History and exam

Key diagnostic factors

common

presence of risk factors

Key risk factors for acquiring HEV infection include living in or travelling to a geographical region endemic for HEV infection; eating raw or undercooked pork, venison, or boar; and living in overcrowded accommodation such as temporary housing or refugee camps.[1][36]​ Hepatitis E may also be acquired via vertical transmission.[39]​ 

Immunocompromised people are at increased risk of developing chronic HEV infection.

uncommon

jaundice/scleral icterus

May occur in some patients with acute HEV infection, following the initial incubation period of 2-8 weeks.[1]

Jaundice may also be a feature of chronic HEV infection. Chronic HEV infection is most commonly found in patients with solid organ transplantation, but has also been associated with other immunosuppressed groups, such as individuals with HIV, those with primary immunodeficiencies, and those receiving chemotherapy.[2]

Jaundice with associated scleral icterus is also a feature of acute liver failure.

asterixis

Asterixis may be seen in acute infection of patients who have no underlying antecedent chronic liver disease. This sign is concerning as it may be an indicator of acute liver failure. Asterixis may also present in patients with acute HEV infection who have underlying chronic liver disease, and can be a sign of progression from compensated to decompensated cirrhosis. Asterixis describes negative myoclonus (involuntary flapping hand movements) detected by extending the arms, dorsiflexing the wrist, and spreading the fingers.

Other diagnostic factors

common

asymptomatic

The majority of patients with acute HEV infection are asymptomatic. It is likely that less than 5% of all patients with acute infection present with an acute hepatitis.[2]

malaise

Acute HEV infection may present as a self-limiting flu-like illness. Malaise is a common symptom, as is fatigue.[1][15]​​

fatigue

Acute HEV infection may present as a self-limiting flu-like illness. Fatigue is a common symptom, as is malaise.[1][15]

uncommon

right upper quadrant tenderness

May occur in some patients with acute HEV infection, as well as in patients with acute liver failure.

fever

Acute HEV infection may present as a self-limiting flu-like illness. Fever is an uncommon symptom, as is anorexia, nausea/vomiting, and arthralgia/arthritis.[1][15]

anorexia

Acute HEV infection may present as a self-limiting flu-like illness. Anorexia is an uncommon symptom, as is fever, nausea/vomiting, and arthralgia/arthritis.[1][15]

nausea/vomiting

Acute HEV infection may present as a self-limiting flu-like illness. Nausea/vomiting is an uncommon symptom, as is fever, anorexia, and arthralgia/arthritis.[1][15]

arthralgia/arthritis

Acute HEV infection may present as a self-limiting flu-like illness. Arthralgia/arthritis is an uncommon symptom, as is fever, anorexia, and nausea/vomiting.[1][15]

abdominal pain

May occur in some patients with acute HEV infection, as well as in patients with acute liver failure.

diarrhoea

May occur in some patients with acute HEV infection.

neurological manifestations

Extrahepatic manifestations of HEV infection can occur after acute infection and with chronic disease. There are a myriad of neurological syndromes associated with HEV, including neuralgic amyotrophy, Guillain-Barré syndrome, and meningoencephalitis; an acute hepatitis with neurological signs and symptoms should raise suspicion for HEV infection.[2]

Patients with acute liver failure may present with neurological symptoms and signs of encephalopathy, which may include confusion, changes in personality, somnolence, and asterixis.[51][52][53]

signs of coagulopathy

Patients with acute liver failure secondary to HEV infection may rarely present with signs of coagulopathy such as bleeding.

Risk factors

strong

born or living in or travel to geographic regions where HEV is endemic

Living in or travelling to HEV-endemic areas, such as Mexico and countries in Africa and Asia, increases the risk of acquiring the infection via faeco-oral transmission (mostly due to drinking contaminated water), which usually occurs in developing countries, especially in regions where sanitation is poor.[1][36]​​​ In developed countries, such as in parts of France, the Netherlands, and the UK, there is an increased risk of infection acquired by food-borne transmission, where sporadic cases have occurred due to consumption of contaminated undercooked or raw pork, wild boar, or deer.[1]

In regions where HEV infection is endemic, the case-to-infection ratio is estimated to be between 1:3 and 1:4.[37]​ Many cases in the US occur in people who have recently travelled to countries where the infection is endemic.[1]

In one study, 18 (38%) of 47 patients with acute hepatitis were positive for antibody to HEV (anti-HEV), and 9 (50%) of these were positive for serum HEV RNA, with epidemiological and molecular analyses strongly indicating that most cases of HEV infection originated from travel to HEV-endemic areas.[36]

immunosuppression

Progression to chronic HEV infection is most commonly associated with patients who are immunosuppressed, such as recipients of solid organ transplants.[15]​ Chronic HEV infection has only been associated with genotypes 3 and 4 and is defined as persistence of HEV replication for 3 or more months.[2]​​[4][5]​​

Chronic infection has less commonly been associated with other immunosuppressed groups, such as people with primary immunodeficiency, those with HIV who have low CD4 T lymphocyte counts, and those undergoing chemotherapy (especially due to haematological malignancies).[2][38]

infected mother (for fetus)

Vertical transmission is associated with increased risk of HEV infection.[34]

One study found that mother-to-child transmission was observed in 46.09% (59/128) of HEV IgM-positive mothers.[39]

weak

person-to-person transmission

People living in crowded camps or temporary housing, such as refugees or people who are internally displaced or those living in military camps, are at increased risk of contracting HEV infection.[1][40]​​​

occupational exposure

HEV genotypes 3 and 4 can be acquired by close association with the animal reservoir, and therefore occupations involving work with animals, such as farm workers and veterinarians, are at increased risk of exposure to HEV.[19][29]

In one study of 859 healthy people, including pig farm workers, forestry workers, and individuals without working contact with animals (control group), anti-HEV antibodies were detected in 26% of the control population in comparison with 36% and 44% of forestry and pig farm workers, respectively.[29]

blood/blood products transfusion

HEV infection after transfusion of blood products has been observed.[22][30][31][32]​​​​ Note that this risk is not applicable universally; in some countries (e.g., the UK), blood donations are screened for HEV before transfusion.

In one study conducted in Brazil, 20.0% (n = 8/40) of multiply transfused thalassaemia patients were found to be anti-HEV IgG positive compared with 11.0% (n = 10/91) of blood donors.[31]

organ transplantation (if organ donor is HEV-positive)

HEV infection can occur in patients following solid organ transplantation.[33]

Note that in some countries, including the UK and Ireland, and some parts of Europe, blood samples from solid organ donors are screened for hepatitis E infection; this is performed post transplant to help inform clinical management decisions in recipients.[25]

In one study carried out in the UK that assessed the transmission of HEV infection in 9 organ donors with detectable HEV plasma viral load who donated 14 kidneys and 6 livers to 20 recipients, all liver recipients had demonstrable HEV RNA in plasma detected at various time points post transplantation.[33]

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