Systemic tropism and extrahepatic manifestations of HEV.
| System | Affected tissues/organs | Main clinical manifestations | Mechanisms/Features | Notes |
|---|---|---|---|---|
| Overall (systemic tropism) | Neural tissue, renal parenchyma, hematopoietic system, pancreatic acini, placental trophoblasts | Multisystem extrahepatic manifestations (neurological, renal, hematologic, pancreatic, endocrine, placental, etc.) | Viral replication occurs in non-hepatic tissues; direct cytopathic effects + immune-mediated injury | More common in immunosuppressed or chronically infected patients |
| Neurological system | Central and peripheral nervous systems | Radiculoplexopathy (most common), meningoencephalitis, Guillain-Barré syndrome; also acute transverse myelitis, aseptic meningitis, neurogenic muscular atrophy, pseudotumor cerebri, bilateral pyramidal tract dysfunction | HEV genotype 3 shows a higher propensity for neurological complications; CNS and PNS involvement may occur independently or concurrently | The most common type of extrahepatic manifestation |
| Hematologic system | Red blood cells, platelets, etc. | Hemolytic anemia (especially in G6PD deficiency), autoimmune hemolytic anemia, severe thrombocytopenia (including immune thrombocytopenic purpura) | Oxidative stress-induced hemolysis; molecular mimicry and immune complex-mediated destruction of blood cells | May precede or coincide with hepatic dysfunction |
| Renal system | Glomeruli (mesangium, capillary loops) | MPGN, IgA nephropathy (recurrence or de novo) | Immune complex deposition and complement activation; mucosal immune dysregulation leading to IgA deposition | Cryoglobulinemia influences severity and treatment |
| Pancreatic system | Pancreatic acinar cells | Acute pancreatitis (ranging from mild to necrotizing) | Mechanism not fully defined; temporal relationship with HEV infection varies | May precede jaundice |
| Rheumatologic system | Joints, synovium, blood vessels | Inflammatory arthropathy (from self-limited to erosive polyarthritis), rheumatoid arthritis-like presentation; cryoglobulinemic vasculitis (arthralgia, purpura, peripheral neuropathy) | Molecular mimicry and immune complex deposition | Symptoms may persist after viral clearance |
| Other autoimmune-related | Myocardium, thyroid, etc. | Myocarditis, thyroiditis | Associated with autoimmune mechanisms | Less frequently reported |
| Obstetric/Placental system | Placental trophoblasts, endothelial cells | Fulminant hepatic failure, miscarriage, intrauterine fetal death | Viral replication leads to apoptosis, tissue necrosis, and inflammatory cytokine cascades | High risk in pregnancy |
G6PD: glucose-6-phosphate dehydrogenase; HEV: hepatitis E virus; MPGN: membranoproliferative glomerulonephritis.
GL: Writing—original draft. EH: Formal analysis. ML: Methodology, Validation. YB: Writing—review & editing. JX: Investigation, Supervision. All authors read and approved the submitted version.
The authors declare that there are no conflicts of interest.
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