Hepatitis E Virus: What More Do We Need to Know?

Hepatitis E virus (HEV) infection is typically a self-limiting, acute illness that spreads through the gastrointestinal tract but replicates in the liver. However, chronic infections are possible in immunocompromised individuals. The HEV virion has two shapes: exosome-like membrane-associated quasi-enveloped virions (eHEV) found in circulating blood or in the supernatant of infected cell cultures and non-enveloped virions ("naked") found in infected hosts' feces and bile to mediate inter-host transmission. Although HEV is mainly spread via enteric routes, it is unclear how it penetrates the gut wall to reach the portal bloodstream. Both virion types are infectious, but they infect cells in different ways. To develop personalized treatment/prevention strategies and reduce HEV impact on public health, it is necessary to decipher the entry mechanism for both virion types using robust cell culture and animal models. The contemporary knowledge of the cell entry mechanism for these two HEV virions as possible therapeutic target candidates is summarized in this narrative review.

Infectious hepatitis E virus is associated with the mature sperm head.

Hepatitis E virus (HEV) is the leading cause of acute viral hepatitis worldwide. HEV associated pregnancy mortality has been reported as up to 30% in humans. Recent findings suggest HEV may elicit effects directly in the reproductive system with HEV protein found in the testis, viral RNA in semen, and viral replication occurring in placental cell types. Using a natural host model for HEV infection, pigs, we demonstrate infectious HEV within the mature spermatozoa and altered sperm viability from HEV infected pigs. HEV isolated from sperm remained infectious suggesting a potential transmission route via sexual partners. Our findings suggest that HEV should be explored as a possible sexually transmittable disease. Our findings propose that infection routes outside of oral and intravenous infection need to be considered for their potential to contribute to higher mortality in HEV infections when pregnancy is involved and in HEV disease in general.

An Immunocompetent Mongolian Gerbil Model for Hepatitis E Virus Genotype 1 Infection.

BACKGROUND & AIMS: Hepatitis E virus (HEV), primarily genotype 1 (HEV-1), causes approximately 20.1 million infections, 44,000 deaths, and 3000 stillbirths annually. Current evidence indicates that HEV-1 is only transmitted in humans. Here, we evaluated whether Mongolian gerbils can serve as animal models for HEV-1 infection. METHODS: Mongolian gerbils were used for HEV-1 and hepatitis E virus genotype 3 infection experiments. HEV infection parameters, including detection of HEV RNA and HEV antigen, liver function assessment, and histopathology, were evaluated. RESULTS: We adapted a clinical isolate of HEV-1 for Mongolian gerbils by serial passaging in feces of aged male gerbils. The gerbil-adapted strain obtained at passage 3 induced a robust, acute HEV infection, characterized by stable fecal virus shedding, elevated liver enzymes, histopathologic changes in the liver, and seroconversion to anti-HEV. An infectious complementary DNA clone of the adapted virus was generated. HEV-1-infected pregnant gerbils showed a high rate of maternal mortality and vertical transmission. HEV RNA or antigens were detected in the liver, kidney, intestine, placenta, testis, and fetus liver. Liver and placental transcriptomic analyses indicated activation of host immunity. Tacrolimus prolonged HEV-1 infection, whereas ribavirin cleared infection. The protective efficacy of a licensed HEV vaccine was validated using this model. CONCLUSIONS: HEV-1 efficiently infected Mongolian gerbils. This HEV-1 infection model will be valuable for investigating hepatitis E immunopathogenesis and evaluating vaccines and antivirals against HEV.

¿Afectación hepática en la listeriosis? Considere una coinfección por virus E de la hepatitis / Liver involvement in listeriosis? Think of a hepatitis E virus coinfection

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El virus de la hepatitis E en los trastornos neurológicos: un caso de síndrome de Parsonage-Turner / Hepatitis E virus in neurological disorders: a case of Parsonage-Turner syndrome

La infección por el virus de la hepatitis E (VHE) es una patología emergente en países industrializados y con un amplio espectro clínico. La hepatitis aguda, en ausencia de inmunocompromiso y embarazo, es una entidad leve y paucisintomática en la mayoría de los pacientes. No obstante, las manifestaciones extrahepáticas, entre ellas las neurológicas, son frecuentes y en ocasiones conllevan secuelas neurológicas permanentes. Reportamos el caso de un paciente inmunocompetente que ingresa por cuadro de parestesias y debilidad en ambas extremidades superiores asociado a elevación anictérica de transaminasas. El diagnóstico, mediante electromiograma y serologías, fue de síndrome de Parsonage-Turner (neuralgia amiotrófica) secundario a VHE. La neuralgia amiotrófica (NA) es una patología axonal desmielinizante que afecta al plexo braquial y se asocia al VHE hasta en un 10% de los casos. Recalcamos la importancia de solicitar serologías del VHE en pacientes con patología neurológica, especialmente con afectación del sistema nervioso periférico. El papel de la ribavirina en estos escenarios está pendiente de esclarecer; no obstante, el diagnóstico y tratamiento precoz podría suponer una mejoría pronóstica, minimizando las secuelas neurológicas

Hepatitis E virus (HEV) infection is an emerging disease in developed countries with a broad clinical spectrum. In the absence of immunodeficiency or pregnancy, it is a mild and almost asymptomatic condition in most cases. However, extrahepatic manifestations, including neurological conditions, are common and may occasionally lead to permanent neurological sequelae. Herein, we report the case of an immunocompetent patient who was admitted to our hospital with paresthesia and weakness in both the upper extremities associated with anicteric-elevated transaminases. The diagnosis was Parsonage-Turner syndrome (neuralgic amyotrophy) secondary to HEV infection. The diagnosis was reached via electromyography and serology tests. Neuralgic amyotrophy (NA) is a demyelinating axonal disease that affects the brachial plexus and is associated with HEV infection in up to 10% of cases. We also emphasize the importance of requesting HEV serology in patients with neurological disease, especially with the involvement of the peripheral nervous system. Although the role of ribavirin remains to be fully determined, early diagnosis and treatment may result in an improved prognosis, thereby minimizing neurological sequelae

Hepatitis aguda por virus de la hepatitis E tras el consumo de carne cruda / Acute hepatitis due to hepatitis E virus after raw meat consumption

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High Clinical Manifestation Rate in an Imported Outbreak of Hepatitis E Genotype 1 Infection in a German Group of Travellers Returning from India

Abstract: Background. There are only few reports about travel-associated, imported tropical hepatitis E virus (HEV) genotype 1 infections within Western travellers. We describe the clinical course of a single outbreak of hepatitis E in a German travellers group returning from India and compare the results of two commercial HEV-seroassays. Material and methods. After identifying hepatitis E in an index patient returning from a journey to India all 24 members of this journey were tested for anti-HEV-IgG and IgM using two commercial seroassays (Wantai and Mikrogen), for HEV-RNA by PCR and HEV-Ag by an antigen-assay (Wantai). Results. 5/24 (21%) individuals were viraemic with viral loads between 580-4,800,000 IU/mL. Bilirubin and ALT levels in these patients ranged from 1.3-14.9 mg/dL (mean 7.3 mg/dL, SD 5.6 mg/dL) and 151-4,820 U/L (mean 1,832U/L, SD 1842U/L), respectively and showed significant correlations with viral loads (r = 0.863, p < 0.001; r = 0.890, p < 0.001). No risk factor for food-borne HEV-transmission was identified. All viraemic patients (5/5) tested positive for anti-HEV-IgG and IgM in the Wantai-assay but only 4/5 in the Mikrogen-assay. Wantai-HEV-antigen-assay was negative in all patients. Six months later all previously viraemic patients tested positive for anti-HEV-IgG and negative for IgM in both assays. However, two non-viremic individuals who initially tested Wantai-IgM-positive stayed positive indicating false positive results. Conclusions. Despite the exact number of exposed individuals could not be determined HEV genotype 1 infections have a high manifestation rate of more than 20%.The Wantai-antigen-test failed, the Wantai-IgMrapid-test and the Mikrogen-IgM-recomblot showed a better performance but still they cannot replace real-time PCR for diagnosing ongoing HEV-infections.

Hepatitis crónica por virus de la hepatitis E tratada con ribavirina / Chronic hepatitis caused by hepatitis E virus and treated with ribavirin

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Infecciones por virus de la hepatitis E en Zaragoza (2011-2015) / Hepatitis E infections in Zaragoza, Spain (2011-2015)

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Tratamiento con ribavirina de la infección crónica por el virus de la hepatitis E en pacientes trasplantados / Treatment with ribavirin of hepatitis E virus chronic infection in transplanted patients

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Hepatitis E: una enfermedad viral emergente / Hepatitis E: An emerging viral disease

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Hepatitis agudas, crónicas y fulminantes por virus de la hepatitis E: 7 años de experiencia (2004-2011) / Acute, chronic and fulminant hepatitis E: Seven years of experience (2004-2011)

OBJETIVO: Estudiar las características clínicas y epidemiológicas de 43 casos de hepatitis aguda, 5 casos de hepatitis fulminante y uno de hepatitis crónica causados por el virus de la hepatitis E (VHE), detectados en un periodo de 7 ańos. Pacientes Cuarenta y nueve (35 varones y 14 mujeres) pacientes atendidos entre 2004 y 2011 en el Hospital Ramón y Cajal, en la Comunidad de Madrid. El diagnóstico se realizó por detección de anticuerpos IgG e IgM anti-VHE y ARN VHE en suero. Se consideró el diagnóstico de hepatitis E aguda cuando el paciente presentaba un cuadro clínico compatible con hepatitis aguda y se detectó IgM anti-VHE y/o ARN VHE en suero; la hepatitis E crónica se definió por la presencia de ARN del VHE en suero por un periodo de tiempo mayor de 6 meses, y el fallo hepático fulminante E cuando se observó un deterioro severo de la función hepática asociado encefalopatía en presencia de IgM anti-VHE y/o ARN VHE en suero. RESULTADOS: La edad media fue de 46,67 y 49,6 ańos en los enfermos con hepatitis aguda y fulminante, respectivamente. Entre los antecedentes epidemiológicos, 13 referían viaje a zonas endémicas, 4 tenían contacto con animales, 4 tenían esteatosis hepática relacionada con consumo de alcohol, 3 consumían regularmente productos de herbolario y 2 bebían agua de arroyos. DISCUSIÓN: El VHE origina hepatitis aguda autolimitada, aunque el 36,73% requirieron hospitalización. Sin embargo, el 10,2% comenzaron con hepatitis fulminante, necesitando trasplante hepático. La hepatitis E crónica es excepcional en inmunocompetentes. El aumento de incidencia es debido a la mayor facilidad de diagnóstico en estos últimos ańos

OBJECTIVE: To study the clinical and epidemiological profiles of in 43cases of acute hepatitis, 5 cases of fulminant hepatitis, and one of chronic hepatitis due to hepatitis E virus (HEV), detected over a 7-year period. PATIENTS: Forty-nine individuals (33male and 10female) treated between 2004 and 2011 in the Hospital Ramón y Cajal (Comunidad de Madrid, Spain). The diagnosis was made by the detection of IgG and IgM anti-HEV and RNA HEV in serum samples. Acute hepatitis E was defined by the presence of IgM anti-HEV and/or RNA HEV in serum, and chronic hepatitis E if the ARN was detectable more than 6months. Fulminant hepatitis E was diagnosed if encephalopathy was observed in addition to IgM anti-HEV and/or RNA HEV in serum. RESULTS: The median age was 46.67 and 49.6years in acute hepatitis E and fulminant hepatitis E, respectively. The risk factors recorded were travel to endemic areas in 13 patients, 4 were in contact with animals, 4suffered from hepatic steatosis due to alcohol consumption, 3consumed uncontrolled foods, and 2drank water from streams. DISCUSSION: HEV is the cause of acute self-limited hepatitis, although 36.73% of the studied cases had to be hospitalised. However a small number of patients, 10.2%, had fulminant hepatitis requiring liver transplant. Chronic hepatitis E is very infrequent in immunocompetent individuals. The increase in incidence of hepatitis E is due to the introduction of better diagnostic tests in recent year

Estado actual de la hepatitis E / Hepatitis E. Current perspectives

La infección por el virus de la hepatitis E (VHE) es una enfermedad muy prevalente en países en vías de desarrollo y según estimaciones de la Organización Mundial de la Salud un tercio de la población mundial tiene contacto con el virus. Sus manifestaciones clínicas y la epidemiología son bien conocidas en países endémicos, pero recientemente se han publicado casos esporádicos en países desarrollados, en pacientes sin ningún antecedente de viajes. Se ha confirmado que la hepatitis E en estos países es una zoonosis, pero aún permanecen desconocidas otras vías de transmisión. Otro aspecto interesante es que el VHE puede producir hepatitis crónicas en trasplantados, inmunodeprimidos por otras causas e incluso en inmunocompetentes. También se han comunicado casos de hepatitis fulminantes y otras manifestaciones extrahepáticas. El diagnóstico se basa en estudios serológicos y detección de ARN del virus en sangre y heces. La vacuna es una buena opción para prevenir esta infección que afecta a un número muy elevado de personas en zonas geográficas deprimidas, pero desafortunadamente no está disponible todavía (AU)

Infection with hepatitis E virus (HEV) is highly prevalent in developing countries and the WHO estimates one third of the world population has had contact with the virus. Its diagnosis and epidemiology are well known in endemic countries but, recently, there have been sporadic cases in developed countries in patients with no history of travel. Currently in these countries, hepatitis E is considered a zoonosis yet there remain to be known other routes of transmission. Another interesting aspect is that HEV can cause chronic hepatitis in transplanted patients, other immunocompromised patients and even in immunocompetent people. There have also been reported cases of fulminant hepatitis and other extrahepatic manifestations. The diagnosis is based on serological studies and detection of viral RNA in blood and feces. The vaccine is a good option to prevent this infection that affects a large number of people in deprived geographical areas but unfortunately it is not available yet (AU)

Hepatitis crónica E / Chronic hepatitis E

El virus de la hepatitis E es un virus ARN del que hay descritos 4 genotipos. Los genotipos 1 y 2 sólo afectan a humanos produciendo cuadros de hepatitis aguda epidémica en regiones endémicas (Asia y África), mientras que los genotipos 3 y 4 son considerados una zoonosis, produciendo cuadros de hepatitis aguda episódica en regiones no endémicas (América y Europa). Sin embargo, en los últimos 3 años han aparecido casos de hepatitis crónica E principalmente en individuos inmunodeprimidos. Por ello realizamos una revisión de los datos hasta ahora conocidos sobre la hepatitis crónica E en cuanto a evolución y tratamiento (AU)

The hepatitis E virus is an RNA virus with 4 genotypes. Genotypes 1 and 2 only affect humans and produce epidemic acute hepatitis in endemic regions (Asia and Africa). Genotypes 3 and 4 are considered a zoonosis and produce episodic acute hepatitis in non-endemic areas (America and Europe). However, in the last 3years there have been cases of chronic HEV hepatitis, mainly in immunosuppressed patients. Here we review the known data of chronic hepatitis E in terms of evolution and treatment (AU)

Hepatitis crónica E en paciente inmunocompetente / Chronic hepatitis E in an immunocompetent patient

El virus de la hepatitis E (VHE) es un virus de la familia Hepeviridae, del que hay descritos 4 genotipos diferentes. Los genotipos 1 y 2 suelen causar hepatitis agudas que cursan como brotes epidémicos en las regiones endémicas de Asia y África. Los genotipos 3 y 4 causan casos de hepatitis aguda esporádicos en Europa y Norteamérica, donde se empieza a considerar una zoonosis. Habitualmente, el cuadro clínico se resuelve de manera espontánea, pero en los últimos años se están detectando casos que evolucionan a hepatopatía crónica principalmente en pacientes inmunodeprimidos (trasplante de órgano sólido, linfomas, virus de la inmunodeficiencia humana [VIH], inmunodeficiencias primarias, pacientes en tratamiento con corticoides e inmunosupresores, etc.). Presentamos a continuación el caso de un varón sano inmunocompetente que presentó un cuadro de hepatitis aguda por VHE, que en el plazo de año y medio evolucionó a hepatopatía crónica, con fibrosis grado III/IV en la biopsia hepática (AU)

Hepatitis E virus (HEV) is a Herpesvirus, with four different genotypes. Genotypes 1 and 2 often cause acute hepatitis, which presents as outbreaks in endemic regions of Asia and Africa. Genotypes 3 and 4 cause sporadic cases of acute hepatitis in Europe and North America, where it is considered a zoonosis. Symptoms usually resolve spontaneously, but in recent years cases have been detected that progress to chronic liver disease mainly in immunocompromised patients (patients with solid organ transplants, lymphoma, human immunodeficiency virus, primary immunodeficiencies, and those under treatment with corticosteroids and immunosuppressive agents..). We report the case of a healthy, immunocompetent man who developed an episode of acute HEV hepatitis, which progressed to chronic liver disease with fibrosis grade III/IV in the liver biopsy within a year and half (AU)

El virus de la hepatitis E: implicaciones zoonóticas / Hepatitis E virus: zoonotic implications

El virus de la hepatitis E (VHE) se transmite principalmente por vía feco-oral a través de aguas y/o alimentos contaminados, y es una de las principales causas de hepatitis agudas en el mundo. La hepatitis E presenta una elevada morbilidad, pero una baja mortalidad, excepto en mujeres embarazadas, en las que puede alcanzar el 30%. El VHE origina tanto casos esporádicos como brotes epidémicos, especialmente en muchas regiones de África, Asia y América Central. En Europa, cada vez se describen más casos autóctonos no relacionados con viajes a zonas consideradas endémicas. Además, el VHE también infecta a diversos animales, incluido el cerdo, y, recientemente, se ha demostrado su carácter zoonótico. De hecho, las secuencias de VHE porcinas y humanas de una zona determinada son más parecidas entre sí que lo que lo son con cepas de la misma especie, pero de distinta zona geográfica, y existen datos que indican que las personas en contacto con cerdos presentan una mayor prevalencia de anticuerpos específicos frente al VHE. Todo ello, ha llevado a un creciente interés por determinar la incidencia de la enfermedad en animales, su posible riesgo zoonótico y sus implicaciones para la sanidad. En el presente artículo se repasan los conocimientos actuales sobre el VHE, con especial énfasis en las posibles consecuencias de su carácter zoonótico

The Hepatitis E virus (HEV) is transmitted primarily by the feco-oral route throughout contaminated water and/or food, and is one of the main causes of acute hepatitis worldwide. Hepatitis E shows a high mobility but a low mortality rate, except in pregnant women, where it can be as high as 30%. HEV causes sporadic cases and epidemic outbreaks, mainly in Africa, Asia and Central America. In Europe, there is an increase in the number of reported autochthonous cases no related with travel to endemic areas. In addition, HEV also infects animals, including pigs, and its zoonotic potential has been recently demonstrated. In fact, porcine and human strains of the same area are genetically more closely related to each other than to strains of the same species but a different geographical region, and there are data suggesting that people in close contact with pigs presents a higher prevalence of specific anti-HEV antibodies. All together, these data have drove to an increase interest in determining the incidence of the disease in animals, its possible zoonotic risk, and its implications for human health. In the present article we revised the current knowledge about HEV, with special emphasis in the possible consequences of its zoonotic potential (AU)

Etiología y patogenia de las hepatitis víricas / Etiology and pathogenesis of viral hepatitis

En sentido estricto, las hepatitis víricas constituyen un conjunto de patologías de origen infeccioso causadas por cinco virus humanos filogenéticamente alejados que han coincidido en desarrollar un acusado tropismo hacia los hepatocitos. En sentido más amplio, el término incluye también las hepatitis agudas por infección por otros virus que no son típicamente hepatotropos, pero que pueden originar esa enfermedad como una complicación de la infección primaria aguda, de la misma forma que originan otras. Los virus de la hepatitis B y C han desarrollado estrategias de persistencia que les permiten establecer infecciones crónicas en un cierto porcentaje de los individuos a los que infectan. La hepatitis vírica crónica, la cirrosis hepática y el carcinoma hepatocelular primario son las principales consecuencias clínicas de esos fenómenos de persistencia viral, que responden a dos mecanismos principales: la inducción de inmunotolerancia y la emergencia y selección de mutantes de escape a la respuesta inmunitaria (AU)

In the strictest sense, the term "viral hepatitis" includes a series of clinical conditions of infectious origin caused by five phylogenetically unrelated human viruses that have developed specific tropism to hepatocytes. In a broader sense, it also includes acute liver diseases due to infection by other viruses that do not display specific liver tropism, but may produce liver disease as a complication of the infection. Hepatitis B and C viruses have, in addition, developed strategies that allow them to establish long-lasting, chronic infections in some patients. Chronic viral hepatitis, liver cirrhosis and primary liver cancer are the main clinical outcomes of these phenomena of viral persistence, which respond to two main mechanisms: induction of immune tolerance in the host, and emergence and selection of viral mutants that are able to escape the immune response (AU)

Nuevos virus de hepatitis / New hepatitis viruses

Desde 1990 se han descrito nuevos virus responsables de hepatitis que hasta ese momento eran catalogadas como No A- No B. El virus de la hepatitis E fue descrito como virus transmisión entérica responsable de brotes epidémicos en Asia y México, documentados retrospectivamente. Es un virus RNA, de la familia Caliciviridae, que produce un cuadro similar al virus de la hepatitis A y no produce infección ni partación crónica. Posterior a 1995 se han identificado por técnicas de genéticas molecular nuevos virus, teóricamente responsables de hepatitis post-transfuncional como el virus de la hepatitis G y el virus TT, pero aún no existe certeza de su verdadero rol patogénico

Hepatitis virales / Viral hepatitis

En esta revisión se describen los virus hepatotropos actualmente conocidos, su epidemiología con referencia especial a los datos nacionales relativos a los virus A, B, C y E; su historia natural y sus aspectos clínicos más relevantes. Se enfatizan, además los diferentes marcadores virales serológicos, para el diagnóstico de infección aguda o crónica. Se incluyen también los diferentes tratamientos y las medidas de prevención (pasivas o activas) recomendadas actualmente