Zapalenie wątroby typu E jako nowe nadchodzące wyzwanie związane z zakażeniem endemicznym
Chair and Department of Infectious Diseases, University of Medical Sciences, Poznań
Head of Chair: prof. Iwona Mozer-Lisewska, MD, PhD
In his classical system of viral hepatitis, MacCallum distinguished two types of the disease: serum hepatitis and infectious hepatitis (1). In subsequent decades, several primary hepatotropic viruses were identified, which helped to extend MacCallum’s classification, following its basic structure, where the major transmission route for infection was the key criterion for classification. According to the extended system, the group of enterically transmitted viruses (mainly via the faecal-oral route) includes hepatitis A and E viruses (HAV and HEV), while the parenterally transmitted viruses include hepatitis B, C and D viruses (HBV, HCV and HDV).
HEV identification was associated with the epidemics of hepatitis of unknown aetiology which occurred among Soviet soldiers stationed in Afghanistan in the 1980s (2). One of the researchers ingested a faecal extract derived from patients. The researcher contracted the disease, and an electron microscope examination of his stools revealed the presence of spheroid virus-like particles of 27 to 30 nm in diameter. The particles reacted with sera from the patients and serum from the researcher taken a few weeks after the infection occurred. It was possible that the new infectious factor was transmitted to other primates (crab-eating macaque, Macaca fascicularis), causing similar symptoms in them. The HEV genome was described at the beginning of the following decade (3, 4).
The first virology analyses suggested that this previously unidentified aetiological factor of enterically transmitted non-A, non-B hepatitis was similar to viruses from the Caliciviridae family and for this reason HEV was classified to this group for a certain time. However, because of significant differences in the organisation of the genome, the virus was finally classified to a separate family, Hepeviridae (genus Hepevirus) (5).
HEV is a small (27-34 nm), spheroid, non-enveloped virus, with icosahedral symmetry, containing a single-strand positive-sense RNA that is approximately 7200 bases in length. The genome is organized in three open reading frames (ORF1-3), limited from both ends (5’ and 3’) with non-coding regions. The product of ORF1 is a large non-structural polyprotein whose components play a key role in virus replication (e.g. RNA-dependent RNA polymerase activity) (6). ORF2 encodes the structural protein of the viral capsid, which contains epitopes inducing the formation of neutralizing antibodies (6). Numerous antigens originating from ORF2 are basic design elements for various serological assays used in the diagnostics of HEV infection. In addition, recombined products of this region have been used for the production of preventive vaccines. The ORF3 derivative is a small-size phosphoprotein linked with the cytoskeleton and the HEV capsid protein (6). It is thought to optimize the conditions in the host cell by facilitating virus replication, inhibiting the mechanisms of natural immune response, and taking part in the process of HEV leaving the infected cell. ORF3 protein is the key substance determining the in vivo infectivity of HEV. HEV replicates in the cytoplasm of the infected host cells.
Although the heterogeneity of HEV strains able to cause the disease in humans is significant (4 genotypes and at least 24 subtypes) (7), all variants represent one serotype of the virus (8). Genotypes 1 and 2 cause infections only in humans and primates, while infections caused by genotypes 3 and 4 also affect certain species of other mammals (domestic swine, wild boar, deer), which can be a source of zoonotic diseases transmitted to humans (9). Anti-HEV and/or HEV-RNA antibodies were found in a wider range of animals (chickens, rabbits, rats, mongooses, ferrets, dogs, cats, goats, cattle, horses and sheep), but it is not known whether this fact has any practical role in the aspect of human disease (10, 11).
The genetic diversity of HEV has important practical implications because individual genotypes are characterized by different geographical coverage and a number of epidemiological particulars. In addition, there are differences in the clinical course of individual variants of the viral infections in humans. The strains belonging to genotype 1 are present in the developing countries of Asia and Africa, genotype 2 was found in Mexico, Chad and Nigeria, but genotype 3 has the widest distribution, occurring throughout the world (except Africa). Finally, genotype 4 is found mainly in Asia, but a small number of cases have also been reported from Western Europe (7, 12, 13).
1. MacCallum FO: Homologous serum jaundice. Lancet 1947; 2: 691-692.
2. Balayan MS, Andjaparidze AG, Savinskaya SS et al.: Evidence for a virus in non-A, non-B hepatitis transmitted via the fecal-oral route. Intervirology 1983; 20: 23-31.
3. Reyes GR, Purdy MA, Kim JP et al.: Isolation of a cDNA from the virus responsible for enterically transmitted non-A, non-B hepatitis. Science 1990; 247: 1335-1339.
4. Tam AW, Smith MM, Guerra ME et al.: Hepatitis E virus (HEV): molecular cloning and sequencing of the full-length viral genome. Virology 1991; 185: 120-131.
5. Emerson SU, Anderson D, Arankalle A et al.: Hepevirus. [In:] Fauquet CM, Mayo MA, Maniloff J et al. (eds.): Virus Taxonomy: VIIIth Report of the ICTV. Elsevier/Academic Press, London 2004: 851-855.
6. Ahmad I, Holla RP, Jameel S: Molecular virology of hepatitis E virus. Virus Res 2011; 161: 47-58.
7. Lu L, Li C, Hagedorn CH: Phylogenetic analysis of global hepatitis E virus sequences: genetic diversity, subtypes and zoonosis. Rev Med Virol 2006; 16: 5-36.
8. Tang X, Yang C, Gu Y et al.: Structural basis for the neutralization and genotype specificity of hepatitis E virus. Proc Natl Acad Sci USA 2011; 108: 10266-10271.
9. Purdy MA, Khudyakov YE: The molecular epidemiology of hepatitis E virus infection. Virus Res 2011; 161: 31-39.
10. Meng XJ: From barnyard to food table: the omnipresence of hepatitis E virus and risk for zoonotic infection and food safety. Virus Res 2011; 161: 23-30.
11. Scobie L, Dalton HR: Hepatitis E: source and route of infection, clinical manifestations and new developments. J Viral Hepat 2013; 20: 1-11.
12. Wichmann O, Schimanski S, Koch J et al.: Phylogenetic and case-control study on hepatitis E virus infection in Germany. J Infect Dis 2008; 198: 1732-1741.
13. Tessè S, Lioure B, Fornecker L et al.: Circulation of genotype 4 hepatitis E virus in Europe: first autochthonous hepatitis E infection in France. J Clin Virol 2012; 54: 197-200.
14. Wawrzynowicz-Syczewska M: Wirusowe zapalenie wątroby typu E. [W:] Cianciara J, Juszczyk J (red.): Choroby zakaźne i pasożytnicze. Wyd. 1, Wydawnictwo Czelej, Lublin 2007: 591-593.
15. Kumar S, Subhadra S, Singh B et al.: Hepatitis E virus: the current scenario. Int J Infect Dis 2013; 17: e228-233.
16. Hamid SS, Atiq M, Shehzad F et al.: Hepatitis E virus superinfection in patients with chronic liver disease. Hepatology 2002; 36: 474-478.
17. Kumar A, Aggarwal R, Naik SR et al.: Hepatitis E virus is responsible for decompensation of chronic liver disease in an endemic region. Indian J Gastroenterol 2004; 23: 59-62.
18. Dawson GJ, Chau KH, Cabal CM et al.: Solid-phase enzyme-linked immunosorbent assay for hepatitis E virus IgG and IgM antibodies utilizing recombinant antigens and synthetic peptides. J Virol Methods 1992; 38: 175-186.
19. Lavanchy D, Morel B, Frei PC: Seroprevalence of hepatitis E virus in Switzerland. Lancet 1994; 344: 747-748.
20. Zaaijer HL, Kok M, Lelie PN et al.: Hepatitis E in the Netherlands: imported and endemic. Lancet 1993; 341: 826.
21. Juszczyk J: Wirusowe zapalenie wątroby typu E. [W:] Juszczyk J: Wirusowe zapalenia wątroby. Wydawnictwo Lekarskie PZWL, Warszawa 1999: 312-319.
22. Mansuy JM, Peron JM, Abravanel F et al.: Hepatitis E in the south west of France in individuals who have never visited an endemic area. J Med Virol 2004; 74: 419-424.
23. Sainokami S, Abe K, Kumagai I et al.: Epidemiological and clinical study of sporadic acute hepatitis E caused by indigenous strains of hepatitis E virus in Japan compared with acute hepatitis A. J Gastroenterol 2004; 39: 640-648.
24. Ijaz S, Arnold E, Banks M et al.: Non-travel-associated hepatitis E in England and Wales: demographic, clinical, and molecular epidemiological characteristics. J Infect Dis 2005; 192: 1166-1172.
25. Dalton HR, Fellows HJ, Gane EJ et al.: Hepatitis E in New Zealand. J Gastroenterol Hepatol 2007; 22: 1236-1240.
26. Borgen K, Herremans T, Duizer E et al.: Non-travel related Hepatitis E virus genotype 3 infections in the Netherlands; a case series 2004-2006. BMC Infect Dis 2008; 8: 61.
27. Fogeda M, Avellón A, Cilla CG et al.: Imported and autochthonous hepatitis E virus strains in Spain. J Med Virol 2009; 81: 1743-1749.
28. Drobeniuc J, Greene-Montfort T, Le NT et al.: Laboratory-based surveillance for hepatitis E virus infection, United States, 2005-2012. Emerg Infect Dis 2013; 19: 218-222.
29. Fukuda S, Sunaga J, Saito N et al.: Prevalence of antibodies to hepatitis E virus among Japanese blood donors: identification of three blood donors infected with a genotype 3 hepatitis E virus. J Med Virol 2004; 73: 554-561.
30. Kaufmann A, Kenfak-Foguena A, Andrè C et al.: Hepatitis E virus seroprevalence among blood donors in southwest Switzerland. PLoS One 2011; 6: e21150.
31. Rapicetta M, Monarca R, Kondili LA et al.: Hepatitis E virus and hepatitis A virus exposures in an apparently healthy high-risk population in Italy. Infection 2013; 41: 69-76.
32. Bendall R, Ellis V, Ijaz S et al.: A comparison of two commercially available anti-HEV IgG kits and a re-evaluation of anti-HEV IgG seroprevalence data in developed countries. J Med Virol 2010; 82: 799-805.
33. Faber MS, Wenzel JJ, Jilg W et al.: Hepatitis E virus seroprevalence among adults, Germany. Emerg Infect Dis 2012; 18: 1654-1657.
34. Meng XJ, Wiseman B, Elvinger F et al.: Prevalence of antibodies to hepatitis E virus in veterinarians working with swine and in normal blood donors in the United States and other countries. J Clin Microbiol 2002; 40: 117-122.
35. Christensen PB, Engle RE, Hjort C et al.: Time trend of the prevalence of hepatitis E antibodies among farmers and blood donors: a potential zoonosis in Denmark. Clin Infect Dis 2008; 47: 1026-1031.
36. Mansuy JM, Bendall R, Legrand-Abravanel F et al.: Hepatitis E virus antibodies in blood donors, France. Emerg Infect Dis 2011; 17: 2309-2312.
37. Takahashi M, Okamoto H: Features of hepatitis E virus infection in humans and animals in Japan. Hepatol Res 2014; 44: 43-58.
38. Berto A, Martelli F, Grierson S et al.: Hepatitis E virus in pork food chain, United Kingdom, 2009-2010. Emerg Infect Dis 2012; 18: 1358-1360.
39. Said B, Ijaz S, Kafatos G et al.: Hepatitis E Incident Investigation Team: Hepatitis E outbreak on cruise ship. Emerg Infect Dis 2009; 15: 1738-1744.
40. Pèron JM, Bureau C, Poirson H et al.: Fulminant liver failure from acute autochthonous hepatitis E in France: description of seven patients with acute hepatitis E and encephalopathy. J Viral Hepat 2007; 14: 298-303.
41. Dalton HR, Stableforth W, Thurairajah P et al.: Autochthonous hepatitis E in Southwest England: natural history, complications and seasonal variation, and hepatitis E virus IgG seroprevalence in blood donors, the elderly and patients with chronic liver disease. Eur J Gastroenterol Hepatol 2008; 20: 784-790.
42. Atiq M, Shire NJ, Barrett A et al.: Hepatitis E virus antibodies in patients with chronic liver disease. Emerg Infect Dis 2009; 15: 479-481.
43. Mansuy JM, Abravanel F, Miedouge M et al.: Acute hepatitis E in south-west France over a 5-year period. J Clin Virol 2009; 44: 74-77.
44. Aggarwal R: Clinical presentation of hepatitis E. Virus Res 2011; 161: 15-22.
45. Khuroo MS: Study of an epidemic of non-A, non-B hepatitis. Possibility of another human hepatitis virus distinct from post-transfusion non-A, non-B type. Am J Med 1980; 68: 818-824.
46. Myint H, Soe MM, Khin T et al.: A clinical and epidemiological study of an epidemic of non-A non-B hepatitis in Rangoon. Am J Trop Med Hyg 1985; 34: 1183-1189.
47. Boccia D, Guthmann JP, Klovstad H et al.: High mortality associated with an outbreak of hepatitis E among displaced persons in Darfur, Sudan. Clin Infect Dis 2006; 42: 1679-1684.
48. Jilani N, Das BC, Husain SA et al.: Hepatitis E virus infection and fulminant hepatic failure during pregnancy. J Gastroenterol Hepatol 2007; 22: 676-682.
49. Bhatia V, Singhal A, Panda SK et al.: A 20-year single-center experience with acute liver failure during pregnancy: is the prognosis really worse? Hepatology 2008; 48: 1577-1585.
50. Kamar N, Bendall R, Legrand-Abravanel F et al.: Hepatitis E. Lancet 2012; 379: 2477-2488.
51. Mechnik L, Bergman N, Attali M et al.: Acute hepatitis E virus infection presenting as a prolonged cholestatic jaundice. J Clin Gastroenterol 2001; 33: 421-422.
52. Tamura A, Shimizu YK, Tanaka T et al.: Persistent infection of hepatitis E virus transmitted by blood transfusion in a patient with T-cell lymphoma. Hepatol Res 2007; 37: 113-120.
53. Kamar N, Selves J, Mansuy JM et al.: Hepatitis E virus and chronic hepatitis in organ-transplant recipients. N Engl J Med 2008; 358: 811-817.
54. Dalton HR, Bendall RP, Keane FE et al.: Persistent carriage of hepatitis E virus in patients with HIV infection. N Engl J Med 2009; 361: 1025-1027.
55. Ollier L, Tieulie N, Sanderson F et al.: Chronic hepatitis after hepatitis E virus infection in a patient with non-Hodgkin lymphoma taking rituximab. Ann Intern Med 2009; 150: 430-431.
56. Dalton HR, Keane FE, Bendall R et al.: Treatment of chronic hepatitis E in a patient with HIV infection. Ann Intern Med 2011; 155: 479-480.
57. Kamar N, Bendall RP, Peron JM et al.: Hepatitis E virus and neurologic disorders. Emerg Infect Dis 2011; 17: 173-179.
58. Fourquet E, Mansuy JM, Bureau C et al.: Severe thrombocytopenia associated with acute autochthonous hepatitis E. J Clin Virol 2010; 48: 73-74.
59. Shah SA, Lal A, Idrees M et al.: Hepatitis E virus-associated aplastic anaemia: the first case of its kind. J Clin Virol 2012; 54: 96-97.
60. Jaroszewicz J, Flisiak R, Kalinowska A et al.: Acute hepatitis E complicated by acute pancreatitis: a case report and literature review. Pancreas 2005; 30: 382-384.
61. Del Bello A, Arnè-Bes MC, Lavayssière L et al.: Hepatitis E virus-induced severe myositis. J Hepatol 2012; 57: 1152-1153.
62. Ali G, Kumar M, Bali SK et al.: Hepatitis E associated immune thrombocytopenia and membranous glomerulonephritis. Indian J Nephrol 2001; 11: 70-72.
63. Kamar N, Weclawiak H, Guilbeau-Frugier C et al.: Hepatitis E virus and the kidney in solid-organ transplant patients. Transplantation 2012; 93: 617-623.
64. Khudyakov Y, Kamili S: Serological diagnostics of hepatitis E virus infection. Virus Res 2011; 161: 84-92.
65. Baylis SA, Blümel J, Mizusawa S et al.: HEV Collaborative Study Group: World Health Organization International Standard to harmonize assays for detection of hepatitis E virus RNA. Emerg Infect Dis 2013; 19: 729-735.
66. Gerolami R, Borentain P, Raissouni F et al.: Treatment of severe acute hepatitis E by ribavirin. J Clin Virol 2011; 52: 60-62.
67. Kamar N, Rostaing L, Abravanel F et al.: Ribavirin therapy inhibits viral replication on patients with chronic hepatitis E virus infection. Gastroenterology 2010; 139: 1612-1618.
68. Kamar N, Rostaing L, Abravanel F et al.: Pegylated interferon-alpha for treating chronic hepatitis E virus infection after liver transplantation. Clin Infect Dis 2010; 50: e30-33.
69. Haagsma EB, Riezebos-Brilman A, van den Berg AP et al.: Treatment of chronic hepatitis E in liver transplant recipients with pegylated interferon alpha-2b. Liver Transpl 2010; 16: 474-477.
70. Chaillon A, Sirinelli A, De Muret A et al.: Sustained virologic response with ribavirin in chronic hepatitis E virus infection in heart transplantation. J Heart Lung Transplant 2011; 30: 841-843.
71. Alric L, Bonnet D, Beynes-Rauzy O et al.: Definitive clearance of a chronic hepatitis E virus infection with ribavirin treatment. Am J Gastroenterol 2011; 106: 1562-1563.
72. Giordani MT, Fabris P, Brunetti E et al.: Hepatitis E and lymphocytic leukemia in man, Italy. Emerg Infect Dis 2013; 19: 2054-2056.
73. Neukam K, Barreiro P, Macías J et al.: Chronic hepatitis E in HIV patients: rapid progression to cirrhosis and response to oral ribavirin. Clin Infect Dis 2013; 57: 465-468.
74. Zhang J, Shih JW, Wu T et al.: Development of the hepatitis E vaccine: from bench to field. Semin Liver Dis 2013; 33: 79-88.
75. Shrestha MP, Scott RM, Joshi DM et al.: Safety and efficacy of a recombinant hepatitis E vaccine. N Engl J Med 2007; 356: 895-903.
76. Zhu FC, Zhang J, Zhang XF et al.: Efficacy and safety of a recombinant HEV vaccine in healthy adults: a large scale, randomised, double-blind, placebo controlled, phase 3 trial. Lancet 2010; 376: 895-902.
77. Park SB: Hepatitis E vaccine debuts. Nature 2012; 491: 21-22.