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Pavlova A, Kocikova B, Dolinska MU, Jackova A. Hepatitis E Virus in the Role of an Emerging Food-Borne Pathogen. Microorganisms 2025; 13:885. [PMID: 40284721 PMCID: PMC12029509 DOI: 10.3390/microorganisms13040885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2025] [Revised: 04/04/2025] [Accepted: 04/07/2025] [Indexed: 04/29/2025] Open
Abstract
Viral hepatitis E represents an important global health problem caused by the hepatitis E virus (HEV). Cases of HEV infection are increasingly associated with food-borne transmissions after the consumption of raw or undercooked food products from infected animals in high-income regions. Although most cases of infection are asymptomatic, severe courses of infection have been reported in specific groups of people, predominantly among pregnant women and immunocompromised patients. The viral nucleic acid of HEV is increasingly being reported in food-producing animals and different products of an animal origin. Even though the incubation period for HEV infection is long, several direct epidemiological links between human cases and the consumption of HEV-contaminated meat and meat products have been described. In this article, we review the current knowledge on human HEV infections, HEV in different food-producing animals and products of an animal origin, as well as the accumulation and resistance to HEV in farm and slaughterhouse environments. We also provide preventive measures to help eliminate HEV from animals, the human population, and the environment.
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Affiliation(s)
| | | | | | - Anna Jackova
- Department of Epizootiology, Parasitology and Protection of One Health, University of Veterinary Medicine and Pharmacy in Kosice, Komenskeho 73, 041 81 Kosice, Slovakia; (A.P.); (B.K.); (M.U.D.)
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Kanda T, Li TC, Takahashi M, Nagashima S, Primadharsini PP, Kunita S, Sasaki-Tanaka R, Inoue J, Tsuchiya A, Nakamoto S, Abe R, Fujiwara K, Yokosuka O, Suzuki R, Ishii K, Yotsuyanagi H, Okamoto H. Recent advances in hepatitis E virus research and the Japanese clinical practice guidelines for hepatitis E virus infection. Hepatol Res 2024; 54:1-30. [PMID: 38874115 DOI: 10.1111/hepr.14062] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 04/22/2024] [Accepted: 05/09/2024] [Indexed: 06/15/2024]
Abstract
Acute hepatitis E was considered rare until reports emerged affirming the existence of hepatitis E virus (HEV) genotypes 3 and 4 infections in Japan in the early 2000s. Extensive studies by Japanese researchers have highlighted the pivotal role of pigs and wild animals, such as wild boars and deer, as reservoirs for HEV, linking them to zoonotic infections in Japan. Currently, when hepatitis occurs subsequent to the consumption of undercooked or grilled pork, wild boar meat, or offal (including pig liver and intestines), HEV infection should be considered. Following the approval of anti-HEV immunoglobulin A antibody as a diagnostic tool for hepatitis E by Japan's Health Insurance System in 2011, the annual number of diagnosed cases of HEV infection has surged. Notably, the occurrence of post-transfusion hepatitis E promoted nationwide screening of blood products for HEV using nucleic acid amplification tests since 2020. Furthermore, chronic hepatitis E has been observed in immunosuppressed individuals. Considering the significance of hepatitis E, heightened preventive measures are essential. The Japan Agency for Medical Research and Development Hepatitis A and E viruses (HAV and HEV) Study Group, which includes special virologists and hepatologists, held a virtual meeting on February 17, 2024. Discussions encompassed pathogenesis, transmission routes, diagnosis, complications, severity factors, and ongoing and prospective vaccination or treatments for hepatitis E. Rigorous assessment of referenced studies culminated in the formulation of recommendations, which are detailed within this review. This comprehensive review presents recent advancements in HEV research and Japanese clinical practice guidelines for HEV infection.
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Affiliation(s)
- Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
- Division of Gastroenterology and Hepatology, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Minamiuonuma, Japan
- Division of Gastroenterology and Hepatology, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, Japan
| | - Tian-Cheng Li
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Masaharu Takahashi
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan
| | - Shigeo Nagashima
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan
| | - Putu Prathiwi Primadharsini
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan
| | - Satoshi Kunita
- Center for Experimental Medicine, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan
| | - Reina Sasaki-Tanaka
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
- Division of Gastroenterology and Hepatology, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, Japan
| | - Jun Inoue
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, Japan
| | - Shingo Nakamoto
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan
| | - Ryuzo Abe
- Department of Emergency Medicine, Oita University, Oita, Japan
| | - Keiichi Fujiwara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan
| | - Osamu Yokosuka
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan
| | - Ryosuke Suzuki
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Koji Ishii
- Department of Quality Assurance and Radiological Protection, National Institute of Infectious Diseases, Tokyo, Japan
| | - Hiroshi Yotsuyanagi
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
- Department of Infectious Diseases and Applied Immunology, Hospital of the Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Hiroaki Okamoto
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan
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Orozco-Cordoba J, Mazas C, Du Pont G, Lamoyi E, Cárdenas G, Fierro NA. Viral Biology and Immune Privilege in the Development of Extrahepatic Manifestations During Hepatitis E Virus Infection. Viral Immunol 2023; 36:627-641. [PMID: 38064537 DOI: 10.1089/vim.2023.0096] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2023] Open
Abstract
Hepatitis E virus (HEV) exhibits tropism toward hepatocytes and thus affects the liver; however, HEV may also affect other tissues, including the heart, kidneys, intestines, testicles, and central nervous system. To date, the pathophysiological links between HEV infection and extrahepatic manifestations have not yet been established. Considering that HEV infects multiple types of cells, the direct effects of virus replication in peripheral tissues represent a plausible explanation for extrahepatic manifestations. In addition, since the immune response is crucial in the development of the disease, the immune characteristics of affected tissues should be revisited to identify commonalities explaining the effects of the virus. This review summarizes the most recent advances in understanding the virus biology and immune-privileged status of specific tissues as major elements for HEV replication in diverse organs. These discoveries may open avenues to explain the multiple extrahepatic manifestations associated with HEV infection and ultimately to design effective strategies for infection control.
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Affiliation(s)
- Javier Orozco-Cordoba
- Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad Universitaria, Mexico City, Mexico
| | - Camila Mazas
- Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad Universitaria, Mexico City, Mexico
| | - Gisela Du Pont
- Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad Universitaria, Mexico City, Mexico
| | - Edmundo Lamoyi
- Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad Universitaria, Mexico City, Mexico
| | - Graciela Cárdenas
- Departamento de Neuroinfectología, Instituto Nacional de Neurología Manuel Velasco Suárez, Mexico City, Mexico
| | - Nora A Fierro
- Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad Universitaria, Mexico City, Mexico
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Takanohashi S, Sugiura T, Koyano A, Ueno T, Rachi H, Shiratori K, Shimasaki M, Igarashi H, Kitayama Y, Togawa A. Complete remission of primary membranous nephropathy following hepatitis E infection. CEN Case Rep 2023; 12:384-389. [PMID: 36864232 PMCID: PMC10620352 DOI: 10.1007/s13730-023-00780-z] [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: 12/28/2022] [Accepted: 02/21/2023] [Indexed: 03/04/2023] Open
Abstract
Primary membranous nephropathy (PMN) is a major cause of nephrotic syndrome in adults. Studies have shown that one-third of PMN cases undergo spontaneous remission, among which are some cases of infection-related complete remission. Herein, we report the case of a 57-year-old man who achieved complete remission of PMN shortly after the onset of acute hepatitis E infection. At the age of 55 years, the patient developed a nephrotic syndrome, and renal biopsy revealed membranous nephropathy, Ehrenreich-Churg stage 1. Treatment with prednisolone (PSL) reduced urinary protein from 7.8 g/gCre to approximately 1 g/gCre but did not lead to complete remission. However, 7 months after starting treatment, he developed an acute hepatitis E infection after consuming wild boar meat. Immediately after the onset of acute hepatitis E, the patient's urinary protein levels decreased to < 0.3 g/gCre. The PSL dose was subsequently reduced and discontinued after 2 years and 8 months, and complete remission was maintained thereafter. We considered that an increase in the number of regulatory T cells (Tregs) caused by acute hepatitis E infection was associated with PMN remission in this patient.
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Affiliation(s)
- Seiko Takanohashi
- Department of Nephrology, Shizuoka Saiseikai General Hospital, 1-1-1 Oshika, Suruga-Ku, Shizuoka, Shizuoka, 431-3192, Japan
| | - Takuya Sugiura
- Department of Nephrology, Shizuoka Saiseikai General Hospital, 1-1-1 Oshika, Suruga-Ku, Shizuoka, Shizuoka, 431-3192, Japan
| | - Akane Koyano
- Department of Nephrology, Shizuoka Saiseikai General Hospital, 1-1-1 Oshika, Suruga-Ku, Shizuoka, Shizuoka, 431-3192, Japan
| | - Tomoko Ueno
- Department of Nephrology, Shizuoka Saiseikai General Hospital, 1-1-1 Oshika, Suruga-Ku, Shizuoka, Shizuoka, 431-3192, Japan
| | - Hiromu Rachi
- Department of Nephrology, Shizuoka Saiseikai General Hospital, 1-1-1 Oshika, Suruga-Ku, Shizuoka, Shizuoka, 431-3192, Japan
| | - Kimitoshi Shiratori
- Department of Nephrology, Shizuoka Saiseikai General Hospital, 1-1-1 Oshika, Suruga-Ku, Shizuoka, Shizuoka, 431-3192, Japan
| | - Megumi Shimasaki
- Department of Nephrology, Shizuoka Saiseikai General Hospital, 1-1-1 Oshika, Suruga-Ku, Shizuoka, Shizuoka, 431-3192, Japan
| | - Hisaki Igarashi
- Department of Pathology, Shizuoka Saiseikai General Hospital, 1-1-1 Oshika, Suruga-Ku, Shizuoka, Shizuoka, 431-3192, Japan
| | - Yasuhiko Kitayama
- Department of Pathology, Shizuoka Saiseikai General Hospital, 1-1-1 Oshika, Suruga-Ku, Shizuoka, Shizuoka, 431-3192, Japan
| | - Akashi Togawa
- Department of Nephrology, Shizuoka Saiseikai General Hospital, 1-1-1 Oshika, Suruga-Ku, Shizuoka, Shizuoka, 431-3192, Japan.
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Kosuta I, Ostojic A, Vujaklija Brajkovic A, Babel J, Simunov B, Sremac M, Mrzljak A. Shifting perspectives in liver diseases after kidney transplantation. World J Hepatol 2023; 15:883-896. [PMID: 37547033 PMCID: PMC10401415 DOI: 10.4254/wjh.v15.i7.883] [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: 03/26/2023] [Revised: 05/15/2023] [Accepted: 06/06/2023] [Indexed: 07/21/2023] Open
Abstract
Liver diseases after kidney transplantation range from mild biochemical abnormalities to severe hepatitis or cirrhosis. The causes are diverse and mainly associated with hepatotropic viruses, drug toxicity and metabolic disorders. Over the past decade, the aetiology of liver disease in kidney recipients has changed significantly. These relates to the use of direct-acting antiviral agents against hepatitis C virus, the increasing availability of vaccination against hepatitis B and a better understanding of drug-induced hepatotoxicity. In addition, the emergence of the severe acute respiratory syndrome coronavirus 2 pandemic has brought new challenges to kidney recipients. This review aims to provide healthcare professionals with a comprehensive understanding of recent advances in the management of liver complications in kidney recipients and to enable them to make informed decisions regarding the risks and impact of liver disease in this population.
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Affiliation(s)
- Iva Kosuta
- Department of Intensive Care Medicine, University Hospital Centre Zagreb, Zagreb 10000, Croatia.
| | - Ana Ostojic
- Department of Gastroenterology and Hepatology, Liver Transplant Center, University Hospital Centre Zagreb, Zagreb 10000, Croatia
| | - Ana Vujaklija Brajkovic
- Department of Intensive Care Medicine, University Hospital Centre Zagreb, Zagreb 10000, Croatia
- School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Jaksa Babel
- Department of Intensive Care Medicine, University Hospital Centre Zagreb, Zagreb 10000, Croatia
| | - Bojana Simunov
- Department of Nephrology, University Hospital Merkur, Zagreb 10000, Croatia
| | - Maja Sremac
- Department of Gastroenterology and Hepatology, Liver Transplant Center, University Hospital Centre Zagreb, Zagreb 10000, Croatia
| | - Anna Mrzljak
- Department of Gastroenterology and Hepatology, Liver Transplant Center, University Hospital Centre Zagreb, Zagreb 10000, Croatia
- School of Medicine, University of Zagreb, Zagreb 10000, Croatia
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El-Mokhtar MA, Kamel AM, El-Sabaa EMW, Mandour SA, Abdelmohsen AS, Moussa AM, Salama EH, Aboulfotuh S, Abdel-Wahid L, Abdel Aziz EM, Azoz NMA, Sayed IM, Elkhawaga AA. Evidence of a Link between Hepatitis E Virus Exposure and Glomerulonephritis Development. Viruses 2023; 15:1379. [PMID: 37376678 DOI: 10.3390/v15061379] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 06/07/2023] [Accepted: 06/08/2023] [Indexed: 06/29/2023] Open
Abstract
Viruses can trigger glomerulonephritis (GN) development. Hepatitis viruses, especially Hepatitis C virus and Hepatitis B viruses, are examples of the viruses that trigger GN initiation or progression. However, the proof of a correlation between GN and Hepatitis E virus infection is not clear. Some studies confirmed the development of GN during acute or chronic HEV infections, mainly caused by genotype 3. While others reported that there is no relation between HEV exposure and GN development. A recent study showed that a reduced glomerular filtration rate was developed in 16% of acute HEV genotype 1 (HEV-1) infections that returned to normal during recovery. HEV-1 is endemic in Egypt with a high seroprevalence among villagers and pregnant women. There is no available data about a link between HEV and GN in Egypt. METHODS GN patients (n = 43) and matched healthy subjects (n = 36) enrolled in Assiut University hospitals were included in this study. Blood samples were screened for hepatotropic pathogens. Tests for HEV markers such as HEV RNA and anti-HEV antibodies (IgM and IgG) were performed. Laboratory parameters were compared in HEV-seropositive and HEV-seronegative GN patients. RESULTS Anti-HEV IgG was detected in 26 (60.5%) out of 43 GN patients. HEV seroprevalence was significantly higher in GN than in healthy controls, suggesting that HEV exposure is a risk factor for GN development. None of the GN patients nor the healthy subjects were positive for anti-HEV IgM or HEV RNA. There was no significant difference between seropositive and seronegative GN patients in terms of age, gender, albumin, kidney function profiles, or liver transaminases. However, anti-HEV IgG positive GN patients had higher bilirubin levels than anti-HEV IgG negative GN patients. HEV-seropositive GN patients had a significantly elevated AST level compared to HEV-seropositive healthy subjects. CONCLUSION exposure to HEV infection could be complicated by the development of GN.
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Affiliation(s)
- Mohamed A El-Mokhtar
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
| | - Ayat M Kamel
- Microbiology and Immunology Department, Faculty of Pharmacy, Assiut University, Assiut 71515, Egypt
| | - Ehsan M W El-Sabaa
- Microbiology and Immunology Department, Faculty of Pharmacy, Assiut University, Assiut 71515, Egypt
| | - Sahar A Mandour
- Department of Microbiology and Immunology, Faculty of Pharmacy, Deraya University, Minia 11566, Egypt
| | - Ahmed Shawkat Abdelmohsen
- Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
| | - Abdelmajeed M Moussa
- Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Aswan University, Aswan 81528, Egypt
| | - Eman H Salama
- Department of Clinical Pathology, Faculty of Medicine, Sohag University, Sohag 82524, Egypt
| | - Sahar Aboulfotuh
- Department of Clinical Pathology, Faculty of Medicine, Sohag University, Sohag 82524, Egypt
| | - Lobna Abdel-Wahid
- Gastroenterology and Hepatology Unit, Internal Medicine Department, Assiut University, Assiut 71515, Egypt
| | - Essam M Abdel Aziz
- Department of Internal Medicine, Nephrology Division, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
| | - Nashwa Mostafa A Azoz
- Department of Internal Medicine, Nephrology Division, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
| | - Ibrahim M Sayed
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
| | - Amal A Elkhawaga
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
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Takakusagi S, Kakizaki S, Takagi H. The Diagnosis, Pathophysiology, and Treatment of Chronic Hepatitis E Virus Infection-A Condition Affecting Immunocompromised Patients. Microorganisms 2023; 11:1303. [PMID: 37317277 PMCID: PMC10220693 DOI: 10.3390/microorganisms11051303] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/01/2023] [Accepted: 05/13/2023] [Indexed: 06/16/2023] Open
Abstract
Hepatitis E is a zoonosis caused by hepatitis E virus (HEV), which was first discovered 40 years ago. Twenty million HEV infections worldwide are estimated each year. Most hepatitis E cases are self-limiting acute hepatitis, but the virus has been recognized to cause chronic hepatitis. Following the first case report of chronic hepatitis E (CHE) in a transplant recipient, CHE has recently been identified as associated with chronic liver damage induced by HEV genotypes 3, 4, and 7-usually in immunocompromised patients such as transplant recipients. In addition, patients infected with HIV and those receiving chemotherapy for malignancy, along with patients with rheumatic disease and COVID-19, have recently been reported as having CHE. CHE can be easily misdiagnosed by usual diagnostic methods of antibody response, such as anti-HEV IgM or IgA, because of the low antibody response in the immunosuppressive condition. HEV RNA should be evaluated in these patients, and appropriate treatments-such as ribavirin-should be given to prevent progression to liver cirrhosis or liver failure. While still rare, cases of CHE in immunocompetent patients have been reported, and care must be taken not to overlook these instances. Herein, we conduct an overview of hepatitis E, including recent research developments and management of CHE, in order to improve our understanding of such cases. The early diagnosis and treatment of CHE should be performed to decrease instances of hepatitis-virus-related deaths around the world.
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Affiliation(s)
- Satoshi Takakusagi
- Department of Gastroenterology and Hepatology, Kusunoki Hospital, 607-22 Fujioka, Fujioka 375-0024, Gunma, Japan;
| | - Satoru Kakizaki
- Department of Clinical Research, National Hospital Organization Takasaki General Medical Center, 36 Takamatsu-cho, Takasaki 370-0829, Gunma, Japan
| | - Hitoshi Takagi
- Department of Gastroenterology and Hepatology, Kusunoki Hospital, 607-22 Fujioka, Fujioka 375-0024, Gunma, Japan;
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Virus-Associated Nephropathies: A Narrative Review. Int J Mol Sci 2022; 23:ijms231912014. [PMID: 36233315 PMCID: PMC9569621 DOI: 10.3390/ijms231912014] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 09/23/2022] [Accepted: 10/06/2022] [Indexed: 12/13/2022] Open
Abstract
While most viral infections cause mild symptoms and a spontaneous favorable resolution, some can lead to severe or protracted manifestations, specifically in immunocompromised hosts. Kidney injuries related to viral infections may have multiple causes related to the infection severity, drug toxicity or direct or indirect viral-associated nephropathy. We review here the described virus-associated nephropathies in order to guide diagnosis strategies and treatments in cases of acute kidney injury (AKI) occurring concomitantly with a viral infection. The occurrence of virus-associated nephropathy depends on multiple factors: the local epidemiology of the virus, its ability to infect renal cells and the patient's underlying immune response, which varies with the state of immunosuppression. Clear comprehension of pathophysiological mechanisms associated with a summary of described direct and indirect injuries should help physicians to diagnose and treat viral associated nephropathies.
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9
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Unmet Needs for the Treatment of Chronic Hepatitis E Virus Infection in Immunocompromised Patients. Viruses 2022; 14:v14102116. [PMID: 36298671 PMCID: PMC9611326 DOI: 10.3390/v14102116] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 09/20/2022] [Accepted: 09/22/2022] [Indexed: 11/17/2022] Open
Abstract
Hepatitis E virus (HEV) is the most prevalent hepatitis virus worldwide. Genotypes 3 (HEV3) and 4 (HEV4) as well as rat HEV can lead to chronic hepatitis E and cirrhosis in immunosuppressed patients. Within the last decade, several options for treating chronic hepatitis have been developed and have achieved a sustained virological response. However, there are still unmet needs such as optimizing immunosuppression to allow HEV clearance with or without ribavirin, as well as alternative therapies to ribavirin that are discussed in this paper.
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10
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Ying D, He Q, Tian W, Chen Y, Zhang X, Wang S, Liu C, Chen Z, Liu Y, Fu L, Yan L, Wang L, Tang Z, Wang L, Zheng Z, Xia N. Urine is a viral antigen reservoir in hepatitis E virus infection. Hepatology 2022; 77:1722-1734. [PMID: 36106666 DOI: 10.1002/hep.32745] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 08/16/2022] [Accepted: 08/18/2022] [Indexed: 12/08/2022]
Abstract
BACKGROUND AND AIMS HEV ORF2 antigen (Ag) in serum has become a tool for diagnosing current HEV infection. Particularly, urinary shedding of HEV Ag has been gaining increasing interest. We aim to uncover the origin, antigenicity, diagnostic performance, and diagnostic significance of Ag in urine in HEV infection. APPROACH AND RESULTS Clinical serum and urine samples from patients with acute and chronic HEV infection were analyzed for their Ag levels. Ag in urine was analyzed by biochemical and proteomic approaches. The origin of urinary Ag and Ag kinetics during HEV infection was investigated in mouse and rabbit models, respectively. We found that both the Ag level and diagnostic sensitivity in urine were higher than in serum. Antigenic protein in urine was an E2s-like dimer spanning amino acids 453-606. pORF2 entered urine from serum in mice i.v. injected with pORF2. Ag in urine originated from the secreted form of pORF2 (ORF2S ) that abundantly existed in hepatitis E patients' serum. HEV Ag was specifically taken up by renal cells and was disposed into urine, during which the level of Ag was concentrated >10-fold, resulting in the higher diagnosing sensitivity of urine Ag than serum Ag. Moreover, Ag in urine appeared 6 days earlier, lasted longer than viremia and antigenemia, and showed good concordance with fecal RNA in a rabbit model. CONCLUSIONS Our findings demonstrated the origin and diagnostic value of urine Ag and provided insights into the disposal of exogenous protein of pathogens by the host kidney.
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Affiliation(s)
- Dong Ying
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, PR China
| | - Qiyu He
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, PR China
| | - Weikun Tian
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, PR China
| | - Yanling Chen
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, PR China
| | - Xiaoping Zhang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, PR China
| | - Siling Wang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, PR China
| | - Chang Liu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, PR China
| | - Zihao Chen
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, PR China
| | - Yu Liu
- Department of Severe Hepatopathy, Shanghai Public Health Clinical Center, Fudan University, Shanghai, PR China
| | - Lijuan Fu
- Department of Infectious Disease, Xiang'an Hospital of Xiamen University, Xiamen, PR China
| | - Li Yan
- Department of Severe Hepatopathy, Shanghai Public Health Clinical Center, Fudan University, Shanghai, PR China
| | - Ling Wang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, PR China
| | - Zimin Tang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, PR China.,NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, School of Public Health, Xiamen University, Xiamen, PR China
| | - Lin Wang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, PR China
| | - Zizheng Zheng
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, PR China
| | - Ningshao Xia
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, PR China
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11
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Darji PI, Patel HA, Darji BP, Sharma A, Halawa A. Is de novo membranous nephropathy suggestive of alloimmunity in renal transplantation? A case report. World J Transplant 2022; 12:15-20. [PMID: 35096553 PMCID: PMC8771595 DOI: 10.5500/wjt.v12.i1.15] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 12/08/2021] [Accepted: 01/06/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Post-transplant nephrotic syndrome (PTNS) in a renal allograft carries a 48% to 77% risk of graft failure at 5 years if proteinuria persists. PTNS can be due to either recurrence of native renal disease or de novo glomerular disease. Its prognosis depends upon the underlying pathophysiology. We describe a case of post-transplant membranous nephropathy (MN) that developed 3 mo after kidney transplant. The patient was properly evaluated for pathophysiology, which helped in the management of the case.
CASE SUMMARY This 22-year-old patient had chronic pyelonephritis. He received a living donor kidney, and human leukocyte antigen-DR (HLA-DR) mismatching was zero. PTNS was discovered at the follow-up visit 3 mo after the transplant. Graft histopathology was suggestive of MN. In the past antibody-mediated rejection (ABMR) might have been misinterpreted as de novo MN due to the lack of technologies available to make an accurate diagnosis. Some researchers have observed that HLA-DR is present on podocytes causing an anti-DR antibody deposition and development of de novo MN. They also reported poor prognosis in their series. Here, we excluded the secondary causes of MN. Immunohistochemistry was suggestive of IgG1 deposits that favoured the diagnosis of de novo MN. The patient responded well to an increase in the dose of tacrolimus and angiotensin converting enzyme inhibitor.
CONCLUSION Exposure of hidden antigens on the podocytes in allografts may have led to subepithelial antibody deposition causing de novo MN.
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Affiliation(s)
- Prakash I Darji
- Department of Nephrology and Renal Transplantation, Zydus Hospitals, Ahmedabad 380059, Gujarat, India
| | - Himanshu A Patel
- Department of Nephrology and Renal Transplantation, Zydus Hospitals, Ahmedabad 380059, Gujarat, India
| | - Bhavya P Darji
- Internship, Department of Medicine, GCS Medical College, Hospital and Research Centre, Ahmedabad 380025, Gujarat, India
| | - Ajay Sharma
- Faculty of Health and Life Science, Institute of Learning and Teaching, University of Liverpool, Liverpool L69 3BX, United Kingdom
- Consultant Transplant Surgeon, Royal Liverpool University Hospitals, Liverpool L7 8XP, United Kingdom
| | - Ahmed Halawa
- Faculty of Health and Life Science, Institute of Learning and Teaching, University of Liverpool, Liverpool L69 3BX, United Kingdom
- Department of Transplantation, Sheffield Teaching Hospitals, Sheffield S10 2JF, United Kingdom
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12
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Wu J, Shi C, Sheng X, Xu Y, Zhang J, Zhao X, Yu J, Shi X, Li G, Cao H, Li L. Prognostic Nomogram for Patients with Hepatitis E Virus-related Acute Liver Failure: A Multicenter Study in China. J Clin Transl Hepatol 2021; 9:828-837. [PMID: 34966646 PMCID: PMC8666371 DOI: 10.14218/jcth.2020.00117] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 03/14/2021] [Accepted: 04/16/2021] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND AND AIMS Timely and effective assessment scoring systems for predicting the mortality of patients with hepatitis E virus-related acute liver failure (HEV-ALF) are urgently needed. The present study aimed to establish an effective nomogram for predicting the mortality of HEV-ALF patients. METHODS The nomogram was based on a cross-sectional set of 404 HEV-ALF patients who were identified and enrolled from a cohort of 650 patients with liver failure. To compare the performance with that of the model for end-stage liver disease (MELD) scoring and CLIF-Consortium-acute-on-chronic liver failure score (CLIF-C-ACLFs) models, we assessed the predictive accuracy of the nomogram using the concordance index (C-index), and its discriminative ability using time-dependent receiver operating characteristics (td-ROC) analysis, respectively. RESULTS Multivariate logistic regression analysis of the development set carried out to predict mortality revealed that γ-glutamyl transpeptidase, albumin, total bilirubin, urea nitrogen, creatinine, international normalized ratio, and neutrophil-to-lymphocyte ratio were independent factors, all of which were incorporated into the new nomogram to predict the mortality of HEV-ALF patients. The area under the curve of this nomogram for mortality prediction was 0.671 (95% confidence interval: 0.602-0.740), which was higher than that of the MELD and CLIF-C-ACLFs models. Moreover, the td-ROC and decision curves analysis showed that both discriminative ability and threshold probabilities of the nomogram were superior to those of the MELD and CLIF-C-ACLFs models. A similar trend was observed in the validation set. CONCLUSIONS The novel nomogram is an accurate and efficient mortality prediction method for HEV-ALF patients.
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Affiliation(s)
- Jian Wu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Department of Laboratory Medicine, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Cuifen Shi
- Department of Infectious Disease, The Second People’s Hospital of Yancheng City, Yancheng, Jiangsu, China
| | - Xinyu Sheng
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yanping Xu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jinrong Zhang
- Department of Laboratory Medicine, The People’s Hospital of Dafeng City, Yancheng, Jiangsu, China
| | - Xinguo Zhao
- Department of Respiration, The Fifth People’s Hospital of Wuxi, Wuxi, Jiangsu, China
| | - Jiong Yu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Xinhui Shi
- Department of Laboratory Medicine, The First People’s Hospital of Yancheng City, Yancheng, Jiangsu, China
| | - Gongqi Li
- Department of Clinical Laboratory, Linyi Traditional Hospital, Linyi, Shandong, China
| | - Hongcui Cao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory for Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases, Hangzhou, Zhejiang, China
| | - Lanjuan Li
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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13
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Wasuwanich P, Sirisreetreerux P, Ingviya T, Kraus ES, Brennan DC, Sue PK, Jackson AM, Oshima K, Philosophe B, Montgomery RA, Karnsakul W. Hepatitis E virus infection and rejection in kidney transplant recipients. Transpl Immunol 2021; 70:101517. [PMID: 34923120 DOI: 10.1016/j.trim.2021.101517] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 12/10/2021] [Accepted: 12/12/2021] [Indexed: 12/27/2022]
Abstract
BACKGROUND Hepatitis E virus (HEV) infection has been associated with immune-mediated kidney diseases in developing countries. However, its relationship with kidney transplant outcomes has never been studied. We investigated the association between HEV infection and kidney graft rejection among kidney transplant recipients (KTRs). METHODS We conducted a matched cohort and longitudinal study utilizing banked sera following kidney transplantation during 1988-2012. Studies with evidence of post-transplantation HEV infection were identified by positive ELISA tests (anti-HEV IgM or anti-HEV IgG seroconversion) or positive HEV PCR and matched to KTR controls with negative HEV ELISA and PCR tests in a 1:5 ratio by age, sex, crossmatch status, immunosuppression era, and time of HEV testing. Outcome data collected included time to first kidney graft rejection, transaminases, and glomerular filtration rates. Log-ranked test was used to analyze survival. RESULTS Of 271 KTRs, 9 (3%) had evidence of post-transplantation HEV infection and were compared to 45 negative, matched controls. Median age at transplantation was 46 years. Kidney graft rejection was reported in 8 (89%) of cases and 21 (47%) of controls. Median time to first episode of kidney graft rejection was 17.4 months in cases and 30.8 months in controls (p = 0.029), with a higher hazard of developing kidney graft rejection in cases (HR = 3.23, 95% CI: 1.19-8.79). Lower mean glomerular filtration rates over time were observed in cases (35 mL/min/1.73m2) versus controls (42.4 mL/min/1.73m2) but did not reach significance (p = 0.24). CONCLUSION Subjects with evidence of post-transplantation HEV infection demonstrated earlier kidney graft rejection compared to controls.
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Affiliation(s)
- Paul Wasuwanich
- Division of Pediatric Gastroenterology, Nutrition, and Hepatology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | - Thammasin Ingviya
- Department of Environmental Health Sciences, Johns Hopkins University, Baltimore, MD, USA; Department of Family and Preventive Medicine, Prince of Songkla University, Songkhla, Thailand
| | - Edward S Kraus
- Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Daniel C Brennan
- Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Paul K Sue
- Division of Pediatric Infectious Diseases, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Annette M Jackson
- Departments of Surgery and Immunology, Duke University, Durham, NC, USA
| | - Kiyoko Oshima
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Benjamin Philosophe
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Robert A Montgomery
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA; NYU Langone Transplant Institute, New York University Langone Health, New York, NY, USA
| | - Wikrom Karnsakul
- Division of Pediatric Gastroenterology, Nutrition, and Hepatology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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14
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Wu J, Xiang Z, Zhu C, Yao Y, Bortolanza M, Cao H, Li L. Extrahepatic manifestations related to hepatitis E virus infection and their triggering mechanisms. J Infect 2021; 83:298-305. [PMID: 34324940 DOI: 10.1016/j.jinf.2021.07.021] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Revised: 07/20/2021] [Accepted: 07/22/2021] [Indexed: 02/07/2023]
Abstract
Hepatitis E virus (HEV) infection has many extrahepatic manifestations as well as liver symptoms. Multiple studies have shown that HEV infection has symptoms related to the nervous system, kidneys, cryoglobulinemia, hematological system, reproductive system, autoimmunity and pancreas. Hence, HEV infection should be considered as a systemic disease, rather than solely a liver disease. The extrahepatic manifestations induced by different genotypes of HEV vary. The severity of these diseases does not necessarily correlate with the severity of HEV infection, and even asymptomatic HEV infection may trigger and cause systemic diseases. Patients with systemic manifestations of HEV infection should have priority for antiviral therapy, which could alleviate or improve the extrahepatic manifestations related to HEV infection. However, the extrahepatic manifestations caused by different genotypes of HEV and their corresponding mechanisms have not been clearly identified. This review discusses the extrahepatic manifestations related to HEV infection and their triggering mechanisms.
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Affiliation(s)
- Jian Wu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China; Department of Clinical Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, 242 Guangji Rd., Suzhou 215008, China
| | - Ze Xiang
- Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Chunxia Zhu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - Yiwen Yao
- Department of Internal Medicine V-Pulmonology, Allergology, Respiratory Intensive Care Medicine, Saarland University Hospital, Homburg 66424, Germany
| | - Mariza Bortolanza
- Department of Internal Medicine V-Pulmonology, Allergology, Respiratory Intensive Care Medicine, Saarland University Hospital, Homburg 66424, Germany
| | - Hongcui Cao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China; Zhejiang Provincial Key Laboratory for Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases, 79 Qingchun Rd, Hangzhou 310003, China.
| | - Lanjuan Li
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
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15
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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: 110] [Impact Index Per Article: 22.0] [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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16
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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: 33] [Impact Index Per Article: 6.6] [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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17
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Uncovering the Roles of miR-214 in Hepatitis E Virus Replication. J Mol Biol 2020; 432:5322-5342. [PMID: 32735806 DOI: 10.1016/j.jmb.2020.07.015] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 07/15/2020] [Accepted: 07/22/2020] [Indexed: 12/11/2022]
Abstract
Viral pathogenesis is a complex event and its regulation involve dynamic interactions with various host factors, of which microRNAs are the key players. In the current study, we have identified the functional importance of an interplay between hepatitis E virus (HEV) and miR-214. Computational analysis indicated that miR-214 binding site is significantly conserved among HEV and related RNA viruses. Intact miR-214 binding site is imperative for HEV replication. miR-214 is an essential host factor for HEV replication. Herein, we demonstrate that miR-214 interacts directly with HEV RNA to enhance HEV replication and HEV genome translation. Augmented translation results in increased levels of HEV ORF2, which is a factor responsible for upregulation of miR-214. HEV usurps host cellular machinery for improving viral fitness and elevates miR-214 expression for amplifying the expression of proviral host factor intracellular active thrombin. This is because miR-214 represses the expression of the negative regulator of thrombin, i.e., protein C. Another viral factor, HEV ORF3, also contributes to the enhancement of intracellular active thrombin. Furthermore, miR-214 directly targets antiviral host factor 2'-5'-oligoadenylate synthetase. Conclusively, we identified a novel mechanism of positive regulation of HEV replication. miR-214 interacts directly with HEV genome and fine-tunes host factors expression. This results in outweighing the proviral factors on the proviral-antiviral axis probably for generating virus supportive environment.
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18
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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: 85] [Impact Index Per Article: 17.0] [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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19
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Fousekis FS, Mitselos IV, Christodoulou DK. Extrahepatic manifestations of hepatitis E virus: An overview. Clin Mol Hepatol 2019; 26:16-23. [PMID: 31601068 PMCID: PMC6940480 DOI: 10.3350/cmh.2019.0082] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 09/16/2019] [Indexed: 12/14/2022] Open
Abstract
Hepatitis E virus (HEV) is a significant health problem with approximately 20 million individuals infected annually. HEV infection has been associated with a wide spectrum of extrahepatic manifestations, including neurological, hematological and renal disorders. Guillain-Barré syndrome and neuralgic amyotrophy are the most frequent neurological manifestations. In addition, HEV infection has been observed with other neurological diseases, such as encephalitis, myelitis and Bell’s palsy. Hematologic manifestations include anemia due to glucose-6-phospate dehydrogonase deficiency, autoimmune hemolytic anemia and severe thrombocytopenia. Membranoproliferative glomerulonephritis and relapse IgA nephropathy with or without coexisting cryoglobulinemia appear to be the most common renal injuries related with HEV infection. Also, HEV infection has been associated with acute pancreatitis and other immune-mediated manifestations, such as arthritis and myocarditis. However, the pathophysiologic mechanisms of HEV-related extrahepatic manifestations are still largely unclear.
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Affiliation(s)
- Fotios S Fousekis
- Department of Gastroenterology and Hepatology, University Hospital of Ioannina, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Ioannis V Mitselos
- Department of Gastroenterology and Hepatology, University Hospital of Ioannina, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Dimitrios K Christodoulou
- Department of Gastroenterology and Hepatology, University Hospital of Ioannina, School of Health Sciences, University of Ioannina, Ioannina, Greece
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20
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Hartard C, Gantzer C, Bronowicki JP, Schvoerer E. Emerging hepatitis E virus compared with hepatitis A virus: A new sanitary challenge. Rev Med Virol 2019; 29:e2078. [PMID: 31456241 DOI: 10.1002/rmv.2078] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2019] [Revised: 07/19/2019] [Accepted: 07/22/2019] [Indexed: 12/21/2022]
Abstract
Hepatitis A (HAV) and E (HEV) viruses are able to cause liver disease in humans. Among the five classical hepatotropic viruses, they are mainly transmitted via the fecal-oral route. Historically, many similarities have thus been described between them according to their incidence and their pathogenicity, especially in countries with poor sanitary conditions. However, recent advances have provided new insights, and the gap is widening between them. Indeed, while HAV infection incidence tends to decrease in developed countries along with public health improvement, HEV is currently considered as an underdiagnosed emerging pathogen. HEV autochthonous infections are increasingly observed and are mainly associated with zoonotic transmissions. Extra hepatic signs resulting in neurological or renal impairments have also been reported for HEV, as well as a chronic carrier state in immunocompromised patients, arguing in favor of differential pathogenesis between those two viruses. Recent molecular tools have allowed studies of viral genome variability and investigation of links between viral plasticity and clinical evolution. The identification of key functional mutations in viral genomes may improve the knowledge of their clinical impact and is analyzed in depth in the present review.
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Affiliation(s)
- Cédric Hartard
- Laboratoire de Virologie, CHRU de Nancy Brabois, Vandœuvre-lès-Nancy, France.,Laboratoire de Chimie Physique et Microbiologie pour les Matériaux et l'Environnement (LCPME), UMR 7564, Vandoeuvre-lès-Nancy, France.,CNRS, LCPME UMR 7564, Nancy, France.,Faculté des Sciences et Technologies, Institut Jean Barriol, Université de Lorraine, Vandœuvre-lès-Nancy, France
| | - Christophe Gantzer
- Laboratoire de Chimie Physique et Microbiologie pour les Matériaux et l'Environnement (LCPME), UMR 7564, Vandoeuvre-lès-Nancy, France.,CNRS, LCPME UMR 7564, Nancy, France.,Faculté des Sciences et Technologies, Institut Jean Barriol, Université de Lorraine, Vandœuvre-lès-Nancy, France
| | | | - Evelyne Schvoerer
- Laboratoire de Virologie, CHRU de Nancy Brabois, Vandœuvre-lès-Nancy, France.,Laboratoire de Chimie Physique et Microbiologie pour les Matériaux et l'Environnement (LCPME), UMR 7564, Vandoeuvre-lès-Nancy, France.,CNRS, LCPME UMR 7564, Nancy, France.,Faculté des Sciences et Technologies, Institut Jean Barriol, Université de Lorraine, Vandœuvre-lès-Nancy, France
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21
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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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22
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Lhomme S, Legrand-Abravanel F, Kamar N, Izopet J. Screening, diagnosis and risks associated with Hepatitis E virus infection. Expert Rev Anti Infect Ther 2019; 17:403-418. [DOI: 10.1080/14787210.2019.1613889] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Sébastien Lhomme
- Department of Virology, National reference center for Hepatitis E Virus, CHU Purpan, Toulouse, France
- Inserm UMR1043, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France
- Université de Toulouse, Toulouse III, Toulouse, France
| | - Florence Legrand-Abravanel
- Department of Virology, National reference center for Hepatitis E Virus, CHU Purpan, Toulouse, France
- Inserm UMR1043, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France
- Université de Toulouse, Toulouse III, Toulouse, France
| | - Nassim Kamar
- Inserm UMR1043, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France
- Université de Toulouse, Toulouse III, Toulouse, France
- Department of Nephrology and Organs Transplantation, CHU Rangueil, Toulouse, France
| | - Jacques Izopet
- Department of Virology, National reference center for Hepatitis E Virus, CHU Purpan, Toulouse, France
- Inserm UMR1043, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France
- Université de Toulouse, Toulouse III, Toulouse, France
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23
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Transmission of a Novel Genotype of Hepatitis E Virus from Bactrian Camels to Cynomolgus Macaques. J Virol 2019; 93:JVI.02014-18. [PMID: 30700602 DOI: 10.1128/jvi.02014-18] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Accepted: 01/18/2019] [Indexed: 12/15/2022] Open
Abstract
Hepatitis E virus (HEV) is zoonotic and a major cause of acute viral hepatitis worldwide. Recently, we identified a novel HEV genotype 8 (HEV8) in Bactrian camels in Xinjiang, China. However, the epidemiology, pathogenicity, and zoonotic potential of HEV8 are unclear. Here, we present the prevalence of HEV8 in China and investigate its pathogenicity and cross-species transmission in cynomolgus macaques. Fresh fecal and milk samples from Bactrian camels collected from four provinces/regions in China were screened for HEV RNA by reverse transcriptase PCR (RT-PCR). An HEV8-positive sample was used to inoculate two cynomolgus macaques to examine the potential for cross-species infection. The pathogenicity of HEV8 was analyzed by testing HEV markers and liver function during the study period and histopathology of liver biopsy specimens at 3, 13, and 25 weeks postinoculation. Extrahepatic replication was tested by using reverse transcriptase quantitative PCR (RT-qPCR) and immunofluorescence assays. The overall prevalence of HEV8 RNA in Chinese Bactrian camels was 1.4% (4/295), and positive samples were found in three different provinces/regions in China. Histopathology confirmed acute and chronic HEV8 infections in the two monkeys. Multiple tissues were positive for HEV RNA and ORF2 proteins. Renal pathology was observed in the monkey with chronic hepatitis. Whole-genome sequencing showed only 1 to 3 mutations in the HEV8 in the fecal samples from the two monkeys compared to that from the camel. HEV8 is circulating in multiple regions in China. Infection of two monkeys with HEV8 induced chronic and systemic infections, demonstrating the high potential zoonotic risk of HEV8.IMPORTANCE It is estimated that one-third of the world population have been exposed to hepatitis E virus (HEV). In developed countries and China, zoonotic HEV strains are responsible for almost all acute and chronic HEV infection cases. It is always of immediate interest to investigate the zoonotic potential of novel HEV strains. In 2016, we discovered a novel HEV genotype, HEV8, in Bactrian camels, but the epidemiology, zoonotic potential, and pathogenicity of the virus were unknown. In the present study, we demonstrated that HEV8 was circulating in multiple regions in China and was capable of infecting cynomolgus macaques, a surrogate for humans, posing high risk of zoonosis. Chronic hepatitis, systemic infection, and renal pathology were observed. Collectively, these data indicate that HEV8 exhibits a high potential for zoonotic transmission. Considering the importance of Bactrian camels as livestock animals, risk groups, such as camelid meat and milk consumers, should be screened for HEV8 infection.
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24
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Marion O, Capelli N, Lhomme S, Dubois M, Pucelle M, Abravanel F, Kamar N, Izopet J. Hepatitis E virus genotype 3 and capsid protein in the blood and urine of immunocompromised patients. J Infect 2019; 78:232-240. [PMID: 30659856 DOI: 10.1016/j.jinf.2019.01.004] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 12/17/2018] [Accepted: 01/12/2019] [Indexed: 12/23/2022]
Abstract
OBJECTIVES Hepatitis E virus genotype 3 (HEV3) is responsible for acute and chronic liver disease in solid organ transplant (SOT) recipients. HEV was recently found in the urine of some acutely and chronically genotype 4-infected patients. METHODS We examined the urinary excretion of HEV3 by 24 consecutive SOT recipients at the acute phase of HEV hepatitis and characterized the excreted virus. RESULTS Urinary HEV RNA was detected in 12 (50%) of the 24 transplanted patients diagnosed with HEV hepatitis. Urinary HEV antigen (Ag) was detected in all but one of the patients (96%). The density of RNA-containing HEV particles in urine was low (1.11-1.12 g/cm3), corresponding to lipid-associated virions. The urinary HEV RNA/Ag detected was not associated with impaired kidney function or de novo proteinuria. Finally, there was more HEV Ag in the serum at the acute phase of HEV infection in SOT recipients whose infection became chronic. CONCLUSIONS HEV3 excreted via the urine of SOT recipients at the acute phase of HEV hepatitis has a lipid envelope. Renal function was not impaired. While urinary HEV Ag was a sensitive indicator of HEV infection, only acute phase serum HEV Ag indicated the development of a chronic infection.
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Affiliation(s)
- Olivier Marion
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France; Inserm UMR1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France
| | - Nicolas Capelli
- Inserm UMR1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France; Laboratory of Virology, CHU Purpan, Toulouse, France
| | - Sebastien Lhomme
- Inserm UMR1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France; Laboratory of Virology, CHU Purpan, Toulouse, France; Université Paul Sabatier, Toulouse, France
| | - Martine Dubois
- Inserm UMR1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France; Laboratory of Virology, CHU Purpan, Toulouse, France
| | | | - Florence Abravanel
- Inserm UMR1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France; Laboratory of Virology, CHU 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
| | - Jacques Izopet
- Inserm UMR1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France; Laboratory of Virology, CHU Purpan, Toulouse, France; Université Paul Sabatier, Toulouse, France.
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25
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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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26
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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: 434] [Impact Index Per Article: 62.0] [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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27
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De Winter BCM, Hesselink DA, Kamar N. Dosing ribavirin in hepatitis E-infected solid organ transplant recipients. Pharmacol Res 2018; 130:308-315. [PMID: 29499270 DOI: 10.1016/j.phrs.2018.02.030] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Revised: 02/06/2018] [Accepted: 02/26/2018] [Indexed: 12/22/2022]
Abstract
Hepatitis E virus (HEV) is the most common cause of viral hepatitis worldwide. Genotypes 1 and 2 (GT1 and GT2) are mainly present in developing countries, while GT3 and GT4 are prevalent in developed and high-income countries. In the majority of cases, HEV causes a self-limiting hepatitis. GT3 and GT4 can be responsible for a chronic hepatitis that can lead to cirrhosis in immunocompromized patients, i.e. solid-organ- and stem-cell-transplant-patients, human immunodeficiency virus-infected patients, and patients receiving chemotherapy or immunotherapy. HEV has also been associated with extra-hepatic manifestations such as neurologic disorders (Guillain-Barré Syndrome and neuralgic amyotrophy) and kidney disease. In patients with chronic hepatitis, reduction of immunosuppression, when possible, is the first therapeutic option. In the remaining patients, ribavirin therapy has been shown to very efficient for treating HEV infection leading to a sustained virological response in nearly 80-85% of patients. However, the mechanism of action of ribavirin in this setting is still unknown, as is the impact of HEV RNA polymerase mutations. There are unmet needs with regard to the treatment of chronic HEV with ribavirin. These include the optimal dosing and duration of treatment, and the potential beneficial effects of therapeutic drug monitoring on the virological response and the incidence of side effects. In the present review, we will provide an overview of HEV epidemiology, its mode of transmission and clinical manifestations, as well as its treatment by ribavirin with a focus on the drug's pharmacokinetics and dosing.
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Affiliation(s)
- Brenda C M De Winter
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, The Netherlands
| | - Dennis A Hesselink
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, The Netherlands; Rotterdam Transplant Group, Division of Nephrology and Organ Transplantation, CHU Rangueil, INSERM U1043, IFR-BMT, Université Paul Sabatier, Toulouse, France
| | - Nassim Kamar
- Department of Internal Medicine, Division of Nephrology and Organ Transplantation, CHU Rangueil, INSERM U1043, IFR-BMT, Université Paul Sabatier, Toulouse, France.
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28
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Membranous Nephropathy and Anti-Podocytes Antibodies: Implications for the Diagnostic Workup and Disease Management. BIOMED RESEARCH INTERNATIONAL 2018; 2018:6281054. [PMID: 29511687 PMCID: PMC5817285 DOI: 10.1155/2018/6281054] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/11/2017] [Revised: 08/31/2017] [Accepted: 10/15/2017] [Indexed: 12/11/2022]
Abstract
The discovery of circulating antibodies specific for native podocyte antigens has transformed the diagnostic workup and greatly improved management of idiopathic membranous nephropathy (iMN). In addition, their identification has clearly characterized iMN as a largely autoimmune disorder. Anti-PLA2R1 antibodies are detected in approximately 70% to 80% and anti-THSD7A antibodies in only 2% of adult patients with iMN. The presence of anti-THSD7A antibodies is associated with increased risk of malignancy. The assessment of PLA2R1 and THSD7A antigen expression in glomerular immune deposits has a better sensitivity than measurement of the corresponding autoantibodies. Therefore, in the presence of circulating anti-podocytes autoantibodies and/or enhanced expression of PLA2R1 and THSD7A antigens MN should be considered as primary MN (pMN). Anti-PLA2R1 or anti-THSD7A autoantibodies have been proposed as biomarkers of autoimmune disease activity and their blood levels should be regularly monitored in pMN to evaluate disease activity and predict outcomes. We propose a revised clinical workup flow for patients with MN that recommends assessment of kidney biopsy for PLA2R1 and THSD7A antigen expression, screening for circulating anti-podocytes antibodies, and assessment for secondary causes, especially cancer, in patients with THSD7A antibodies. Persistence of anti-podocyte antibodies for 6 months or their increase in association with nephrotic proteinuria should lead to the introduction of immunosuppressive therapies. Recent data have reported the efficacy and safety of new specific therapies targeting B cells (anti-CD20 antibodies, inhibitors of proteasome) in pMN which should lead to an update of currently outdated treatment guidelines.
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29
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Abstract
Hepatitis E virus (HEV) infection can lead to acute and chronic hepatitis as well as to extrahepatic manifestations such as neurological and renal disease; it is the most common cause of acute viral hepatitis worldwide. Four genotypes are responsible for most infection in humans, of which HEV genotypes 1 and 2 are obligate human pathogens and HEV genotypes 3 and 4 are mostly zoonotic. Until quite recently, HEV was considered to be mainly responsible for epidemics of acute hepatitis in developing regions owing to contamination of drinking water supplies with human faeces. However, HEV is increasingly being recognized as endemic in some developed regions. In this setting, infections occur through zoonotic transmission or contaminated blood products and can cause chronic hepatitis in immunocompromised individuals. HEV infections can be diagnosed by measuring anti-HEV antibodies, HEV RNA or viral capsid antigen in blood or stool. Although an effective HEV vaccine exists, it is only licensed for use in China. Acute hepatitis E is usually self-limiting and does not require specific treatment. Management of immunocompromised individuals involves lowering the dose of immunosuppressive drugs and/or treatment with the antiviral agent ribavirin.
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30
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Pischke S, Hartl J, Pas SD, Lohse AW, Jacobs BC, Van der Eijk AA. Hepatitis E virus: Infection beyond the liver? J Hepatol 2017; 66:1082-1095. [PMID: 27913223 DOI: 10.1016/j.jhep.2016.11.016] [Citation(s) in RCA: 176] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Revised: 11/13/2016] [Accepted: 11/20/2016] [Indexed: 02/07/2023]
Abstract
Hepatitis E virus (HEV) infections are not limited to the liver but may also affect other organs. Several diseases, including Guillain-Barré syndrome, neuralgic amyotrophy, glomerulonephritis, cryoglobulinemia, pancreatitis, lymphoma, thrombopenia, meningitis, thyroiditis and myocarditis have been observed in the context of hepatitis E. To date, the definite pathophysiological links between HEV and extrahepatic manifestations are not yet established. However, it is suggested that HEV infection might be causative based on serological studies, case series, in vitro data and animal models. In particular, neuronal and renal diseases as well as pancreatitis seem to be caused by HEV, while a causative relationship between HEV and other diseases is more doubtful. Either direct cytopathic tissue damage by extrahepatic replication, or immunological processes induced by an overwhelming host immune response, are possible origins of HEV-associated extrahepatic manifestations. Hepatologists should be aware of the possibility that acute or chronically HEV-infected patients could develop extrahepatic manifestations. Neurologists, nephrologists, rheumatologists and other groups of physicians should consider HEV infection as a potential differential diagnosis when observing one of the diseases described in this review. Ribavirin and steroids have been used in small groups of patients with extrahepatic manifestations of HEV, but the efficacy of these drugs still needs to be verified by large, multicenter studies. This article comprehensively reviews the published literature regarding HEV and extrahepatic manifestations. We discuss the probability of specific extrahepatic diseases being caused by previous or ongoing HEV infection, and summarize the published knowledge about antiviral treatment in extrahepatic disorders.
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Affiliation(s)
- Sven Pischke
- Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
| | - Johannes Hartl
- Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Suzan D Pas
- Department of Viroscience, Erasmus MC University Medical Center Rotterdam, Netherlands
| | - Ansgar W Lohse
- Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Bart C Jacobs
- Department of Neurology and Immunology, Erasmus MC University Medical Center Rotterdam, Netherlands
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31
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Hartl J, Wehmeyer MH, Pischke S. Acute Hepatitis E: Two Sides of the Same Coin. Viruses 2016; 8:E299. [PMID: 27827877 PMCID: PMC5127013 DOI: 10.3390/v8110299] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Revised: 10/04/2016] [Accepted: 10/17/2016] [Indexed: 12/12/2022] Open
Abstract
The relevance of acute hepatitis E virus (HEV) infections has been underestimated for a long time. In the past, HEV infection had been interpreted falsely as a disease limited to the tropics until the relevance of autochthonous HEV infections in the Western world became overt. Due to increased awareness, the incidence of diagnosed autochthonous HEV infections (predominantly genotype 3) in industrialized countries has risen within the last decade. The main source of infections in industrialized countries seems to be infected swine meat, while infections with the tropical HEV genotypes 1 and 2 usually are mainly transmitted fecal-orally by contaminated drinking water. In the vast majority of healthy individuals, acute HEV infection is either clinically silent or takes a benign self-limited course. In patients who develop a symptomatic HEV infection, a short prodromal phase with unspecific symptoms is followed by liver specific symptoms like jaundice, itching, uncoloured stool and darkened urine. Importantly, tropical HEV infections may lead to acute liver failure, especially in pregnant women, while autochthonous HEV infections may lead to acute-on-chronic liver failure in patients with underlying liver diseases. Immunosuppressed individuals, such as transplant recipients or human immunodeficiency virus (HIV)-infected patients, are at risk for developing chronic hepatitis E, which may lead to liver fibrosis and cirrhosis in the long term. Importantly, specific treatment options for hepatitis E are not approved by the regulation authorities, but off-label ribavirin treatment seems to be effective in the treatment of chronic HEV-infection and may reduce the disease severity in patients suffering from acute liver failure.
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Affiliation(s)
- Johannes Hartl
- First Medical Department, University Medical Center Hamburg-Eppendorf, University Hospital Hamburg Eppendorf (UKE), 20246 Hamburg, Germany.
| | - Malte H Wehmeyer
- First Medical Department, University Medical Center Hamburg-Eppendorf, University Hospital Hamburg Eppendorf (UKE), 20246 Hamburg, Germany.
| | - Sven Pischke
- First Medical Department, University Medical Center Hamburg-Eppendorf, University Hospital Hamburg Eppendorf (UKE), 20246 Hamburg, Germany.
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32
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Kamar N, Marion O, Abravanel F, Izopet J, Dalton HR. Extrahepatic manifestations of hepatitis E virus. Liver Int 2016; 36:467-72. [PMID: 27005692 DOI: 10.1111/liv.13037] [Citation(s) in RCA: 79] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Accepted: 11/25/2015] [Indexed: 02/06/2023]
Abstract
Hepatitis E virus can cause acute, fulminant and chronic hepatitis and has been associated with a range of extrahepatic manifestations. Guillain-Barré syndrome, neuralgic amyotrophy and encephalitis are the main neurological manifestations associated with acute and chronic hepatitis E virus infection. Renal injuries have been also reported, including membranoproliferative glomerulonephritis with or without cryoglobulinemia and membranous glomerulonephritis. Acute pancreatitis, haematological disorders and other autoimmune extrahepatic manifestations of hepatitis E virus, such as myocarditis and thyroiditis, have been also reported. In this comprehensive article, we review all published reports describing hepatitis E virus-associated extrahepatic manifestations.
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Affiliation(s)
- Nassim Kamar
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France.,INSERM U1043, IFR-BMT, CHU Purpan, Toulouse, France.,Université Paul Sabatier, Toulouse, France
| | - Olivier Marion
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - Florence Abravanel
- INSERM U1043, IFR-BMT, CHU Purpan, Toulouse, France.,Université Paul Sabatier, Toulouse, France.,Department of Virology, CHU Purpan, Toulouse, France
| | - Jacques Izopet
- INSERM U1043, IFR-BMT, CHU Purpan, Toulouse, France.,Université Paul Sabatier, Toulouse, France.,Department of Virology, CHU Purpan, Toulouse, France
| | - Harry R Dalton
- Cornwall Gastrointestinal Unit, Royal Cornwall Hospital and European Centre for the Environment and Human Health, University of Exeter Medical School, Truro, UK
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33
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Hepatobiliary Quiz Answers-17 (2016). J Clin Exp Hepatol 2016; 6:73-6. [PMID: 27194902 PMCID: PMC4862109 DOI: 10.1016/j.jceh.2016.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
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34
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Marion O, Abravanel F, Lhomme S, Izopet J, Kamar N. Hepatitis E in Transplantation. Curr Infect Dis Rep 2016; 18:8. [DOI: 10.1007/s11908-016-0515-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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35
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Guinault D, Ribes D, Delas A, Milongo D, Abravanel F, Puissant-Lubrano B, Izopet J, Kamar N. Hepatitis E Virus-Induced Cryoglobulinemic Glomerulonephritis in a Nonimmunocompromised Person. Am J Kidney Dis 2015; 67:660-3. [PMID: 26682764 DOI: 10.1053/j.ajkd.2015.10.022] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2015] [Accepted: 10/16/2015] [Indexed: 12/16/2022]
Abstract
Hepatitis E virus (HEV)-related kidney disease and symptomatic cryoglobulinemia have been observed in solid-organ transplant recipients. However, HEV RNA in the cryoprecipitate has not yet been assessed. We report what to our knowledge is the first documented case of autochthonous HEV-induced cryoglobulinemic crescentic and membranoproliferative glomerulonephritis in an immunocompetent man with no notable medical history. He presented with edema, hypertension, increased serum creatinine level, and nephrotic syndrome. Type II cryoglobulinemia with monoclonal immunoglobulin G (IgG) κ light chain was detected. Anti-HEV IgG and IgM, as well as HEV RNA, were detected in serum and cryoprecipitate. Histologic analysis of a kidney biopsy specimen revealed features of crescentic and membranoproliferative glomerulonephritis. After HEV clearance, kidney and liver parameters improved and HEV RNA and cryoglobulinemia were undetectable. Hence, we conclude that HEV can cause severe kidney disease and should be considered in cases of unexplained glomerular disease.
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Affiliation(s)
- Damien Guinault
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - David Ribes
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - Audrey Delas
- Laboratory of Pathology, Institut Universitaire du Cancer de Toulouse, Toulouse, France; Université Paul Sabatier, Toulouse, France
| | - David Milongo
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France; Laboratory of Pathology, Institut Universitaire du Cancer de Toulouse, Toulouse, France
| | - Florence Abravanel
- Université Paul Sabatier, Toulouse, France; Laboratory of Virology, CHU Purpan, Toulouse, France; INSERM U1043, IFR-BMT, CHU Purpan, Toulouse, France
| | | | - Jacques Izopet
- Université Paul Sabatier, Toulouse, France; Laboratory of Virology, CHU Purpan, Toulouse, France; INSERM U1043, IFR-BMT, CHU Purpan, Toulouse, France
| | - Nassim Kamar
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France; Université Paul Sabatier, Toulouse, France; INSERM U1043, IFR-BMT, CHU Purpan, Toulouse, France.
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36
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Peters van Ton AM, Gevers TJG, Drenth JPH. Antiviral therapy in chronic hepatitis E: a systematic review. J Viral Hepat 2015; 22:965-973. [PMID: 25760481 DOI: 10.1111/jvh.12403] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Accepted: 02/12/2015] [Indexed: 12/24/2022]
Abstract
Hepatitis E viral infection can lead to a chronic infection in immunocompromised patients, resulting in progressive liver disease and cirrhosis. Isolated cases have shown that treatment with ribavirin or pegylated interferon-α can result in viral eradication. This systematic review evaluated efficacy and safety of both treatments in chronic hepatitis E. A systematic literature search was performed on PubMed, Web of Science and clinicaltrials.gov for articles and abstracts. The keywords '"Hepatitis E" or HEV' AND 'ribavirin or Rebetol or Copegus' OR 'pegylated interferon OR peginterferon' were combined. The primary outcome was sustained viral response (SVR). Secondary endpoints include rapid viral response (RVR), relapse rates and side effects. Twenty-four studies matched our criteria, representing a total of 105 ribavirin-treated and 8 pegylated interferon-treated patients. The majority of patients had a solid organ transplant. Sixty-four per cent of ribavirin-treated patients achieved a SVR at 6 months after treatment cessation compared to 2/8 peginterferon-treated patients. Ribavirin was relatively well tolerated with the main side effect being anaemia, requiring dose reduction in 28% of patients. Peginterferon leads to acute transplant rejection in 2/8 patients. Ribavirin monotherapy appears to be an effective and safe treatment in all immunocompromised patients with chronic hepatitis E. The use of pegylated interferon in transplant patients may lead to transplant rejection and is not recommended. Therefore, ribavirin should be the antiviral treatment of choice in chronic hepatitis E.
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Affiliation(s)
- A M Peters van Ton
- Department of Gastroenterology & Hepatology, Radboud UMC, Nijmegen, The Netherlands
| | - T J G Gevers
- Department of Gastroenterology & Hepatology, Radboud UMC, Nijmegen, The Netherlands
| | - J P H Drenth
- Department of Gastroenterology & Hepatology, Radboud UMC, Nijmegen, The Netherlands
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37
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Bazerbachi F, Haffar S, Garg SK, Lake JR. Extra-hepatic manifestations associated with hepatitis E virus infection: a comprehensive review of the literature. Gastroenterol Rep (Oxf) 2015; 4:1-15. [PMID: 26358655 PMCID: PMC4760069 DOI: 10.1093/gastro/gov042] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2015] [Accepted: 07/09/2015] [Indexed: 02/07/2023] Open
Abstract
Background and aims: Hepatitis E virus (HEV) infection is a significant public health problem that afflicts almost 20 million individuals annually and causes acute liver injury in 3.5 million, with approximately 56 000 deaths. As with other viral hepatitides, extra-hepatic manifestations could represent an important aspect of this infection. The spectrum of these manifestations is still emerging. Acute pancreatitis and neurological, musculoskeletal, hematological, renal, and other immune-mediated manifestations have been described. The aim of this article is to comprehensively review the published literature of extra-hepatic manifestations associated with HEV infection. Data sources: We searched the PubMed database using the MeSH term “hepatitis E” and each of the extra-hepatic manifestations associated with HEV infection. No language or date restrictions were set in these searches. Searches retrieving articles with non-A, non-B hepatitis were excluded. Additional articles were identified through the reference lists of included articles. Results: Several extra-hepatic manifestations associated with HEV infection have been published. The temporal association between some extra-hepatic manifestations and HEV infection and the exclusion of other possible etiologies suggests that HEV infection could have caused some of them. According to the available data, HEV infection appears to be strongly associated with acute pancreatitis, neurological disorders (with primarily dominant peripheral nerve involvement, most commonly manifested as Guillain-Barré syndrome, followed by neuralgic amyotrophy), hematological diseases (hemolytic anemia due to glucose phosphate dehydrogenase deficiency, and severe thrombocytopenia), glomerulonephritis, and mixed cryoglobulinemia. More data are needed to clarify whether an association exists with musculoskeletal or other immune-mediated manifestations. Conclusions: HEV infection should be considered in patients with acute pancreatitis, Guillain-Barré syndrome, neuralgic amyotrophy, hemolytic anemia due to glucose phosphate dehydrogenase deficiency, severe thrombocytopenia, glomerulonephritis, and mixed cryoglobulinemia. Alternatively, signs and symptoms of these conditions should be sought in patients with acute or chronic HEV infection. More data are needed to confirm the role of HEV in other extra-hepatic disorders.
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Affiliation(s)
- Fateh Bazerbachi
- Division of Gastroenterology and Hepatology, University of Minnesota, Minneapolis, MN 55455, USA
| | - Samir Haffar
- Department of Gastroenterology and Hepatology, University of Damascus, Damascus, Syrian Arab Republic
| | - Sushil K Garg
- Division of Gastroenterology and Hepatology, University of Minnesota, Minneapolis, MN 55455, USA
| | - John R Lake
- Division of Gastroenterology and Hepatology, University of Minnesota, Minneapolis, MN 55455, USA
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38
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Murali AR, Kotwal V, Chawla S. Chronic hepatitis E: A brief review. World J Hepatol 2015; 7:2194-2201. [PMID: 26380044 PMCID: PMC4561773 DOI: 10.4254/wjh.v7.i19.2194] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Revised: 07/28/2015] [Accepted: 08/20/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis E viral infection has traditionally been considered an acute, self-limited, water borne disease similar to hepatitis A, endemic to developing countries. However, over the past decade, zoonotic transmission and progression to chronicity in human patients has been identified, resulting in persistently elevated transaminase levels, progressive liver injury and cirrhosis. In addition to liver injury, neurological, renal and rheumatological manifestations have also been reported. Chronic hepatitis E occurs mainly in immunosuppressed individuals such as transplant recipients, human immunodeficiency virus patients with low CD4 counts and in patients with hematological malignancies receiving chemotherapy. Diagnosis is established by persistent elevation of hepatitis E virus RNA in the stool or serum. This population often requires treatment with antiviral agents, particularly ribavirin, as spontaneous clearance with reduction in immunosuppression occurs only in about a third of the patients. The purpose of this review, is to further discuss the clinical presentation, and recent advances in diagnosis, treatment and prophylaxis of chronic hepatitis E.
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Affiliation(s)
- Arvind R Murali
- Arvind R Murali, Department of Gastroenterology and Hepatology, University of Iowa Hospitals and Clinics, Iowa City, IA 52246, United States
| | - Vikram Kotwal
- Arvind R Murali, Department of Gastroenterology and Hepatology, University of Iowa Hospitals and Clinics, Iowa City, IA 52246, United States
| | - Saurabh Chawla
- Arvind R Murali, Department of Gastroenterology and Hepatology, University of Iowa Hospitals and Clinics, Iowa City, IA 52246, United States
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39
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Del Bello A, Guilbeau-Frugier C, Josse AG, Rostaing L, Izopet J, Kamar N. Successful treatment of hepatitis E virus-associated cryoglobulinemic membranoproliferative glomerulonephritis with ribavirin. Transpl Infect Dis 2015; 17:279-83. [PMID: 25708383 DOI: 10.1111/tid.12353] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2014] [Revised: 11/29/2014] [Accepted: 12/11/2014] [Indexed: 02/06/2023]
Abstract
Hepatitis E virus genotype-3 (HEV3) infection can cause chronic hepatitis in immunosuppressed patients and induce extra-hepatic manifestations, such as neurological symptoms, kidney injuries, and immune-mediated thrombocytopenia. Very few cases of HEV-induced kidney manifestations have been reported. Herein, we report, for the first time, a case of de novo membranoproliferative glomerulonephritis that occurred in a kidney transplant patient who developed a chronic HEV3 infection, which was successfully treated with ribavirin.
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Affiliation(s)
- A Del Bello
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France; Université Paul Sabatier, Toulouse, France
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40
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Kamar N, Abravanel F, Lhomme S, Rostaing L, Izopet J. Hepatitis E virus: chronic infection, extra-hepatic manifestations, and treatment. Clin Res Hepatol Gastroenterol 2015; 39:20-7. [PMID: 25150374 DOI: 10.1016/j.clinre.2014.07.005] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2014] [Accepted: 07/07/2014] [Indexed: 02/04/2023]
Abstract
Hepatitis E virus (HEV) infection is a worldwide disease. An improved understanding of the natural history of HEV infection has been achieved within the last decade. Several reservoirs and transmission modes have been identified. It is an underdiagnosed disease because of the use of low-sensitivity serological assays; however, diagnostics tools, including nucleic-acid tests, have improved. HEV infection is usually an acute self-limiting disease, but causes chronic infection with rapidly progressive cirrhosis in adult and pediatric organ-transplant-patients. HEV infection evolves to chronic hepatitis in nearly 60% of HEV-infection solid-organ-transplant patients. HEV can also cause extra-hepatic manifestations, such as neurological symptoms and kidney injury. Reducing immunosuppression in transplant patients can lead to HEV clearance in one-third of patients with chronic hepatitis. The use of anti-viral therapies, such as pegylated-interferon and ribavirin, has been found to efficaciously treat HEV infection.
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Affiliation(s)
- Nassim Kamar
- Department of Nephrology and Organ Transplantation, CHU Rangueil, TSA 50032, 31059 Toulouse cedex 9, France; Inserm U1043, IFR-BMT, CHU Purpan, Toulouse, France; Université Paul-Sabatier, Toulouse, France.
| | - Florence Abravanel
- Inserm U1043, IFR-BMT, CHU Purpan, Toulouse, France; Université Paul-Sabatier, Toulouse, France; Laboratory of Virology, CHU Purpan, Toulouse, France
| | - Sebastien Lhomme
- Inserm U1043, IFR-BMT, CHU Purpan, Toulouse, France; Université Paul-Sabatier, Toulouse, France; Laboratory of Virology, CHU Purpan, Toulouse, France
| | - Lionel Rostaing
- Department of Nephrology and Organ Transplantation, CHU Rangueil, TSA 50032, 31059 Toulouse cedex 9, France; Inserm U1043, IFR-BMT, CHU Purpan, Toulouse, France; Université Paul-Sabatier, Toulouse, France
| | - Jacques Izopet
- Inserm U1043, IFR-BMT, CHU Purpan, Toulouse, France; Université Paul-Sabatier, Toulouse, France; Laboratory of Virology, CHU Purpan, Toulouse, France
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41
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Verna EC. Hepatitis viruses and liver transplantation: evolving trends in antiviral management. Clin Liver Dis 2014; 18:575-601. [PMID: 25017077 DOI: 10.1016/j.cld.2014.05.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Viral hepatitis is both a leading indication for liver transplant (LT) and an important cause of posttransplant graft loss and mortality. Treatment and prevention of hepatitis B virus in LT recipients, with the observed corresponding improvement in post-LT outcomes, is among the great success stories in transplantation. By comparison, treatment of hepatitis C virus with safe and effective regimens is only just becoming a reality. Chronic hepatitis E virus infection in LT recipients represents a newly described phenomenon that can also lead to graft loss; early diagnosis and treatment may be key in the management of these patients.
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Affiliation(s)
- Elizabeth C Verna
- Division of Digestive and Liver Diseases, Center for Liver Disease and Transplantation, Columbia University College of Physicians and Surgeons, 622 West 168th Street, New York, NY 10032, USA.
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