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Pathogenesis of cholestatic hepatitis C

  • Geoffrey W. McCaughan
    Correspondence
    Corresponding author. Address: Centenary Institute, Locked Bag No. 6, Newtown, NSW 2042, Australia. Tel.: +61 2 9565 6100; fax: +61 2 9565 6101.
    Affiliations
    AW Morrow Gastroenterology and Liver Centre, Centenary Institute, Royal Prince Alfred Hospital and Sydney University, Sydney, Australia
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  • David G. Bowen
    Affiliations
    AW Morrow Gastroenterology and Liver Centre, Centenary Institute, Royal Prince Alfred Hospital and Sydney University, Sydney, Australia
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Open AccessPublished:October 29, 2010DOI:https://doi.org/10.1016/j.jhep.2010.09.010

      Keywords

      Introduction

      Recurrence of hepatitis C in the hepatic allograft occurs within 24 h of reperfusion, but usually does not result in any HCV-specific pathology in the first three weeks post-transplantation [
      • Guerrero R.B.
      • Batts K.P.
      • Burgart L.J.
      • Barrett S.L.
      • Germer J.J.
      • Poterucha J.J.
      • et al.
      Early detection of hepatitis C allograft reinfection after orthotopic liver transplantation: a molecular and histologic study.
      ]. Acute hepatitis (biochemical and histological) generally subsequently occurs in the first 3–4 months, before the establishment of chronic hepatitis and its sequelae [
      • Guerrero R.B.
      • Batts K.P.
      • Burgart L.J.
      • Barrett S.L.
      • Germer J.J.
      • Poterucha J.J.
      • et al.
      Early detection of hepatitis C allograft reinfection after orthotopic liver transplantation: a molecular and histologic study.
      ]. An uncommon variant of this early recurrence is a cholestatic injury termed cholestatic hepatitis C [
      • Dickson R.C.
      • Caldwell S.H.
      • Ishitani M.B.
      • Lau J.Y.
      • Driscoll C.J.
      • Stevenson W.C.
      • et al.
      Clinical and histologic patterns of early graft failure due to recurrent hepatitis C in four patients after liver transplantation.
      ].

      Definition of cholestatic hepatitis C

      The ILTS Consensus Conference defined cholestatic hepatitis C in 2002 [
      • Wiesner R.H.
      • Sorrell M.
      • Villamil F.
      Report of the first International Liver Transplantation Society expert panel consensus conference on liver transplantation and hepatitis C.
      ]. Importantly, it uses the term cholestatic hepatitis C, not fibrosing cholestatic hepatitis C, as fibrosis is not as prominent as that seen in hepatitis B virus (HBV)-associated fibrosing cholestatic hepatitis (FCH), and may not be present in early biopsies.
      Cholestatic hepatitis C was defined by the following:
      • A.
        Occurs more than one month post-transplantation.
      • B.
        The patient is significantly immunosuppressed.
      • C.
        Serum bilirubin is greater than 100 μmol/L or 6 mg/dl.
      • D.
        SAP and GTT are greater than five times the upper limit of normal.
      • E.
        Hepatitis C viral (HCV) load is very high (not defined, but certainly more than 6 log10).
      • F.
        Histological features of hepatocyte ballooning, particularly in zone 3.
      • G.
        Absence of hepatic artery thrombosis and biliary strictures.
      All of these features should be present to make the diagnosis.

      Natural history of cholestatic HCV

      Invariably, cholestatic hepatitis C occurs between 2 and 6 months post-transplantation. One of the key reasons for identifying and separating this entity is that allograft injury is rapidly progressive, and may result in allograft failure within months of onset. It is usually resistant to antiviral therapy, although isolated reports of successful outcomes have been observed [
      • Gopal D.V.
      • Rosen H.R.
      Duration of antiviral therapy for cholestatic HCV recurrence may need to be indefinite.
      ,
      • Bolkhir A.
      • Brunt E.M.
      • Solomon H.S.
      • Hayashi P.H.
      Sustained resolution of fibrosing cholestatic hepatitis C despite viremic relapse after stopping pegylated interferon and ribavirin therapy.
      ]. One case of HCV clearance has been reported following significant reduction in immunosuppressive therapy [
      • Doughty A.L.
      • Zekry A.
      • Spencer J.D.
      • Turhan S.
      • Painter D.
      • McCaughan G.W.
      Spontaneous clearance of hepatitis C virus infection post-liver transplant is associated with rapidly changing quasispecies: a single case report.
      ].

      Pathogenesis of cholestatic HCV

      These patients have among the highest viral loads in serum and liver, with levels of viral replication uncommon in the non-immunosuppressed state [
      • Doughty A.L.
      • Spencer J.D.
      • Cossart Y.E.
      • McCaughan G.W.
      Cholestatic hepatitis after liver transplantation is associated with persistently high serum hepatitis C virus RNA levels.
      ]. Thus, overall, the injury is thought to be a result of direct viral cytoxicity as a consequence of over immunosuppression (Fig. 1):
      Figure thumbnail gr1
      Fig. 1Pathogenesis of cholestatic hepatitis C post-liver transplantation.
      (1) Initial and subsequent immunosuppression with high dose corticosteroid leads to (2) increased HCV entry into hepatocytes via upregulation of entry receptors occludin and scavenger receptor B1 (SRB1), combined with enhanced spread of the virus from cell to cell [
      • Ciesek S.
      • Steinmann E.
      • Iken M.
      • Ott M.
      • Helfritz F.A.
      • Wappler I.
      • et al.
      Glucocorticosteroids increase cell entry by hepatitis C virus.
      ]. In addition, in the face of high level immunosuppression, there is (3) a failure to mount a detectable HCV-specific T cell response, in contrast to recurrent non-cholestatic hepatitis C [
      • Rosen H.R.
      • Hinrichs D.J.
      • Gretch D.R.
      • Koziel M.J.
      • Chou S.
      • Houghton M.
      • et al.
      Association of multispecific CD4(+) response to hepatitis C and severity of recurrence after liver transplantation.
      ], and (4) a predominantly Th2 intrahepatic cytokine response (IL-4/1L-10), unlike the more predominantly Th1 (IL-2/INF-γ) response seen in non-cholestatic hepatitis C [
      • Zekry A.
      • Bishop G.A.
      • Bowen D.G.
      • Gleeson M.M.
      • Guney S.
      • Painter D.M.
      • et al.
      Intrahepatic cytokine profiles associated with posttransplantation hepatitis C virus-related liver injury.
      ]. The outcome of these factors leads to (5) high-level viral replication, a central feature of this condition. In support of the absence of effective immune selection pressure in this setting, (6) viral quasi-species remain unaltered during the progression of this entity, again in contrast to the situation observed in non-cholestatic recurrence [
      • Doughty A.L.
      • Painter D.M.
      • McCaughan G.W.
      Post-transplant quasispecies pattern remains stable over time in patients with recurrent cholestatic hepatitis due to hepatitis C virus.
      ]. Quasi-species diversity is likely shaped by neutralizing antibodies present at the time of transplantation [
      • Fafi-Kremer S.
      • Fofana I.
      • Soulier E.
      • Carolla P.
      • Meuleman P.
      • Leroux-Roels G.
      • et al.
      Viral entry and escape from antibody-mediated neutralization influence hepatitis C virus reinfection in liver transplantation.
      ].
      Other molecular features include (7) the highest-level expression of interferon-stimulated genes (ISGs), probably related to the very high viral loads, (8) increased gene expression of cell death pathways, and a decrease in coagulation pathway and complement system genes. Unusually, IL-17 signaling gene expression was upregulated in cholestatic HCV samples including over expression of genes including CCL2, CXCL1, CXCL5, IL8, JUN, among others. (Ref. [
      • Mas V.
      • Maluf D.
      • Archer K.
      • Posner P.
      • Stravitz T.
      • Fisher R.
      Molecular pathogenesis of hepatitis virus recurrence post-liver transplantation.
      ] and V. Mas, personal communication)
      (9) High levels of IL-8 are also observed, and may reflect in vitro evidence of direct viral stimulation of IL-8 production, potentially impairing the antiviral type I IFN response [
      • Polyak S.J.
      • Khabar K.S.
      • Paschal D.M.
      • Ezelle H.J.
      • Duverlie G.
      • Barber G.N.
      • et al.
      Hepatitis C virus nonstructural 5A protein induces interleukin-8, leading to partial inhibition of the interferon-induced antiviral response.
      ,
      • Balasubramanian A.
      • Ganju R.K.
      • Groopman J.E.
      Hepatitis C virus and HIV envelope proteins collaboratively mediate interleukin-8 secretion through activation of p38 MAP kinase and SHP2 in hepatocytes.
      ]. In addition, it is known that viral proteins may induce (10) oxidative stress pathways and mitochondrial dysfunction [
      • Abdalla M.Y.
      • Ahmad I.M.
      • Spitz D.R.
      • Schmidt W.N.
      • Britigan B.E.
      Hepatitis C virus-core and non structural proteins lead to different effects on cellular antioxidant defenses.
      ]. The mechanisms and role of IL-17 expression in this condition remains unclear; however, may relate to significant intrahepatic non-specific inflammatory responses, which may be a reaction to viral cytopathic effects, rather than a cause.
      Thus it seems that in this situation, impaired antiviral immunity leads to viral escape from immune pressure and immune selection, with a spiraling process of viral replication and direct toxicity, observed in the histological features of (11) hepatic inflammation, with hepatocyte ballooning and severe cholestasis. This compares to non-cholestatic HCV recurrence, where there is evidence of immune recognition, and the allograft damage processes are not dissimilar to the non-immunosuppressed state.

      Pathogenesis – implications for management

      An understanding of the pathogenesis and natural history of this condition quickly leads to the conclusion that extremely high levels of HCV should be avoided. Thus, it is hard to not recommend that HCV loads be monitored in the first 3 months post-liver transplantation, although there is absolutely no consensus on this; if loads are high, immunosuppression should be reduced accordingly in a preemptive manner. Once cholestatic HCV does occur, the viral load must then be brought under control in as rapid a fashion as possible. This involves a dramatic reduction or even a cessation in immunosuppression, combined with the introduction of antiviral therapies providing the patient can tolerate this, therapeutic maneuvers that are sometimes not possible. In the future, the use of direct antiviral agents, such as HCV polymerase and/or HCV protease inhibitors may considerably improve outcomes: we look forward to that day.

      Conflict of interest

      The authors who have taken part in this work declare that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

      References

        • Guerrero R.B.
        • Batts K.P.
        • Burgart L.J.
        • Barrett S.L.
        • Germer J.J.
        • Poterucha J.J.
        • et al.
        Early detection of hepatitis C allograft reinfection after orthotopic liver transplantation: a molecular and histologic study.
        Mod Pathol. 2000; 13: 229-237
        • Dickson R.C.
        • Caldwell S.H.
        • Ishitani M.B.
        • Lau J.Y.
        • Driscoll C.J.
        • Stevenson W.C.
        • et al.
        Clinical and histologic patterns of early graft failure due to recurrent hepatitis C in four patients after liver transplantation.
        Transplantation. 1996; 61: 701-705
        • Wiesner R.H.
        • Sorrell M.
        • Villamil F.
        Report of the first International Liver Transplantation Society expert panel consensus conference on liver transplantation and hepatitis C.
        Liver Transpl. 2003; 9: S1-S9
        • Gopal D.V.
        • Rosen H.R.
        Duration of antiviral therapy for cholestatic HCV recurrence may need to be indefinite.
        Liver Transpl. 2003; 9: 348-353
        • Bolkhir A.
        • Brunt E.M.
        • Solomon H.S.
        • Hayashi P.H.
        Sustained resolution of fibrosing cholestatic hepatitis C despite viremic relapse after stopping pegylated interferon and ribavirin therapy.
        Liver Transpl. 2007; 13: 309-311
        • Doughty A.L.
        • Zekry A.
        • Spencer J.D.
        • Turhan S.
        • Painter D.
        • McCaughan G.W.
        Spontaneous clearance of hepatitis C virus infection post-liver transplant is associated with rapidly changing quasispecies: a single case report.
        Liver Transpl. 2000; 6: 648-653
        • Doughty A.L.
        • Spencer J.D.
        • Cossart Y.E.
        • McCaughan G.W.
        Cholestatic hepatitis after liver transplantation is associated with persistently high serum hepatitis C virus RNA levels.
        Liver Transpl Surg. 1998; 4: 15-21
        • Ciesek S.
        • Steinmann E.
        • Iken M.
        • Ott M.
        • Helfritz F.A.
        • Wappler I.
        • et al.
        Glucocorticosteroids increase cell entry by hepatitis C virus.
        Gastroenterology. 2010; 138: 1875-1884
        • Rosen H.R.
        • Hinrichs D.J.
        • Gretch D.R.
        • Koziel M.J.
        • Chou S.
        • Houghton M.
        • et al.
        Association of multispecific CD4(+) response to hepatitis C and severity of recurrence after liver transplantation.
        Gastroenterology. 1999; 117: 926-932
        • Zekry A.
        • Bishop G.A.
        • Bowen D.G.
        • Gleeson M.M.
        • Guney S.
        • Painter D.M.
        • et al.
        Intrahepatic cytokine profiles associated with posttransplantation hepatitis C virus-related liver injury.
        Liver Transpl. 2002; 8: 292-301
        • Doughty A.L.
        • Painter D.M.
        • McCaughan G.W.
        Post-transplant quasispecies pattern remains stable over time in patients with recurrent cholestatic hepatitis due to hepatitis C virus.
        J Hepatol. 2000; 32: 126-134
        • Fafi-Kremer S.
        • Fofana I.
        • Soulier E.
        • Carolla P.
        • Meuleman P.
        • Leroux-Roels G.
        • et al.
        Viral entry and escape from antibody-mediated neutralization influence hepatitis C virus reinfection in liver transplantation.
        J Exp Med. 2010; 207: 2019-2031
        • Mas V.
        • Maluf D.
        • Archer K.
        • Posner P.
        • Stravitz T.
        • Fisher R.
        Molecular pathogenesis of hepatitis virus recurrence post-liver transplantation.
        Am J Transpl. 2010; 10: 134
        • Polyak S.J.
        • Khabar K.S.
        • Paschal D.M.
        • Ezelle H.J.
        • Duverlie G.
        • Barber G.N.
        • et al.
        Hepatitis C virus nonstructural 5A protein induces interleukin-8, leading to partial inhibition of the interferon-induced antiviral response.
        J Virol. 2001; 75: 6095-6106
        • Balasubramanian A.
        • Ganju R.K.
        • Groopman J.E.
        Hepatitis C virus and HIV envelope proteins collaboratively mediate interleukin-8 secretion through activation of p38 MAP kinase and SHP2 in hepatocytes.
        J Biol Chem. 2003; 278: 35755-35766
        • Abdalla M.Y.
        • Ahmad I.M.
        • Spitz D.R.
        • Schmidt W.N.
        • Britigan B.E.
        Hepatitis C virus-core and non structural proteins lead to different effects on cellular antioxidant defenses.
        J Med Virol. 2005; 76: 489-497