Questions

Hepatitis E virus — Questions

Study questions about Hepatitis E virus — exam-style, clinical-scenario and FAQ.

Mock Exam mode

Sit this set one question at a time. Multiple-choice questions mark themselves; written questions reveal a tickable mark scheme so you can score your own answer. You get a combined score at the end.

8 questions: 3 MCQ, 5 written.

High-priority (past-paper) questions only

A complete answer contrasts the host range, transmission, geography and clinical pattern of the two genotypes, and identifies the setting in which chronicity occurs.

Genotype 1

Genotype 1 is human-restricted and transmitted faeco-orally through contaminated water. It causes the large epidemic and endemic disease of Asia and Africa, affecting predominantly young adults. It produces acute, self-limited hepatitis in most people but is notably severe in pregnancy, where third-trimester infection causes fulminant hepatic failure with high maternal and fetal mortality. Genotype 1 does not establish chronic infection in immunocompetent hosts.

Genotype 3

Genotype 3 is zoonotic. Its reservoir is pigs, wild boar and deer, and humans are infected through undercooked meat (and occasionally through transfusion of blood components). It predominates in high-income settings in Europe, North America and parts of Asia, where it causes sporadic autochthonous (locally acquired) infection rather than waterborne epidemics. It affects older people, often with comorbidity, and is usually subclinical or mildly icteric.

Chronic infection

Chronic hepatitis E, defined as persistence of HEV RNA beyond three months, is caused almost exclusively by the zoonotic genotypes 3 and 4 in immunosuppressed hosts: solid-organ transplant recipients on calcineurin inhibitors, people with haematological malignancy or on chemotherapy, and advanced HIV. Genotypes 1 and 2 are not associated with chronicity. Chronic genotype 3 infection can progress to cirrhosis if untreated, yet often responds to reducing immunosuppression or to ribavirin.

A complete answer names the responsible genotypes, quantifies the maternal and fetal risk, and gives the leading explanations for the severity.

The clinical problem

The waterborne genotypes 1 and 2 acquired in the third trimester can progress to fulminant hepatic failure. Genotype 1 is the most common and best-documented cause, but genotype 2 also poses a severe threat, with high maternal mortality and miscarriage rates reported during outbreaks. Maternal case-fatality in outbreak settings is high, in the order of 20 to 30%, far exceeding the mortality of hepatitis E in non-pregnant adults or of other acute viral hepatitides in pregnancy. Fetal and neonatal outcomes are also poor, with high rates of miscarriage, stillbirth, premature delivery and vertical transmission. This severity is a feature of the genotype 1 and 2 epidemics of Asia and Africa; the zoonotic genotype 3 of high-income settings does not show the same risk in pregnancy.

Proposed mechanisms

The reason for the exaggerated severity is not fully settled, but several contributing factors are recognised:

Higher viral replication: pregnant women with hepatitis E tend to have higher HEV viral loads.
Hormonal influence: the high oestrogen and progesterone levels of pregnancy modulate viral replication and the immune response.
Immune adaptation of pregnancy: the shift away from a T-helper-1 response that protects the fetus may blunt antiviral immunity, allowing more severe hepatic injury.

Hepatitis E is therefore an important cause of maternal mortality during outbreaks, and supportive care with prompt recognition of acute liver failure is essential, since ribavirin is contraindicated in pregnancy.

A complete answer separates the serological and molecular tests, states their limitations, and explains why the strategy shifts in immunosuppression.

The immunocompetent patient

In an immunocompetent person with acute hepatitis, diagnosis rests first on serology:

Anti-HEV IgM indicates recent infection and is the usual front-line test. Its sensitivity and specificity vary considerably between commercial assays, so a negative IgM does not fully exclude infection and a single positive may need confirmation.
Anti-HEV IgG rising or seroconverting between paired samples supports recent infection; a single IgG reflects past exposure.
HEV RNA by reverse transcription polymerase chain reaction (RT-PCR) in serum or stool confirms active infection and is useful early, before antibodies appear, and where serology is equivocal.

The immunosuppressed patient

Serology is unreliable in immunosuppression because the patient may not mount a detectable antibody response, so anti-HEV IgM and IgG can be falsely negative despite active infection. Diagnosis therefore depends on HEV RNA detection in serum and stool, which is the reference test in this group. An HEV antigen assay is an alternative marker where available. Because chronic hepatitis E is defined by persistence of HEV RNA beyond three months, repeat RNA testing is used both to make the diagnosis of chronicity and to monitor the response to reduced immunosuppression or ribavirin. Every transplant or haematology patient with unexplained persistently deranged liver enzymes should be tested for HEV RNA.

A complete answer covers the genotypes circulating in Africa, the epidemiological pattern (endemic seroprevalence versus explosive outbreaks), the populations most affected, and the public-health response.

Genotypes and transmission

Africa is dominated by the human-restricted genotypes 1 and 2, transmitted faeco-orally through water contaminated with human sewage. Genotype 1 circulates across much of sub-Saharan Africa and North Africa; genotype 2 was first described in Mexico but also occurs in West Africa (Nigeria, Chad). These contrast with the zoonotic genotypes 3 and 4 of high-income settings, which are acquired from undercooked pork and game and are uncommon in Africa.

Endemic burden and outbreaks

Hepatitis E virus (HEV) shows high background seroprevalence in many African populations, reflecting widespread exposure through unsafe water. Superimposed on this are large waterborne epidemics, characteristically where sanitation breaks down. Outbreaks have been recorded in Namibia and in refugee and internally-displaced-person camps across sub-Saharan Africa (for example in South Sudan, Chad, and Uganda), often during the rainy season when latrines flood.

Populations at greatest risk

The defining feature of genotype 1 disease is its severity in pregnant women, particularly in the third trimester, where it causes fulminant hepatic failure with case-fatality of ~20 to 30% and high rates of fetal loss and stillbirth. This makes HEV a major cause of maternal mortality during African outbreaks.

South African data

South African seroprevalence has ranged widely, from ~2 to 43% in studies between 1990 and 2020, concentrated in Gauteng and the Western Cape and rising with age. Early surveys among canoeists, students, and rural and urban community participants pointed to contaminated water as the probable exposure, though they relied on older, less reliable assays. More recent Western Cape work tells a zoonotic story: the first Southern African genotype 3 case was described in 2013 in an HIV-positive person, followed by a case in a transplant recipient, and blood-donor cohorts have shown seroprevalences of around ~25 to 28% with pork consumption as a significant risk factor and a fulminant genotype 3 liver-failure case reported. Hepatitis E virus RNA has been detected in local pig herds and in pork products in Cape Town, supporting foodborne transmission, while a single RNA-positive genotype 3 donation was found among 10,000 screened blood donations. Seroprevalence among pregnant women in Pretoria was low, at ~3%.

Public-health response

Control rests on water, sanitation, and hygiene: securing safe drinking water, sanitary excreta disposal, and case isolation during outbreaks. The licensed recombinant vaccine is manufactured and used in China and is not yet deployed in African programmes, though it has been considered for outbreak use in high-risk groups. Diagnosis in outbreaks relies on anti-HEV IgM serology, with HEV RNA confirmation where laboratory capacity allows.

Genotype 3 hepatitis E is zoonotic. Its animal reservoir is pigs, wild boar and deer, and humans acquire it by eating undercooked meat (pork products, game, and occasionally shellfish that have concentrated the virus). It causes sporadic autochthonous (locally acquired) infection in high-income settings, which is why this patient has no travel history. Transfusion-transmitted HEV from viraemic blood donors is the recognised secondary route, and has prompted donor screening in several countries.

A describes the genotype 1 and 2 waterborne route of Asian and African epidemics, not genotype 3. B describes the bloodborne and sexual routes of hepatitis B and C; HEV spreads this way only through transfusion. D overstates vertical transmission, which matters for genotype 1 in pregnancy but is not the dominant route for genotype 3. E is incorrect: HEV is not a respiratory pathogen.

This is chronic hepatitis E (HEV RNA persisting beyond three months), seen almost exclusively with the zoonotic genotypes 3 and 4 in immunosuppressed hosts. The evidence-based first step is to reduce immunosuppression where the graft allows, particularly calcineurin inhibitors such as tacrolimus, because this restores the host response and clears the virus in a meaningful minority of patients. If viraemia persists, ribavirin monotherapy is the usual next step and clears most remaining cases.

A overstates interferon: it can clear chronic HEV but carries a rejection risk in organ recipients, so ribavirin is preferred. B is a category error, since nucleos(t)ide analogues target the HBV reverse transcriptase and have no activity against HEV. C is false in the immunosuppressed, where genotype 3 readily becomes chronic and can progress to cirrhosis if ignored. E is the wrong direction: more immunosuppression worsens HEV replication and persistence.

Hepatitis E virus (HEV) is a small non-enveloped, positive-sense single-stranded RNA virus (Baltimore class IV) in the family Hepeviridae. Under current taxonomy the human virus is the species Paslahepevirus balayani in the genus Paslahepevirus. The genome is about 7.2 kilobases, capped, and carries three open reading frames: ORF1 encodes the non-structural polyprotein (methyltransferase, protease, helicase, RNA-dependent RNA polymerase), ORF2 the capsid, and ORF3 a small phosphoprotein that acts as an ion channel and is needed for virion release. In blood the particle is quasi-enveloped by host membrane, whereas in bile and faeces it is non-enveloped.

A describes a picornavirus organisation (a single polyprotein). C describes hepatitis B (Hepadnaviridae, DNA, reverse transcription). D describes hepatitis C (Flaviviridae, enveloped, single polyprotein). E describes hepatitis D (circular negative-sense RNA with a ribozyme).

A complete answer establishes that hepatitis E is more than a liver disease, names the principal neurological and renal syndromes, and notes the genotype association.

Neurological disease

Neurological injury is the best-characterised extrahepatic manifestation of hepatitis E virus (HEV), reported in a notable proportion of symptomatic genotype 3 infections in case series from Europe. The two most recognised syndromes are:

Guillain-Barre syndrome: an acute immune-mediated demyelinating polyradiculoneuropathy causing ascending weakness, temporally linked to acute HEV infection.
Neuralgic amyotrophy (Parsonage-Turner syndrome): severe shoulder-girdle pain followed by patchy upper-limb weakness, often bilateral in HEV-associated cases.

Other reported neurological associations include encephalitis, myelitis, meningoradiculitis and peripheral neuropathy. HEV RNA can sometimes be detected in cerebrospinal fluid, suggesting both direct and immune-mediated mechanisms.

Renal and haematological disease

Renal involvement includes acute kidney injury and glomerulonephritis, including membranoproliferative glomerulonephritis with cryoglobulinaemia. Haematological associations include thrombocytopenia and aplastic anaemia, and acute pancreatitis is also described.

Practical relevance

The breadth of these associations means HEV should be considered in a patient presenting with one of these neurological syndromes and deranged liver enzymes, even without prominent hepatitic symptoms, particularly in regions where genotype 3 circulates.

High priorityExam-styleCompare the epidemiology of hepatitis E virus genotypes 1 and 3, and state which genotypes cause chronic infection and under what circumstances. [6]
Model answer
A complete answer contrasts the host range, transmission, geography and clinical pattern of the two genotypes, and identifies the setting in which chronicity occurs.

Genotype 1

Genotype 1 is human-restricted and transmitted faeco-orally through contaminated water. It causes the large epidemic and endemic disease of Asia and Africa, affecting predominantly young adults. It produces acute, self-limited hepatitis in most people but is notably severe in pregnancy, where third-trimester infection causes fulminant hepatic failure with high maternal and fetal mortality. Genotype 1 does not establish chronic infection in immunocompetent hosts.

Genotype 3

Genotype 3 is zoonotic. Its reservoir is pigs, wild boar and deer, and humans are infected through undercooked meat (and occasionally through transfusion of blood components). It predominates in high-income settings in Europe, North America and parts of Asia, where it causes sporadic autochthonous (locally acquired) infection rather than waterborne epidemics. It affects older people, often with comorbidity, and is usually subclinical or mildly icteric.

Chronic infection

Chronic hepatitis E, defined as persistence of HEV RNA beyond three months, is caused almost exclusively by the zoonotic genotypes 3 and 4 in immunosuppressed hosts: solid-organ transplant recipients on calcineurin inhibitors, people with haematological malignancy or on chemotherapy, and advanced HIV. Genotypes 1 and 2 are not associated with chronicity. Chronic genotype 3 infection can progress to cirrhosis if untreated, yet often responds to reducing immunosuppression or to ribavirin.
High priorityExam-styleExplain why hepatitis E in pregnancy is dangerous, including the genotypes involved, the magnitude of the risk, and the proposed mechanisms. [5]
Model answer
A complete answer names the responsible genotypes, quantifies the maternal and fetal risk, and gives the leading explanations for the severity.

The clinical problem

The waterborne genotypes 1 and 2 acquired in the third trimester can progress to fulminant hepatic failure. Genotype 1 is the most common and best-documented cause, but genotype 2 also poses a severe threat, with high maternal mortality and miscarriage rates reported during outbreaks. Maternal case-fatality in outbreak settings is high, in the order of 20 to 30%, far exceeding the mortality of hepatitis E in non-pregnant adults or of other acute viral hepatitides in pregnancy. Fetal and neonatal outcomes are also poor, with high rates of miscarriage, stillbirth, premature delivery and vertical transmission. This severity is a feature of the genotype 1 and 2 epidemics of Asia and Africa; the zoonotic genotype 3 of high-income settings does not show the same risk in pregnancy.

Proposed mechanisms

The reason for the exaggerated severity is not fully settled, but several contributing factors are recognised:
- Higher viral replication: pregnant women with hepatitis E tend to have higher HEV viral loads.
- Hormonal influence: the high oestrogen and progesterone levels of pregnancy modulate viral replication and the immune response.
- Immune adaptation of pregnancy: the shift away from a T-helper-1 response that protects the fetus may blunt antiviral immunity, allowing more severe hepatic injury.
Hepatitis E is therefore an important cause of maternal mortality during outbreaks, and supportive care with prompt recognition of acute liver failure is essential, since ribavirin is contraindicated in pregnancy.
High priorityExam-styleOutline the diagnostic approach to suspected acute hepatitis E in an immunocompetent patient, and explain how it differs in an immunosuppressed patient. [6]
Model answer
A complete answer separates the serological and molecular tests, states their limitations, and explains why the strategy shifts in immunosuppression.

The immunocompetent patient

In an immunocompetent person with acute hepatitis, diagnosis rests first on serology:
- Anti-HEV IgM indicates recent infection and is the usual front-line test. Its sensitivity and specificity vary considerably between commercial assays, so a negative IgM does not fully exclude infection and a single positive may need confirmation.
- Anti-HEV IgG rising or seroconverting between paired samples supports recent infection; a single IgG reflects past exposure.
- HEV RNA by reverse transcription polymerase chain reaction (RT-PCR) in serum or stool confirms active infection and is useful early, before antibodies appear, and where serology is equivocal.
The immunosuppressed patient

Serology is unreliable in immunosuppression because the patient may not mount a detectable antibody response, so anti-HEV IgM and IgG can be falsely negative despite active infection. Diagnosis therefore depends on HEV RNA detection in serum and stool, which is the reference test in this group. An HEV antigen assay is an alternative marker where available. Because chronic hepatitis E is defined by persistence of HEV RNA beyond three months, repeat RNA testing is used both to make the diagnosis of chronicity and to monitor the response to reduced immunosuppression or ribavirin. Every transplant or haematology patient with unexplained persistently deranged liver enzymes should be tested for HEV RNA.
High priorityExam-styleWrite short notes on hepatitis E virus in Africa. [6]
Model answer
A complete answer covers the genotypes circulating in Africa, the epidemiological pattern (endemic seroprevalence versus explosive outbreaks), the populations most affected, and the public-health response.

Genotypes and transmission

Africa is dominated by the human-restricted genotypes 1 and 2, transmitted faeco-orally through water contaminated with human sewage. Genotype 1 circulates across much of sub-Saharan Africa and North Africa; genotype 2 was first described in Mexico but also occurs in West Africa (Nigeria, Chad). These contrast with the zoonotic genotypes 3 and 4 of high-income settings, which are acquired from undercooked pork and game and are uncommon in Africa.

Endemic burden and outbreaks

Hepatitis E virus (HEV) shows high background seroprevalence in many African populations, reflecting widespread exposure through unsafe water. Superimposed on this are large waterborne epidemics, characteristically where sanitation breaks down. Outbreaks have been recorded in Namibia and in refugee and internally-displaced-person camps across sub-Saharan Africa (for example in South Sudan, Chad, and Uganda), often during the rainy season when latrines flood.

Populations at greatest risk

The defining feature of genotype 1 disease is its severity in pregnant women, particularly in the third trimester, where it causes fulminant hepatic failure with case-fatality of ~20 to 30% and high rates of fetal loss and stillbirth. This makes HEV a major cause of maternal mortality during African outbreaks.

South African data

South African seroprevalence has ranged widely, from ~2 to 43% in studies between 1990 and 2020, concentrated in Gauteng and the Western Cape and rising with age. Early surveys among canoeists, students, and rural and urban community participants pointed to contaminated water as the probable exposure, though they relied on older, less reliable assays. More recent Western Cape work tells a zoonotic story: the first Southern African genotype 3 case was described in 2013 in an HIV-positive person, followed by a case in a transplant recipient, and blood-donor cohorts have shown seroprevalences of around ~25 to 28% with pork consumption as a significant risk factor and a fulminant genotype 3 liver-failure case reported. Hepatitis E virus RNA has been detected in local pig herds and in pork products in Cape Town, supporting foodborne transmission, while a single RNA-positive genotype 3 donation was found among 10,000 screened blood donations. Seroprevalence among pregnant women in Pretoria was low, at ~3%.

Public-health response

Control rests on water, sanitation, and hygiene: securing safe drinking water, sanitary excreta disposal, and case isolation during outbreaks. The licensed recombinant vaccine is manufactured and used in China and is not yet deployed in African programmes, though it has been considered for outbreak use in high-risk groups. Diagnosis in outbreaks relies on anti-HEV IgM serology, with HEV RNA confirmation where laboratory capacity allows.
MCQ
A 60-year-old man in a high-income country with no travel history develops an acute hepatitis and is found to have genotype 3 hepatitis E. Which route of transmission is most characteristic of this infection?
- A. Faeco-oral from drinking water contaminated with human sewage
- B. Percutaneous and sexual, as for hepatitis B and C
- C. Zoonotic foodborne from undercooked pork or game
- D. Vertical from mother to infant around delivery
- E. Respiratory, through aerosolised particles
Show answer
Correct answer: C
Genotype 3 hepatitis E is zoonotic. Its animal reservoir is pigs, wild boar and deer, and humans acquire it by eating undercooked meat (pork products, game, and occasionally shellfish that have concentrated the virus). It causes sporadic autochthonous (locally acquired) infection in high-income settings, which is why this patient has no travel history. Transfusion-transmitted HEV from viraemic blood donors is the recognised secondary route, and has prompted donor screening in several countries.

A describes the genotype 1 and 2 waterborne route of Asian and African epidemics, not genotype 3. B describes the bloodborne and sexual routes of hepatitis B and C; HEV spreads this way only through transfusion. D overstates vertical transmission, which matters for genotype 1 in pregnancy but is not the dominant route for genotype 3. E is incorrect: HEV is not a respiratory pathogen.
MCQ
A kidney transplant recipient on tacrolimus has persistently raised transaminases, and hepatitis E virus RNA is detectable in serum on two samples three months apart. What is the most appropriate first management step?
- A. Start pegylated interferon alfa for 12 months
- B. Begin lifelong tenofovir disoproxil fumarate
- C. Observe only, since hepatitis E is self-limiting
- D. Reduce immunosuppression where the graft allows
- E. Increase immunosuppression to dampen liver injury
Show answer
Correct answer: D
This is chronic hepatitis E (HEV RNA persisting beyond three months), seen almost exclusively with the zoonotic genotypes 3 and 4 in immunosuppressed hosts. The evidence-based first step is to reduce immunosuppression where the graft allows, particularly calcineurin inhibitors such as tacrolimus, because this restores the host response and clears the virus in a meaningful minority of patients. If viraemia persists, ribavirin monotherapy is the usual next step and clears most remaining cases.

A overstates interferon: it can clear chronic HEV but carries a rejection risk in organ recipients, so ribavirin is preferred. B is a category error, since nucleos(t)ide analogues target the HBV reverse transcriptase and have no activity against HEV. C is false in the immunosuppressed, where genotype 3 readily becomes chronic and can progress to cirrhosis if ignored. E is the wrong direction: more immunosuppression worsens HEV replication and persistence.
MCQ
Which option correctly describes the classification and genome of hepatitis E virus?
- A. Non-enveloped positive-sense RNA, Picornaviridae, single open reading frame
- B. Non-enveloped positive-sense RNA, Hepeviridae, three open reading frames
- C. Enveloped partly double-stranded DNA, Hepadnaviridae, reverse transcription
- D. Enveloped positive-sense RNA, Flaviviridae, single polyprotein
- E. Non-enveloped circular RNA, ribozyme, single protein
Show answer
Correct answer: B
Hepatitis E virus (HEV) is a small non-enveloped, positive-sense single-stranded RNA virus (Baltimore class IV) in the family Hepeviridae. Under current taxonomy the human virus is the species Paslahepevirus balayani in the genus Paslahepevirus. The genome is about 7.2 kilobases, capped, and carries three open reading frames: ORF1 encodes the non-structural polyprotein (methyltransferase, protease, helicase, RNA-dependent RNA polymerase), ORF2 the capsid, and ORF3 a small phosphoprotein that acts as an ion channel and is needed for virion release. In blood the particle is quasi-enveloped by host membrane, whereas in bile and faeces it is non-enveloped.

A describes a picornavirus organisation (a single polyprotein). C describes hepatitis B (Hepadnaviridae, DNA, reverse transcription). D describes hepatitis C (Flaviviridae, enveloped, single polyprotein). E describes hepatitis D (circular negative-sense RNA with a ribozyme).
Exam-styleDescribe the extrahepatic manifestations of hepatitis E virus infection, with emphasis on the neurological syndromes. [5]
Model answer
A complete answer establishes that hepatitis E is more than a liver disease, names the principal neurological and renal syndromes, and notes the genotype association.

Neurological disease

Neurological injury is the best-characterised extrahepatic manifestation of hepatitis E virus (HEV), reported in a notable proportion of symptomatic genotype 3 infections in case series from Europe. The two most recognised syndromes are:
- Guillain-Barre syndrome: an acute immune-mediated demyelinating polyradiculoneuropathy causing ascending weakness, temporally linked to acute HEV infection.
- Neuralgic amyotrophy (Parsonage-Turner syndrome): severe shoulder-girdle pain followed by patchy upper-limb weakness, often bilateral in HEV-associated cases.
Other reported neurological associations include encephalitis, myelitis, meningoradiculitis and peripheral neuropathy. HEV RNA can sometimes be detected in cerebrospinal fluid, suggesting both direct and immune-mediated mechanisms.

Renal and haematological disease

Renal involvement includes acute kidney injury and glomerulonephritis, including membranoproliferative glomerulonephritis with cryoglobulinaemia. Haematological associations include thrombocytopenia and aplastic anaemia, and acute pancreatitis is also described.

Practical relevance

The breadth of these associations means HEV should be considered in a patient presenting with one of these neurological syndromes and deranged liver enzymes, even without prominent hepatitic symptoms, particularly in regions where genotype 3 circulates.