Advertisement

Hepatopathology of flaviviruses

  • Adam L. Bailey
    Correspondence
    Corresponding authors.
    Affiliations
    Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Heath, University of Wisconsin–Madison, Madison, WI, USA
    Search for articles by this author
  • Michael S. Diamond
    Correspondence
    Corresponding authors.
    Affiliations
    Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA

    Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA

    Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA

    The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA
    Search for articles by this author
Published:August 15, 2022DOI:https://doi.org/10.1016/j.jhep.2022.05.024
      Acute hepatitis can be caused by a variety of viruses, many of which are uncommon in the United States. Diagnosis requires virus-specific molecular and/or antigen-based tests, but disease severity can be assessed using a set of classical liver function tests. An increase in alanine aminotransferase (ALT) levels in serum is an early and specific indicator of hepatocyte damage. ALT concentrations are proportional to the degree of hepatocyte injury but can be elevated even in subclinical cases. Derangements in hepatic excretory function (as measured by blood concentrations of bilirubin), synthetic function (prolongation of the prothrombin time), and metabolic function (hyperammonemia) indicate progressively more serious liver dysfunction.
      Among viruses capable of causing hepatitis are the flaviviruses (i.e., Flavivirus genus), which includes a diverse group of medically important viruses with positive-sense, non-segmented, single-stranded RNA genomes enveloped in a lipid membrane. In contrast to the blood-borne human viruses found in the larger Flaviviridae family (i.e., hepatitis C virus and human pegivirus), all medically important flaviviruses are transmitted to humans via the bite of an infected arthropod (i.e., tick or mosquito). Transmission of these viruses is linked to seasonal and local changes in arthropod activity, and anti-vector countermeasures (e.g., elimination of breeding grounds and insecticides) are often the most effective means of prevention. To date, only vaccines against Japanese encephalitis (JEV), yellow fever, Dengue (in virus-experienced individuals), and tick-borne encephalitis viruses are used in humans. Cross-protective immunity – and the peculiar phenomenon of antibody-dependent enhancement (ADE) of heterologous flavivirus infection – have complicated vaccine development for members of this family.
      Closely related Flaviviruses are grouped into “complexes” that share genetic, ecological, and epidemiological features: differences between mammalian host(s), vector species, and/or locations often distinguish viruses within a complex.
      • Rathore A.P.S.
      • St. John A.L.
      Cross-reactive immunity among flaviviruses.
      Herein, we discuss differences between flavivirus complexes with regards to hepatopathology, drawing attention to specific viruses when necessary. While several flaviviruses are not discussed due to their lack of medical relevance, it should be noted that seemingly obscure flaviviruses can emerge from relative obscurity, as demonstrated by the West Nile virus (WNV) and Zika virus epidemics in the Americas in 1999-2003 and 2015-2016, respectively.
      Viruses in the JEV complex (e.g., JEV, WNV, and St. Louis encephalitis virus) and the Spondweni virus complex (e.g., Zika virus) are globally distributed. While most infections are asymptomatic, symptomatic cases initially present as non-specific viral syndromes that are often accompanied by a diffuse maculopapular rash on the torso and extremities. Although immortalized hepatocyte cell lines support robust replication by many of these flaviviruses, this infection may be due to defective immune signaling in these cells. Indeed, substantive injury to the liver, as reflected by elevated ALT concentration in serum, is rare (i.e., case-reportable). Instead, encephalitis and/or congenital transmission are the main causes of morbidity and mortality for these complexes of flaviviruses.
      • Sejvar J.
      Clinical manifestations and outcomes of West Nile virus infection.
      ,
      • Halani S.
      • Tombindo P.E.
      • O’Reilly R.
      • Miranda R.N.
      • Erdman L.K.
      • Whitehead C.
      • et al.
      Clinical manifestations and health outcomes associated with Zika virus infections in adults: a systematic review.
      The Tick-borne flavivirus (TBFV) complex has a global distribution, with Powassan virus (POWV) the only one endemic to North America. Although human TBFV infections are sporadic and rare, the case-fatality rate can be high (1-40%). The disease course is biphasic, with the initial phase characterized by a severe flu-like viral syndrome accompanied by hemorrhagic findings (the bleeding manifestations do not typically occur with POWV infection). The pathophysiology of hemorrhage in these infections remains poorly understood but is attributed to endothelial dysfunction and injury. Although a mild elevation in serum liver enzymes (ALT <5x upper limit of reference range) is seen during this period in ∼80% of cases, the degree of liver damage is unlikely to cause meaningful functional defects. A subset of cases progress to a second disease phase, which features neurological manifestations characteristic of a central nervous system viral infection. The ensuing encephalitis can result in death (1-20% case fatality rate) or permanent and debilitating neurological sequelae.
      • Gupta N.
      • Chunduru K.
      • Safeer K.M.
      • Saravu K.
      Clinical and laboratory profile of patients with Kyasanur forest disease: a single-centre study of 192 patients from Karnataka, India.
      ,
      • Patil D.R.
      • Yadav P.D.
      • Shete A.
      • Chaubal G.
      • Mohandas S.
      • Sahay R.R.
      • et al.
      Study of Kyasanur forest disease viremia, antibody kinetics, and virus infection in target organs of Macaca radiata.
      Four dengue serotypes comprise the dengue virus complex, with each serotype eliciting an antibody response capable of facilitating ADE, and more severe forms of dengue, upon subsequent infection with a distinct serotype. Mild liver injury with elevations in serum liver enzymes is not uncommon during infection. However, ∼0.3% of dengue cases develop severe liver complications characterized by jaundice, hepatomegaly, markedly elevated serum liver enzymes (ALT ∼10x upper limit of reference range), hyperammonemia, and prolonged prothrombin time; these abnormalities carry a poor prognosis. Histological examination of the liver shows midzonal necrosis with or without an acute multi-leukocytic infiltrate. The pathophysiology of this relatively rare manifestation of dengue remains poorly understood, as animal models do not recapitulate this aspect of dengue disease.
      • Kye Mon K.
      • Nontprasert A.
      • Kittitrakul C.
      • Tangkijvanich P.
      • Leowattana W.
      • Poovorawan K.
      Incidence and clinical outcome of acute liver failure caused by dengue in a hospital for tropical diseases, Thailand.
      ,
      • Seneviratne S.L.
      • Malavige G.N.
      • de Silva H.J.
      Pathogenesis of liver involvement during dengue viral infections.
      The yellow fever virus (YFV) complex contains YFV, the sole member of the flavivirus genus that consistently causes severe liver injury. At present, YFV is found only in Africa and South America, although its potential for spread to other areas is of concern, as its global distribution was more widespread in prior centuries.
      • Douam F.
      • Ploss A.
      Yellow fever virus: knowledge gaps impeding the fight against an old foe.
      After mosquito inoculation, YFV can infect and cause dysfunction in multiple visceral organs, although its most distinguishing feature is the hepatopathology observed in severe cases. Signs of liver damage often present within ∼3 days of flu-like symptom onset, at a time when most patients are improving clinically. A subset (∼30%) of patients progress to the highly-lethal “toxic” phase, which is characterized by fulminant hepatic failure (ALT >20x upper limit of reference range), visceral organ damage, and coagulopathy.
      • Kallas E.G.
      • D’Elia Zanella L.G.F.A.B.
      • Moreira C.H.V.
      • Buccheri R.
      • Diniz G.B.F.
      • Castiñeiras A.C.P.
      • et al.
      Predictors of mortality in patients with yellow fever: an observational cohort study.
      Histology of the liver shows necrosis/apoptosis of hepatocytes and Kupffer cells most prominently in the midzone accompanied by microvesicular fatty change. Despite this degree of injury, leukocyte infiltrates are scarce. Coagulopathy in severe yellow fever is a key contributor to mortality, yet it is complex, with coagulation factor consumption compounding a synthesis defect resulting from hepatocyte destruction. Although hepatocyte infection and injury is a central feature of YFV pathogenesis, damage to extrahepatic tissues (e.g., kidney) contributes to YF disease in poorly understood ways.
      • Monath T.P.
      • Barrett A.D.
      Pathogenesis and pathophysiology of yellow fever.
      In extremely rare (∼1:1,000,000) cases, the YFV vaccine can cause a severe and even fatal YF-like disease known as YF vaccine-associated viscerotropic disease (YEL-AVD).
      In summary, the flaviviruses are arthropod-borne RNA viruses that cause hundreds of millions of infections annually. Liver disease is rare among most flavivirus infections, although a small fraction of TBEV and dengue infections can result in moderate to severe liver injury. In contrast, liver manifestations are common among YFV infections, and a substantial proportion of symptomatic infections can progress to hepatic failure, coagulopathy, and death.

      Financial support

      ALB: DP5OD029608, MSD: R01-AI073755.

      Authors' contributions

      Both authors contributed equally to this work.

      Conflict of interest

      The authors declare no conflicts of interest that pertain to this work.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following is the supplementary data to this article:

      References

        • Rathore A.P.S.
        • St. John A.L.
        Cross-reactive immunity among flaviviruses.
        Front Immunol. 2020; 11: 334
        • Sejvar J.
        Clinical manifestations and outcomes of West Nile virus infection.
        Viruses. 2014; 6: 606-623
        • Halani S.
        • Tombindo P.E.
        • O’Reilly R.
        • Miranda R.N.
        • Erdman L.K.
        • Whitehead C.
        • et al.
        Clinical manifestations and health outcomes associated with Zika virus infections in adults: a systematic review.
        PLoS Negl Trop Dis. 2021; 15e0009516
        • Gupta N.
        • Chunduru K.
        • Safeer K.M.
        • Saravu K.
        Clinical and laboratory profile of patients with Kyasanur forest disease: a single-centre study of 192 patients from Karnataka, India.
        J Clin Virol. 2021; 135104735
        • Patil D.R.
        • Yadav P.D.
        • Shete A.
        • Chaubal G.
        • Mohandas S.
        • Sahay R.R.
        • et al.
        Study of Kyasanur forest disease viremia, antibody kinetics, and virus infection in target organs of Macaca radiata.
        Sci Rep. 2020; 1012561
        • Kye Mon K.
        • Nontprasert A.
        • Kittitrakul C.
        • Tangkijvanich P.
        • Leowattana W.
        • Poovorawan K.
        Incidence and clinical outcome of acute liver failure caused by dengue in a hospital for tropical diseases, Thailand.
        Am J Trop Med Hyg. 2016; 95: 1338-1344
        • Seneviratne S.L.
        • Malavige G.N.
        • de Silva H.J.
        Pathogenesis of liver involvement during dengue viral infections.
        Trans R Soc Trop Med Hyg. 2006; 100: 608-614
        • Douam F.
        • Ploss A.
        Yellow fever virus: knowledge gaps impeding the fight against an old foe.
        Trends Microbiol. 2018; 26: 913-928
        • Kallas E.G.
        • D’Elia Zanella L.G.F.A.B.
        • Moreira C.H.V.
        • Buccheri R.
        • Diniz G.B.F.
        • Castiñeiras A.C.P.
        • et al.
        Predictors of mortality in patients with yellow fever: an observational cohort study.
        Lancet Infect Dis. 2019; 19: 750-758
        • Monath T.P.
        • Barrett A.D.
        Pathogenesis and pathophysiology of yellow fever.
        Adv Virus Res. 2003; 60: 343-395