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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 [
]. Acute hepatitis (biochemical and histological) generally subsequently occurs in the first 3–4 months, before the establishment of chronic hepatitis and its sequelae [
]. 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 [
(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 [
]. 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 [
], 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 [
]. 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 [
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. [
(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 [
Hepatitis C virus and HIV envelope proteins collaboratively mediate interleukin-8 secretion through activation of p38 MAP kinase and SHP2 in hepatocytes.
]. 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.
Hepatitis C virus and HIV envelope proteins collaboratively mediate interleukin-8 secretion through activation of p38 MAP kinase and SHP2 in hepatocytes.
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