Hepatology Snapshot
Pathogenesis of cholestatic hepatitis C Geoffrey W. McCaughan⇑, David G. Bowen AW Morrow Gastroenterology and Liver Centre, Centenary Institute, Royal Prince Alfred Hospital and Sydney University, Sydney, Australia
Introduction Recurrence of hepatitis C in the hepatic allograft occurs within 24 h of reperfusion, but usually does not result in any HCVspecific pathology in the first three weeks post-transplantation [1]. Acute hepatitis (biochemical and histological) generally subsequently occurs in the first 3–4 months, before the establishment of chronic hepatitis and its sequelae [1]. An uncommon variant of this early recurrence is a cholestatic injury termed cholestatic hepatitis C [2].
Definition of cholestatic hepatitis C The ILTS Consensus Conference defined cholestatic hepatitis C in 2002 [3]. 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. B. C. D.
Occurs more than one month post-transplantation. The patient is significantly immunosuppressed. Serum bilirubin is greater than 100 lmol/L or 6 mg/dl. 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 Keywords: Hepatitis C virus; Liver transplant; Immuno-suppression; Viral recurrence; Cholestasis. Received 3 June 2010; received in revised form 23 September 2010; accepted 23 September 2010 ⇑ Corresponding author. Address: Centenary Institute, Locked Bag No. 6, Newtown, NSW 2042, Australia. Tel.: +61 2 9565 6100; fax: +61 2 9565 6101. E-mail address:
[email protected] (G.W. McCaughan).
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 [4,5]. One case of HCV clearance has been reported following significant reduction in immunosuppressive therapy [6].
Pathogenesis of cholestatic HCV These patients have among the highest viral loads in serum and liver, with levels of viral replication uncommon in the nonimmunosuppressed state [7]. Thus, overall, the injury is thought to be a result of direct viral cytoxicity as a consequence of over immunosuppression (Fig. 1): (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 [8]. 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 [9], and (4) a predominantly Th2 intrahepatic cytokine response (IL-4/1L-10), unlike the more predominantly Th1 (IL-2/INF-c) response seen in non-cholestatic hepatitis C [10]. 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 [11]. Quasispecies diversity is likely shaped by neutralizing antibodies present at the time of transplantation [12]. 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. [13] 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 [14,15]. In addition, it is known that viral proteins may induce (10) oxidative stress pathways and mitochondrial dysfunction [16]. The
Journal of Hepatology 2011 vol. 54 j 392–394
JOURNAL OF HEPATOLOGY
1. “OVERIMMUNOSUPPRESSION” Corticosteroids
CD4+ Th cells
2. Increased HCV entry 3. Failure of HCV-specific T cell response
Th1 cytokines
4.Predominantly Th2 Intrahepatic cytokine response
Hepatocyte Occludin Occludin SRB1 SRB1
SRB1
SRB1
IL-4 / IL-10
SRB1
5. INCREASED HCV REPLICATION
SRB1 2. Increased cell-to-cell spread
6. Stable viral quasispecies Diversity related to neutralizing antibodies?
Nucleus
ISG 7. High level ISG induction
9. Induction of IL-8 and resistance to type I IFN
8. Activation of cell death pathway.
IL-8
Overexpression of IL-17, CCl2, CxCl1, CxCL5 IL-8, JUN and V Mas
10. Oxidative stress
11. Hepatic inflammation Hepatocyte ballooning Severe cholestasis Eventual allograft failure
Fig. 1. Pathogenesis of cholestatic hepatitis C post-liver transplantation.
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Hepatology Snapshot 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 postliver 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
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