minimization, ribavirin therapy to novel direct-acting antiviral regimens. Herein, we aim to explore epidemiology, prevalence, risk factor, diagnosis, and management of hepatitis E virus infection giving special attention to liver transplant recipients.
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Affiliation(s)
- Abhilash Perisetti
- Department of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Passisd Laoveeravat
- Department of Internal Medicine, Texas Tech University Health Sciences, Lubbock, Texas
| | - Sumant Inamdar
- Department of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Lubbock, Texas
| | - Benjamin Tharian
- Department of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Lubbock, Texas
| | - Ragesh Thandassery
- Central Arkansas Veterans Healthcare System, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Hemant Goyal
- The Wright Center for Graduate Medical Education, Scranton, Pennsylvania
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31
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Istrate A, Rădulescu AL. A comparison of hepatitis E and A in a teaching hospital in Northwestern Romania. Acute hepatitis E - a mild disease? Med Pharm Rep 2020; 93:30-38. [PMID: 32133444 PMCID: PMC7051815 DOI: 10.15386/mpr-1487] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 11/20/2019] [Accepted: 12/09/2019] [Indexed: 12/13/2022] Open
Abstract
Background and aims The incidence of locally acquired hepatitis E has increased in recent years across Europe. There are only few data on hepatitis E in Romania. The purpose of our research was to describe and compare hepatitis E and hepatitis A in adult patients. Methods We included all consecutive adult patients with hepatitis E and hepatitis A admitted to the Teaching Hospital of Infectious Diseases, Cluj-Napoca, Romania between January 2017 and August 2019. Results Hepatitis E incidence increased in 2018–2019 compared to 2017. The average age in hepatitis E (n=48) patients was 50.6 versus 39.1 years in hepatitis A (n=152, not including 262 minors) and two-thirds of the patients in both groups were men. Compared to hepatitis A, patients with hepatitis E presented significantly less modified AST and ALT, bilirubin, prothrombin index and INR levels. We found more comorbidities in hepatitis E patients adjusted for age and gender. Severe forms were found in 5 (3.3%) hepatitis A patients, compared to 12 (25%) of hepatitis E patients, of which 3 died. Ribavirin treatment was considered in 9 patients with acute-on-chronic hepatitis E, immunosuppression, cancers or neurological manifestations, showing good results. Conclusions We observed an increased number of hepatitis E cases. Although laboratory results were less modified compared to hepatitis A, we found a higher number of severe hepatitis E cases. Ribavirin treatment seems to be beneficial in patients with preexisting conditions.
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Affiliation(s)
- Alexandru Istrate
- Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.,Department of Epidemiology, Clinical Hospital of Infectious Diseases, Cluj-Napoca, Romania
| | - Amanda Lelia Rădulescu
- Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.,Department of Epidemiology, Clinical Hospital of Infectious Diseases, Cluj-Napoca, Romania
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Lhomme S, Marion O, Abravanel F, Izopet J, Kamar N. Clinical Manifestations, Pathogenesis and Treatment of Hepatitis E Virus Infections. J Clin Med 2020; 9:E331. [PMID: 31991629 PMCID: PMC7073673 DOI: 10.3390/jcm9020331] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 01/14/2020] [Accepted: 01/22/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis throughout the world. Most infections are acute but they can become chronic in immunocompromised patients, such as solid organ transplant patients, patients with hematologic malignancy undergoing chemotherapy and those with a human immunodeficiency virus (HIV) infection. Extra-hepatic manifestations, especially neurological and renal diseases, have also been described. To date, four main genotypes of HEV (HEV1-4) were described. HEV1 and HEV2 only infect humans, while HEV3 and HEV4 can infect both humans and animals, like pigs, wild boar, deer and rabbits. The real epidemiology of HEV has been underestimated because most infections are asymptomatic. This review focuses on the recent advances in our understanding of the pathophysiology of acute HEV infections, including severe hepatitis in patients with pre-existing liver disease and pregnant women. It also examines the mechanisms leading to chronic infection in immunocompromised patients and extra-hepatic manifestations. Acute infections are usually self-limiting and do not require antiviral treatment. Conversely, a chronic HEV infection can be cleared by decreasing the dose of immunosuppressive drugs or by treating with ribavirin for 3 months. Nevertheless, new drugs are needed for those cases in which ribavirin treatment fails.
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Affiliation(s)
- Sébastien Lhomme
- Virology Laboratory, National Reference Center for Hepatitis E Virus, Toulouse Purpan University Hospital, 31300 Toulouse, France; (F.A.); (J.I.)
- INSERM UMR1043, Center for Pathophysiology of Toulouse Purpan, 31300 Toulouse, France;
- Université Toulouse III Paul Sabatier, 31330 Toulouse, France
| | - Olivier Marion
- INSERM UMR1043, Center for Pathophysiology of Toulouse Purpan, 31300 Toulouse, France;
- Université Toulouse III Paul Sabatier, 31330 Toulouse, France
- Department of Nephrology and Organs Transplantation, Toulouse Rangueil University Hospital, 31400 Toulouse, France
| | - Florence Abravanel
- Virology Laboratory, National Reference Center for Hepatitis E Virus, Toulouse Purpan University Hospital, 31300 Toulouse, France; (F.A.); (J.I.)
- INSERM UMR1043, Center for Pathophysiology of Toulouse Purpan, 31300 Toulouse, France;
- Université Toulouse III Paul Sabatier, 31330 Toulouse, France
| | - Jacques Izopet
- Virology Laboratory, National Reference Center for Hepatitis E Virus, Toulouse Purpan University Hospital, 31300 Toulouse, France; (F.A.); (J.I.)
- INSERM UMR1043, Center for Pathophysiology of Toulouse Purpan, 31300 Toulouse, France;
- Université Toulouse III Paul Sabatier, 31330 Toulouse, France
| | - Nassim Kamar
- INSERM UMR1043, Center for Pathophysiology of Toulouse Purpan, 31300 Toulouse, France;
- Université Toulouse III Paul Sabatier, 31330 Toulouse, France
- Department of Nephrology and Organs Transplantation, Toulouse Rangueil University Hospital, 31400 Toulouse, France
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Rivero-Juarez A, Vallejo N, Lopez-Lopez P, Díaz-Mareque AI, Frias M, Vallejo A, Caballero-Gómez J, Rodríguez-Velasco M, Molina E, Aguilera A. Ribavirin as a First Treatment Approach for Hepatitis E Virus Infection in Transplant Recipient Patients. Microorganisms 2019; 8:E51. [PMID: 31888090 PMCID: PMC7022260 DOI: 10.3390/microorganisms8010051] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 12/23/2019] [Accepted: 12/23/2019] [Indexed: 02/06/2023] Open
Abstract
The hepatitis E virus (HEV) is the major cause of acute hepatitis of viral origin worldwide. Despite its usual course as an asymptomatic self-limited hepatitis, there are highly susceptible populations, such as those with underlying immunosuppression, which could develop chronic hepatitis. In this situation, implementation of therapy is mandatory in the sense to facilitate viral clearance. Currently, there are no specific drugs approved for HEV infection, but ribavirin (RBV), the drug of choice, is used for off-label treatment. Here, we present two cases of chronic HEV infection in transplant patients, reviewing and discussing the therapeutic approach available in the literature. The use of RBV for the treatment of an HEV infection in organ transplant patients seems to be effective. The recommendation of 12 weeks of therapy is adequate in terms of efficacy. Nevertheless, there are important issues that urgently need to be assessed, such as optimal duration of therapy and drug dosage.
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Affiliation(s)
- Antonio Rivero-Juarez
- Infectious Diseases Unit, Clinical Virology and Zoonoses research group, Hospital Universitario Reina Sofía de Córdoba, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, 14006 Cordoba, Spain; (P.L.-L.); (M.F.); (J.C.-G.)
| | - Nicolau Vallejo
- Digestive Unit, Complexo Hospitalario Universitario de Santiago, 15705 Santiago de Compostela, Spain; (N.V.); (E.M.)
| | - Pedro Lopez-Lopez
- Infectious Diseases Unit, Clinical Virology and Zoonoses research group, Hospital Universitario Reina Sofía de Córdoba, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, 14006 Cordoba, Spain; (P.L.-L.); (M.F.); (J.C.-G.)
| | - Ana Isabel Díaz-Mareque
- Nephrology Unit, Complexo Hospitalario Universitario de Santiago, 15705 Santiago de Compostela, Spain;
| | - Mario Frias
- Infectious Diseases Unit, Clinical Virology and Zoonoses research group, Hospital Universitario Reina Sofía de Córdoba, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, 14006 Cordoba, Spain; (P.L.-L.); (M.F.); (J.C.-G.)
| | - Aldara Vallejo
- Microbiology Unit, Complexo Hospitalario Universitario de Santiago, University of Santiago de Compostela, 15705 Santiago de Compostela, Spain; (A.V.); (M.R.-V.); (A.A.)
| | - Javier Caballero-Gómez
- Infectious Diseases Unit, Clinical Virology and Zoonoses research group, Hospital Universitario Reina Sofía de Córdoba, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, 14006 Cordoba, Spain; (P.L.-L.); (M.F.); (J.C.-G.)
- Animal Health Department, University of Cordoba-Agrifood Excellence International Campus (ceiA3), 15705 Cordoba, Spain
| | - María Rodríguez-Velasco
- Microbiology Unit, Complexo Hospitalario Universitario de Santiago, University of Santiago de Compostela, 15705 Santiago de Compostela, Spain; (A.V.); (M.R.-V.); (A.A.)
| | - Esther Molina
- Digestive Unit, Complexo Hospitalario Universitario de Santiago, 15705 Santiago de Compostela, Spain; (N.V.); (E.M.)
| | - Antonio Aguilera
- Microbiology Unit, Complexo Hospitalario Universitario de Santiago, University of Santiago de Compostela, 15705 Santiago de Compostela, Spain; (A.V.); (M.R.-V.); (A.A.)
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Chauhan A, Webb G, Ferguson J. Clinical presentations of Hepatitis E: A clinical review with representative case histories. Clin Res Hepatol Gastroenterol 2019; 43:649-657. [PMID: 30808575 PMCID: PMC6864596 DOI: 10.1016/j.clinre.2019.01.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 01/03/2019] [Accepted: 01/21/2019] [Indexed: 02/04/2023]
Abstract
Hepatitis E virus (HEV) typically causes an acute, self-limiting hepatitis and is among the commonest cause of such presentations. Hepatitis E viral infection is also increasingly recognized as a cause of chronic hepatitis amongst the immunocompromised, particularly amongst solid organ transplant recipients. Chronic HEV infection remains an underdiagnosed disease and chronic infection can lead to rapidly progressive liver fibrosis and cirrhosis. This review examines current understanding of the HEV. We illustrate typical clinical presentations, management strategies [(based upon guidelines from both the British Transplant Society (BTS) and European Association for the study of liver (EASL)] and outcomes of HEV infection in different cohorts of patients by highlighting select transplant and non-transplant patient cases, from one of the largest tertiary Hepatology centres in Europe.
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Affiliation(s)
- Abhishek Chauhan
- NIHR Birmingham Biomedical Research Centre, United Kingdom; Liver unit, University Hospitals Birmingham, United Kingdom; Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom.
| | - Gwilym Webb
- Liver unit, University Hospitals Birmingham, United Kingdom; Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom
| | - James Ferguson
- Liver unit, University Hospitals Birmingham, United Kingdom
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Okano H, Nakano T, Ito R, Tanaka A, Hoshi Y, Matsubayashi K, Asakawa H, Nose K, Tsuruga S, Tochio T, Kumazawa H, Isono Y, Tanaka H, Matsusaki S, Sase T, Saito T, Mukai K, Nishimura A, Kawakami K, Nagashima S, Takahashi M, Okamoto H. The spontaneous clearance of hepatitis E virus (HEV) and emergence of HEV antibodies in a transfusion-transmitted chronic hepatitis E case after completion of chemotherapy for acute myeloid leukemia. Clin J Gastroenterol 2019; 13:252-259. [PMID: 31342463 DOI: 10.1007/s12328-019-01024-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 07/18/2019] [Indexed: 01/01/2023]
Abstract
A 64-year-old woman was infected with hepatitis E virus (HEV) during chemotherapy for leukemia. By retrospective analyses of stored serum from the blood products and the patient, the source of the infection was determined to be platelet concentration (PC) transfused during chemotherapy. The partial nucleotide sequence of the HEV strain isolated from the donated PC and that from the patient's sera was identical and was subgenotype 3b. Clinical indicators such as alanine aminotransferase, HEV RNA titer, and anti-HEV antibodies in the serum were investigated from the beginning of the infection until 1 year after the termination of HEV infection. HEV RNA had propagated over 6 months and then cleared spontaneously after the completion of chemotherapy. Anti-HEV antibodies appeared in the serum just before the clearance of HEV RNA. Interestingly, HEV RNA was detected in the patient's urine, spinal fluid, and saliva. The HEV RNA titers in those samples were much lower than in the serum and feces. No renal, neurological, or salivary gland disorders appeared during the follow-up. We observed virological and biochemical progress and cure of transfusion-transmitted chronic hepatitis E in the patient despite an immunosuppressive status during and after chemotherapy against hematological malignancy.
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Affiliation(s)
- Hiroshi Okano
- Department of Gastroenterology, Suzuka General Hospital, 1275-53 Yasuzuka-cho, Suzuka, Mie, 513-8630, Japan.
| | - Tatsunori Nakano
- Department of Internal Medicine, Fujita Health University Nanakuri Memorial Hospital, 424-1 Oodori-cho, Tsu, Mie, 514-1295, Japan
| | - Ryugo Ito
- Department of Hematology and Oncology, Suzuka General Hospital, 1275-53 Yasuzuka-cho, Suzuka, Mie, 513-8630, Japan
| | - Ami Tanaka
- Central Blood Institute, Blood Service Headquarters, Japanese Red Cross Society, 1-1-3 Shiba-Daimon, Minato-ku, Tokyo, 105-8521, Japan
| | - Yuji Hoshi
- Central Blood Institute, Blood Service Headquarters, Japanese Red Cross Society, 1-1-3 Shiba-Daimon, Minato-ku, Tokyo, 105-8521, Japan
| | - Keiji Matsubayashi
- Central Blood Institute, Blood Service Headquarters, Japanese Red Cross Society, 1-1-3 Shiba-Daimon, Minato-ku, Tokyo, 105-8521, Japan
| | - Hiroki Asakawa
- Department of Gastroenterology, Suzuka General Hospital, 1275-53 Yasuzuka-cho, Suzuka, Mie, 513-8630, Japan
| | - Kenji Nose
- Department of Gastroenterology, Suzuka General Hospital, 1275-53 Yasuzuka-cho, Suzuka, Mie, 513-8630, Japan
| | - Satomi Tsuruga
- Department of Gastroenterology, Suzuka General Hospital, 1275-53 Yasuzuka-cho, Suzuka, Mie, 513-8630, Japan
| | - Tomomasa Tochio
- Department of Gastroenterology, Suzuka General Hospital, 1275-53 Yasuzuka-cho, Suzuka, Mie, 513-8630, Japan
| | - Hiroaki Kumazawa
- Department of Gastroenterology, Suzuka General Hospital, 1275-53 Yasuzuka-cho, Suzuka, Mie, 513-8630, Japan
| | - Yoshiaki Isono
- Department of Gastroenterology, Suzuka General Hospital, 1275-53 Yasuzuka-cho, Suzuka, Mie, 513-8630, Japan
| | - Hiroki Tanaka
- Department of Gastroenterology, Suzuka General Hospital, 1275-53 Yasuzuka-cho, Suzuka, Mie, 513-8630, Japan
| | - Shimpei Matsusaki
- Department of Gastroenterology, Suzuka General Hospital, 1275-53 Yasuzuka-cho, Suzuka, Mie, 513-8630, Japan
| | - Tomohiro Sase
- Department of Gastroenterology, Suzuka General Hospital, 1275-53 Yasuzuka-cho, Suzuka, Mie, 513-8630, Japan
| | - Tomonori Saito
- Department of Gastroenterology, Suzuka General Hospital, 1275-53 Yasuzuka-cho, Suzuka, Mie, 513-8630, Japan
| | - Katsumi Mukai
- Department of Gastroenterology, Suzuka General Hospital, 1275-53 Yasuzuka-cho, Suzuka, Mie, 513-8630, Japan
| | - Akira Nishimura
- Department of Gastroenterology, Suzuka General Hospital, 1275-53 Yasuzuka-cho, Suzuka, Mie, 513-8630, Japan
| | - Keiki Kawakami
- Department of Hematology and Oncology, Suzuka General Hospital, 1275-53 Yasuzuka-cho, Suzuka, Mie, 513-8630, Japan
| | - Shigeo Nagashima
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan
| | - Masaharu Takahashi
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan
| | - Hiroaki Okamoto
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan
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Horvatits T, Schulze Zur Wiesch J, Lütgehetmann M, Lohse AW, Pischke S. The Clinical Perspective on Hepatitis E. Viruses 2019; 11:E617. [PMID: 31284447 PMCID: PMC6669652 DOI: 10.3390/v11070617] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 06/26/2019] [Accepted: 07/03/2019] [Indexed: 12/17/2022] Open
Abstract
Every year, there are an estimated 20 million hepatitis E virus (HEV) infections worldwide, leading to an estimated 3.3 million symptomatic cases of hepatitis E. HEV is largely circulating in the west and is associated with several hepatic and extrahepatic diseases. HEV Genotype 1 and 2 infections are waterborne and causative for epidemics in the tropics, while genotype 3 and 4 infections are zoonotic diseases and are mainly transmitted by ingestion of undercooked pork in industrialized nations. The clinical course of these infections differs: genotype 1 and 2 infection can cause acute illness and can lead to acute liver failure (ALF) or acute on chronic liver failure (ACLF) with a high mortality rate of 20% in pregnant women. In contrast, the majority of HEV GT-3 and -4 infections have a clinically asymptomatic course and only rarely lead to acute on chronic liver failure in elderly or patients with underlying liver disease. Immunosuppressed individuals infected with genotype 3 or 4 may develop chronic hepatitis E, which then can lead to life-threatening cirrhosis. Furthermore, several extra-hepatic manifestations affecting various organs have been associated with ongoing or previous HEV infections but the causal link for many of them still needs to be proven. There is no approved specific therapy for the treatment of acute or chronic HEV GT-3 or -4 infections but off-label use of ribavirin has been demonstrated to be safe and effective in the majority of patients. However, in approximately 15% of chronically HEV infected patients, cure is not possible.
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Affiliation(s)
- Thomas Horvatits
- Department of Medicine, University Medical Center Hamburg-Eppendorf, 22527 Hamburg, Germany
- German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel and Heidelberg Partner sites, 22527 Hamburg, Germany
| | - Julian Schulze Zur Wiesch
- Department of Medicine, University Medical Center Hamburg-Eppendorf, 22527 Hamburg, Germany
- German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel and Heidelberg Partner sites, 22527 Hamburg, Germany
| | - Marc Lütgehetmann
- German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel and Heidelberg Partner sites, 22527 Hamburg, Germany
- Institute of Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, 22527 Hamburg, Germany
| | - Ansgar W Lohse
- Department of Medicine, University Medical Center Hamburg-Eppendorf, 22527 Hamburg, Germany
- German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel and Heidelberg Partner sites, 22527 Hamburg, Germany
| | - Sven Pischke
- Department of Medicine, University Medical Center Hamburg-Eppendorf, 22527 Hamburg, Germany.
- German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel and Heidelberg Partner sites, 22527 Hamburg, Germany.
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Kamar N, Pischke S. Acute and Persistent Hepatitis E Virus Genotype 3 and 4 Infection: Clinical Features, Pathogenesis, and Treatment. Cold Spring Harb Perspect Med 2019; 9:cshperspect.a031872. [PMID: 29735575 DOI: 10.1101/cshperspect.a031872] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Hepatitis E virus (HEV) genotype (gt)3 and 4 infections are prevalent in industrialized and high-income countries. Although most HEV gt3 and gt4 infections are clinically silent, acute infection may be symptomatic in some patients. In persons with underlying liver disease and in elderly men, HEV infections may present as acute or acute-on-chronic liver failure. Chronic hepatitis may develop in immunosuppressed individuals, including transplant recipients, human immunodeficiency virus (HIV)-infected patients, and persons with hematologic malignancy undergoing chemotherapy, and may progress to life-threatening liver cirrhosis. Extrahepatic manifestations of infection may include neurological and renal disease. Although there is no approved specific therapy for the treatment of acute or chronic HEV gt3 or gt4 infection, off-label use of ribavirin appears to be capable of eliminating chronic HEV infection, and may reduce disease severity in patients suffering from acute liver failure.
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Affiliation(s)
- Nassim Kamar
- Department of Nephrology and Organ Transplantation, Université Paul Sabatier, Toulouse 31059, France
| | - Sven Pischke
- Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany
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Spicatoside A derived from Liriope platyphylla root ethanol extract inhibits hepatitis E virus genotype 3 replication in vitro. Sci Rep 2019; 9:4397. [PMID: 30867434 PMCID: PMC6416393 DOI: 10.1038/s41598-019-39488-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Accepted: 12/18/2018] [Indexed: 12/15/2022] Open
Abstract
Hepatitis E virus (HEV) is the causative agent of hepatitis E in humans worldwide. Although hepatitis E is self-limiting without chronic infection development, HEV infection often leads to severe liver diseases causing high mortality in pregnant women in addition to chronic hepatitis and cirrhosis in immunosuppressed patients. In this study, we investigated the effect of a Liriope platyphylla ethanol extract (LPE) on HEV replication. Interestingly, LPE suppressed replication of the genotype 3 HEV replicon. Sequential solvent fractionation revealed that the ethyl acetate (EA) fraction of LPE exerts the most potent inhibitory effects. With the aid of activity-guided fractionation and multi-step column chromatography, spicatoside A was subsequently isolated in the EA fraction of LPE and specifically shown to exert inhibitory effects on replication of the genotype 3 HEV replicon. In addition, spicatoside A interfered with replication of the HEV genotype 3 strain 47832c and expression of HEV ORF2 capsid proteins. Our findings clearly support the potential utility of spicatoside A as an effective anti-HEV agent.
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Chronic Hepatitis E in Rheumatology and Internal Medicine Patients: A Retrospective Multicenter European Cohort Study. Viruses 2019; 11:v11020186. [PMID: 30813268 PMCID: PMC6410237 DOI: 10.3390/v11020186] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 02/04/2019] [Accepted: 02/19/2019] [Indexed: 12/23/2022] Open
Abstract
Objectives: Hepatitis E virus (HEV) infection is a pandemic with regional outbreaks, including in industrialized countries. HEV infection is usually self-limiting but can progress to chronic hepatitis E in transplant recipients and HIV-infected patients. Whether other immunocompromised hosts, including rheumatology and internal medicine patients, are at risk of developing chronic HEV infection is unclear. Methods: We conducted a retrospective European multicenter cohort study involving 21 rheumatology and internal medicine patients with HEV infection between April 2014 and April 2016. The underlying diseases included rheumatoid arthritis (n = 5), psoriatic arthritis (n = 4), other variants of chronic arthritis (n = 4), primary immunodeficiency (n = 3), systemic granulomatosis (n = 2), lupus erythematosus (n = 1), Erdheim–Chester disease (n = 1), and retroperitoneal fibrosis (n = 1). Results: HEV infection lasting longer than 3 months was observed in seven (33%) patients, including two (40%) patients with rheumatoid arthritis, three (100%) patients with primary immunodeficiency, one (100%) patient with retroperitoneal fibrosis and one (100%) patient with systemic granulomatosis. Patients with HEV infection lasting longer than 3 months were treated with methotrexate without corticosteroids (n = 2), mycophenolate mofetil/prednisone (n = 1), and sirolimus/prednisone (n = 1). Overall, 8/21 (38%) and 11/21 (52%) patients cleared HEV with and without ribavirin treatment, respectively. One patient experienced an HEV relapse after initially successful ribavirin therapy. One patient (5%) was lost to follow-up, and no patients died from hepatic complications. Conclusion: Rheumatology and internal medicine patients, including patients treated with methotrexate without corticosteroids, are at risk of developing chronic HEV infection. Rheumatology and internal medicine patients with abnormal liver tests should be screened for HEV infection.
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Meister TL, Bruening J, Todt D, Steinmann E. Cell culture systems for the study of hepatitis E virus. Antiviral Res 2019; 163:34-49. [PMID: 30653997 DOI: 10.1016/j.antiviral.2019.01.007] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 01/08/2019] [Accepted: 01/13/2019] [Indexed: 12/26/2022]
Abstract
Hepatitis E virus (HEV) is the causative agent of hepatitis E in humans and is the leading cause of enterically-transmitted viral hepatitis worldwide. Increasing numbers of HEV infections, together with no available specific anti-HEV treatment, contributes to the pathogen's major health burden. A robust cell culture system is required for virologic studies and the development of new antiviral drugs. Unfortunately, like other hepatitis viruses, HEV is difficult to propagate in conventional cell lines. Many different cell culture systems have been tested using various HEV strains, but viral replication usually progresses very slowly, and infection with low virion counts results in non-productive HEV replication. However, recent progress involving generation of cDNA clones and passaging primary patient isolates in distinct cell lines has improved in vitro HEV propagation. This review describes various approaches to cultivate HEV in cellular and animal models and how these systems are used to study HEV infections and evaluate anti-HEV drug candidates.
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Affiliation(s)
- Toni L Meister
- Ruhr-University Bochum, Faculty of Medicine, Department of Molecular and Medical Virology, Bochum, Germany
| | - Janina Bruening
- Ruhr-University Bochum, Faculty of Medicine, Department of Molecular and Medical Virology, Bochum, Germany
| | - Daniel Todt
- Ruhr-University Bochum, Faculty of Medicine, Department of Molecular and Medical Virology, Bochum, Germany.
| | - Eike Steinmann
- Ruhr-University Bochum, Faculty of Medicine, Department of Molecular and Medical Virology, Bochum, Germany.
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Marion O, Lhomme S, Del Bello A, Abravanel F, Esposito L, Hébral AL, Lavayssière L, Cointault O, Ribes D, Izopet J, Kamar N. Monitoring hepatitis E virus fecal shedding to optimize ribavirin treatment duration in chronically infected transplant patients. J Hepatol 2019; 70:206-209. [PMID: 30563687 DOI: 10.1016/j.jhep.2018.09.011] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2018] [Revised: 09/10/2018] [Accepted: 09/11/2018] [Indexed: 01/22/2023]
Affiliation(s)
- Olivier Marion
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France; Inserm UMR1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France
| | - Sébastien Lhomme
- Laboratory of Virology, CHU Purpan, Toulouse, France; Inserm UMR1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France; Université Paul Sabatier, Toulouse, France
| | - Arnaud Del Bello
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - Florence Abravanel
- Laboratory of Virology, CHU Purpan, Toulouse, France; Inserm UMR1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France; Université Paul Sabatier, Toulouse, France
| | - Laure Esposito
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - Anne Laure Hébral
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - Laurence Lavayssière
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - Olivier Cointault
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - David Ribes
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - Jacques Izopet
- Laboratory of Virology, CHU Purpan, Toulouse, France; Inserm UMR1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France; Université Paul Sabatier, Toulouse, France
| | - Nassim Kamar
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France; Inserm UMR1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France; Université Paul Sabatier, Toulouse, France.
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Webb GW, Dalton HR. Hepatitis E: an underestimated emerging threat. Ther Adv Infect Dis 2019; 6:2049936119837162. [PMID: 30984394 PMCID: PMC6448100 DOI: 10.1177/2049936119837162] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Accepted: 02/08/2019] [Indexed: 12/22/2022] Open
Abstract
Hepatitis E virus (HEV) is the most common cause of viral hepatitis in the world. It is estimated that millions of people are infected every year, resulting in tens of thousands of deaths. However, these estimates do not include industrialized regions and are based on studies which employ assays now known to have inferior sensitivity. As such, this is likely to represent a massive underestimate of the true global burden of disease. In the developing world, HEV causes large outbreaks and presents a significant public-health problem. Until recently HEV was thought to be uncommon in industrialized countries, and of little relevance to clinicians in these settings. We now know that this is incorrect, and that HEV is actually very common in developed regions. HEV has proved difficult to study in vitro, with reliable models only recently becoming available. Our understanding of the lifecycle of HEV is therefore incomplete. Routes of transmission vary by genotype and location: endemic regions experience large waterborne epidemics, while sporadic cases in industrialized regions are zoonotic infections likely spread via the food chain. Both acute and chronic infection has been observed, and a wide range of extrahepatic manifestations have been reported. This includes neurological, haematological and renal conditions. As the complete clinical phenotype of HEV infection is yet to be characterized, a large proportion of cases go unrecognized or misdiagnosed. In many cases HEV infection does not feature in the differential diagnosis due to a lack of knowledge and awareness of the disease amongst clinicians. In combination, these factors have contributed to an underestimation of the threat posed by HEV. Improvements are required in terms of recognition and diagnosis of HEV infection if we are to understand the natural history of the disease, improve management and reduce the burden of disease around the world.
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Affiliation(s)
- Glynn W. Webb
- University of Manchester NHS Foundation Trust, 7 Radnor Rd London NW6 6TT Manchester, UK
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Todt D, Meister TL, Steinmann E. Hepatitis E virus treatment and ribavirin therapy: viral mechanisms of nonresponse. Curr Opin Virol 2018; 32:80-87. [PMID: 30384328 DOI: 10.1016/j.coviro.2018.10.001] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 09/27/2018] [Accepted: 10/04/2018] [Indexed: 02/07/2023]
Abstract
Hepatitis E virus (HEV) can cause chronic infections in immunosuppressed patients with adverse clinical outcomes. Intervention strategies are limited with ribavirin (RBV) being the only main therapeutic option as off-label drug. Recent reports on RBV monotherapy failures show a coherence with the presence of certain single nucleotide variants (SNVs) and in-frame insertions in the hypervariable region of open reading frame 1 in the HEV genome. Importantly, some of the alterations were present in the viral population as minor variant before RBV administration. Individualized infection medicine by early detection of emerging viral variants in patients could improve treatment outcome and prognosis.
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Affiliation(s)
- Daniel Todt
- Department of Molecular and Medical Virology, Ruhr-University Bochum, Bochum, Germany
| | - Toni Luise Meister
- Department of Molecular and Medical Virology, Ruhr-University Bochum, Bochum, Germany
| | - Eike Steinmann
- Department of Molecular and Medical Virology, Ruhr-University Bochum, Bochum, Germany.
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44
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Anang S, Kaushik N, Surjit M. Recent Advances Towards the Development of a Potent Antiviral Against the Hepatitis E Virus. J Clin Transl Hepatol 2018; 6:310-316. [PMID: 30271744 PMCID: PMC6160310 DOI: 10.14218/jcth.2018.00005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Revised: 02/19/2018] [Accepted: 03/23/2018] [Indexed: 12/18/2022] Open
Abstract
Hepatitis E virus (HEV) is one of the leading causes of acute viral hepatitis. It also causes acute liver failure and acute-on-chronic liver failure in many patients, such as those suffering from other infections/liver injuries or organ transplant/chemotherapy recipients. Despite widespread sporadic and epidemic incidents, there is no specific treatment against HEV, justifying an urgent need for developing a potent antiviral against it. This review summarizes the known antiviral candidates and provides an overview of the potential targets for the development of specific antivirals against HEV.
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Affiliation(s)
- Saumya Anang
- Virology Laboratory, Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, Haryana, India
| | - Nidhi Kaushik
- Virology Laboratory, Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, Haryana, India
| | - Milan Surjit
- Virology Laboratory, Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, Haryana, India
- *Correspondence to: Milan Surjit, Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, PO Box No. 04, Faridabad-121001, Haryana, India. Tel: +91-129-2876-318, Fax: +91-129-2876400, E-mail:
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45
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Gupta E, Agarwala P. Hepatitis E Virus Infection: An Old Virus with a New Story! Indian J Med Microbiol 2018; 36:317-323. [DOI: 10.4103/ijmm.ijmm_18_149] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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46
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Bettinger D, Schlabe S, Pischke S, Mallmann MR, Keyver-Paik MD, Kuhn W, Strassburg CP, Thimme R, Spengler U. Ribavirin in Acute Hepatitis E Infection in Patients with Gynecological Cancer: A Case Series. J Clin Transl Hepatol 2018; 6:237-240. [PMID: 29951369 PMCID: PMC6018315 DOI: 10.14218/jcth.2017.00063] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Revised: 11/23/2017] [Accepted: 12/14/2017] [Indexed: 12/16/2022] Open
Abstract
Hepatitis E virus infection is usually a self-limited disease. However, during the last years there has been growing evidence for prolonged and chronic infection occurring in patients with immunosuppression. Also patients with malignant and rheumatic diseases have been identified to be at risk for chronic hepatitis E. However, their course and prognosis are not well characterized and there have been no reports of hepatitis E virus infection in patients with gynecological cancer. Here, we report three Caucasian females with breast and ovarian cancers presenting with elevation of aminotransferase levels during anticancer treatment. Although only few or no clinical hints suggested hepatitis E virus infection, the diagnosis of hepatitis E virus infection was confirmed by seroconversion, which might occur with some delay, and/or by polymerase chain reaction. While two patients had a self-limited course, the third patient with a high-risk oncological constellation required ribavirin in order to resume chemotherapy. These cases highlight the need for hepatitis E virus testing in patients with gynecological cancer and elevated aminotransferase levels. Further, these cases show that in selected high-risk patients, ribavirin treatment may be necessary based on the decision of a multidisciplinary team.
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Affiliation(s)
- Dominik Bettinger
- Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Berta-Ottenstein-Programme, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- *Correspondence to: Dominik Bettinger, Department of Medicine II, Medical Center University of Freiburg, Hugstetter Str. 55, Freiburg 79106, Germany. Tel: +49-761-270-32440, Fax: +49-761-270-32440, E-mail:
| | - Stefan Schlabe
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
- Center for Integrated Oncology Cologne/Bonn, Bonn, Germany
| | - Sven Pischke
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Michael R. Mallmann
- Department of Obstetrics and Gynecology, University of Cologne, Cologne, Germany
| | - Mignon-Denise Keyver-Paik
- Center for Integrated Oncology Cologne/Bonn, Bonn, Germany
- Department of Obstetrics and Gynecology, University of Bonn, Bonn, Germany
| | - Walther Kuhn
- Center for Integrated Oncology Cologne/Bonn, Bonn, Germany
- Department of Obstetrics and Gynecology, University of Bonn, Bonn, Germany
| | - Christian P. Strassburg
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
- Center for Integrated Oncology Cologne/Bonn, Bonn, Germany
| | - Robert Thimme
- Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Ulrich Spengler
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
- Center for Integrated Oncology Cologne/Bonn, Bonn, Germany
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47
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Nicot F, Jeanne N, Roulet A, Lefebvre C, Carcenac R, Manno M, Dubois M, Kamar N, Lhomme S, Abravanel F, Izopet J. Diversity of hepatitis E virus genotype 3. Rev Med Virol 2018; 28:e1987. [PMID: 29939461 DOI: 10.1002/rmv.1987] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Revised: 05/12/2018] [Accepted: 05/21/2018] [Indexed: 12/27/2022]
Abstract
Hepatitis E virus genotype 3 (HEV-3) can lead to chronic infection in immunocompromised patients, and ribavirin is the treatment of choice. Recently, mutations in the polymerase gene have been associated with ribavirin failure but their frequency before treatment according to HEV-3 subtypes has not been studied on a large data set. We used single-molecule real-time sequencing technology to sequence 115 new complete genomes of HEV-3 infecting French patients. We analyzed phylogenetic relationships, the length of the polyproline region, and mutations in the HEV polymerase gene. Eighty-five (74%) were in the clade HEV-3efg, 28 (24%) in HEV-3chi clade, and 2 (2%) in HEV-3ra clade. Using automated partitioning of maximum likelihood phylogenetic trees, complete genomes were classified into subtypes. Polyproline region length differs within HEV-3 clades (from 189 to 315 nt). Investigating mutations in the polymerase gene, distinct polymorphisms between HEV-3 subtypes were found (G1634R in 95% of HEV-3e, G1634K in 56% of HEV-3ra, and V1479I in all HEV-3efg, clade HEV-3ra, and HEV-3k strains). Subtype-specific polymorphisms in the HEV-3 polymerase have been identified. Our study provides new complete genome sequences of HEV-3 that could be useful for comparing strains circulating in humans and the animal reservoir.
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Affiliation(s)
- Florence Nicot
- Centre National de Référence du virus de l'hépatite E, Laboratoire de Virologie, Hôpital Purpan, CHU de Toulouse, Toulouse, France
| | - Nicolas Jeanne
- Centre National de Référence du virus de l'hépatite E, Laboratoire de Virologie, Hôpital Purpan, CHU de Toulouse, Toulouse, France
| | - Alain Roulet
- Plateforme Génomique, Centre INRA Occitanie-Toulouse, Castanet-Tolosan, France
| | - Caroline Lefebvre
- Centre National de Référence du virus de l'hépatite E, Laboratoire de Virologie, Hôpital Purpan, CHU de Toulouse, Toulouse, France
| | - Romain Carcenac
- Centre National de Référence du virus de l'hépatite E, Laboratoire de Virologie, Hôpital Purpan, CHU de Toulouse, Toulouse, France
| | - Maxime Manno
- Plateforme Génomique, Centre INRA Occitanie-Toulouse, Castanet-Tolosan, France
| | - Martine Dubois
- Centre National de Référence du virus de l'hépatite E, Laboratoire de Virologie, Hôpital Purpan, CHU de Toulouse, Toulouse, France
| | - Nassim Kamar
- Center of Pathophysiology, Toulouse Purpan, INSERM, U1043, Toulouse, France.,Université Toulouse III Paul-Sabatier, Toulouse, France.,Service de néphrologie, Dialyse et Transplantation d'Organe, Hôpital Rangueil, CHU de Toulouse, Toulouse, France
| | - Sébastien Lhomme
- Centre National de Référence du virus de l'hépatite E, Laboratoire de Virologie, Hôpital Purpan, CHU de Toulouse, Toulouse, France.,Center of Pathophysiology, Toulouse Purpan, INSERM, U1043, Toulouse, France.,Université Toulouse III Paul-Sabatier, Toulouse, France
| | - Florence Abravanel
- Centre National de Référence du virus de l'hépatite E, Laboratoire de Virologie, Hôpital Purpan, CHU de Toulouse, Toulouse, France.,Center of Pathophysiology, Toulouse Purpan, INSERM, U1043, Toulouse, France.,Université Toulouse III Paul-Sabatier, Toulouse, France
| | - Jacques Izopet
- Centre National de Référence du virus de l'hépatite E, Laboratoire de Virologie, Hôpital Purpan, CHU de Toulouse, Toulouse, France.,Center of Pathophysiology, Toulouse Purpan, INSERM, U1043, Toulouse, France.,Université Toulouse III Paul-Sabatier, Toulouse, France
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48
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Gong W, Liu L, Li M, Wang L, Zhang M, Luo Z, Sridhar S, Woo PCY, Wang L. Evaluation of antiviral efficacy of Chinese traditional medicine Babao Dan in rabbits infected with hepatitis E virus. J Gen Virol 2018; 99:1036-1043. [PMID: 29923821 DOI: 10.1099/jgv.0.001089] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Hepatitis E virus (HEV) is a major cause of acute viral hepatitis. Patients with chronic hepatitis B superinfected with HEV may progress to liver failure. Babao Dan (BD) is a traditional Chinese medicine widely used as an auxiliary option for the treatment of chronic hepatitis and liver cancer in China. This study aimed to evaluate the effect of BD on the management of HEV infection in a rabbit model. Sixty-two specific-pathogen-free (SPF) rabbits were divided randomly into five groups and treated with BD or placebo for 2 weeks. All rabbits were inoculated intravenously with rabbit HEV after initial administration. Then, rabbits were administered BD or ribavirin or placebo at 2 weeks post-inoculation (wpi) until faecal virus shedding showed negative. The duration of faecal virus shedding and levels of HEV RNA in faeces were reduced, and anti-HEV antibodies were detected in all rabbits in groups treated with BD before or after inoculation. Ribavirin treatment rapidly cleared HEV infection in SPF rabbits, but anti-HEV antibodies remained negative in 50 % of rabbits treated with ribavirin. These results indicate that ribavirin treatment was more effective in clearing HEV infection, while administration of BD before or after inoculation was effective in clearing HEV infection. Further clinical studies are warranted.
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Affiliation(s)
- Wanyun Gong
- 1Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, PR China
| | - Lin Liu
- 1Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, PR China
| | - Manyu Li
- 1Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, PR China
| | - Lin Wang
- 1Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, PR China
| | - Mingyu Zhang
- 1Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, PR China
| | - Zhengxin Luo
- 1Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, PR China
| | - Siddharth Sridhar
- 2Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, PR China
| | - Patrick C Y Woo
- 2Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, PR China
| | - Ling Wang
- 1Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, PR China
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49
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Dalton HR, Kamar N, Baylis SA, Moradpour D, Wedemeyer H, Negro F. EASL Clinical Practice Guidelines on hepatitis E virus infection. J Hepatol 2018; 68:1256-1271. [PMID: 29609832 DOI: 10.1016/j.jhep.2018.03.005] [Citation(s) in RCA: 424] [Impact Index Per Article: 60.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Accepted: 03/09/2018] [Indexed: 02/08/2023]
Abstract
Infection with hepatitis E virus (HEV) is a significant cause of morbidity and mortality, representing an important global health problem. Our understanding of HEV has changed completely over the past decade. Previously, HEV was thought to be limited to certain developing countries. We now know that HEV is endemic in most high-income countries and is largely a zoonotic infection. Given the paradigm shift in our understanding of zoonotic HEV and that locally acquired HEV is now the commonest cause of acute viral hepatitis in many European countries, the focus of these Clinical Practice Guidelines will be on HEV genotype 3 (and 4).
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50
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Fraga M, Doerig C, Moulin H, Bihl F, Brunner F, Müllhaupt B, Ripellino P, Semela D, Stickel F, Terziroli Beretta-Piccoli B, Aubert V, Telenti A, Greub G, Sahli R, Moradpour D. Hepatitis E virus as a cause of acute hepatitis acquired in Switzerland. Liver Int 2018; 38:619-626. [PMID: 28834649 DOI: 10.1111/liv.13557] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Accepted: 08/14/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND Autochthonous hepatitis E is increasingly recognized as zoonotic infection in western countries. Serological assays have varying sensitivity and specificity. METHODS We implemented molecular testing to identify and characterize acute hepatitis E acquired in Switzerland. RESULTS Ninety-three cases of mostly symptomatic acute hepatitis E acquired in Switzerland were documented by PCR between November 2011 and December 2016. Median HEV RNA was 7.5 x 104 IU/mL (range, 5.3 to 4.7 x 107 IU/mL). HEV genotyping was successful in 78 patients, revealing genotype 3 in 75 and genotype 4 in three patients. Phylogenetic analyses revealed a few limited geographical and temporal clusters. Of the 91 patients with available anti-HEV IgM serology, four were negative; three of these were also IgG-negative, likely as a result of immunosuppression, and one was IgG-positive, a constellation compatible with HEV reinfection. Median age of the patients was 58 years (range, 20-80 years); 71 (76.3%) were men and 49 of these (69.0%) were ≥ 50 years old. The clinical course was particularly severe in patients with underlying chronic liver disease, with fatal outcome in two patients. Six patients (6.5%) presented with neuralgic amyotrophy. CONCLUSIONS Nucleic acid-based diagnosis reveals HEV as a relevant cause of acute hepatitis in Switzerland. Middle-aged and elderly men constitute the majority of symptomatic patients. Testing for HEV should be included early in the diagnostic workup of acute hepatitis and of neuralgic amyotrophy, a typical extrahepatic manifestation of HEV genotype 3 infection.
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Affiliation(s)
- Montserrat Fraga
- Division of Gastroenterology and Hepatology, University Hospital Lausanne, Lausanne, Switzerland
| | - Christopher Doerig
- Division of Gastroenterology and Hepatology, University Hospital Lausanne, Lausanne, Switzerland
| | - Hervé Moulin
- Institute of Microbiology, University Hospital Lausanne, Lausanne, Switzerland
| | - Florian Bihl
- Hepatology Service, Ente Ospedaliero Cantonale Ticino, Lugano and University Hospital Geneva, Geneva, Switzerland
| | - Felix Brunner
- Hepatology, University Clinic for Visceral Surgery and Medicine, University Hospital Berne, Berne, Switzerland
| | - Beat Müllhaupt
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | | | - David Semela
- Division of Gastroenterology and Hepatology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland
| | - Felix Stickel
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | | | - Vincent Aubert
- Division of Immunology and Allergy, University Hospital Lausanne, Lausanne, Switzerland
| | - Amalio Telenti
- Institute of Microbiology, University Hospital Lausanne, Lausanne, Switzerland
| | - Gilbert Greub
- Institute of Microbiology, University Hospital Lausanne, Lausanne, Switzerland
| | - Roland Sahli
- Institute of Microbiology, University Hospital Lausanne, Lausanne, Switzerland
| | - Darius Moradpour
- Division of Gastroenterology and Hepatology, University Hospital Lausanne, Lausanne, Switzerland
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