Hepatitis E natural history

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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

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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