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Kanda T, Sasaki-Tanaka R, Yokoo T, Hayashi K, Kamimura H, Tsuchiya A, Terai S. Cholestasis in hepatitis E virus infection. World J Hepatol 2025; 17:99899. [PMID: 40308815 PMCID: PMC12038413 DOI: 10.4254/wjh.v17.i4.99899] [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: 08/02/2024] [Revised: 09/21/2024] [Accepted: 10/09/2024] [Indexed: 04/25/2025] Open
Abstract
Hepatitis E virus (HEV) infection causes acute hepatitis, chronic hepatitis, particularly in compromised hosts, and various extrahepatic manifestations. HEV infection is reportedly associated with biliary-pancreatic diseases, such as gallstones, cholangitis, choledocholithiasis, and acute pancreatitis. Severe jaundice and prolonged cholestasis are also atypical manifestations of HEV infection. The mechanism and genes involved in cholestasis, namely sinusoidal uptake of blood, bile salt synthesis and secretion from hepatocytes to the canaliculus, have been elucidated. HEV infection triggers severe jaundice and prolonged cholestasis in patients with genetic variants in adenosine triphosphatase phospholipid transporting 8B1, adenosine triphosphate-binding cassette (ABC) protein B4, ABCB11, Myosin VB, and/or farnesoid X receptor (FXR/NR1H4). Although prolonged cholestasis associated with these gene mutations does not seem to be specific to HEV infection, these mutations may be risk factors related to the severity of HEV infection. The use of the pregnane X receptor agonist rifampicin and the peroxisome proliferator-activated receptor activator bezafibrate may be useful for the treatment of cholestasis. These studies provide new insights into understanding the mechanisms of severe jaundice and prolonged cholestasis caused by HEV infection.
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Affiliation(s)
- Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Minamiuonuma 949-7302, Niigata, Japan.
| | - Reina Sasaki-Tanaka
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8520, Japan
| | - Takeshi Yokoo
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8520, Japan
| | - Kazunao Hayashi
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8520, Japan
| | - Hiroteru Kamimura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8520, Japan
| | - Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8520, Japan
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8520, Japan
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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: 0] [Impact Index Per Article: 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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Zimmer V, Bohle RM, Weber SN, Lammert F, Jüngst C. Benign recurrent intrahepatic cholestasis (BRIC)-like episode associated with ATP8B1 variation underlying protracted cholestatic course of acute hepatitis E virus infection. Dig Liver Dis 2018; 50:206-207. [PMID: 29191380 DOI: 10.1016/j.dld.2017.10.022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Revised: 09/21/2017] [Accepted: 10/28/2017] [Indexed: 12/11/2022]
Affiliation(s)
- Vincent Zimmer
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.
| | - Rainer M Bohle
- Institute of Pathology, Saarland University Medical Center, Saarland University, Homburg, Germany.
| | - Susanne N Weber
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.
| | - Christoph Jüngst
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.
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Pourbaix A, Ouali N, Soussan P, Roque Afonso AM, Péraldi MN, Rondeau E, Peltier J. Evidence of hepatitis E virus transmission by renal graft. Transpl Infect Dis 2017; 19. [PMID: 27775205 DOI: 10.1111/tid.12624] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Revised: 04/26/2016] [Accepted: 09/09/2016] [Indexed: 01/20/2023]
Abstract
Hepatitis E virus (HEV) can cause chronic infection among immunocompromised patients, especially solid organ transplant recipients, and can evolve to cirrhosis. Several modes of transmission are known. Here we describe the first two cases, to our knowledge, of HEV infection transmitted by a kidney graft from the same infected donor that led to chronic hepatitis. Consequently, systematic screening of donors by HEV serology and HEV RNA detection by polymerase chain reaction, particularly in endemic regions, should be considered.
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Affiliation(s)
- Annabelle Pourbaix
- Department of Renal ICU and Kidney Transplantation, Tenon Hospital, Paris, France
| | - Nacera Ouali
- Department of Renal ICU and Kidney Transplantation, Tenon Hospital, Paris, France
| | | | | | | | - Eric Rondeau
- Department of Renal ICU and Kidney Transplantation, Tenon Hospital, Paris, France
| | - Julie Peltier
- Department of Renal ICU and Kidney Transplantation, Tenon Hospital, Paris, France
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Abstract
Background: Viral hepatitis is an infection that has been reported to be present throughout the year, but some particular months are associated with higher incidences. The primary objective was to review and report on the current knowledge and evidence that existed on seasonality of different type of acute viral hepatitis worldwide in order to develop recommendations for future research, prevention and control. Materials and Methods: A systematic literature review was performed to identify all the primary reports and studies published during 1970-2013 on acute hepatitis A, B, C and E (AHA, AHB, AHC and AHE) in human subjects by searching PubMed, reference lists of major articles and correspondence with scientific experts. For each report or study included, the following information was extracted (as applicable to study): Location (country and setting), study population (number of cases, patients), seasonal or monthly rate and study duration. Results: There is no definite and consistent seasonal pattern has been observed on AHA; AHB; AHE and AHC, although evidence points towards spring and summer peak for hepatitis A, B, C and E. Multiple source of transmission such as; summer travel to an endemic area, swimming habits of the population in hot months, increase sexual contact, tattoo, poor hygiene and environmental sanitation and food habits (feco-oral transmission of viral hepatitis) probably exists and should be further investigated through analytical and epidemiological.
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Affiliation(s)
- Auda Fares
- Albert-Schlangen, Str.36 Bedburg-Germany
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Haïm-Boukobza S, Ferey MP, Vétillard AL, Jeblaoui A, Pélissier E, Pelletier G, Teillet L, Roque-Afonso AM. Transfusion-transmitted hepatitis E in a misleading context of autoimmunity and drug-induced toxicity. J Hepatol 2012; 57:1374-8. [PMID: 22885386 DOI: 10.1016/j.jhep.2012.08.001] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2012] [Revised: 07/16/2012] [Accepted: 08/02/2012] [Indexed: 01/18/2023]
Abstract
Hepatitis E is currently diagnosed after all other causes of hepatitis have been excluded. Moreover, HEV testing is not performed to prevent blood transmission in developed countries. We report here on the case of a patient with acute hepatitis while receiving potentially hepatotoxic medications for autoimmune disorders, with low-level autoimmune markers and negative "standard" viral markers; it was finally determined that he was suffering from transfusion-transmitted hepatitis E.
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Affiliation(s)
- Stéphanie Haïm-Boukobza
- National Reference Center for Hepatitis A and E, APHP, Paul Brousse Hospital, Department of Virology, Villejuif, France
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Scotto G, Martinelli D, Giammario A, Prato R, Fazio V. Prevalence of Antibodies to Hepatitis E Virus in Immigrants: A Seroepidemiological Survey in the District of Foggia (Apulia-Southern Italy). J Med Virol 2012. [DOI: 10.1002/jmv.23400] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Acharya SK, Panda SK. Hepatitis E: water, water everywhere - now a global disease. J Hepatol 2011; 54:9-11. [PMID: 20970217 DOI: 10.1016/j.jhep.2010.08.008] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2010] [Accepted: 08/05/2010] [Indexed: 12/20/2022]
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Transmission routes and risk factors for autochthonous hepatitis E virus infection in Europe: a systematic review. Epidemiol Infect 2009; 138:145-66. [PMID: 19804658 DOI: 10.1017/s0950268809990847] [Citation(s) in RCA: 138] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Increasing numbers of non-travel-associated hepatitis E virus (HEV) infections have been reported in Europe in recent years. Our objective was to review the evidence on risk factors and transmission routes of autochthonous HEV infection and hepatitis E in Europe in order to develop recommendations for future research, prevention and control. A systematic literature review was performed to identify all primary reports and studies published during 1998-2008 on hepatitis E in humans and animals in Europe by searching Pubmed, reference lists of major articles and international conference proceedings. Each of the 106 included studies was categorized into one of three evidence levels (EL) based on study design and diagnostic methodology. The evidence was generally weak (73 were assigned to EL1, two to both EL1 and EL2, and 30 to EL2), further compounded by the use of poorly validated serological assays in some studies. Only one case-control study was assigned to EL3. Persons with autochthonous hepatitis E infection were on average older than the general population and predominantly male. There was no evidence for one main transmission route of HEV infection or risk factor for hepatitis E. However, zoonotic transmission seemed likely and person-to-person transmission too inefficient to cause clinical disease. Multiple routes of transmission probably exist and should be further investigated through analytical studies and reliable diagnostic kits. Based on current evidence that points to zoonotic transmission from pigs, thorough cooking of all porcine products, prevention of cross-contamination in the kitchen and improved education for occupationally exposed people (e.g. pig farmers, veterinarians and sewage workers) may help prevent HEV infection. Although evidence for parenteral transmission is limited, it is recommended that a risk assessment is undertaken.
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Amini-Bavil-Olyaee S, Trautwein C, Tacke F. Hepatitis E vaccine: current status and future prospects. Future Virol 2009. [DOI: 10.2217/17460794.4.2.143] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
HEV, a positive ssRNA and nonenveloped virus, is endemic in many developing countries and one of the most frequent causes of acute hepatitis after fecal–oral transmission. Pregnant women are at particular risk for a fatal course of disease, including maternal and fetal mortality. Recent reports indicate that HEV genotype 3, possibly related to zoonotic transmission, may cause chronic hepatitis in some immunosuppressed organ transplant patients. Various approaches have been conducted to develop HEV vaccines, but only one candidate, a recombinant HEV (rHEV) vaccine generated from Spodoptera frugiperda-9 cells by baculoviruses expressing the HEV capsid antigen, has reached clinical Phase I and II trials so far. These trials suggest that the rHEV vaccine is safe and can prevent clinically overt acute hepatitis E in high-risk populations. We herein review the different approaches in HEV-vaccine development and critically discuss the current status and future directions of the rHEV vaccine used in clinical trials.
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Affiliation(s)
| | - Christian Trautwein
- Department of Medicine III, RWTH-University Hospital Aachen, Aachen, Germany
| | - Frank Tacke
- Department of Medicine III, RWTH-University Hospital Aachen, Aachen, Germany
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Abstract
PURPOSE OF REVIEW Hepatitis E is an emerging infectious disease. This review will focus on recent advances in the zoonotic transmission, global distribution and control of hepatitis E. RECENT FINDINGS Hepatitis E virus infection is known to cause waterborne epidemics and sporadic infections in developing countries. Recently, there have been several reports on zoonotic foodborne autochthonous infections of hepatitis E in developed countries. Hepatitis E typically causes self-limited acute infection. Recent reports have documented hepatitis E virus causing chronic hepatitis and cirrhosis in patients after solid organ transplantation. High incidence and severity of hepatitis E in pregnant women have been re-confirmed. The reason for high mortality in pregnant women remains ill understood. A recombinant hepatitis E vaccine has been evaluated in a phase 2, randomized, placebo-controlled trial in Nepal and was found to be well tolerated and efficacious. SUMMARY There has been considerable advance in understanding the epidemiology of hepatitis E virus infections in western countries. The occurrence of chronic hepatitis in organ transplant recipients opens a new chapter in hepatitis E epidemiology. The report on an efficacious and well tolerated recombinant vaccine gives hope for control of the disease in the near future.
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Affiliation(s)
- Mohammad S Khuroo
- Digestive Disease Centre, Dr Khuroo's Medical Clinic, Srinagar, India.
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Spahr L, Morard I, Mentha G, Hadengue A, Giostra E. Spontaneous Resolution of Brain Edema in Fulminant Hepatic Failure due to Hepatitis E. Case Rep Gastroenterol 2008; 2:424-7. [PMID: 21897793 PMCID: PMC3166805 DOI: 10.1159/000164618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Fulminant hepatic failure is characterized by the presence of hepatic encephalopathy in the setting of acute liver injury that occurs in a noncirrhotic organ. Brain edema is the ultimate complication of advanced hepatic encephalopathy as it often leads to cerebral herniation and death. Thus, the presence of fulminant hepatic failure indicates the need for urgent liver transplantation to prevent death or irreversible brain damage. We report a very unusual evolution of fulminant hepatic failure complicated by brain edema and hepatic coma in a 45-year-old woman admitted with acute viral hepatitis E infection.
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Affiliation(s)
- Laurent Spahr
- Gastroenterology and Hepatology, University Hospital, Geneva, Switzerland
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Abstract
PURPOSE OF REVIEW This is a concise review of recent developments in the field of viral hepatitis, based on publications between December 2006 and November 2007. RECENT FINDINGS Hepatitis A vaccine has similar efficacy to immune globulin as postexposure prophylaxis. Entecavir is a potent antiviral agent with a low rate of drug resistance in nucleoside-naïve chronic hepatitis B patients but it is not as effective in lamivudine-refractory patients. A combination of adefovir and lamivudine is preferred to adefovir monotherapy for lamivudine-refractory hepatitis B patients. Two orally administered hepatitis C protease inhibitors, telaprevir and boceprevir, were shown to have antiviral activity in hepatitis C genotype 1 patients. A 16-week course of pegylated interferon and ribavirin resulted in a lower rate of sustained virologic response compared with the standard 24-week course. Patients with hepatitis C-related cirrhosis who achieved sustained virologic response to antiviral therapy remain at risk for hepatocellular carcinoma. A novel recombinant hepatitis E vaccine was shown to be safe and effective in preventing infection. SUMMARY Advances have been made in the prevention of hepatitis A and hepatitis E. It is likely that specifically targeted antiviral therapies for hepatitis C will be available in the next few years.
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