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Hepatitis E

This page is about clinical aspects of the disease.  For microbiologic aspects of the causative organism(s), see Hepatitis E Virus.

For patient information click here

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Synonyms and keywords: Hep E; HEV; HEV infection; Viral hepatitis type E

Overview

Overview

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Hepatitis E is an acute viral hepatitis (liver inflammation) caused by infection with a virus called hepatitis E virus (HEV). Infection with this virus was first documented in 1955 during an outbreak in New Delhi, India.[1] [2]

Overview

Historical Perspective

Pathophysiology

Causes

Epidemiology and Demographics

Risk Factors

Screening

Differentiating Hepatitis E from other Diseases

Natural History, Complications and Prognosis

History and Symptoms

Physical Examination

Laboratory Findings

Medical Therapy

Prevention

Cost-Effectiveness of Therapy

Future or Investigational Therapies

References

  1. ↑ Gupta DN, Smetana HF (1957). “The histopathology of viral hepatitis as seen in the Delhi epidemic (1955-56)”. Indian J. Med. Res. 45 (Suppl.): 101–13. PMID 13438544.

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Historical Perspective

Historical Perspective

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

The hepatitis E virus (HEV) was discovered in 1980 by a soviet researcher. Its most recent ancestor is thought to have evolved between 536 and 1344 years ago. It has evolved into two initial clades, that lately would be classified and divided in 4 different genotypes. Genotypes 1, 3 and 4 have seen their effective population sizes increased during the 20th century.

Historical Perspective

In 1980, the hepatitis E virus was discovered during the occupation of Afghanistan by the soviet troops. The virus was responsible for an outbreak of the disease among the troops. In order to make the discovery, a member of the research team ingested fecal extract from the affected soldiers, and became sick. The virus was then detected in the stool of the researcher by electron microscopy.[1]

After this discovery, the HEV was identified as responsible for many endemic cases of hepatitis in developing countries. Today, HEV is the most common global cause of viral hepatitis.[1]

The most recent common ancestor of Hepatitis E evolved between 536 and 1344 years ago.[2] It diverged into two clades—an anthropotropic and an enzootic form – which subsequently evolved into genotypes 1 and 2 and genotypes 3 and 4 respectively. The divergence dates for the various genotypes are as follows: Genotypes 1/2 367–656 years ago; Genotypes 3/4 417–679 years ago. For the most recent common ancestor of the various viruses themselves: Genotype 1 between 87 and 199 years ago; Genotype 3 between 265 and 342 years ago; and Genotype 4 between 131 and 266 years ago. The anthropotropic strains (genotypes 1 and 2) have evolved more recently than the others suggesting that this virus was originally a zoonosis.

In 1983, the virus particle was first visualised.[3]

In 1990, hepatitis E virus was only molecularly cloned.[4]

The use of an avian strain confirmed the proposed topology of the genotypes 1–4 and suggested that the genus may have evolved throughout the years.[2] The use of a rat sequence also confirmed this topology and estimated that the date of divergence from the swine/human strains was 7.44×104 years ago (range 2.1×104 to 1.4×105 years ago). Since this date is approximately coincident with the advent of agriculture, the virus may have originally infected rats and subsequently spread to pigs and then to humans. Additional work is required to support or refute this possibility, as very few sequences have been isolated from species other than humans and suids.

Genotypes 1, 3 and 4 have all increased their effective population sizes in the 20th century.[2] The population size of genotype 1 increased noticeably in the last 30–35 years, while genotypes 3 and 4 have only began to increase their population sized in the late 19th century.

References

  1. ↑ 1.0 1.1 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.
  2. ↑ 2.0 2.1 2.2 Tavis, John E.; Purdy, Michael A.; Khudyakov, Yury E. (2010). “Evolutionary History and Population Dynamics of Hepatitis E Virus”. PLoS ONE. 5 (12): e14376. doi:10.1371/journal.pone.0014376. ISSN 1932-6203.
  3. ↑ Balayan MS, Andjaparidze AG, Savinskaya SS; et al. (1983). “Evidence for a virus in non-A, non-B hepatitis transmitted via the fecal-oral route”. Intervirology. 20 (1): 23–31. PMID 6409836.
  4. ↑ Reyes GR, Purdy MA, Kim JP; et al. (1990). “Isolation of a cDNA from the virus responsible for enterically transmitted non-A, non-B hepatitis”. Science. 247 (4948): 1335–9. doi:10.1126/science.2107574. PMID 2107574.

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Pathophysiology

Pathophysiology

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]

Other noted routes of transmission include:[5][7]

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]

Organ Transplanted Patients
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
Anti-HEV IgM and anti-HEV IgG may be negative
Seroconversion may not occur
PCR should make the diagnosis

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]

Microscopic Pathology

Patients who develop chronic liver disease often have changes in liver histology. These may include:[2]

In severe cases, these changes may evolve to fibrosis and cirrhosis.[2][13]

References

  1. ↑ 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. ↑ 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.
  3. ↑ 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.
  4. ↑ 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. ↑ 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.
  6. ↑ 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.
  7. ↑ Hoofnagle JH, Nelson KE, Purcell RH (2012). “Hepatitis E.” N Engl J Med. 367 (13): 1237–44. doi:10.1056/NEJMra1204512. PMID 23013075.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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. ↑ 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. ↑ 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.
  14. ↑ 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.
  15. ↑ 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. ↑ 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.

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Causes

Causes

This page is about microbiologic aspects of the organism(s).  For clinical aspects of the disease, see Hepatitis E.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]


Overview

The hepatitis E virus (HEV) is the causative agent of hepatitis E. It is a member of the genus Hepevirus that belongs to the Hepeviridae family. It is a nonenveloped, single-stranded positive-sense RNA virus. The genome of HEV contains 3 Open reading frames: ORF 1, ORF 2, and ORF 3. The RNA genome acts as a template for viral replication, structural and nonstructural protein synthesis. Five different genotypes have been identified, all belonging to the same serotype. Depending on the genotype, epidemiological and clinical manifestations will be different: genotypes 1 and 2 only cause disease in humans, and are transmitted through water and fecal-oral route, while genotypes 3 and 4 cause disease in animals, having humans as accidental hosts, and are transmitted through the consumption of undercook meat. The HEV replicates within the host cell’s cytoplasm, however, its cellular receptor, and mechanism of entry remain unknown.

Taxonomy

Viruses; ssRNA viruses; ssRNA positive-strand viruses; Hepeviridae; Hepevirus; Hepatitis E virus[1]

Biology

Hepatitis E virus Centers for Disease Control and Prevention[2]

The viral particles are 27 to 34 nanometers in diameter, nonenveloped, and contain a single-strand of positive-sense RNA that is approximately 7200 bases in length, polyadenylated at the 3′ terminus, and capped at the 5’terminus.[3][4][5]

The genome of HEV contains 3 Open reading frames:

Genotypes

In order to study the biology of the virus and develop new treatment drugs, HEV must be grown in culture systems, such as:

  • PLC/PRF/5 cell line of hepatic carcinoma, A549 cell line of lung carcinoma, and fecal samples from an infected patient[13]
  • HepG2/C3A cell line of hepatoma[14]

Molecular studies of HEV lead to the classification of the virus into 4 genotypes:[3][15][16][17][18][6][19][20][21]

Genotypes
Genotype Characteristics
HEV1
HEV2
  • Restricted to humans
  • Responsible for epidemic hepatitis
  • Water-borne disease in developing countries
  • Fecal-oral route of transmission
  • Predominant in Central America and Africa
  • Classified in 2 subgenotypes
HEV3
  • Infects humans (accidental host) and other mammalian species, such as pigs, deer, shellfish and rodents (zoonosis)
  • Responsible for autochthonous hepatitis E in developed and developing countries
  • Worldwide distribution
  • Consumption of undercooked pork
  • Classified in 3 subgenotypes
  • Important zoonotic transmission
HEV4
  • Infects humans (accidental host) and other mammalian species, such as pigs, deer, shellfish and rodents (zoonosis)
  • Responsible for autochthonous hepatitis E in developed and developing countries
  • Most frequent in southeast Asia
  • Consumption of undercooked pork
  • Classified in 7 subgenotypes
  • Important zoonotic transmission
HEV5
  • Recently identified in birds (Avian HEV)

Despite the epidemiological and clinical differences, the different genotypes are thought to belong to one same serotype, after studies with cross-neutralization.[22] Evidence shows that HEV has evolved and adapted to a series of hosts, until finally being able to infect humans. HEV subgenotypes in humans and pigs have been associated, also suggesting zoonotic transmission.[3][23][24]

Life Cycle

The hepatitis E virus replicates in the cytoplasm of the host cell. The genomic RNA serves as template chain for replication and encodes nonstructural proteins, while subgenomic RNA produces capsid proteins. Different recombination events may lead to changes in viral replication, tissue tropism and pathogenesis of the virus.[7]

Tropism

Hepatitis D shows tropism for hepatocytes, however, the host cell receptor has not been identified.[9]

Natural Reservoir

The natural reservoir of HEV is yet to be identified. Different observations have suggested different reservoirs:

  • Prolonged fecal shedding from patients with history of the disease has been suggested. However, the duration of viral shedding in feces is not compatible with this hypothesis.[25]
  • Environmental reservoir was suggested following detection of HEV in sewages.[26]
  • Continuous fecal shedding from asymptomatic patients was suggested as a form of maintenance of the virus, contaminating water supplies.[27]
  • The existence of an animal reservoir is supported by the detection of anti-HEV antibodies in different animal species.[27]

References

  1. ↑ “Hepatitis E virus taxonomy”.
  2. ↑ “http://phil.cdc.gov/phil/details.asp”. External link in |title= (help)
  3. ↑ 3.0 3.1 3.2 3.3 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.
  4. ↑ Reyes GR, Purdy MA, Kim JP, Luk KC, Young LM, Fry KE; et al. (1990). “Isolation of a cDNA from the virus responsible for enterically transmitted non-A, non-B hepatitis”. Science. 247 (4948): 1335–9. PMID 2107574.
  5. ↑ Tam AW, Smith MM, Guerra ME, Huang CC, Bradley DW, Fry KE; et al. (1991). “Hepatitis E virus (HEV): molecular cloning and sequencing of the full-length viral genome”. Virology. 185 (1): 120–31. PMID 1926770.
  6. ↑ 6.0 6.1 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.
  7. ↑ 7.0 7.1 Hoofnagle JH, Nelson KE, Purcell RH (2012). “Hepatitis E.” N Engl J Med. 367 (13): 1237–44. doi:10.1056/NEJMra1204512. PMID 23013075.
  8. ↑ Li TC, Yamakawa Y, Suzuki K, Tatsumi M, Razak MA, Uchida T; et al. (1997). “Expression and self-assembly of empty virus-like particles of hepatitis E virus”. J Virol. 71 (10): 7207–13. PMC 192060. PMID 9311793.
  9. ↑ 9.0 9.1 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.
  10. ↑ Xing L, Wang JC, Li TC, Yasutomi Y, Lara J, Khudyakov Y; et al. (2011). “Spatial configuration of hepatitis E virus antigenic domain”. J Virol. 85 (2): 1117–24. doi:10.1128/JVI.00657-10. PMC 3020005. PMID 21068233.
  11. ↑ Yamada K, Takahashi M, Hoshino Y, Takahashi H, Ichiyama K, Nagashima S; et al. (2009). “ORF3 protein of hepatitis E virus is essential for virion release from infected cells”. J Gen Virol. 90 (Pt 8): 1880–91. doi:10.1099/vir.0.010561-0. PMID 19339479.
  12. ↑ Emerson SU, Nguyen HT, Torian U, Burke D, Engle R, Purcell RH (2010). “Release of genotype 1 hepatitis E virus from cultured hepatoma and polarized intestinal cells depends on open reading frame 3 protein and requires an intact PXXP motif”. J Virol. 84 (18): 9059–69. doi:10.1128/JVI.00593-10. PMC 2937629. PMID 20610720.
  13. ↑ Tanaka T, Takahashi M, Kusano E, Okamoto H (2007). “Development and evaluation of an efficient cell-culture system for Hepatitis E virus”. J Gen Virol. 88 (Pt 3): 903–11. doi:10.1099/vir.0.82535-0. PMID 17325363.
  14. ↑ Shukla P, Nguyen HT, Torian U, Engle RE, Faulk K, Dalton HR; et al. (2011). “Cross-species infections of cultured cells by hepatitis E virus and discovery of an infectious virus-host recombinant”. Proc Natl Acad Sci U S A. 108 (6): 2438–43. doi:10.1073/pnas.1018878108. PMC 3038723. PMID 21262830.
  15. ↑ Dalton HR, Bendall R, Ijaz S, Banks M (2008). “Hepatitis E: an emerging infection in developed countries”. Lancet Infect Dis. 8 (11): 698–709. doi:10.1016/S1473-3099(08)70255-X. PMID 18992406.
  16. ↑ Lu L, Li C, Hagedorn CH (2006). “Phylogenetic analysis of global hepatitis E virus sequences: genetic diversity, subtypes and zoonosis”. Rev Med Virol. 16 (1): 5–36. doi:10.1002/rmv.482. PMID 16175650.
  17. ↑ Tei S, Kitajima N, Takahashi K, Mishiro S (2003). “Zoonotic transmission of hepatitis E virus from deer to human beings”. Lancet. 362 (9381): 371–3. doi:10.1016/S0140-6736(03)14025-1. PMID 12907011.
  18. ↑ Colson P, Borentain P, Queyriaux B, Kaba M, Moal V, Gallian P; et al. (2010). “Pig liver sausage as a source of hepatitis E virus transmission to humans”. J Infect Dis. 202 (6): 825–34. doi:10.1086/655898. PMID 20695796.
  19. ↑ Goens SD, Perdue ML (2004). “Hepatitis E viruses in humans and animals”. Anim Health Res Rev. 5 (2): 145–56. PMID 15984321.
  20. ↑ Meng XJ (2010). “Recent advances in Hepatitis E virus”. J Viral Hepat. 17 (3): 153–61. doi:10.1111/j.1365-2893.2009.01257.x. PMID 20040046.
  21. ↑ Meng XJ (2011). “From barnyard to food table: the omnipresence of hepatitis E virus and risk for zoonotic infection and food safety”. Virus Res. 161 (1): 23–30. doi:10.1016/j.virusres.2011.01.016. PMC 3126906. PMID 21316404.
  22. ↑ Tang X, Yang C, Gu Y, Song C, Zhang X, Wang Y; et al. (2011). “Structural basis for the neutralization and genotype specificity of hepatitis E virus”. Proc Natl Acad Sci U S A. 108 (25): 10266–71. doi:10.1073/pnas.1101309108. PMC 3121834. PMID 21642534.
  23. ↑ Legrand-Abravanel F, Mansuy JM, Dubois M, Kamar N, Peron JM, Rostaing L; et al. (2009). “Hepatitis E virus genotype 3 diversity, France”. Emerg Infect Dis. 15 (1): 110–4. doi:10.3201/eid1501.080296. PMC 2660688. PMID 19116067.
  24. ↑ Purdy MA, Khudyakov YE (2010). “Evolutionary history and population dynamics of hepatitis E virus”. PLoS One. 5 (12): e14376. doi:10.1371/journal.pone.0014376. PMC 3006657. PMID 21203540.
  25. ↑ Aggarwal R, Kini D, Sofat S, Naik SR, Krawczynski K (2000). “Duration of viraemia and faecal viral excretion in acute hepatitis E.” Lancet. 356 (9235): 1081–2. doi:10.1016/S0140-6736(00)02737-9. PMID 11009149.
  26. ↑ Ippagunta SK, Naik S, Sharma B, Aggarwal R (2007). “Presence of hepatitis E virus in sewage in Northern India: frequency and seasonal pattern”. J Med Virol. 79 (12): 1827–31. doi:10.1002/jmv.21017. PMID 17935174.
  27. ↑ 27.0 27.1 Aggarwal R, Jameel S (2011). “Hepatitis E.” Hepatology. 54 (6): 2218–26. doi:10.1002/hep.24674. PMID 21932388.
Epidemiology and Demographics

Epidemiology and Demographics

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Overview

An estimated 20 million HEV infections and 3.3 million acute cases occur annually worldwide with an estimated 56 600 deaths.[1] HEV displays different epidemiological and clinical characteristics between developing and developed countries.[2] In the United States, studies show an incidence of 700 cases per 100,000 of the overall population, and a seroprevalence of 21,000 per 100,000 persons. Clinical manifestations of hepatitis E are more frequent among adult patients. When compared to men, women have a smaller rate of hepatitis E (20,4% vs 21,6%). Pregnant women are more prone to develop severe cases of the disease. In developed countries, the disease often occurs as small outbreaks, commonly transmitted by ingestion of undercooked meat. In developing countries, the disease may occur as an epidemic, or as outbreaks, and is often associated with genotypes 1 and 2, which are transmitted through the ingestion of contaminated water.

Prevalence

Levels of endemicity for HEVAdapted from Center for Disease Control and Prevention(CDC)[2]

In the United States, the seroprevalence of hepatitis E is 21,000 per 100,000 (21%) of the overall population.[3]

Incidence

The estimated annual incidence of hepatitis E in the United States is 700 per 100,000 (0.7%) of the overall population.[4]

Age

Clinical manifestations of hepatitis E are highest in young adults aged 15 to 49 years.[2] The rate of anti-HEV antibodies increases with age. According to a survey conducted in the US from 1988 to 1994, this rate can range from 10% (6 to 10 years) to 40% (>60 years).[5]

Gender

Women have a smaller rate of anti-HEV antibodies (20.4%) than men (21.6%).[3]

Pregnant Women

Although pregnant women have the same exposure to the virus as other people, due to their micronutrient status and cytokine levels, they are more prone to the severe form of the disease. [6]

In outbreak-prone areas, pregnant women (whether infected sporadically or during an epidemic) are at risk of progressing to liver failure and death after infection. Miscarriages and neonatal death occur commonly as a result of HEV infection.[2]

Race

After adjusting to age, the rate of anti-HEV antibodies was noted to be higher in non-hispanic whites (22.1%) than among blacks (14.5%).[5]

Developed Countries

Small outbreaks and individual cases of hepatitis E are often related to consumption of undercook pork, shellfish, as well as to blood transfusions.[6][7][8][9] The rate of anti-HEV antibodies is lower than in developing countries. [6]

Developing Countries

Hepatitis E may occur either as a sporadic case, or as an epidemic disease. It is often caused by genotypes 1 (Asia) and 2 (Central America and Africa).[10] Anti-HEV antibodies were detected in 30 to 80% of adults.[6]

The highest seroprevalence rates are observed in regions with low standards of sanitation, which increase the risk of viral transmission. Over 60% of all HEV infections and 65% of all hepatitis E deaths occur in East and South Asia, where seroprevalence rates of 25% are common in some age groups. In Egypt, half the population older than five years is serologically positive for the hepatitis E virus.[1]

Men in developing countries manifest symptoms of hepatitis E 2 to 5 times more than women during outbreaks.[11][12]

References

  1. ↑ 1.0 1.1 “Hepatitis E”.
  2. ↑ 2.0 2.1 2.2 2.3 “Hepatitis E Epidemiology”.
  3. ↑ 3.0 3.1 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.
  4. ↑ Kantala T, Maunula L, von Bonsdorff CH, Peltomaa J, Lappalainen M (2009). “Hepatitis E virus in patients with unexplained hepatitis in Finland”. J Clin Virol. 45 (2): 109–13. doi:10.1016/j.jcv.2009.03.006. PMID 19376741.
  5. ↑ 5.0 5.1 Kuniholm MH, Purcell RH, McQuillan GM, Engle RE, Wasley A, Nelson KE (2009). “Epidemiology of hepatitis E virus in the United States: results from the Third National Health and Nutrition Examination Survey, 1988-1994”. J Infect Dis. 200 (1): 48–56. doi:10.1086/599319. PMC 2762746. PMID 19473098.
  6. ↑ 6.0 6.1 6.2 6.3 Hoofnagle JH, Nelson KE, Purcell RH (2012). “Hepatitis E.” N Engl J Med. 367 (13): 1237–44. doi:10.1056/NEJMra1204512. PMID 23013075.
  7. ↑ Boxall E, Herborn A, Kochethu G, Pratt G, Adams D, Ijaz S; et al. (2006). “Transfusion-transmitted hepatitis E in a ‘nonhyperendemic’ country”. Transfus Med. 16 (2): 79–83. doi:10.1111/j.1365-3148.2006.00652.x. PMID 16623913.
  8. ↑ Matsubayashi K, Kang JH, Sakata H, Takahashi K, Shindo M, Kato M; et al. (2008). “A case of transfusion-transmitted hepatitis E caused by blood from a donor infected with hepatitis E virus via zoonotic food-borne route”. Transfusion. 48 (7): 1368–75. doi:10.1111/j.1537-2995.2008.01722.x. PMID 18651907.
  9. ↑ Wichmann O, Schimanski S, Koch J, Kohler M, Rothe C, Plentz A; et al. (2008). “Phylogenetic and case-control study on hepatitis E virus infection in Germany”. J Infect Dis. 198 (12): 1732–41. doi:10.1086/593211. PMID 18983248.
  10. ↑ Purcell RH, Emerson SU (2008). “Hepatitis E: an emerging awareness of an old disease”. J Hepatol. 48 (3): 494–503. doi:10.1016/j.jhep.2007.12.008. PMID 18192058.
  11. ↑ Zhuang H, Cao XY, Liu CB, Wang GM (1991). “Epidemiology of hepatitis E in China”. Gastroenterol Jpn. 26 Suppl 3: 135–8. PMID 1909252.
  12. ↑ Aggarwal R, Kumar R, Pal R, Naik S, Semwal SN, Naik SR (2002). “Role of travel as a risk factor for hepatitis E virus infection in a disease-endemic area”. Indian J Gastroenterol. 21 (1): 14–8. PMID 11871830.
Risk Factors

Risk Factors

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Overview

Common risk factors in the development of hepatitis e include contamination of water supplies, poor sanitation, ingestion of undercooked meat and shellfish, travel to regions where HEV is endemic, and chronic liver disease[1][2].

Risk Factors

Risk factors for infection with hepatitis E virus include:[1][2]

  • Never having contracted HEV
  • Poor sanitation in large areas of the world
  • HEV shedding in feces
  • Contamination of water supplies
  • Ingestion of undercooked meat and shellfish

The following groups of people have increased risk of infection with hepatitis E virus:[1][2]

  • Persons residing in areas where extended community outbreaks exist
  • International travelers to regions of the world where HEV is endemic
  • Refugees residing in overcrowded temporary camps following catastrophes, especially in:
    • Sudan
    • Somalia
    • Kenya
    • Ethiopia
  • Persons who have chronic liver disease
  • Persons working with non-human primates, pigs, cows, sheep and goats

References

  1. ↑ 1.0 1.1 1.2 “Hepatitis E” (PDF).
  2. ↑ 2.0 2.1 2.2 “Hepatitis E”.

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Screening

Screening

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Overview

Blood transfusions should be screened for hepatitis E virus in order to prevent transmission of the virus.[1] Due to the low prevalence of the virus in developed countries, it may not be cost-effective to screen organ or blood donors for the presence of the virus. However, due to its high prevalence in endemic areas, in developing countries, organ and blood donations should be tested for the presence of HEV RNA.[2]

References

  1. ↑ 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.
  2. ↑ 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.

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Differentiating Hepatitis E from other Diseases

Differentiating Hepatitis E from other Diseases

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Overview

Hepatitis E must be differentiated from other diseases that cause fever, nausea, vomiting, jaundice, hepatomegaly, icteric sclera, elevated ALT and AST, such as viral hepatitis (caused by other etiologic agents), alcoholic hepatitis, and autoimmune hepatitis.

Differential Diagnosis

Shown below is a table that summarizes the findings that differentiate hepatitis E from other conditions that cause fever, nausea, vomiting, jaundice, hepatomegaly, and icteric sclera.[1][2]

Disease Findings
Viral Hepatitis A Symptoms are similar to the ones of hepatitis E. Similarly, hepatitis A, caused by the hepatitis A virus, produces a self-limited disease, rarely causing complications.
Viral Hepatitis B Symptoms are similar to the ones of hepatitis E; however, hepatitis B is a life-threatening condition caused by the hepatitis B virus, that may lead to the development of cirrhosis and liver cancer. Serologic testing will help differentiate these two conditions.
Viral Hepatitis C Symptoms are similar to the ones of hepatitis E. Hepatitis C, caused by the hepatitis C virus, can cause acute and/or chronic hepatitis. Serologic testing will help differentiate these two conditions.
Viral Hepatitis D Symptoms are similar to the ones of hepatitis E, however, hepatitis D is a serious liver disease caused by infection with the Hepatitis D virus. Hepatitis D only occurs among people who are infected with the hepatitis B virus (HBV). It may complicate into cirrhosis and hepatocellular carcinoma. Serologic testing will help differentiate these two conditions.
Alcoholic Hepatitis Symptoms are similar to the ones of hepatitis E, however, alcoholic hepatitis is related to the excessive use of alcohol. Alcoholic hepatitis presents more often with ascites. Alcoholic hepatitis often leads to cirrhosis and liver failure, if alcohol use is not decreased. Serologic testing will help differentiate these two conditions. Also laboratory results show ALT<AST in alcoholic hepatitis (inverse from viral hepatitis, which is ALT>AST).
Autoimmune Hepatitis Autoimmune hepatitis occurs when the body’s immune system attacks the hepatocytes. It often affects young females and may present with signs of acute hepatitis or chronic liver disease. Serologic testing will help differentiate these two conditions.

References

  1. ↑ “Hepatitis E”.
  2. ↑ “Hepatitis E (CDC)”.

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Natural History, Complications and Prognosis

Natural History, Complications and Prognosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Overview

Most patients with the acute form of hepatitis E are asymptomatic. Acute hepatitis E progresses according to the following stages: incubation, which usually lasts a mean of 40 days; prodrome or preicteric phase; and symptomatic or icteric phase. The prodromal phase starts with unspecific symptoms, such as fever, weakness, malaise, anorexia, nausea and vomiting, and abdominal pain. The icteric phase usually begins with jaundice, follows the offset of the prodromal symptoms, and may include cholestatic symptoms, such as acholic stools and dark-colored urine. Pregnant women may experience more severe forms of the disease, possibly progressing into hepatic failure. Chronic hepatitis E is commonly found in immunocompromised patients, such as those infected with HIV, undergoing chemotherapy, or with a history of organ transplant. Complications of hepatitis E may include: cirrhosis and liver failure. Extra-hepatic complications may also be noted: peripheral neuropathy; encephalitis; acute transverse myelitis; and Guillain-Barré syndrome. The prognosis of hepatitis E is good in asymptomatic cases, however, immunocompromised patients and pregnant women have higher mortality rates.

Natural History

Hepatitis E is often asymptomatic, particularly in children.[1] Patients in highly endemic areas often present anicteric hepatitis, without developing symptoms. In these cases, the disease is only identifiable by HEV viremia, with elevated liver enzymes and normal bilirubin levels.[2] Although the severity of the disease is poorly understood, it has been associated with an higher viral load.[3] Hepatitis E may be classified in acute and chronic disease.[4]

Acute Hepatitis E

In endemic areas, hepatitis E commonly presents as anicteric hepatitis, or as acute icteric hepatitis. The clinical course of acute hepatitis E progresses according to the following phases:[5][6][7][8][2]

Clinical Course
Stage of Infection Symptoms
Incubation period
Prodromal or Preicteric Phase
  • Lasts for a few days
  • Viremia lasts for few weeks after symptom onset
  • Initial symptoms are unspecific and may include:
Symptomatic or Icteric Phase
  • Follows the disappearance of prodromal symptoms
  • Self-limited
  • Lasts a few weeks
  • Symptoms and findings may include:

Pregnant women may experience more severe cases of hepatitis, possibly progressing into hepatic failure. The more complicated course of the disease is thought to be due to the characteristic immunity and hormonal changes that occur during pregnancy.[9][10] Additionally, fatal outcomes of hepatitis E in pregnant women were associated with the decrease of progesterone receptors.[11]

Viral superinfection may occur in patients with chronic liver disease (symptomatic or asymptomatic) of any etiology. These patients may present with severe “acute on chronic” liver disease.[2][12] Superinfection and liver decompensation are associated with poor outcomes.

In areas with lower disease prevalence, hepatitis E may present as:[6]

The typical hepatitis E patient in these areas is an old male, with either alcohol consumption, or other underlying liver disease. Possibly due to the older age and existence of concomitant disorders, the mortality rate is higher in these regions.[2]

Chronic Hepatitis E

Chronic infection is defined by detection of HEV RNA in blood, or in stool, for more than 6 months. The predominant genotype causing chronic infection is HEV3, as HEV 1 and HEV 2 have not been reported in chronic disease.[5] Although it might occur in immunocompetent adults, chronic disease is commonly found in immunocompromised patients, such as:[4]

Liver disease in some of these patients progresses to fibrosis and cirrhosis.[4][13][16]

Complications

Common complications of hepatitis E include:

Extra-Hepatic

Hepatitis E may also present with extra-hepatic manifestations, including:[4][17][18]

Newborns of Infected Mothers

Newborns from mothers infected with HEV have a mortality rate of about 50%.[26] These infants may show:[2]

  • Icteric hepatitis
  • Anicteric hepatitis

Prognosis

Hepatitis E is self-limited in most immunocompetent patients. For these cases the prognosis is good. Immunocompromised patients, and those with end-stage liver disease are at higher risk of developing chronic hepatitis and other complications. This last group of patients has poor prognosis.[5]

References

  1. ↑ Buti M, Plans P, Domínguez A, Jardi R, Rodriguez Frias F, Esteban R; et al. (2008). “Prevalence of hepatitis E virus infection in children in the northeast of Spain”. Clin Vaccine Immunol. 15 (4): 732–4. doi:10.1128/CVI.00014-08. PMC 2292657. PMID 18321881.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 Aggarwal R, Jameel S (2011). “Hepatitis E.” Hepatology. 54 (6): 2218–26. doi:10.1002/hep.24674. PMID 21932388.
  3. ↑ Kar P, Jilani N, Husain SA, Pasha ST, Anand R, Rai A; et al. (2008). “Does hepatitis E viral load and genotypes influence the final outcome of acute liver failure during pregnancy?”. Am J Gastroenterol. 103 (10): 2495–501. doi:10.1111/j.1572-0241.2008.02032.x. PMID 18785952.
  4. ↑ 4.0 4.1 4.2 4.3 Hoofnagle JH, Nelson KE, Purcell RH (2012). “Hepatitis E.” N Engl J Med. 367 (13): 1237–44. doi:10.1056/NEJMra1204512. PMID 23013075.
  5. ↑ 5.0 5.1 5.2 5.3 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.
  6. ↑ 6.0 6.1 Dalton HR, Stableforth W, Thurairajah P, Hazeldine S, Remnarace R, Usama W; et al. (2008). “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. 20 (8): 784–90. doi:10.1097/MEG.0b013e3282f5195a. PMID 18617784.
  7. ↑ Borgen K, Herremans T, Duizer E, Vennema H, Rutjes S, Bosman A; et al. (2008). “Non-travel related Hepatitis E virus genotype 3 infections in the Netherlands; a case series 2004 – 2006”. BMC Infect Dis. 8: 61. doi:10.1186/1471-2334-8-61. PMC 2413240. PMID 18462508.
  8. ↑ Zhang S, Wang J, Yuan Q, Ge S, Zhang J, Xia N; et al. (2011). “Clinical characteristics and risk factors of sporadic Hepatitis E in central China”. Virol J. 8: 152. doi:10.1186/1743-422X-8-152. PMC 3082222. PMID 21453549.
  9. ↑ 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.
  10. ↑ Navaneethan U, Al Mohajer M, Shata MT (2008). “Hepatitis E and pregnancy: understanding the pathogenesis”. Liver Int. 28 (9): 1190–9. doi:10.1111/j.1478-3231.2008.01840.x. PMC 2575020. PMID 18662274.
  11. ↑ Bose PD, Das BC, Kumar A, Gondal R, Kumar D, Kar P (2011). “High viral load and deregulation of the progesterone receptor signaling pathway: association with hepatitis E-related poor pregnancy outcome”. J Hepatol. 54 (6): 1107–13. doi:10.1016/j.jhep.2010.08.037. PMID 21145845.
  12. ↑ Kumar A, Aggarwal R, Naik SR, Saraswat V, Ghoshal UC, Naik S (2004). “Hepatitis E virus is responsible for decompensation of chronic liver disease in an endemic region”. Indian J Gastroenterol. 23 (2): 59–62. PMID 15176538.
  13. ↑ 13.0 13.1 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.
  14. ↑ Ollier L, Tieulie N, Sanderson F, Heudier P, Giordanengo V, Fuzibet JG; et al. (2009). “Chronic hepatitis after hepatitis E virus infection in a patient with non-Hodgkin lymphoma taking rituximab”. Ann Intern Med. 150 (6): 430–1. PMID 19293084.
  15. ↑ Dalton HR, Bendall RP, Keane FE, Tedder RS, Ijaz S (2009). “Persistent carriage of hepatitis E virus in patients with HIV infection”. N Engl J Med. 361 (10): 1025–7. doi:10.1056/NEJMc0903778. PMID 19726781.
  16. ↑ Grewal P, Kamili S, Motamed D (2014). “Chronic hepatitis E in an immunocompetent patient: a case report”. Hepatology. 59 (1): 347–8. doi:10.1002/hep.26636. PMID 23913727.
  17. ↑ 17.0 17.1 17.2 Kamar N, Weclawiak H, Guilbeau-Frugier C, Legrand-Abravanel F, Cointault O, Ribes D; et al. (2012). “Hepatitis E virus and the kidney in solid-organ transplant patients”. Transplantation. 93 (6): 617–23. doi:10.1097/TP.0b013e318245f14c. PMID 22298032.
  18. ↑ Kamar N, Izopet J, Cintas P, Garrouste C, Uro-Coste E, Cointault O; et al. (2010). “Hepatitis E virus-induced neurological symptoms in a kidney-transplant patient with chronic hepatitis”. Am J Transplant. 10 (5): 1321–4. doi:10.1111/j.1600-6143.2010.03068.x. PMID 20346067.
  19. ↑ Mandal K, Chopra N (2006). “Acute transverse myelitis following hepatitis E virus infection”. Indian Pediatr. 43 (4): 365–6. PMID 16651680.
  20. ↑ Kejariwal D, Roy S, Sarkar N (2001). “Seizure associated with acute hepatitis E.” Neurology. 57 (10): 1935. PMID 11723302.
  21. ↑ Dixit VK, Abhilash VB, Kate MP, Jain AK (2006). “Hepatitis E infection with Bell’s palsy”. J Assoc Physicians India. 54: 418. PMID 16909746.
  22. ↑ Santos L, Mesquita JR, Rocha Pereira N, Lima-Alves C, Serrão R, Figueiredo P; et al. (2013). “Acute hepatitis E complicated by Guillain-Barre syndrome in Portugal, December 2012–a case report”. Euro Surveill. 18 (34). PMID 23987830.
  23. ↑ van Eijk JJ, Madden RG, van der Eijk AA, Hunter JG, Reimerink JH, Bendall RP; et al. (2014). “Neuralgic amyotrophy and hepatitis E virus infection”. Neurology. 82 (6): 498–503. doi:10.1212/WNL.0000000000000112. PMC 3937863. PMID 24401685.
  24. ↑ Deniel C, Coton T, Brardjanian S, Guisset M, Nicand E, Simon F (2011). “Acute pancreatitis: a rare complication of acute hepatitis E.” J Clin Virol. 51 (3): 202–4. doi:10.1016/j.jcv.2011.04.009. PMID 21628104.
  25. ↑ Colson P, Payraudeau E, Leonnet C, De Montigny S, Villeneuve L, Motte A; et al. (2008). “Severe thrombocytopenia associated with acute hepatitis E virus infection”. J Clin Microbiol. 46 (7): 2450–2. doi:10.1128/JCM.02295-07. PMC 2446901. PMID 18480231.
  26. ↑ Khuroo MS, Kamili S, Khuroo MS (2009). “Clinical course and duration of viremia in vertically transmitted hepatitis E virus (HEV) infection in babies born to HEV-infected mothers”. J Viral Hepat. 16 (7): 519–23. doi:10.1111/j.1365-2893.2009.01101.x. PMID 19228284.
  27. ↑ Naik SR, Aggarwal R, Salunke PN, Mehrotra NN (1992). “A large waterborne viral hepatitis E epidemic in Kanpur, India”. Bull World Health Organ. 70 (5): 597–604. PMC 2393368. PMID 1464145.
  28. ↑ Tsega E, Krawczynski K, Hansson BG, Nordenfelt E (1993). “Hepatitis E virus infection in pregnancy in Ethiopia”. Ethiop Med J. 31 (3): 173–81. PMID 8404882.

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Diagnosis

Diagnosis

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