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Yadav, K.K.; Kenney, S.P. Extrahepatic Replication of Hepatitis E Virus (HEV). Encyclopedia. Available online: (accessed on 21 June 2024).
Yadav KK, Kenney SP. Extrahepatic Replication of Hepatitis E Virus (HEV). Encyclopedia. Available at: Accessed June 21, 2024.
Yadav, Kush Kumar, Scott P. Kenney. "Extrahepatic Replication of Hepatitis E Virus (HEV)" Encyclopedia, (accessed June 21, 2024).
Yadav, K.K., & Kenney, S.P. (2023, March 22). Extrahepatic Replication of Hepatitis E Virus (HEV). In Encyclopedia.
Yadav, Kush Kumar and Scott P. Kenney. "Extrahepatic Replication of Hepatitis E Virus (HEV)." Encyclopedia. Web. 22 March, 2023.
Extrahepatic Replication of Hepatitis E Virus (HEV)

Hepatitis E virus (HEV) is an emerging viral disease known to cause acute viral hepatitis globally. Various genotypes of HEV have been identified that produce genotype specific lesions depending on the HEV targeted population. Extrahepatic existence of HEV was related to clinical manifestations via different case reports, case–control studies, and prospective studies. Knowledge about HEV-related extrahepatic diseases is very important for clinicians.

hepatitis E extrahepatic

1. Introduction

Hepatitis E virus (HEV) is the primary cause of acute viral hepatitis in humans [1]. Clinical manifestations include asymptomatic infection, generally seen in immunocompetent individuals, acute self-limiting hepatitis, persistent hepatitis in immunosuppressed and pregnant populations, and extrahepatic manifestations [2]. HEV was reported to cause about 70,000 deaths and 3000 stillbirths annually [3].
The recent reclassification of the family Hepeviridae comprises two subfamilies: Orthohepevirinae and Parahepevirinae. A collection of terrestrial and arboreal animals are included on the infection list of the four genera within the Orthohepevirinae. Most cases of hepatitis E in humans are caused by the species Paslahepevirus balayani, which consist of eight genotypes (gt1–gt8), five of which are infectious to humans (gt1–gt4, gt7) [4][5]. HEV (gt1 and gt2) are obligated to humans, while HEV gt3 and HEV gt4 have zoonotic importance, as they travel via the food chain (pig and undercooked pork products) to develop a disease in humans [6]. Avihepevirus, Rocahepevirus, and Chirohepevirus are the other three genera predominantly circulating in birds, rodents, and bats, respectively. Notably, Rocahepevirus species ratti (rat HEV) was initially isolated from rats but was believed to have negligible zoonotic ability because of extreme genetic and antigenic divergence from HEV gt1 [7][8]. Recently, it was revealed that rat HEV can cause disease in humans via reports from Hong Kong [9][10][11].
HEV is a single stranded, positive-sense RNA virus with a 7.2 kb genome size. It is comprised of three open reading frames (ORFs), while some strains (Paslahepevirus gt1) also contain a fourth ORF, ORF4 [12][13][14][15]. The largest ORF in size is ORF1 (1693 amino acids) that encodes for nonstructural proteins (Burma strain). The translation of ORF2 (660 amino acids) and ORF3 (112–114 amino acids) is from the subgenomic RNA that encodes for structural proteins and a phosphoprotein/viroporin, respectively. Distinct functional domains: (a) methyl transferase (MT), (b) Y domain, (c) papain-like cysteine protease (PCP), (d) proline-rich hinge domain, (e) X domain, (f) RNA helicase, and (g) RNA-dependent RNA polymerase (RdRp) were reported in ORF1 based on computer-aided alignment and similarity prediction of the nucleotide sequence [2][16].
The shortage of appropriate in vitro models and in vivo models led to difficulties in understanding the pathogenesis of HEV failing to mimic the complete pathology demonstrated in humans [17][18]. Even though the fecal-oral route is considered as the main mode of HEV spread, the journey of virus particles from gastrointestinal tract to the liver and then to different organs has not been elaborated well. A very recent meta-assessment in 2018 revealed HEV prevalence up to 9% in the USA, 4.2% in Brazil, and up to 1% in the Caribbean [19]. Extrahepatic replication related to HEV acute and chronic infections have been reported by several publications [20]. Temporal associations between the infection and the extra-hepatic manifestations were made after eliminating other potential etiologies that could imitate these types of manifestations.

2. Extrahepatic Replication of HEV

2.1. Insights of Extrahepatic Replication

Even though HEV is known as a primary cause for acute hepatitis cases, chronic, and extrahepatic clinical diseases pertaining to different body systems cannot be neglected. Successful HEV replication in an organ can only be defined either by the presence of a negative-strand-specific reverse transcriptase PCR/in situ hybridization for replication complex RNA or via immunohistochemistry (IHC)/immunofluorescence assays (IFA) targeting the subgenomic RNA encoded proteins. Some HEV reports lacked the information on the negative sense RNA and IHC, limiting our complete understanding on the replication sites of HEV.
Multiple studies evaluating the vertical transmission of gt1 HEV in the fetus highlighted the successful in vitro HEV replication in the stromal cells [21], placental cells [22], both proven by IFA, and ex vivo replication in the maternal fetal interface recognized by in situ hybridization [23]. Additionally, HEV antigen was reported via IHC in the maternal and fetal side of the placental tissues collected from the HEV positive pregnant individuals after delivery [24].
The blood–testis barrier and blood–brain barriers limit immune cell trafficking into the immune privileged sites such as the testis and central nervous system, respectively [25]. There was very little knowledge about the replication of HEV in the immune privileged sites. Recently, the existence of gt3 HEV was demonstrated in the cerebrospinal fluid (CSF) [26] via the presence of a negative strand RNA in pigs and gt4 HEV via IHC in the macaque’s testis [27].
The female reproductive organs’ role in the HEV pathogenesis was one of the prime research interest areas for several years. Extensive research was conducted to understand the factors enhancing HEV virulence in pregnant women [2]. HEV tissue tropism in the ovary, ovum, and uterus was demonstrated in various species such as rabbits via IHC [28] and in BALB/c mice [29] via the detection of negative strand RNA. Even after 40 years of HEV discovery, the mechanisms behind HEV pregnancy mortality were not identified. Furthermore, pathology of HEV infection in the non-pregnant female reproductive system is completely unknown.
Of the various organs, the pancreas was extensively reported to harbor HEV replication. HEV was associated with 2.1% of acute pancreatitis cases, particularly in young males [30]. Experimental inoculation of miniature pigs with HEV gt3 demonstrated higher titers of HEV in the pancreas than the liver, highlighting necroptosis [31]. Interestingly, HEV antigens were described earlier in lymphoid tissues even before the noted classical organ of infection, “liver” via IHC [31].
It is very interesting to note that extrahepatic replication related to HEV is not limited to a genotype. From the listed studies, extrahepatic replication in males and non-pregnant females are related to gt3/gt4 HEV. One of the studies reported no evidence of gt1 HEV in the male reproductive system of humans [32]. However, an exception was seen when gt1 HEV acute infection was related to the digestive disorder, acalculous cholesystitis [33]. HEV gt1 was related with the female reproductive organs only during the pregnancy. Genotype specific lesions illustrate the need to understand the mechanisms behind the extrahepatic replication of HEV.

2.2. Pathogenesis of Extrahepatic Replication

There are many unknowns in the pathogenesis of extrahepatic manifestations due to HEV infection. Direct or indirect mechanisms were postulated with HEV induced pathogenesis. Direct mechanisms include HEV replication in the infected tissues, developing cellular damage. However, indirect mechanisms relate to cross-reactive immune triggers, development of immune complexes, or by indicated secondary infection [34]. Direct mechanisms were reported in vitro supporting the complete replication of HEV viral RNA and translation of viral capsid protein in some tissue types such as neuronal cells and human neuronal derived cells [35][36]. On the other side, humoral and cellular immune responses are responsible for the indirect mechanisms and are expected to be relevant in the pathogenesis of extrahepatic manifestations.
Remarkably, extrahepatic clinical manifestations are easily seen in immunocompetent patients rather than immunocompromised patients [37][38][39]. One report demonstrated that neurological manifestations were significantly more common in immunocompetent patients [n = 137] than immunocompromised patients [n = 63] (22.6% as compared to 3.2%) [37]. Similarly, a second report demonstrated neuralgic amyotrophy only in immunocompetent patients [38]. Likewise, pleiotropic neurologic disorders were reported in HEV-infected immunocompetent patients [39]. Such findings imply that immune-mediated mechanisms could be responsible for these extra hepatic disease manifestations.
Four decades of research advancements in HEV clearly demonstrated that the liver is not the only organ where HEV replication occurred. Neuronal cells, intestines, and human placenta are also important replication sites for HEV in humans [22][23][36][40][41]. Out of the 10 organ systems described in the human body, HEV was shown to affect all of these systems (nervous and musculoskeletal, cardiovascular, digestive, endocrine, integumentary, renal, respiratory, immune, reproductive systems) causing lesions. Thus, these extrahepatic manifestations need to be studied and characterized for the correct diagnosis of HEV infection.


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