Forum on Liver TransplantationWhat determines the natural history of recurrent hepatitis C after liver transplantation?
Section snippets
Natural history
Three patterns of recurrence have been described with differences in clinical presentation, prognosis, pathogenesis and therapeutic strategies (Fig. 1) [1], [2], [3], [4], [5], [6]. The commonest response to persistent HCV infection is the evolution over time to chronic hepatitis in a similar way to what has been described in the non-transplant patient but occurring at a viral set at least one log higher. Disease progression in these patients is typically accelerated compared to that observed
Viral-related variables
While viral factors do not appear to influence outcome in the immune competent host, data in the liver transplant recipient remain controversial.
Host-related variables
In the immune-competent population, the most powerful predictors of disease severity and progression are those related to the host. In the liver transplant setting, similar variables, both in the recipient and the donor, have been found to influence the outcome.
Immune status. The immune system is clearly implicated in the pathogenesis of liver injury due to HCV [1], [4], [10]. In fact, it is likely that the immunosuppressed status, typical of the transplant setting, is the most powerful
Immunosuppressive drugs (Table 1)
Data on the effect of corticosteroids on HCV-disease progression are controversial. Several studies have clearly shown that the use of corticosteroid boluses to treat acute cellular rejection is harmful to HCV infected recipients [1], [2], [3], [4], [5], [8], [9], [10]. Their use leads to an increased frequency of acute hepatitis, earlier time to recurrence, higher risk of progressing to graft cirrhosis or developing cholestatic hepatitis and greater risk of early post-transplant mortality. In
Age of the donor
The age of the donor has been found to be independently associated with disease severity, disease progression, graft and patient survival [1], [2], [3], [9], [22], [25], [29], [30], [31]. In one series, only 14% of the recipients who received an organ from a donor younger than 30 developed recurrent HCV-related cirrhosis; in contrast, 45 and 52% of those receiving the organ from donors aged 31–59 or older than 59 developed graft cirrhosis, respectively (P<0.0001) [29]. In another study, the
Ischemic time
Prolonged rewarming time during allograft implantation has been associated with severe recurrent disease [1]. In one study, the risk of severe HCV disease at 1 year was 19 and 65% for rewarming times of 30 and 90 min, respectively [35]. If these data were confirmed, special emphasis should be done to minimize rewarming time or alternatively to provide the donor graft with nutritional enhancement that may reduce rewarming ischemic injury.
Type of surgery: cadaveric vs donor related liver surgery:
Coinfection with other viruses
Patients who develop cytomegalovirus (CMV) infection following transplantation may be at increased risk of severe HCV recurrence [1], [9], [25]. The reasons for a positive association between CMV and HCV-disease are unknown but likely relate to induction of immune-deficiencies, release of tumor necrosis factor by CMV or the existence of cross-reactive immunological responses. Coinfection with HBV may influence histologic disease severity but results are conflicting [1], [9], [36]. In one study,
Predictive models of outcome
Although several attempts have been made to identify predictors of severe HCV recurrence, none have provided satisfactory explanation to the variation among individuals or groups in the outcome of recurrent HCV. A second step has been to create models that may more accurately predict outcome than single variables. Validation of these models is however required before they can be generalized.
Which factors determine the delayed onset of severe hepatitis C?
Delayed hepatitis C-related severe liver damage occurs in approximately one third of recipients with initial benign recurrence, defined as stable histology (F 0 or 1) during the first 3 years post-transplantation [6]. In these cases, progression to severe disease is not linear and the patients develop a sudden acceleration in fibrosis following an initial period of stabilization. The presence of some degree of fibrosis at baseline, and even more, the combination of some fibrosis and elevated
Which factors determine the development of fibrosing cholestatis hepatitis?
Fibrosing cholestatic hepatitis typically develops in the context of profound immunosuppression [1], [2], [3], [4]. While there are few studies focusing on specific risk factors associated with this pattern of recurrence, the highest rates of severe cholestatic hepatitis have been reported in patients treated with high levels of Tac (trough levels of approximately 15 ng/dl) or CyA (trough levels around 300–400 ng/dl), and in those receiving multiple pulses of methyl-prednisolone and/or OKT3 [1],
Which factors determine the decompensation of HCV-related graft cirrhosis?
There is only one published study that has defined the natural history of HCV-related graft cirrhosis, including predictors of clinical decompensation [38]. Thirty-nine patients with clinically compensated graft cirrhosis were evaluated; 46% developed at least one episode of decompensation at a mean of 8 months. The cumulative probability of decompensation was 8, 17, and 42% at 1, 6 and 12 months, respectively. The most frequent event was ascites. Patient survival rates dropped once
Histology as a means to predicting outcome
Most determinants of severe disease are pathogenically implicated in the outcome of recurrent hepatitis C. There are additional parameters that, while not directly implicated, may however help the clinician in early recognizing the patient at risk of accelerated progression. Several studies have shown an association between the early timing of recurrence (within 6 months) [1], [2], [3], [39] and some histological findings (significant steatosis, ballooning degeneration, cholestasis, and
Acknowledgements
This work was in part supported by a grant from the Instituto de Salud Carlos III (C03/02).
References (45)
- et al.
Hepatitis C and liver transplantation
J Hepatol
(2001) - et al.
Report of the first international liver transplant society consensus conference on liver transplantation and hepatitis C
Liver Transpl
(2003) The natural history and outcome of liver transplantation in hepatitis C virus-infected recipients
Liver Transpl
(2003)- et al.
Mechanisms of HCV reinfection and allograft damage after liver transplantation
J Hepatol
(2004) - et al.
HCV-related fibrosis progression following liver transplantation: increase in recent years
J Hepatol
(2000) - et al.
Delayed onset of severe hepatitis C-related liver damage following liver transplantation: a matter of concern?
Liver Transpl
(2003) Liver biopsy, viral kinetics, and the impact of viremia on severity of hepatitis C virus recurrence
Liver Transpl
(2003)Host and donor pre- and post-liver transplant risk factors impacting on HCV recurrence
Liver Transpl
(2003)The role of immunosuppression in recurrence of hepatitis C
Liver Transpl
(2003)- et al.
Hepatitis C virus kinetics during and immediately after liver transplantation
Hepatology
(2002)
Cyclosporin A suppresses replication of hepatitis C virus genome in cultured hepatocytes
Hepatology
The effect of anti-interleukin-2 receptor therapy on the course of hepatitis C recurrence after liver transplantation
Liver Transpl
Slowly tapering off steroids protects the graft against hepatitis C recurrence after liver transplantation
Liver Transpl
A model to predict severe HCV-related disease following liver transplantation
Hepatology
A prospective randomized trial of Mycophenolate Mofetil in liver transplant recipients with hepatitis C
Liver Transpl
Impact of cytomegalovirus infection, year of transplantation, and donor age on outcomes after liver transplantation for hepatitis C
Liver Transpl
Histological recurrence and progresión of hepatitis C after orthotopic liver transplantation: influence of immunosuppressive regimens
Liver Transpl
Contribution of donor age to the recent decrease in patient survival among HCV-infected liver transplant recipients
Hepatology
Evaluation of donor hepatic iron concentration as a factor of early fibrotic progression after liver transplantation
J Hepatol
Prolonged rewarming time during allograft implantation predisposes to recurrent hepatitis C infection after liver transplantation
Liver Transpl
Transplantation for alcoholic liver disease
J Hepatol
Natural history of clinically compensated HCV-related graft cirrhosis following liver transplantation
Hepatology
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