Elsevier

Journal of Hepatology

Volume 40, Issue 3, March 2004, Pages 368-374
Journal of Hepatology

Short Reviews on Liver Transplantation
Mechanisms of HCV reinfection and allograft damage after liver transplantation

https://doi.org/10.1016/j.jhep.2004.01.014Get rights and content

Introduction

The hepatitis C virus (HCV) is not eliminated from the host by liver transplantation. The HCV reinfects the allograft in all cases, resulting in varying degrees of allograft damage [1], [2]. This review addresses the issue of allograft reinfection itself and its consequences. Implications for therapeutic strategies in HCV infected liver allograft recipients are subsequently discussed. Before we do that, however, some understanding of HCV related liver damage per se is required.

Section snippets

Mechanisms of HCV liver damage in the non-transplant setting

Acute HCV infection has been studied in humans and chimpanzees. In chimpanzees, acute HCV infection is associated with the generation of a polyclonal and multispecific antigen specific response, at the humoral and cellular level [3]. At the humoral level, it has been demonstrated that the level of antibody production was relatively low compared to that seen in other chronic infections [4]. With respect to the cellular response, vigorous T cell responses have been associated with viral clearance

Allograft reinfection

Following/during a liver transplant procedure, reinfection of the liver allograft has been recognised at the virological level. A recent study, in which sampling for HCV RNA in serum began in the operative period itself, concluded that it was likely an initial round of infection occurred during reperfusion of the allograft [33]. This is much earlier than reported in previous studies. Further studies have confirmed much earlier recurrence during an analysis of HCV quasispecies [34], [35]. Also,

Acute allograft hepatitis

As mentioned previously the initial biochemical and histological hepatitis usually occurs between 1 and 3 months post-transplant. It is characterised by a rising serum alanine transaminase level and sometimes an elevated bilirubin to moderate levels (<100 umol/l). The biopsy shows a portal and lobular infiltrate, with councilman bodies, characteristic of hepatitis in the non-transplant setting [35]. There also may be additional injury from other causes. There is a peak of serum HCV levels at

Cholestatic HCV infection

A small number of patients (<10%), may develop a severe liver injury characterised by progressive jaundice (bilirubin >100 umol/l) and biochemical cholestasis (serum alkaline phosphatase (SAP)) >500 U/l, gamma glutamyl transpeptidase (GGT) >1000 U/l), so called cholestatic HCV [40], [41], [42], [43], [44], [45], [46], [47]. This usually begins to set in by 1 month and may progress over a 3–6 month period to liver failure. The histology varies from severe centrizonal hepatocyte ballooning with

Chronic hepatitic HCV disease

The commonest response to persistent HCV infection in the allograft is the evolution over time (6–12 months) to chronic hepatitis. There are few, if any, studies that have examined the specific immune response against HCV in this setting. The study by Rosen et al. [52] that examined mild HCV infection (presumably chronic HCV) found a detectable CD4 response in 30% of patients but no correlation was made with viral burden or degree of liver injury (except as a comparison with cholestatic HCV).

Does an understanding of HCV related allograft damage explain more rapid progression post-transplant?

The above data informs us that HCV in the liver allograft is not characterised by unusual or deviated immune responses (the exception is cholestatic HCV). Instead, even in the presence of immunosuppression (IS), the increased viral load stimulates a similar type of response to that seen in chronic HCV without IS. Indeed, this response is even more vigorous under IS. It seems as though in the competition between IS having an anti inflammatory role and more HCV having an inflammatory stimulatory

Implications for HCV treatment strategies and levels of immunosuppression

The data discussed above indicating HCV reinfection at the time of allograft reperfusion suggested that if induction corticosteroid therapy is omitted, then there is a delay in the rate of return of HCV replication to pre-transplant levels [33]. In that study, a second phase decline in serum HCV RNA levels was only observed in patients who did not receive corticosteroid therapy. However, by 1–3 months transplant all these patients had return of virus to pre-transplant levels. Also prednisolone

Relationship between levels of immunosuppression and cholestatic HCV

There is no doubt that cholestatic HCV only occurs in the setting of significant ‘over’ immunosuppression. It is seen in all forms of solid organ and bone marrow transplantation as well as in HIV infection. High levels of immunosuppression essentially cause cholestatic HCV by suppressing immune and inflammatory responses to such an extent that the HCV load increases to levels, where the HCV itself may have direct cytopathic effects. Although specific protocols have not been directly linked to

Relationship between immunosuppressive therapies and chronic hepatitic liver injury

As discussed above, this chronic hepatitic disease post-transplant, seems to take place in the presence of more virus, more cellular proliferation and apoptosis than pre-transplant. However, the viral load is brought under control and a significant intrahepatic TH1 like inflammatory process takes place. Furthermore this process seems to be more aggressive than a decade ago. What do we know about specific immunosuppressive therapies on these processes? Once again corticosteroid therapy seems to

Conclusions

HCV infection in the allograft occurs in the setting of higher viral burden than non-transplant. Infection occurs early and is associated with immune cell infiltration and hepatocyte apoptosis. Cholestatic HCV seems to be a disease of direct HCV hepatocyte injury in the setting of extreme levels of virus whilst chronic hepatitic HCV seems to behave at the molecular/cellular level in a similar fashion to the non-transplant setting with activation of TH1 inflammatory, pro-fibrotic and

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