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Invited Comment/ Editorial “Hepatitis E – It is not always about the liver” Sandy, Natascha Silva1, Vieira Neto, Ronan José 2 1. Division of Gastroenterology, Hepatology and Nutrition and the Transplant and Regenerative Medicine Center, SickKids Hospital. Department of Pediatrics, University of Toronto, Toronto, ON, Canada. 2. Division of Neurology and Stroke Program, Toronto Western Hospital. University Health Network, Toronto, On, Canada. Address correspondence to Natascha Silva Sandy, MD, Division of Gastroenterology, Hepatology and Nutrition, SickKids Hospital, 555 University Ave, M5G 1X8, Toronto, ON, Canada (e-mail: natascha.silvasandy@sickkids.ca) See “Neurological manifestations of hepatitis E virus infection: An overview”. by Jha et al - World J Gastroenterol 2021; 27(18): 2090-2104 [DOI: 10.3748/wjg.v27.i18.2090] Initially called "non-A, non-B hepatitis", the Hepatitis E Virus (HEV) was first described in the 1980s, in a hepatitis epidemic in India, transmitted via the fecal-oral route.(1) Since then, we have consolidated good knowledge about the biological behavior of this virus, and a few well-established facts about HEV have been described. Molecular characterization of HEV revealed several genotypes, and four (HEV genotypes 1 to 4) were recognized as responsible for or most infections in humans(2). Epidemiological and clinical data have documented that the majority of individuals who acquire HEV will be either asymptomatic or will present with a "flu-like" illness, but the most well-known facet of this infection is the presentation with “icteric hepatitis”, reported in 5%–40% of affected individuals.(2, 3) Another widespread observation about HEV infection is that there is a mortality rate among pregnant females, as well as in individuals with underlying chronic liver disease.(2) Nevertheless recently, what we know about this virus has been challenged by recent studies reporting emerging new data on the epidemiology as well as on the epidemiology and clinical presentation of HEV. Notably, an important concept that was changed was the initial belief that this virus could not cause chronic infection, as chronic hepatitis was consistently reported in immunosuppressed patients, including patients who have received a solid-organ transplant, patients with hematological patients and HIV-positive patients.(4) The majority of studies on Hepatitis E Virus (HEV) Infection have been conducted in Asia, as HEV is reported to be highly endemic in several parts of Asia the Middle East, Africa, and Central America.(5) But recently, many studies have recognized the impact of HEV infection in other countries.(6) Over the past decades, in regions like in different countries in Europe – which were not the traditionally recognized areas of HEV outbreaks, the number of cases of HEV infection is steadily increasing.(2, 6-8) On the clinical side, extrahepatic Manifestations of HEV, including a range of neurological, renal, pancreatic, and haematological disorders are also becoming increasingly recognized, particularly neurological injury.(9, 10) In this issue of the journal, Jha et al. (11) summarize evidence of neurological manifestations of HEV infection in a mini-review that provides a comprehensive overview of the involvement of both the peripheral nervous system and central nervous system secondary to the infection. As reported by the authors, manifestations may include Neuralgic amyotrophy, Guillain-Barré syndrome, Meningoencephalitis, Cerebral ischemia, Seizures, Transverse myelitis, Mononeuritis multiplex, Peripheral neuropathy, Cranial nerve neuropathy, Myositis, Myasthenia gravis and Meningoradiculitis. Each of these manifestations being relative rare, with a total number of cases reported varying from 1 to 64. The increasing interest in this facet of the disease may reveal that the extent of neurological finings secondary to HEV may go beyond these descriptions, as many of these neurological manifestations are often described as idiopathic but testing for HEV infection is not routine. Unfortunately, the evidence to fully understand the neurologic impact of HEV is still scarce. Until we can fully understand the importance of HEV in neurologic syndromes, prospective multicenter studies – like the one by Dalton et al., even if they are to find a small number of cases (11 out of 464 patients presenting with acute non-traumatic neurological injury in that study)(10) and reviews grouping theses cases together, like the one present in this current edition of the Word Journal of Gastroenterology by Jha et al. (11) are of great importance. REFERENCES 1. Balayan MS, Andjaparidze AG, Savinskaya SS, Ketiladze ES, Braginsky DM, Savinov AP, et al. Evidence for a virus in non-A, non-B hepatitis transmitted via the fecal-oral route. Intervirology. 1983;20(1):23-31. 2. Kamar N, Dalton HR, Abravanel F, Izopet J. Hepatitis E virus infection. Clin Microbiol Rev. 2014;27(1):116-38. 3. Kamar N, Izopet J, Pavio N, Aggarwal R, Labrique A, Wedemeyer H, et al. Hepatitis E virus infection. Nat Rev Dis Primers. 2017;3:17086. 4. Kamar N, Bendall R, Legrand-Abravanel F, Xia N-S, Ijaz S, Izopet J, et al. Hepatitis E. The Lancet. 2012;379(9835):2477-88. 5. Aggarwal R. Hepatitis E: Historical, contemporary and future perspectives. J Gastroenterol Hepatol. 2011;26 Suppl 1:72-82. 6. Frias M, López-López P, Rivero A, Rivero-Juarez A. Role of Hepatitis E Virus Infection in Acute-on-Chronic Liver Failure. Biomed Res Int. 2018;2018:9098535. 7. Ijaz S, Arnold E, Banks M, Bendall RP, Cramp ME, Cunningham R, et al. Non-travel-associated hepatitis E in England and Wales: demographic, clinical, and molecular epidemiological characteristics. J Infect Dis. 2005;192(7):1166-72. 8. Nijskens CM, Pas SD, Cornelissen J, Caliskan K, Hoek RA, Hesselink DA, et al. Hepatitis E virus genotype 3 infection in a tertiary referral center in the Netherlands: Clinical relevance and impact on patient morbidity. J Clin Virol. 2016;74:82-7. 9. Dalton HR, Kamar N, van Eijk JJ, McLean BN, Cintas P, Bendall RP, et al. Hepatitis E virus and neurological injury. Nat Rev Neurol. 2016;12(2):77-85. 10. Dalton HR, van Eijk JJJ, Cintas P, Madden RG, Jones C, Webb GW, et al. Hepatitis E virus infection and acute non-traumatic neurological injury: A prospective multicentre study. J Hepatol. 2017;67(5):925-32. 11. Jha AK, Kumar G, Dayal VM, Ranjan A, Suchismita A. Neurological manifestations of hepatitis E virus infection: An overview. World J Gastroenterol 2021; 27(18): 2090-2104 [DOI: 10.3748/wjg.v27.i18.2090] Author contributions: Sandy NS and Vieira Neto reviewed the original manuscript, wrote and revised the letter.

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