Hepatitis E

Infectious Disease MONDO:0005788 Pathograph 10 Show in embeddings browser Liver Disease Viral Hepatitis

Infection with hepatitis E virus (HEV), a major cause of acute viral hepatitis worldwide with approximately 20 million infections annually. The disease is best understood as two epidemiologically and clinically distinct entities sharing one virus species. Genotypes 1 and 2 are human-restricted, spread by faecally contaminated water in developing countries, and cause epidemic acute hepatitis with a strikingly high mortality in pregnancy. Genotypes 3 and 4 are zoonotic, acquired in developed countries from undercooked meat, and are usually asymptomatic in immunocompetent hosts but establish chronic infection and cirrhosis in immunocompromised patients - the only hepatitis E arm that becomes chronic. Both acute and chronic infection can produce extrahepatic manifestations. The outcome is determined chiefly by the host immune response rather than by viral virulence. Chronic infection is treated with reduction of immunosuppression followed by off-label ribavirin, though no agent is licensed for the indication; the Hecolin vaccine is licensed only in China and none is FDA-approved.

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5
Pathophys.
2
Phenotypes
2
Gaps
10
Pathograph
4
Medical Actions
?

Discussions and Knowledge Gaps

2
Why does hepatitis E cause up to 30% mortality in pregnant women when the same infection is usually asymptomatic and self-limited outside pregnancy?
KNOWLEDGE GAP hev_pregnancy_mortality_mechanism
Attached to
pathophysiology#Severe Acute Hepatitis and Fulminant Failure
The pregnancy case fatality of hepatitis E is unmatched by any other hepatitis virus and is the single most consequential unexplained feature of the disease. It is not attributable to viral virulence, since the same genotypes cause mild or asymptomatic disease in non-pregnant hosts, which points at the host response node upstream. Candidate explanations - hormonal modulation of immunity, a shifted T-helper balance, altered viral replication in pregnancy - are not settled, and the review literature explicitly lists outstanding questions about HEV immune responses. Curators should record the association without asserting a mechanism.
Proposed experiments
Longitudinal immune profiling of HEV infection in pregnancy
hev_pregnancy_immune_profiling
Comparing innate sensing, interferon induction, and HEV-specific T and B cell responses between pregnant and non-pregnant patients infected in the same outbreak would separate a host-immunity explanation from a viral-replication one.
Chronic hepatitis E is treated with reduction of immunosuppression and off-label ribavirin, but neither is licensed for the indication and neither has been tested in a randomized trial. What is their true efficacy?
KNOWLEDGE GAP hev_chronic_therapy_unlicensed
Attached to
pathophysiology#Chronic HEV Infection in the Immunocompromised Host
The gap here is one of licensing and trial evidence, not of therapy. An effective standard of care exists and is curated on this entry: reduction of immunosuppressive therapy first, then off-label ribavirin monotherapy, with pegylated interferon-alpha as salvage. What is missing is that no agent is approved for this indication and the evidence base is observational - retrospective series and case reports rather than randomized trials - so optimal duration, the handling of polymerase-mutant treatment failure, and the management of ribavirin-induced anaemia are all unsettled. Curators should not read the absence of a licensed drug as an absence of treatment; an earlier revision of this entry made exactly that error.
Proposed experiments
Randomized antiviral trial in chronic HEV infection
hev_chronic_antiviral_trial
A randomized trial in transplant recipients with persistent HEV viraemia, powered on sustained virological clearance and fibrosis progression, would convert the current observational standard of care into licensed, trial-grade evidence and settle optimal treatment duration.
⚙

Pathophysiology

5
Hepatotropic HEV Infection and Replication
Acquired HEV reaches the liver and replicates in hepatocytes. Infection is established in the great majority of exposed people; what varies is whether it produces disease, which is decided downstream by the host response rather than at this node.
hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
liver UBERON:0002107 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in liver (UBERON:0002107). UBERON:0002107 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Host Immune Response Determining Infection Outcome The innate and adaptive immune response to the infected hepatocyte determines whether the virus is cleared, causes symptomatic hepatitis, or persists.
Show evidence (1 reference)
PMID:39039260 SUPPORT Other
"Hepatitis E virus (HEV) infections are a major cause of acute viral hepatitis in humans worldwide."
Establishes HEV infection as a leading cause of acute hepatitis, the starting point of this chain. Evidence source is OTHER because this is a review.
Host Immune Response Determining Infection Outcome
The decisive node of hepatitis E. In immunocompetent individuals the majority of infections remain asymptomatic and lead to spontaneous clearance, with only 5-16% developing symptomatic acute hepatitis. A growing body of evidence indicates that the host immune response to different HEV genotypes is the critical determinant of the distinct outcomes. Two host states break the usual outcome in opposite directions: immunosuppression permits persistence, and pregnancy converts a self-limited illness into one with up to 30% mortality.
adaptive immune response GO:0002250 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves adaptive immune response (GO:0002250). GO:0002250 is a biological process from the Gene Ontology. response to virus GO:0009615 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves response to virus (GO:0009615). GO:0009615 is a biological process from the Gene Ontology.
Downstream
Acute Hepatitis Symptomatic host inflammatory injury manifests as acute viral hepatitis.
Chronic HEV Infection in the Immunocompromised Host When the adaptive response is insufficient to clear the virus, genotype 3 infection persists.
Severe Acute Hepatitis and Fulminant Failure In pregnancy and in some genotype 1 and 3 infections the acute hepatitis becomes fulminant.
Extrahepatic Manifestations Immune-mediated injury outside the liver accompanies both acute and chronic infection; the intermediates linking the antiviral host response to the neurological and renal manifestations are not established.
Show evidence (2 references)
PMID:39039260 SUPPORT Other
"A growing body of evidence suggests that the host immune response to infection with different HEV genotypes is a critical determinant of distinct HEV infection outcomes."
States the central claim of this node - that outcome is set by host immunity interacting with genotype rather than by viral virulence alone. Evidence source is OTHER because this is a review.
PMID:39039260 SUPPORT Other
"In immunocompetent individuals, the majority of HEV infections remain asymptomatic and lead to spontaneous clearance of the virus, and only a minority of individuals with infection (5-16%) experience symptoms of acute viral hepatitis."
Quantifies the usual outcome in an intact host, against which the immunosuppressed and pregnancy branches are the exceptions. Evidence source is OTHER because this is a review.
Chronic HEV Infection in the Immunocompromised Host
Genotype 3 HEV establishes chronic infection in immunocompromised patients - most importantly solid-organ transplant recipients - and can progress to cirrhosis. This is the only chronic arm of hepatitis E and it is entirely host-determined: the same virus in an immunocompetent host is cleared. No treatment has been approved for chronic HEV infection.
liver UBERON:0002107 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in liver (UBERON:0002107). UBERON:0002107 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Cirrhosis Chronic genotype 3 infection can progress to cirrhosis in immunocompromised patients.
Show evidence (2 references)
PMID:37376687 SUPPORT Other
"Hepatitis E virus 1 and HEV3 can lead to fulminant hepatitis, and HEV3 can lead to chronic hepatitis and cirrhosis in immunocompromised patients."
Assigns chronic infection and cirrhosis specifically to genotype 3 in immunocompromised hosts, the scoping claim of this node. Evidence source is OTHER because this is a review.
PMID:37376687 SUPPORT Other
"However, infection in immunocompromised individuals can lead to chronic HEV infection."
Confirms that immunocompromise is the host condition permitting persistence. Evidence source is OTHER because this is a review.
Severe Acute Hepatitis and Fulminant Failure
Genotypes 1 and 3 can cause fulminant hepatitis. The most striking severity modifier is pregnancy: HEV infection can cause up to 30% mortality in pregnant women, a case fatality unmatched by any other hepatitis virus and concentrated in genotype 1 epidemics. The mechanism of this pregnancy-specific severity is not established.
Show evidence (2 references)
PMID:39039260 SUPPORT Other
"However, HEV infections can cause up to 30% mortality in pregnant women, become chronic in immunocompromised patients and cause extrahepatic manifestations."
Records the pregnancy case-fatality figure alongside the other two outcome-modifying host states. Evidence source is OTHER because this is a review.
PMID:37376687 SUPPORT Other
"Hepatitis E virus 1 and HEV3 can lead to fulminant hepatitis"
Assigns fulminant hepatitis to genotypes 1 and 3. Evidence source is OTHER because this is a review.
Extrahepatic Manifestations
Both acute and chronic HEV infection can produce manifestations outside the liver, most prominently neurological. These are curated as a distinct arm rather than as complications of liver failure, because they occur in patients whose hepatitis is mild or absent.
Show evidence (1 reference)
PMID:37376687 SUPPORT Other
"Both acute and chronic HEV infections can have extrahepatic manifestations."
Establishes that extrahepatic disease occurs in both arms of the infection. Evidence source is OTHER because this is a review.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Hepatitis E Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

2
Acute Hepatitis OCCASIONAL Clinical HP:0200119 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Acute hepatitis (HP:0200119). HP:0200119 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39039260 SUPPORT Other
"only a minority of individuals with infection (5-16%) experience symptoms of acute viral hepatitis"
Provides the 5-16% figure supporting the OCCASIONAL frequency band recorded here. Evidence source is OTHER because this is a review.
Cirrhosis Clinical HP:0001394 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cirrhosis (HP:0001394). HP:0001394 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37376687 SUPPORT Other
"HEV3 can lead to chronic hepatitis and cirrhosis in immunocompromised patients"
Documents cirrhosis as an outcome restricted to chronic genotype 3 infection in immunocompromised hosts. Evidence source is OTHER because this is a review.
💊

Medical Actions

4
Supportive Care for Acute Infection
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Platform: Other
Acute hepatitis E in an immunocompetent host requires no specific treatment; the majority of patients clear the virus spontaneously. The therapeutic problem in hepatitis E is not the acute illness but the chronic arm, for which nothing is approved.
Show evidence (1 reference)
PMID:37376687 SUPPORT Other
"No specific treatment is required for acute HEV infection, no treatment has been approved in chronic infection, and no HEV vaccine has been approved by the (United States) Food and Drug Administration."
States all three components of the current therapeutic position: none needed for acute disease, none approved for chronic disease, and no FDA-approved vaccine. Evidence source is OTHER because this is a review.
Reduction of Immunosuppressive Therapy
Action: Therapeutic ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Therapeutic Procedure (NCIT:C49236). NCIT:C49236 is a clinical intervention from the NCI Thesaurus. NCIT:C49236
Platform: Other
In chronic hepatitis E the persistence of the virus is a consequence of an inadequate host T cell response, so the first therapeutic move is to restore that response by lowering immunosuppression where the underlying transplant or disease indication permits. This acts on the host side of the module's central effector rather than on the virus, and it clears a substantial fraction of cases without any antiviral. It is attempted before ribavirin.
Mechanism Target:
ACTIVATES Host Immune Response Determining Infection Outcome — Withdrawing or lowering immunosuppression restores the T cell response that determines whether HEV is cleared, moving the host back toward the clearance outcome this node governs.
Show evidence (1 reference)
PMID:37376687 SUPPORT Other
"Currently, the first-line treatment is ribavirin after reduction of immunosuppressive therapy, if possible"
Establishes reduction of immunosuppression as the first step of chronic HEV management, ahead of antiviral therapy. Evidence source is OTHER because this is a review of the clinical literature.
Show evidence (1 reference)
PMID:39039260 SUPPORT Other
"A growing body of evidence suggests that the host immune response to infection with different HEV genotypes is a critical determinant of distinct HEV infection outcomes."
Supplies the rationale for a host-directed rather than virus-directed first move: outcome is set by the host immune response, so restoring it is itself a treatment. Evidence source is OTHER because this is a review.
Ribavirin
Action: Antiviral TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Antiviral Therapy (NCIT:C16119). NCIT:C16119 is a clinical intervention from the NCI Thesaurus. NCIT:C16119
Agent: ribavirin CHEBI:63580 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses ribavirin (CHEBI:63580). CHEBI:63580 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Off-label ribavirin monotherapy, typically for about three months, is the first-line antiviral for chronic hepatitis E and is used when reduction of immunosuppression is not possible or does not clear the virus. It is not licensed for this indication and has not been tested in a randomized trial, but it achieves sustained virological response in a large share of treated patients and is the accepted standard of care. Treatment failure is associated with point mutations in the viral polymerase (notably G1634R), and pegylated interferon-alpha is the salvage option after ribavirin failure.
Mechanism Target:
INHIBITS Chronic HEV Infection in the Immunocompromised Host — Ribavirin suppresses HEV replication in the persistently infected host, clearing the viraemia that defines this node and halting its progression to cirrhosis.
Show evidence (1 reference)
PMID:37376687 SUPPORT Other
"These patients subsequently developed cirrhosis within 3 years; they were treated with ribavirin monotherapy, which cleared the infection."
Documents ribavirin monotherapy clearing established chronic infection in patients who had already progressed to cirrhosis - the node this link targets. Evidence source is OTHER because this is a review summarising reported cases.
Show evidence (2 references)
PMID:37376687 SUPPORT Other
"Currently, the first-line treatment is ribavirin after reduction of immunosuppressive therapy, if possible"
Establishes ribavirin as first-line antiviral therapy for chronic HEV, sequenced after reduction of immunosuppression. Evidence source is OTHER because this is a review.
PMID:37376687 SUPPORT Other
"For example, multiple point mutations in the viral polymerase of genotype 3 HEV have been associated with ribavirin treatment failure in organ transplant recipients."
Marked PARTIAL because it bounds the efficacy claim: polymerase mutations cause ribavirin failure, which is why a salvage option is needed. Evidence source is OTHER because this is a review.
Pegylated Interferon Alpha (Salvage)
Action: Antiviral TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Antiviral Therapy (NCIT:C16119). NCIT:C16119 is a clinical intervention from the NCI Thesaurus. NCIT:C16119
Platform: Other
Reserved for chronic hepatitis E that fails ribavirin. Its use is constrained by the transplant setting in which most chronic HEV occurs, since interferon carries a risk of graft rejection.
Mechanism Target:
INHIBITS Chronic HEV Infection in the Immunocompromised Host — Interferon-alpha suppresses HEV replication through a host-directed antiviral state, offering a second route to clearing the persistent infection when direct antiviral therapy has failed.
Show evidence (1 reference)
PMID:37376687 SUPPORT Other
"In patients who fail ribavirin treatment, pegylated interferon-alpha should be considered."
States the salvage indication this treatment occupies. Evidence source is OTHER because this is a review.
Show evidence (1 reference)
PMID:37376687 SUPPORT Other
"Treatment of chronic HEV infection has been studied using ribavirin, pegylated interferon-alpha, and sofosbuvir."
Places pegylated interferon-alpha among the agents studied for chronic HEV infection. Evidence source is OTHER because this is a review.
🦠

Infectious Agent

1
Hepatitis E virus (HEV)
A positive-strand RNA virus of the family Hepeviridae. Four main genotypes infect humans and divide sharply by ecology: genotypes 1 and 2 are human-restricted and waterborne, genotypes 3 and 4 are zoonotic and foodborne. The genotype largely determines the clinical entity, so it is curated here as a property of the agent rather than as disease severity.
Paslahepevirus balayani NCBITaxon:1678143 NCBI Taxonomy (NCBITaxon)
Show evidence (1 reference)
PMID:37376687 SUPPORT Other
"There are four main genotypes of HEV. Genotype 1 and genotype 2 are common in developing countries and are transmitted by contaminated water from a fecal-oral route. Genotype 3 and genotype 4 are common in developed countries and can lead to occasional transmission to humans via undercooked meat."
Establishes the four-genotype structure and the epidemiological split that organises this entry. Evidence source is OTHER because this is a review.
↔️

Transmission

2
Waterborne Faecal-Oral Transmission (Genotypes 1 and 2)
Genotypes 1 and 2 spread by the faecal-oral route through contaminated water, producing large epidemics in settings with inadequate sanitation.
Show evidence (1 reference)
PMID:37376687 SUPPORT Other
"Genotype 1 and genotype 2 are common in developing countries and are transmitted by contaminated water from a fecal-oral route."
Documents the transmission route for the human-restricted genotypes. Evidence source is OTHER because this is a review.
Zoonotic Foodborne Transmission (Genotypes 3 and 4)
Genotypes 3 and 4 are zoonotic, maintained in animal reservoirs and transmitted to humans through undercooked meat. This is the dominant route in developed countries and explains why hepatitis E is now recognised as an endemic rather than imported infection there.
Show evidence (1 reference)
PMID:37376687 SUPPORT Other
"Genotype 3 and genotype 4 are common in developed countries and can lead to occasional transmission to humans via undercooked meat."
Documents the zoonotic foodborne route for the animal-reservoir genotypes. Evidence source is OTHER because this is a review.
{ }

Source YAML

click to show 
name: Hepatitis E
creation_date: "2026-08-22T00:00:00Z"
category: Infectious Disease
description: >-
  Infection with hepatitis E virus (HEV), a major cause of acute viral hepatitis
  worldwide with approximately 20 million infections annually. The disease is
  best understood as two epidemiologically and clinically distinct entities
  sharing one virus species. Genotypes 1 and 2 are human-restricted, spread by
  faecally contaminated water in developing countries, and cause epidemic acute
  hepatitis with a strikingly high mortality in pregnancy. Genotypes 3 and 4 are
  zoonotic, acquired in developed countries from undercooked meat, and are
  usually asymptomatic in immunocompetent hosts but establish chronic infection
  and cirrhosis in immunocompromised patients - the only hepatitis E arm that
  becomes chronic. Both acute and chronic infection can produce extrahepatic
  manifestations. The outcome is determined chiefly by the host immune response
  rather than by viral virulence. Chronic infection is treated with reduction of
  immunosuppression followed by off-label ribavirin, though no agent is licensed
  for the indication; the Hecolin vaccine is licensed only in China and none is
  FDA-approved.
disease_term:
  preferred_term: hepatitis E virus infection
  term:
    id: MONDO:0005788
    label: hepatitis E virus infection
parents:
- Liver Disease
- Viral Hepatitis
infectious_agent:
- name: Hepatitis E virus (HEV)
  description: >-
    A positive-strand RNA virus of the family Hepeviridae. Four main genotypes
    infect humans and divide sharply by ecology: genotypes 1 and 2 are
    human-restricted and waterborne, genotypes 3 and 4 are zoonotic and
    foodborne. The genotype largely determines the clinical entity, so it is
    curated here as a property of the agent rather than as disease severity.
  infectious_agent_term:
    preferred_term: Paslahepevirus balayani
    term:
      id: NCBITaxon:1678143
      label: Paslahepevirus balayani
  evidence:
  - reference: PMID:37376687
    reference_title: "Hepatitis E Virus Infections: Epidemiology, Genetic Diversity, and Clinical Considerations."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      There are four main genotypes of HEV. Genotype 1 and genotype 2 are common
      in developing countries and are transmitted by contaminated water from a
      fecal-oral route. Genotype 3 and genotype 4 are common in developed
      countries and can lead to occasional transmission to humans via undercooked
      meat.
    explanation: >-
      Establishes the four-genotype structure and the epidemiological split that
      organises this entry. Evidence source is OTHER because this is a review.
agent_life_cycle:
  description: >-
    Hepatitis E virus runs two separate cycles that the genotype decides.
    Genotypes 1 and 2 are confined to humans and move through contaminated
    water. Genotypes 3 and 4 are maintained in animals, principally domestic
    pigs and wild boar, which carry the virus without becoming ill, and reach
    people through undercooked meat. There is no arthropod vector.
  hosts:
  - preferred_term: Homo sapiens
    role: >-
      Host for all four human genotypes, and the only host of the
      human-restricted genotypes 1 and 2
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  - preferred_term: domestic pig
    role: >-
      Reservoir host for the zoonotic genotypes 3 and 4, infected without
      clinical signs
    term:
      id: NCBITaxon:9825
      label: Sus scrofa domesticus
  - preferred_term: wild boar
    role: Reservoir host for the zoonotic genotypes 3 and 4
    term:
      id: NCBITaxon:9823
      label: Sus scrofa
  - preferred_term: deer
    role: >-
      Wildlife host implicated as a source of genotype 3 and 4 foodborne
      infection
    term:
      id: NCBITaxon:9850
      label: Cervidae
  life_cycle_stages:
  - name: Asymptomatic carriage in the porcine and wildlife reservoir
    description: >-
      Domestic pigs and wild boar are the principal reservoirs of genotypes 3
      and 4, and deer and other mammals also carry them; the reservoir animals
      are infected without showing clinical signs.
    evidence:
    - reference: PMID:28944602
      reference_title: "Hepatitis E virus and related viruses in wild, domestic and zoo animals: A review."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Domestic pig and wild boar represent the most important reservoirs for these genotypes."
      explanation: >-
        Names the two principal reservoir hosts recorded here for genotypes 3
        and 4.
    - reference: PMID:28944602
      reference_title: "Hepatitis E virus and related viruses in wild, domestic and zoo animals: A review."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "The reservoir animals get infected with HEV without showing any clinical symptoms."
      explanation: >-
        Supports recording the reservoir stage as asymptomatic carriage, which
        is why the animals are a silent source.
    - reference: PMID:37376687
      reference_title: "Hepatitis E Virus Infections: Epidemiology, Genetic Diversity, and Clinical Considerations."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Genotypes 3 and 4 are responsible for sporadic cases of hepatitis E in Europe and East Asia, where they infect a wide range of mammals, such as swine, deer, rabbits, and humans"
      explanation: >-
        Supports deer as a host of the zoonotic genotypes alongside swine.
  - name: Zoonotic foodborne transmission to humans
    description: >-
      Eating undercooked meat from a reservoir animal transfers genotype 3 or 4
      to people, which is the dominant route where those genotypes circulate.
    evidence:
    - reference: PMID:37376687
      reference_title: "Hepatitis E Virus Infections: Epidemiology, Genetic Diversity, and Clinical Considerations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "The risk factor for HEV infection in this study was suspected to be foodborne, i.e., from eating undercooked pig, deer, and boar."
      explanation: >-
        Names pig, deer, and boar as the meat sources behind human infection in
        a transplant-recipient survey. Graded HUMAN_CLINICAL for that survey,
        with quote_role REVIEW_SYNTHESIS because this review is reporting it.
  - name: Human-restricted waterborne cycle of genotypes 1 and 2
    description: >-
      Genotypes 1 and 2 have no animal reservoir and are maintained
      person-to-person through faecally contaminated water.
    evidence:
    - reference: PMID:28944602
      reference_title: "Hepatitis E virus and related viruses in wild, domestic and zoo animals: A review."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Whereas the HEV genotypes 1 and 2 are mainly confined to humans, genotypes 3 and 4 are also found in animals and can be zoonotically transmitted to humans."
      explanation: >-
        Separates the human-restricted genotypes from the zoonotic ones, which
        is the division this life cycle is organised around.
    - reference: PMID:37376687
      reference_title: "Hepatitis E Virus Infections: Epidemiology, Genetic Diversity, and Clinical Considerations."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Genotype 1 and genotype 2 are common in developing countries and are transmitted by contaminated water from a fecal-oral route."
      explanation: >-
        Supports the waterborne route of the human-restricted cycle. Copied from
        the transmission block with its grading unchanged.
  evidence:
  - reference: PMID:28944602
    reference_title: "Hepatitis E virus and related viruses in wild, domestic and zoo animals: A review."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "In particular, genotypes 3 and 4 infections are documented in many domestic, wildlife and zoo animal species."
    explanation: >-
      Supports the breadth of the animal reservoir for the zoonotic genotypes,
      of which the hosts recorded here are the ones named as most important.
  notes: >-
    Deer is bound at family level (NCBITaxon:9850, Cervidae) because the cited
    sources say deer without naming a species. No vectors are recorded: HEV has
    no arthropod vector. No stage is bound to an OPL life-cycle-stage term,
    which covers protozoan and helminth stages only.
transmission:
- name: Waterborne Faecal-Oral Transmission (Genotypes 1 and 2)
  description: >-
    Genotypes 1 and 2 spread by the faecal-oral route through contaminated
    water, producing large epidemics in settings with inadequate sanitation.
  evidence:
  - reference: PMID:37376687
    reference_title: "Hepatitis E Virus Infections: Epidemiology, Genetic Diversity, and Clinical Considerations."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Genotype 1 and genotype 2 are common in developing countries and are
      transmitted by contaminated water from a fecal-oral route.
    explanation: >-
      Documents the transmission route for the human-restricted genotypes.
      Evidence source is OTHER because this is a review.
- name: Zoonotic Foodborne Transmission (Genotypes 3 and 4)
  description: >-
    Genotypes 3 and 4 are zoonotic, maintained in animal reservoirs and
    transmitted to humans through undercooked meat. This is the dominant route
    in developed countries and explains why hepatitis E is now recognised as an
    endemic rather than imported infection there.
  evidence:
  - reference: PMID:37376687
    reference_title: "Hepatitis E Virus Infections: Epidemiology, Genetic Diversity, and Clinical Considerations."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Genotype 3 and genotype 4 are common in developed countries and can lead
      to occasional transmission to humans via undercooked meat.
    explanation: >-
      Documents the zoonotic foodborne route for the animal-reservoir genotypes.
      Evidence source is OTHER because this is a review.
pathophysiology:
- name: Hepatotropic HEV Infection and Replication
  description: >-
    Acquired HEV reaches the liver and replicates in hepatocytes. Infection is
    established in the great majority of exposed people; what varies is whether
    it produces disease, which is decided downstream by the host response rather
    than at this node.
  role: trigger
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:39039260
    reference_title: "Hepatitis E virus: from innate sensing to adaptive immune responses."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Hepatitis E virus (HEV) infections are a major cause of acute viral
      hepatitis in humans worldwide.
    explanation: >-
      Establishes HEV infection as a leading cause of acute hepatitis, the
      starting point of this chain. Evidence source is OTHER because this is a
      review.
  downstream:
  - target: Host Immune Response Determining Infection Outcome
    causal_link_type: DIRECT
    description: >-
      The innate and adaptive immune response to the infected hepatocyte
      determines whether the virus is cleared, causes symptomatic hepatitis, or
      persists.

- name: Host Immune Response Determining Infection Outcome
  description: >-
    The decisive node of hepatitis E. In immunocompetent individuals the
    majority of infections remain asymptomatic and lead to spontaneous clearance,
    with only 5-16% developing symptomatic acute hepatitis. A growing body of
    evidence indicates that the host immune response to different HEV genotypes
    is the critical determinant of the distinct outcomes. Two host states break
    the usual outcome in opposite directions: immunosuppression permits
    persistence, and pregnancy converts a self-limited illness into one with up
    to 30% mortality.
  role: central_effector
  biological_scale: ORGANISM
  biological_processes:
  - preferred_term: adaptive immune response
    term:
      id: GO:0002250
      label: adaptive immune response
  - preferred_term: response to virus
    term:
      id: GO:0009615
      label: response to virus
  evidence:
  - reference: PMID:39039260
    reference_title: "Hepatitis E virus: from innate sensing to adaptive immune responses."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A growing body of evidence suggests that the host immune response to
      infection with different HEV genotypes is a critical determinant of
      distinct HEV infection outcomes.
    explanation: >-
      States the central claim of this node - that outcome is set by host
      immunity interacting with genotype rather than by viral virulence alone.
      Evidence source is OTHER because this is a review.
  - reference: PMID:39039260
    reference_title: "Hepatitis E virus: from innate sensing to adaptive immune responses."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In immunocompetent individuals, the majority of HEV infections remain
      asymptomatic and lead to spontaneous clearance of the virus, and only a
      minority of individuals with infection (5-16%) experience symptoms of
      acute viral hepatitis.
    explanation: >-
      Quantifies the usual outcome in an intact host, against which the
      immunosuppressed and pregnancy branches are the exceptions. Evidence
      source is OTHER because this is a review.
  downstream:
  - target: Acute Hepatitis
    causal_link_type: DIRECT
    description: Symptomatic host inflammatory injury manifests as acute viral hepatitis.
  - target: Chronic HEV Infection in the Immunocompromised Host
    causal_link_type: DIRECT
    description: >-
      When the adaptive response is insufficient to clear the virus,
      genotype 3 infection persists.
  - target: Severe Acute Hepatitis and Fulminant Failure
    causal_link_type: DIRECT
    description: >-
      In pregnancy and in some genotype 1 and 3 infections the acute hepatitis
      becomes fulminant.
  - target: Extrahepatic Manifestations
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Immune-mediated injury outside the liver accompanies both acute and
      chronic infection; the intermediates linking the antiviral host response
      to the neurological and renal manifestations are not established.

- name: Chronic HEV Infection in the Immunocompromised Host
  description: >-
    Genotype 3 HEV establishes chronic infection in immunocompromised
    patients - most importantly solid-organ transplant recipients - and can
    progress to cirrhosis. This is the only chronic arm of hepatitis E and it is
    entirely host-determined: the same virus in an immunocompetent host is
    cleared. No treatment has been approved for chronic HEV infection.
  role: consequence
  biological_scale: ORGANISM
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:37376687
    reference_title: "Hepatitis E Virus Infections: Epidemiology, Genetic Diversity, and Clinical Considerations."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Hepatitis E virus 1 and HEV3 can lead to fulminant hepatitis, and HEV3 can
      lead to chronic hepatitis and cirrhosis in immunocompromised patients.
    explanation: >-
      Assigns chronic infection and cirrhosis specifically to genotype 3 in
      immunocompromised hosts, the scoping claim of this node. Evidence source
      is OTHER because this is a review.
  - reference: PMID:37376687
    reference_title: "Hepatitis E Virus Infections: Epidemiology, Genetic Diversity, and Clinical Considerations."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      However, infection in immunocompromised individuals can lead to chronic
      HEV infection.
    explanation: >-
      Confirms that immunocompromise is the host condition permitting
      persistence. Evidence source is OTHER because this is a review.
  downstream:
  - target: Cirrhosis
    causal_link_type: DIRECT
    description: Chronic genotype 3 infection can progress to cirrhosis in immunocompromised patients.

- name: Severe Acute Hepatitis and Fulminant Failure
  description: >-
    Genotypes 1 and 3 can cause fulminant hepatitis. The most striking severity
    modifier is pregnancy: HEV infection can cause up to 30% mortality in
    pregnant women, a case fatality unmatched by any other hepatitis virus and
    concentrated in genotype 1 epidemics. The mechanism of this
    pregnancy-specific severity is not established.
  role: consequence
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:39039260
    reference_title: "Hepatitis E virus: from innate sensing to adaptive immune responses."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      However, HEV infections can cause up to 30% mortality in pregnant women,
      become chronic in immunocompromised patients and cause extrahepatic
      manifestations.
    explanation: >-
      Records the pregnancy case-fatality figure alongside the other two
      outcome-modifying host states. Evidence source is OTHER because this is a
      review.
  - reference: PMID:37376687
    reference_title: "Hepatitis E Virus Infections: Epidemiology, Genetic Diversity, and Clinical Considerations."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Hepatitis E virus 1 and HEV3 can lead to fulminant hepatitis
    explanation: >-
      Assigns fulminant hepatitis to genotypes 1 and 3. Evidence source is OTHER
      because this is a review.

- name: Extrahepatic Manifestations
  description: >-
    Both acute and chronic HEV infection can produce manifestations outside the
    liver, most prominently neurological. These are curated as a distinct arm
    rather than as complications of liver failure, because they occur in
    patients whose hepatitis is mild or absent.
  role: consequence
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:37376687
    reference_title: "Hepatitis E Virus Infections: Epidemiology, Genetic Diversity, and Clinical Considerations."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Both acute and chronic HEV infections can have extrahepatic
      manifestations.
    explanation: >-
      Establishes that extrahepatic disease occurs in both arms of the
      infection. Evidence source is OTHER because this is a review.
phenotypes:
- category: Clinical
  name: Acute Hepatitis
  description: >-
    Symptomatic acute viral hepatitis, occurring in a minority (5-16%) of
    immunocompetent infected individuals.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Acute hepatitis
    term:
      id: HP:0200119
      label: Acute hepatitis
  evidence:
  - reference: PMID:39039260
    reference_title: "Hepatitis E virus: from innate sensing to adaptive immune responses."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      only a minority of individuals with infection (5-16%) experience symptoms
      of acute viral hepatitis
    explanation: >-
      Provides the 5-16% figure supporting the OCCASIONAL frequency band
      recorded here. Evidence source is OTHER because this is a review.
- category: Clinical
  name: Cirrhosis
  description: >-
    Cirrhosis develops from chronic genotype 3 infection in immunocompromised
    patients. It does not occur in immunocompetent hosts, in whom the infection
    is cleared.
  phenotype_term:
    preferred_term: Cirrhosis
    term:
      id: HP:0001394
      label: Cirrhosis
  evidence:
  - reference: PMID:37376687
    reference_title: "Hepatitis E Virus Infections: Epidemiology, Genetic Diversity, and Clinical Considerations."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      HEV3 can lead to chronic hepatitis and cirrhosis in immunocompromised
      patients
    explanation: >-
      Documents cirrhosis as an outcome restricted to chronic genotype 3
      infection in immunocompromised hosts. Evidence source is OTHER because
      this is a review.
treatments:
- name: Supportive Care for Acute Infection
  description: >-
    Acute hepatitis E in an immunocompetent host requires no specific treatment;
    the majority of patients clear the virus spontaneously. The therapeutic
    problem in hepatitis E is not the acute illness but the chronic arm, for
    which nothing is approved.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:37376687
    reference_title: "Hepatitis E Virus Infections: Epidemiology, Genetic Diversity, and Clinical Considerations."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      No specific treatment is required for acute HEV infection, no treatment
      has been approved in chronic infection, and no HEV vaccine has been
      approved by the (United States) Food and Drug Administration.
    explanation: >-
      States all three components of the current therapeutic position: none
      needed for acute disease, none approved for chronic disease, and no
      FDA-approved vaccine. Evidence source is OTHER because this is a review.
- name: Reduction of Immunosuppressive Therapy
  description: >-
    In chronic hepatitis E the persistence of the virus is a consequence of an
    inadequate host T cell response, so the first therapeutic move is to restore
    that response by lowering immunosuppression where the underlying transplant
    or disease indication permits. This acts on the host side of the module's
    central effector rather than on the virus, and it clears a substantial
    fraction of cases without any antiviral. It is attempted before ribavirin.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Therapeutic Procedure
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  target_mechanisms:
  - target: Host Immune Response Determining Infection Outcome
    treatment_effect: ACTIVATES
    description: >-
      Withdrawing or lowering immunosuppression restores the T cell response
      that determines whether HEV is cleared, moving the host back toward the
      clearance outcome this node governs.
    evidence:
    - reference: PMID:37376687
      reference_title: "Hepatitis E Virus Infections: Epidemiology, Genetic Diversity, and Clinical Considerations."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Currently, the first-line treatment is ribavirin after reduction of
        immunosuppressive therapy, if possible
      explanation: >-
        Establishes reduction of immunosuppression as the first step of chronic
        HEV management, ahead of antiviral therapy. Evidence source is OTHER
        because this is a review of the clinical literature.
  evidence:
  - reference: PMID:39039260
    reference_title: "Hepatitis E virus: from innate sensing to adaptive immune responses."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A growing body of evidence suggests that the host immune response to
      infection with different HEV genotypes is a critical determinant of
      distinct HEV infection outcomes.
    explanation: >-
      Supplies the rationale for a host-directed rather than virus-directed
      first move: outcome is set by the host immune response, so restoring it is
      itself a treatment. Evidence source is OTHER because this is a review.
- name: Ribavirin
  description: >-
    Off-label ribavirin monotherapy, typically for about three months, is the
    first-line antiviral for chronic hepatitis E and is used when reduction of
    immunosuppression is not possible or does not clear the virus. It is not
    licensed for this indication and has not been tested in a randomized trial,
    but it achieves sustained virological response in a large share of treated
    patients and is the accepted standard of care. Treatment failure is
    associated with point mutations in the viral polymerase (notably G1634R),
    and pegylated interferon-alpha is the salvage option after ribavirin failure.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Antiviral Therapy
    term:
      id: NCIT:C16119
      label: Antiviral Therapy
    therapeutic_agent:
    - preferred_term: ribavirin
      term:
        id: CHEBI:63580
        label: ribavirin
  target_mechanisms:
  - target: Chronic HEV Infection in the Immunocompromised Host
    treatment_effect: INHIBITS
    description: >-
      Ribavirin suppresses HEV replication in the persistently infected host,
      clearing the viraemia that defines this node and halting its progression
      to cirrhosis.
    evidence:
    - reference: PMID:37376687
      reference_title: "Hepatitis E Virus Infections: Epidemiology, Genetic Diversity, and Clinical Considerations."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        These patients subsequently developed cirrhosis within 3 years; they
        were treated with ribavirin monotherapy, which cleared the infection.
      explanation: >-
        Documents ribavirin monotherapy clearing established chronic infection
        in patients who had already progressed to cirrhosis - the node this link
        targets. Evidence source is OTHER because this is a review summarising
        reported cases.
  evidence:
  - reference: PMID:37376687
    reference_title: "Hepatitis E Virus Infections: Epidemiology, Genetic Diversity, and Clinical Considerations."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Currently, the first-line treatment is ribavirin after reduction of
      immunosuppressive therapy, if possible
    explanation: >-
      Establishes ribavirin as first-line antiviral therapy for chronic HEV,
      sequenced after reduction of immunosuppression. Evidence source is OTHER
      because this is a review.
  - reference: PMID:37376687
    reference_title: "Hepatitis E Virus Infections: Epidemiology, Genetic Diversity, and Clinical Considerations."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      For example, multiple point mutations in the viral polymerase of genotype
      3 HEV have been associated with ribavirin treatment failure in organ
      transplant recipients.
    explanation: >-
      Marked PARTIAL because it bounds the efficacy claim: polymerase mutations
      cause ribavirin failure, which is why a salvage option is needed. Evidence
      source is OTHER because this is a review.
- name: Pegylated Interferon Alpha (Salvage)
  description: >-
    Reserved for chronic hepatitis E that fails ribavirin. Its use is
    constrained by the transplant setting in which most chronic HEV occurs,
    since interferon carries a risk of graft rejection.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Antiviral Therapy
    term:
      id: NCIT:C16119
      label: Antiviral Therapy
  target_mechanisms:
  - target: Chronic HEV Infection in the Immunocompromised Host
    treatment_effect: INHIBITS
    description: >-
      Interferon-alpha suppresses HEV replication through a host-directed
      antiviral state, offering a second route to clearing the persistent
      infection when direct antiviral therapy has failed.
    evidence:
    - reference: PMID:37376687
      reference_title: "Hepatitis E Virus Infections: Epidemiology, Genetic Diversity, and Clinical Considerations."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        In patients who fail ribavirin treatment, pegylated interferon-alpha
        should be considered.
      explanation: >-
        States the salvage indication this treatment occupies. Evidence source
        is OTHER because this is a review.
  evidence:
  - reference: PMID:37376687
    reference_title: "Hepatitis E Virus Infections: Epidemiology, Genetic Diversity, and Clinical Considerations."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Treatment of chronic HEV infection has been studied using ribavirin,
      pegylated interferon-alpha, and sofosbuvir.
    explanation: >-
      Places pegylated interferon-alpha among the agents studied for chronic HEV
      infection. Evidence source is OTHER because this is a review.
discussions:
- discussion_id: hev_pregnancy_mortality_mechanism
  kind: KNOWLEDGE_GAP
  prompt: >-
    Why does hepatitis E cause up to 30% mortality in pregnant women when the
    same infection is usually asymptomatic and self-limited outside pregnancy?
  attaches_to:
  - "pathophysiology#Severe Acute Hepatitis and Fulminant Failure"
  rationale: >-
    The pregnancy case fatality of hepatitis E is unmatched by any other
    hepatitis virus and is the single most consequential unexplained feature of
    the disease. It is not attributable to viral virulence, since the same
    genotypes cause mild or asymptomatic disease in non-pregnant hosts, which
    points at the host response node upstream. Candidate explanations - hormonal
    modulation of immunity, a shifted T-helper balance, altered viral replication
    in pregnancy - are not settled, and the review literature explicitly lists
    outstanding questions about HEV immune responses. Curators should record the
    association without asserting a mechanism.
  proposed_experiments:
  - experiment_id: hev_pregnancy_immune_profiling
    name: Longitudinal immune profiling of HEV infection in pregnancy
    description: >-
      Comparing innate sensing, interferon induction, and HEV-specific T and B
      cell responses between pregnant and non-pregnant patients infected in the
      same outbreak would separate a host-immunity explanation from a
      viral-replication one.
- discussion_id: hev_chronic_therapy_unlicensed
  kind: KNOWLEDGE_GAP
  prompt: >-
    Chronic hepatitis E is treated with reduction of immunosuppression and
    off-label ribavirin, but neither is licensed for the indication and neither
    has been tested in a randomized trial. What is their true efficacy?
  attaches_to:
  - "pathophysiology#Chronic HEV Infection in the Immunocompromised Host"
  rationale: >-
    The gap here is one of licensing and trial evidence, not of therapy. An
    effective standard of care exists and is curated on this entry: reduction of
    immunosuppressive therapy first, then off-label ribavirin monotherapy, with
    pegylated interferon-alpha as salvage. What is missing is that no agent is
    approved for this indication and the evidence base is observational -
    retrospective series and case reports rather than randomized trials - so
    optimal duration, the handling of polymerase-mutant treatment failure, and
    the management of ribavirin-induced anaemia are all unsettled. Curators
    should not read the absence of a licensed drug as an absence of treatment;
    an earlier revision of this entry made exactly that error.
  proposed_experiments:
  - experiment_id: hev_chronic_antiviral_trial
    name: Randomized antiviral trial in chronic HEV infection
    description: >-
      A randomized trial in transplant recipients with persistent HEV viraemia,
      powered on sustained virological clearance and fibrosis progression, would
      convert the current observational standard of care into licensed,
      trial-grade evidence and settle optimal treatment duration.