Hepatitis E pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]
Overview
Consensus has not been reached regarding the complete pathogenesis of HEV. Evidence shows that the virus exposes its RNA within the host cell's cytoplasm, where it is translated into a negative RNA strand that contains ORFs 1, 2 and 3 that are involved in the replication of the virus. HEV is not cytopathic, and the manifestations of the disease result from the body's immune response towards the infected cells. The transmission of the disease depends on the genotype of the virus. It may be transmitted through ingestion of contaminated water, in genotypes 1 and 2, or ingestion of uncooked meat, genotypes 3 and 4. Acute hepatitis E has been noted to progress to chronic disease in HIV infected patients with a low CD4 count. Solid organ transplanted patients are commonly asymptomatic, or have mild symptoms of the disease. 60% of infected patients with an organ transplant, develop chronic hepatitis E, and 10% develop liver cirrhosis. Infection is usually due to HEV genotype 3, and diagnostic studies should be based on the identification of HEV RNA by PCR technique. Histological changes of the liver of patients with chronic disease include: portal hepatitis; lymphocytic infiltrates; necrosis; and fibrosis.
Pathogenesis
The cellular receptor for HEV and the mode of entry of the virus into the host cell are yet to be identified.[1] However, heparin sulfate proteoglycans are known to be required for the attachment to target cells and infection. A proposed theory for the replication of virus is that, once within the host cell, HEV exposes its RNA, which is then translated into proteins (ORF1) that will be responsible for the production of a negative-strand RNA. This newly produced strand will serve as a template for new RNAs. The new RNAs, are translated to ORF2 and ORF3. The ORF proteins will then transport the RNA into new virions that will use cellular lipids and ORF3 for their formation.[2][3]
Similarly to other hepatitis viruses, HEV is not cytopathic. The host's immune response towards the infected cells is the cause of liver injury.[2]
Although the pathogenesis behind the increased mortality of infected pregnant women is not completely understood, it is thought to be associated with hepatocyte injury from endotoxins, and an increased Th2 response.[4]
Transmission
Hepatitis E is mainly transmitted through the fecal-oral route. In developing countries it occurs mostly from the ingestion of contaminated water.[5] Although person to person transmission is uncommon, a recent case in Uganda has suggested possible transmission among persons living in the same house.[6]
Some genotypes are more associated with a specific route of transmission:[5]
- Genotypes 1 and 2 - waterborne transmission
- Genotypes 3 and 4 - ingestion of uncooked meat
Other noted routes of transmission include:[5][7]
- Transmission through blood transfusions
- Transmission through organ transplants
- Vertical transmission from an infected mother to the fetus
Associated Conditions
HIV Co-Infection
There is a low incidence of persistent infection with HEV in HIV patients.[8][9][10] However, acute HEV infection in these patients, particularly in those with low levels of CD4, is associated with progression to chronic disease.[5]
Organ Transplant Recipients
Chronic hepatitis E is associated with organ transplants, including liver, kidney and heart.[11][12][13] Cases have been reported in which liver transplants carrying HEV, lead to rapid liver cirrhosis.[14] Patients who have received a solid organ transplant, with elevated levels of liver enzymes, in the absence of other causes of hepatitis, should be evaluated for HEV RNA.[15]
Chronic hepatitis E in organ transplanted patients commonly has the following features:[5][16]
| Parameter | Features |
|---|---|
| Clinical Manifestations | Mild symptoms or asymptomatic Jaundice is present in few patients |
| ALT Levels at Diagnosis | Mild ALT elevation (≈300 IU/L) |
| Viral Genotype | Genotype 3 |
| Diagnostic Techniques |
Inaccurate serologic tests |
| Outcomes | 60% infected patients develop chronic hepatitis E 10% infected patients develop liver cirrhosis |
Failure to clear the virus after acute infection may be explained by:[12][16]
- Level of immunosuppression
- Period between infection and latest episode of acute rejection
- Time since organ transplant
- Low leukocytes levels
- Low lymphocyte count
- Low levels of T-cells
Microscopic Pathology
Patients who develop chronic liver disease often have changes in liver histology. These may include:[2]
- Portal hepatitis
- Lymphocytic infiltrates
- Necrosis
- Fibrosis
In severe cases, these changes may evolve to fibrosis and cirrhosis.[2][13]
References
- ↑ Kalia M, Chandra V, Rahman SA, Sehgal D, Jameel S (2009). "Heparan sulfate proteoglycans are required for cellular binding of the hepatitis E virus ORF2 capsid protein and for viral infection". J Virol. 83 (24): 12714–24. doi:10.1128/JVI.00717-09. PMC 2786843. PMID 19812150.
- ↑ 2.0 2.1 2.2 2.3 Aggarwal R, Jameel S (2011). "Hepatitis E." Hepatology. 54 (6): 2218–26. doi:10.1002/hep.24674. PMID 21932388.
- ↑ Nagashima S, Takahashi M, Tanaka T, Yamada K, Nishizawa T; et al. (2011). "A PSAP motif in the ORF3 protein of hepatitis E virus is necessary for virion release from infected cells". J Gen Virol. 92 (Pt 2): 269–78. doi:10.1099/vir.0.025791-0. PMID 21068219.
- ↑ Pal R, Aggarwal R, Naik SR, Das V, Das S, Naik S (2005). "Immunological alterations in pregnant women with acute hepatitis E." J Gastroenterol Hepatol. 20 (7): 1094–101. doi:10.1111/j.1440-1746.2005.03875.x. PMID 15955220.
- ↑ 5.0 5.1 5.2 5.3 5.4 Kamar N, Bendall R, Legrand-Abravanel F, Xia NS, Ijaz S, Izopet J; et al. (2012). "Hepatitis E." Lancet. 379 (9835): 2477–88. doi:10.1016/S0140-6736(11)61849-7. PMID 22549046.
- ↑ Howard CM, Handzel T, Hill VR, Grytdal SP, Blanton C, Kamili S; et al. (2010). "Novel risk factors associated with hepatitis E virus infection in a large outbreak in northern Uganda: results from a case-control study and environmental analysis". Am J Trop Med Hyg. 83 (5): 1170–3. doi:10.4269/ajtmh.2010.10-0384. PMC 2963989. PMID 21036857.
- ↑ Hoofnagle JH, Nelson KE, Purcell RH (2012). "Hepatitis E." N Engl J Med. 367 (13): 1237–44. doi:10.1056/NEJMra1204512. PMID 23013075.
- ↑ Kenfak-Foguena A, Schöni-Affolter F, Bürgisser P, Witteck A, Darling KE, Kovari H; et al. (2011). "Hepatitis E Virus seroprevalence and chronic infections in patients with HIV, Switzerland". Emerg Infect Dis. 17 (6): 1074–8. doi:10.3201/eid/1706.101067. PMC 3358194. PMID 21749774.
- ↑ Keane F, Gompels M, Bendall R, Drayton R, Jennings L, Black J; et al. (2012). "Hepatitis E virus coinfection in patients with HIV infection". HIV Med. 13 (1): 83–8. doi:10.1111/j.1468-1293.2011.00942.x. PMID 21819531.
- ↑ Kaba M, Richet H, Ravaux I, Moreau J, Poizot-Martin I, Motte A; et al. (2011). "Hepatitis E virus infection in patients infected with the human immunodeficiency virus". J Med Virol. 83 (10): 1704–16. doi:10.1002/jmv.22177. PMID 21837786.
- ↑ Pischke S, Suneetha PV, Baechlein C, Barg-Hock H, Heim A, Kamar N; et al. (2010). "Hepatitis E virus infection as a cause of graft hepatitis in liver transplant recipients". Liver Transpl. 16 (1): 74–82. doi:10.1002/lt.21958. PMID 19866448.
- ↑ 12.0 12.1 Kamar N, Selves J, Mansuy JM, Ouezzani L, Péron JM, Guitard J; et al. (2008). "Hepatitis E virus and chronic hepatitis in organ-transplant recipients". N Engl J Med. 358 (8): 811–7. doi:10.1056/NEJMoa0706992. PMID 18287603.
- ↑ 13.0 13.1 Gérolami R, Moal V, Colson P (2008). "Chronic hepatitis E with cirrhosis in a kidney-transplant recipient". N Engl J Med. 358 (8): 859–60. doi:10.1056/NEJMc0708687. PMID 18287615.
- ↑ Schlosser B, Stein A, Neuhaus R, Pahl S, Ramez B, Krüger DH; et al. (2012). "Liver transplant from a donor with occult HEV infection induced chronic hepatitis and cirrhosis in the recipient". J Hepatol. 56 (2): 500–2. doi:10.1016/j.jhep.2011.06.021. PMID 21798217.
- ↑ Wedemeyer H, Pischke S, Manns MP (2012). "Pathogenesis and treatment of hepatitis e virus infection". Gastroenterology. 142 (6): 1388–1397.e1. doi:10.1053/j.gastro.2012.02.014. PMID 22537448.
- ↑ 16.0 16.1 Kamar N, Garrouste C, Haagsma EB, Garrigue V, Pischke S, Chauvet C; et al. (2011). "Factors associated with chronic hepatitis in patients with hepatitis E virus infection who have received solid organ transplants". Gastroenterology. 140 (5): 1481–9. doi:10.1053/j.gastro.2011.02.050. PMID 21354150.