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Second Forum on Liver Transplantation:
Liver transplantation for hepatitis C: how to control the virus?
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Journal of Hepatology
(April 2005)
Pierre-Alain Clavien*email address
Department of Visceral and Transplantation Surgery, University Hospital Zurich, Ramistrasse 100, Zurich 8091, Switzerland
This second Forum on Liver Transplantation will focus on hepatitis C, which is the current leading indication for transplantation in industrialized countries, with an increasing incidence of infection worldwide. The major issue with hepatitis C virus is its inevitable reappearance in the graft with rapid evolution to severe recurrent forms of liver diseases and cirrhosis in many patients. Therefore, several strategies have been proposed to overcome this negative pattern. Marina Berenguer presents in an excellent review the natural history of recurrent hepatitis C after liver transplantation. She provides compelling evidence that no single factor can predict which patients will ultimately progress to cirrhosis after transplantation from those with a benign course. The main risk factors include high viral load at the time of transplantation or early following surgery, the infection by HCV genotype 1b, the use of older donors, and immuno-suppression. She provides a useful survey of the various immunosuppressive agents related to their impact on recurrent hepatitis C after liver transplantation. Greg Everson addresses the question whether we should treat patients with chronic hepatitis C on the waiting list for liver transplantation. This question remains largely open, but is worth exploring further as pre-transplant therapies currently prevent a fourth of recurrent hepatitis C after surgery. However, these treatments are often poorly tolerated in this sick population of patients awaiting a graft. Isabelle Morard and Franco Negro look at the approach of treating patients after transplantation. The current data on preemptive therapy, i.e. treating patients early after transplantation prior to apparent recurrences, has been disappointing. The best approach rather seems to selectively treat recipients when histological evidence of progressive liver fibrosis or inflammation develops. Laura Llado, Jose Castellote and Juan Figueras address the difficult issue of re-transplanting patients with severe recurrent forms of Hepatitis C. They propose a very conservative approach, where redo transplantation should be limited to those with late recurrence, stable renal function, and who have not yet been treated fully with antiviral therapy. Finally, Yasuhiko Sugawara and Masatoshi Makuuchi provide an excellent discussion on the benefits vs. risks of living related liver transplantation for hepatitis C cirrhosis. They conclude that the earlier reported dramatically poorer outcomes using living donor grafts may be related to the learning curve and lack of effective antiviral therapies, and that recent data including their own series from Tokyo suggest comparable results in patients receiving a cadaveric and living donor grafts. They however emphasize the need to identify associated strategies such as preemptive therapies to minimize the risk of severe recurrent diseases.
With this Forum the readers will gather a comprehensive overview of our current knowledge and remaining questions on hepatitis C related to liver transplantation, and the challenges ahead, particularly considering the increasing number of long term patients transplanted for hepatitis C related liver diseases.
From now on we will also publish at the end of each Forum letters related to the previous Forum to serve as a platform to discuss controversial issues. Here we propose two letters related to the article by R. Freeman on the MELD system currently used for organ allocation in the US.
What determines the natural history of recurrent hepatitis C after liver transplantation?
Marina Berenguer
Hospital Universitario La FE, Servicio de Medicina Digestiva, Avda Campanar 21, Valencia 46009, Spain
Article Outline
- 1. Natural history
- 2. Which factors impact on the course of recurrent chronic hepatitis C ?
- 2.1. Viral-related variables
- 2.1.1. Post-transplantation HCV RNA levels
- 2.1.2. Pretransplantation HCV RNA levels
- 2.1.3. HCV genotype
- 2.1.4. HCV diversity
- 3. Host-related variables
- 4. Iatrogenic variables
- 4.1. Immunosuppressive drugs
- 4.2. Antifibrotic agents
- 5. Donor-related variables
- 5.1. Age of the donor
- 5.2. Donor steatosis
- 5.3. Donor hepatic iron concentration
- 5.4. Donor immunogenetic background
- 5.5. Anti-HCV status of the donor
- 6. Surgical-related variables
- 6.1. Ischemic time
- 7. Other variables
- 7.1. Coinfection with other viruses
- 7.2. Alcohol consumption
- 8. Predictive models of outcome
- 9. Which factors determine the delayed onset of severe hepatitis C?
- 10. Which factors determine the development of fibrosing cholestatis hepatitis?
- 11. Which factors determine the decompensation of HCV-related graft cirrhosis?
- 12. Histology as a means to predicting outcome
- References
Hepatitis C virus (HCV) cirrhosis is the most common indication for liver transplantation in developed countries. Re-infection of liver allografts is virtually universal and occurs at reperfusion [1,2]. A significant increase in viral load is typically observed following transplantation, presumably as a consequence of the administration of immunosuppressive agents for the prevention and treatment of rejection. In this setting, HCV mediated liver injury follows a more aggressive course compared to the non-immunosuppressed state, leading to recurrent disease and allograft failure in a substantial proportion of patients [1-3]. While it seems evident that the immune suppressed status 'per se' modifies the natural history of hepatitis C in liver transplant recipients, the effect of several other factors on determining both the pattern and severity of recurrence still remains a matter of intense research. Identifying the factors, whether present prior to transplantation or developing in the post-transplant setting, that impact on the natural history of recurrent hepatitis C is of paramount importance not only to target those at high risk of severe recurrence with current imperfect and difficult-to-tolerate antiviral therapies but also to improve organ allocation and patient management. In this review, I will summarize the available data regarding risk factors associated with cholestatic hepatitis, severe chronic recurrent hepatitis and severe but delayed-onset hepatitis. I will also describe the determinants of higher mortality in this population, and those associated with clinical decompensation among recipients with established recurrent HCV-related allograft cirrhosis.
1. Natural history
Three patterns of recurrence have been described with differences in clinical presentation, prognosis, pathogenesis and therapeutic strategies [1-6]. 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 in the immune competent host [1-6]. Progression in patients with this pattern of recurrence may follow two distinct pathways: a linear rate of fibrosis progression 5 and a delayed onset of progression 6. Regardless of the pathway used, the hepatitis C driven fibrosis response in the allograft leads to the development of graft cirrhosis in approximately 25% of recipients (range: 8-44%) after a follow up of 5-10 years [1-7]. Liver damage in this setting is believed to involve host-mediated immune responses over-stimulated by the increased viral load 4. Cholestatis hepatitis is an infrequent but extremely severe pattern of recurrence that leads in 50% of patients to graft failure within a few months of onset [1-4]. A cytopathic mechanism of allograft damage is thought to be involved given the concurrence of extremely high viral burdens, reduced immune response with intrahepatic non-specific Th2 cytokine response, and unusual histology characterized by little inflammation and severe centrizonal hepatocyte ballooning 4. In a substantial proportion of infected recipients, progression is not apparent, at least for the first decade, and liver injury remains mild or absent despite high viral burden.
There are a number of factors that potentially contribute to disease progression [1-10]. In addition to those already known from the immune competent patient, there are unique variables in the transplant setting that further complicate the difficult interactions between the host and the virus. These variables include surgical related factors, particularly the time of ischemia and reperfusion injury and donor-related factors such as age, histocompatibility between donor and recipient, immunologic chimerism and the use of immunosuppressive medications.
2. Which factors impact on the course of recurrent chronic hepatitis C ?
2.1. 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.
2.1.1. Post-transplantation HCV RNA levels
Serum HCV RNA concentrations increase rapidly in the post-transplantation period to peak by the fourth post-operative month 11. The relationship between levels of viremia and the long-term outcome of post-transplant HCV infection is contradictory. In some studies, early post-transplantation viral load has been shown to influence late post-transplantation outcome 10. Sreekumar and colleagues found that HCV RNA at 4 months was the most sensitive (82 and 71%) and specific (61 and 62%) predictor of increased histological activity index (³3) and increased fibrosis (³2) at 3 years post-transplantation 10. Interestingly, immunosuppression is likely the most important determinant of post-transplantation viremia. In one study, differences in early kinetics could be attributed to the use or not of corticosteroids 11. Following an initial decline, HCV RNA levels increased rapidly in patients receiving corticosteroids as part of the immunosuppressive regime, while they continued to decline in the first post-transplant week in those on a steroid-free immunosuppression protocol. Furthermore, prednisolone withdrawal protocols that are complete very early post-transplantation (within the first 2 weeks) seem to be associated with relatively low levels of viremia 10. In addition, corticosteroid treatment for acute cellular rejection is associated with significant increases in viremia (4- to 100-fold increase) 10. The effects of other immunosuppressive agents on viral replication are generally controversial or preliminary. Two studies have suggested that the addition of mycophenolate mofetil (MMF) to stable organ transplant recipients is associated with increased viral replication 12. The information on calcineurin inhibitors is also controversial. Watashi et al. recently showed an inhibitory effect of cyclosporine A (CyA) on HCV protein expression and replicon RNA levels, effect that was not detected with tacrolimus (Tac) 13. In vivo data though, have not shown differences in viral load between patients immunosuppressed with either CyA or Tac 10. The effect of azathioprine on viral load has not been carefully evaluated, possibly due to the confounding effect of concomitant steroid use. In one study using the replicon system, azathioprine was found to inhibit HCV replication 14. Precise data in the human model is missing. Data on interleukin-2 receptor monoclonal antibodies (IL2R) are also lacking. In one study, viral load was significantly greater at both 4 months and 1 year in patients whose induction regimen consisted of daclizumab-MMF-steroids compared to those treated with the standard combination Tac-steroids 15. Whether this differences was related to MMF, IL2R antibodies or the combination of both drugs remains unknown. The impact of other immunosuppressive agents, including sirolimus, everolimus and OKT3 is unknown.
2.1.2. Pretransplantation HCV RNA levels
Several although not all studies have shown that, as described for HBV, level of viremia pre-transplantation predicts the occurrence and/or severity of recurrent hepatitis C [4,8]. In one study, recipients with increased HCV replication within the explanted liver (defined by a relative quantitative HCV negative-strand RNA:18S rRNA ratio >2.5) were found to be at increased risk for the development of post-transplant biochemical hepatitis, increased rate of allograft fibrosis and increased rate of mortality compared with recipients with relatively low replication 8. These results paralleled those obtained in a prior study, where increased serum genomic viral load prior to transplantation (>1logMeq/mL) was also predictive of mortality 8. Interestingly, non-HCV infections and non-infectious causes, but paradoxically not HCV-induced liver damage, were the primary causes of death and/or retransplantation. The positive and negative predictive values of fast intrahepatic replication to predict mortality were 40 and 100%. If confirmed in larger series, this information could be useful in identifying HCV-infected recipients at high risk of severe outcome.
2.1.3. HCV genotype
The effect of the infecting genotype on the outcome of recurrent hepatitis C is still unclear [1-3]. Some studies, particularly from European centers, have implicated genotype 1b in a more severe post-transplantation disease compared to non-1b genotype. Interestingly, fibrosis progression appears to be faster in centers where the prevalence of genotype 1b is very high 5, thus indirectly implicating this genotype in a more aggressive course of the disease. The mechanisms by which accelerated fibrogenesis is more often seen in patients infected with genotype 1b may be an increased rate of FAS-mediated hepatocellular apoptosis 16. In addition, preliminary data suggest that different strains belonging to genotype 1b may be involved in the pathogenesis of severe liver injury [17,18].
2.1.4. HCV diversity
The genetic nature and evolution of the virus have been implicated in the pathogenesis of progressive HCV disease. Results, generally inconclusive, need to be interpreted with caution due to a series of limitations in most studies, including: (i) only a limited number of clones are generally evaluated at each time point and hence, sequenced variants may not always be fully representative of the whole population of circulating quasispecies; (ii) while studies based on the hypervariable region-1, a putative target for neutralizing antibodies, are common, data using other potentially relevant regions are missing; (iii) small number of patients; (iv) different methodologies applied to assess HCV heterogeneity; (v) differences between studies in both the end-points chosen and the sequence time-points [1,4]. Notwithstanding these caveats, based on available data, several conclusions can be made regarding the evolution and effect of HCV quasispecies. First, in the early weeks following transplantation viral quasispecies becomes more homogenous than pretransplantation, likely as a result of the 'bottleneck' effect caused by the implantation of the new graft and the lack of selective pressure due to the strong immunosuppression 4. This pattern of genetic evolution is particularly evident in patients with the fibrosing cholestatic pattern of recurrence where extremely potent immune suppression inhibits the cellular response to the virus, leading to the preferential replication of a few genetically divergent quasispecies 4. Second, pre-transplantation quasispecies composition may have an effect on long-term outcome. It has been suggested that a less complex quasispecies composition prior to transplantation is associated with a more severe posttransplant HCV disease 19. Third, genetic diversification appears to increase in patients with mild recurrence, possibly as a consequence of immune pressure in the context of immune restoration 4. Finally, data regarding the impact of early post-transplant HCV quasispecies on long-term outcome are controversial 4.
3. 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 determinant of post-transplantation disease progression. While this assumption comes mainly from indirect findings, there are recent studies specifically addressing the impact of immune suppression on viral replication and disease progression (see iatrogenic variables).
Race. In a few studies, non-Caucasians were found to have higher rates of fibrosis progression and lower survival [1,5]. This association deserves further analysis.
Gender. Female gender has been associated with severe recurrent hepatitis C and low survival in some studies 9. Reasons, which explain this association, are lacking. Interestingly, the opposite trend is described in immune competent patients.
Pre-transplantation disease progression. In one study, a lack of association was observed between pre- and post-transplantation fibrosis progression 5, suggesting that variables present either at or post-transplantation are more important in influencing disease progression than genetic or viral variables unique to the individual.
4. Iatrogenic variables
4.1. Immunosuppressive drugs
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 [1-5,8-10]. 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 addition, high cumulative doses of corticosteroids have also been associated with higher risk of severe fibrosis and mortality. While recent preliminary data suggest that complete avoidance of corticosteroids may be beneficial 20, the effect of early corticosteroid withdrawal remains controversial [1-3,21,22]. Indeed, there is some evidence that a rapid reduction in the doses of corticosteroids, strategy proposed by several authors as a means to improving outcome may, in fact, be harmful to HCV infected patients and, in part, responsible for the worsening in disease progression observed in recent years [1-4,22]. Unfortunately, most studies addressing this question are retrospective in nature and, hence, unable to prove a conclusive time-frame of events. Similarly, the data with MMF are also confusing [1-3,10,12,15,22-25]. There are two large randomized trials that have compared MMF to azathioprine in a maintenance immunosuppressive regimen with no differences in outcomes 10. Similar results were obtained in a large study comparing triple (with MMF) to double immunosuppressive therapy in HCV-infected transplant recipients 23. Some retrospective studies trying to define determinants of severe outcome have however found a correlation between the use of MMF and both a greater risk of progressing to severe hepatitis and a reduced survival [22,25]. In addition, data from other solid organ transplant recipients infected with HCV also suggest that the use of MMF is associated with increased viremia and higher risk of developing severe liver disease, particularly cholestatic hepatitis [1,4,12]. In contrast to these observations, one study suggested that the effect is related to the dose used, so that patients who receive a relatively high exposure to MMF have improved outcomes (reduced HCV RNA levels at 3 months and decreased incidence of allograft fibrosis at 1 year) over patients who receive a lower exposure to MMF 24. Interestingly, in this study, the incidence of fibrosis was similar among all studied groups at 2 years. The mechanism by which this drug may adversely affect the outcome of HCV-infected recipients is largely speculative. In a recent study, viral load was found to double in stable liver transplant recipients 3 months after changing azathioprine to MMF 12. It is hence likely that the immunosuppressive properties of MMF outweigh the antiviral ones. The data on monoclonal antibody induction immunosuppression are also controversial. Two controlled and randomized trials have suggested no effect on survival 10. In contrast, in a retrospective study comparing a cohort of patients treated with IL2-receptor antibodies in combination with MMF to a historical group of patients treated with the standard combination Tac and steroids, the rate of recurrence, and most specifically the stage of fibrosis at 1 year were significantly higher in the former than in the latter group 15. Data on calcineurin inhibitors are less confusing. While in a few studies, differences were found between CyA and Tac, the overall evidence suggests that results are similar with either drug [10,26]. There are very few studies focusing on azathioprine with discrepant results [1,27]. A large retrospective study based on protocol liver biopsies highlights that the negative effect may be the abrupt and early discontinuation of azathioprine as opposed to its use or not 22. In fact, it is generally believed that the outcome is probably not related with the use of a specific drug but rather with (i) the dose and drug level achieved, reflecting overall immunosuppression, and (ii) the way the dose of the drug is modified. A potential hypothesis is that the substantial and abrupt changes in immunosuppression have the greatest adverse influence on outcomes in HCV-infected patients. A strong initial immunosuppression might lead to an inadequate immunologic clearance of HCV virions contributing to the high levels of viremia typically observed in the early period post-transplantation. Increased levels of viremia and hence of antigenemia are associated with increased immunologically-mediated liver injury, particularly following 'partial immune restoration'. In this setting, global immunosuppression, and not a single immunosuppressive agent, would dominate the effect. This would explain why corticosteroid boluses and OKT3 use for the treatment of rejection are particularly harmful to HCV infected patients, while either steroid avoidance or maintaining low levels of corticosteroids, but not abrupt and rapid steroid withdrawal, may be beneficial.
4.2. Antifibrotic agents
Angiotensin-II has been suggested to be a major regulator of liver fibrogenesis and experimental data with agents blocking its effect suggest that they may lead to a substantial reduction in fibrosis. In one recent retrospective study, liver transplant recipients who received angiotensin converting-enzyme ACE inhibitors or angiotensin-II receptor antagonists showed a reduced development of cirrhosis compared with patients who did not receive these drugs 28. While interesting, this observation needs to be prospectively validated before recommending the use of these specific anti-hypertensive agents to reduce HCV-induced fibrosis progression.
5. Donor-related variables
5.1. 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 [1-3,9,22,25,29-31]. 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 median rate of fibrosis progression increased from 0.6 units/year in patients who received organs from donors younger than 40 years to 2.7 units/years in those using allografts from donors older than 50 years 30. In a recent large study in which old donor allografts (>50 years) constituted 49% of the donor pool, severe fibrosis at 12 months was observed in 26% of old donor recipients but only in 8% of young donor recipients 31. Differences in donor age between centers and the changing donor profile with the increasing use of older donors may account for the discrepancies regarding HCV-related disease progression post-transplantation and the observed worsening in outcomes in recent years in some centers. This observation has important implications for donor liver allocation, in that older donors might be more appropriate for HCV negative recipients in whom the adverse effects of donor age appear to be less deleterious [29,31]. The effect of donor age correlates with data from the immunocompetent population where age at the time of infection is an important determinant of fibrosis. The mechanism by which older age is associated with an accelerated course of the disease is not completely understood, either in immune competent or in liver transplant recipients. Age-related immune changes in liver response, liver steatosis, iron content, pre-existent fibrosis, and telomeres or replicative senescence may be some of the key factors that determine the increased susceptibility of the older liver to HCV-related fibrosis.
5.2. Donor steatosis
Allograft steatosis may be one of the mechanisms whereby older donors are associated with worse outcome. In one study, macrovesicular steatosis on early liver biopsies correlated with an increased rate of fibrosis progression 9. More data are awaited on this important issue.
5.3. Donor hepatic iron concentration
Iron is a known pro-fibrogenic agent that plays a role as a co-morbid factor in hepatitis C. Its concentration in the liver increases with age. In one recent study, a graft hepatic iron concentration >1200ug/gdw was associated with early fibrosis progression due to recurrent hepatitis C in female recipients 32.
5.4. Donor immunogenetic background
It is increasingly accepted that genetics play a major role in host immune responses to infectious pathogens. Regulatory mechanisms that control cytokine production, including TNF-alfa, operate in part at the gene level, and in that sense, mutations in these genes may influence the production of cytokines. In one study, Rosen et al. evaluated the significance of polymorphisms at positions -238 and -308 of the TNF-alfa gene promoter (mutations associated with susceptibility to active hepatitis after HCV exposure in immunocompetent patients) in liver donors on the severity/outcome of recurrent HCV. They found that time to recurrence was shorter and the hepatic activity index greater in those who received an organ from donors with TNF-alfa-308 allele 33. These data suggest that a specific donor TNF-alfa genotype, known to be associated with high TNF-alfa production, may contribute to the accelerated graft injury observed in liver transplant recipients with HCV infection. If these preliminary data were confirmed and technology allowing for fast screening were developed, appropriate matching of donors and recipients based on genetic information could become a means to maximize favorable outcome. A few studies have unsuccessfully attempted to establish a link between specific donor/recipient HLA matches and the severity of liver disease after transplantation [1,9] (Table 2).
5.5. Anti-HCV status of the donor
The course of HCV disease is not affected by the use of anti-HCV (+) HCV-RNA (+) grafts. Several series have demonstrated that HCV-infected recipients receiving these type of grafts have a similar survival and progression of HCV disease than those receiving uninfected grafts 34. Strict patient information and use of organs with little or no fibrosis and only minimal inflammation are mandatory.
6. Surgical-related variables
6.1. 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 90min, 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:
(This will be discussed by Sugawara and Makuuchi in the current Forum)
7. Other variables
7.1. 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, coinfected patients appeared to have milder histological course than patients infected only with HCV 36. Although viral interactions could explain this phenomenon, the passive transmission of protective antibodies against HCV in coinfected patients receiving HBIg during the pre-HCV era is a more likely explanation.
7.2. Alcohol consumption
A substantial proportion of patients have end-stage liver disease caused by both alcohol and chronic HCV infection. In fact, liver disease appears to be more severe and accelerated in patients with alcoholism and chronic HCV infection compared with those with HCV who have never abused alcohol. One may also hypothesized that given this synergism in the immune competent population patient, the post-transplant outcome may be worse in patients with both aetiologies as compared to those transplanted for only one of the two. Data on this issue are surprisingly limited. None of the studies, which have looked at predictive variables of worse histological and/or clinical outcome have found that a history of significant alcohol consumption pre-transplantation was associated with a more aggressive disease following transplantation [1,9]. Preliminary data from our centre suggest that patients with mixed aetiologies have a histological outcome post-transplantation that is worse than that seen in patients undergoing transplantation for HCV alone; based on protocol liver biopsies, only 25% of patients transplanted for mixed aetiologies had normal or minimally abnormal liver biopsies after a prolonged follow-up compared to 59% in the HCV (+) group 37. More data are needed to address this question.
8. 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.
9. Which factors determine the delayed onset of severe hepatitis C?
return to Article Outline
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 liver enzymes at 3 years post-transplantation, appears to predict this sudden change in progression with 70% of the patients with these predictive factors developing this acceleration as opposed to 5% of those without these factors 6. Other variables previously implicated in the progression of recurrent hepatitis C, including demographics, non-alcoholic steatohepatitisÑvariables (diabetes, hyperlipidemia, obesity), and the use of specific drugs (renin-angiotensin inhibitors, ursodeoxicolic acid) were not found to be associated with outcome.
10. Which factors determine the development of fibrosing cholestatis hepatitis?
Fibrosing cholestatic hepatitis typically develops in the context of profound immunosuppression [1-4]. 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 15ng/dl) or CyA (trough levels around 300-400ng/dl), and in those receiving multiple pulses of methyl-prednisolone and/or OKT3 [1,4,9].
11. 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 decompensation developed (93, 61, and 41% at 1, 6 and 12 months, respectively). Variables associated with decompensation included a high Child-Pugh score (>A) and low albumin level (<3.5mg/dl) at diagnosis of graft cirrhosis, and a short interval between transplantation and the development of cirrhosis.
12. 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) [1-3,39] and some histological findings (significant steatosis, ballooning degeneration, cholestasis, and confluent necrosis) 1 and subsequent disease progression. The activity observed in the first-year liver biopsy was found in two studies to be strongly associated with the subsequent risk of developing cirrhosis, with only 3-10% of those with mild hepatitis developing cirrhosis compared to 30-60% in those with moderate to severe activity 1. The hepatic activity index seen either on protocol biopsies at 4 months (hepatic activity index >3) or at histological recurrence (³9) has been shown to correlate with rapid progression of fibrosis [8,9,39].
In conclusion, pre-transplant or early post-transplant recognition of patients with high risk of severe outcome post-transplantation is desirable since these patients can be targeted for early intervention. It is likely that it is the interplay between the immune system and the virus, modulated by both the immunogenetic background, such as the HLA system, and the quality of the graft that shapes the outcome post-transplantation. While many studies have described positive and negative associations, no single factor is capable of accurately differentiating which patients will ultimately progress to cirrhosis from those with a more benign process. The combination of several of these factors may however be used to define the patient at high risk of severe recurrence. Based on the available data, the major determinants of accelerated allograft fibrosis include high viral load at transplantation (>1Meq/mL) and/or early following transplantation (>10Meq/mL at 4 months), the infection by HCV genotype 1b, the use of grafts from donors older than 50 years, a net state of immunosuppression generally but not always in the context of rejection therapy, and the abrupt changes in immune suppression. In addition, histology may help in predicting subsequent fibrosis progression. Allocation of young donors to HCV-infected recipients, pre-transplantation antiviral therapy and avoidance of events that lead to immune evasion, particularly a rationale use of immunosuppression and adequate prophylaxis of CMV infection, are potential strategies to improve the outcome in HCV-infected patients. Their real efficacy though needs to be proved by prospective well-designed trials.
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Abbreviations: CMV, cytomegalovirus, CyA, cyclosporine A neural, HBV, hepatitis B virus, HBIg, hepatitis B immune globulins, HCV, Hepatitis C virus, IL2R, interleukin-2 receptor monoclonal antibodies, OLT, Orthotopic Liver transplantation, LDLT, living donor liver transplantation, MMF, mycophenolate mofetil, TNF, tumor necrosis factor, Tac, tacrolimus
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