Hepatitis C recurrence is more severe after living donor compared to cadaveric liver transplantation
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Hepatitis C recurrence is more severe after living donor compared to cadaveric liver transplantation
Volume 40, Issue 3, September 2004
Montserrat Garcia-Retortillo 1, Xavier Forns 1 *, Josep M. Llovet 1, Miquel Navasa 1, Anna Feliu 1, Anna Massaguer 1, Miquel Bruguera 1, Josep Fuster 2, Juan Carlos Garcia-Valdecasas 2, Antoni Rimola 1
1Liver Unit, Hospital Clinic, Institut de Malalties Digestives, Institut d'Investigacions Biom�diques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
2Hepatic Surgery and Transplantation Unit, Hospital Clinic, Institut de Malalties Digestives, Institut d'Investigacions Biom�diques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Preliminary reports suggested that hepatitis C virus (HCV) infection has a more aggressive course following living donor liver transplantation (LDLT) compared to cadaveric liver transplantation (CLT). The aim of this prospective study was to establish if HCV disease recurrence differs between LDLT and CLT.
A cohort of 116 consecutive HCV-infected patients undergoing 117 LTs in a single center from March 2000 to August 2003 were followed-up, including systematic liver biopsies. Severe recurrence (SR) was defined as biopsy-proven cirrhosis and/or the occurrence of clinical decompensation. After a median follow-up of 22 months (2.6-44 months), 26 (22%) patients developed SR (decompensation in 12), involving 17 (18%) of 95 patients undergoing CLT and 9 (41%) of 22 undergoing LDLT.
The 2-year probability of presenting SR was significantly higher in LDLT compared to CLT (45% vs. 22%, P = .019). By univariate analysis LDLT (P = .019) and an ALT higher than 80 IU/L 3 months after LT (P = .022) were predictors of SR. In 93 patients from whom a liver biopsy was available 3 months after LT, a lobular necroinflammatory score >1 (P < .01), LDLT (P < .01), and biliary complications (P = .046) were associated with SR. However, the only variables independently associated with SR were LDLT (odds ratio [OR], = 2.8; 95% CI,1.19-6.6; P = .024) and a lobular necroinflammatory score >1 (OR, 3.1; 95% CI, 1.2-8; P = .013).
In conclusion, HCV recurrence is more severe in LDLT compared to CLT. Although our results were based on a single-center experience, they should be considered in the decision-making process of transplant programs, since severe HCV recurrence may ultimately compromise graft and patient survival.
Hepatitis C virus (HCV)-related cirrhosis is the leading indication for liver transplantation (LT) in the United States and Europe. More than half of the patients on the waiting list are infected with HCV. Regretfully, HCV recurrence is universal after LT and leads to chronic hepatitis and liver cirrhosis in a significant proportion of patients. Although initial reports failed to demonstrate an impact of HCV infection on survival, Forman et al. have recently shown that graft and patient survival after LT were significantly lower in HCV-infected patients compared to noninfected individuals.
Several variables have been associated with a more severe HCV disease recurrence after LT, such as a high pretransplantation viral load, old donor age, the presence of significant graft steatosis, and the administration of steroid boluses. It is important to state, however, that most studies are retrospective and that there is a lack of homogeneity in the definition of severe HCV recurrence after LT.
With the limited pool of cadaveric donors, living donor liver transplantation (LDLT) has become the most feasible alternative to cadaveric liver transplantation (CLT) for patients with end-stage liver disease or hepatocellular carcinoma (HCC). Nowadays, more than 3,000 LDLTs have been performed worldwide using the right hepatic lobe. Despite this high number of procedures, the enthusiasm for LDLT is tempered by the need for a highly skilled group of senior liver surgeons, the elevated surgical-related morbidity, and the rare but potential donor mortality. In addition, the applicability of LDLT is low, and only one fourth or less of the potential recipients undergo the procedure.
The scientific community assumed that outcomes after LDLT and CLT were comparable, and this assumption provided the rationale to propose LDLT in patients awaiting CLT. Consequently, cost-effectiveness analyses were run with those assumptions. Although there are studies reporting similar outcomes for both groups, others suggest that HCV disease recurrence has an earlier and more severe course in LDLT compared to CLT. We started a LDLT program in March 2000 in patients on the waiting list for CLT. This program was expanded to patients with HCC exceeding the conventional criteria in 2001.The present prospective study was aimed at assessing if the outcome of HCV infection differed between CLT and LDLT. For this purpose, a cohort of 116 consecutive HCV-infected patients undergoing LT in a single institution between March 2000 and August 2003 were followed, including the performance of systematic liver biopsies.
The outcome of HCV disease recurrence after LDLT is still controversial. Our data, though limited to a single center, show that LDLT is a strong and independent predictor of severe HCV disease recurrence following transplantation. Accordingly, the 2-year probability of presenting SR was significantly higher in LDLT compared to CLT (45% vs. 22%). This study has some relevant differences from previous reports. First, we designed a prospective study specifically aimed at assessing whether HCV disease recurrence was different between both types of transplantation. Although the numbers of patients (116) and events are small, the strength of the differences after a median follow-up of 22 months prevents us to expand the series with additional cases. More importantly, severe recurrence was defined by the presence of cirrhosis in a follow-up liver biopsy or by the occurrence of clinical decompensation. This definition allows an unbiased classification of patients and represents a relevant
event in the natural history of HCV disease recurrence. Finally, patients were recruited in a single center, and the same standard of care was established. Additionally, all relevant variables that might influence HCV disease recurrence were included in the analysis, and, except for factors inherently related to living donation (and the type of calcineurin inhibitor), patients receiving the graft of a living donor or a cadaveric donor were comparable.
The mechanisms that might explain the more aggressive course of HCV recurrence after LDLT are unknown. Theoretically, there are variables specifically linked to LDLT that might prevent from severe HCV disease recurrence, such as the young donor age, the lack of significant steatosis of the graft, and the short ischemia time during surgery. On the contrary, other variables might affect negatively HCV disease recurrence, such as an increased HLA donor-recipient matching, the type of immunosuppression, a high incidence of biliary complications following transplantation, and liver regeneration.
Our initial hypothesis was that either biliary complications or liver regeneration (or both) would accelerate liver fibrosis in patients undergoing LDLT. Biliary complications are frequent in the latter group, and it is well known that persistent cholestasis induces fibrogenesis. Despite the lack of homogeneity in the definition of biliary complications among reported series, the incidence of biliary leaks or stenosis in our cohort was very high. Three reasons might explain this high incidence: first, the prospective nature of data collection (including even minor leakages); second, the high frequency of double and multiple biliary anastomoses in our LDLT series; and third, the learning curve. Despite this center-specific issue, neither the multivariate analysis nor the follow-up of a small cohort of anti-HCV negative LDLT recipients support an independent predictive value of biliary complications on the severity of HCV disease recurrence. However, a synergistic effect of persistent
cholestasis on HCV-infected grafts cannot be excluded.
Biochemical markers of hepatitis increased earlier and reached significantly higher levels in patients undergoing LDLT compared to CLT, strongly suggesting that hepatitis C recurrence is a distinct process in those patients. In fact, the occurrence of cholestatic hepatitis was significantly more frequent in LDLT compared to CLT. One of the key differences between LDLT and CLT is liver regeneration. In vitro, HCV internal ribosome entry site activity and replication were found to be higher in actively dividing cells, and it is possible that viral translation may be enhanced by factors that stimulate the regeneration of hepatocytes. Moreover, there are experimental data suggesting that liver regeneration induces LDL receptor _expression, which might facilitate HCV entrance into the hepatocytes. The absence of significant differences in viral load between LDLT and CLT at the analyzed time points does not exclude increased viral production in regenerating cells, as viral load also
depends on the number of cells producing viral particles and on viral clearance mechanisms.
Regretfully, this study presents several caveats. First, the limited number of patients who underwent LDLT did not allow a thorough analysis of the variables that predict SR among them. Our data suggest that patients who experienced a greater increase in liver volume during the first weeks following LDLT had a higher probability of developing SR afterward. Though the increase in liver size cannot be use as a direct marker of the degree of regeneration, this increase might support a negative influence of liver regeneration on HCV disease recurrence. These results should be further confirmed in extensive series. Second, the relatively short follow-up of this cohort did not allow a consistent analysis of graft and patient survival. However, it is well established that around 40% of patients with compensated HCV graft cirrhosis will develop clinical decompensation within the first year following the diagnosis. Once decompensation occurs, survival is lower than 50% at 1 year, whereas
retransplantation leads to disappointing results. The expected decrease in graft or even patient survival derived from this scenario might make LDLT a non-cost-effective approach in HCV-infected patients. Possible alternatives would be to restrict LDLT to very long waiting times and/or high dropout rate settings, limiting LDLT to non-HCV-infected patients (at least during the learning curve), or to treat HCV infection before LDLT. Implementation of any of these strategies would require confirmation of our results in other prospective series.
In summary, our data indicate that LDLT is a strong predictor of severe HCV disease recurrence after transplantation. Although the data need to be validated, the more aggressive course of HCV infection in LDLT compared to cadaveric transplantation should be considered in LDLT programs, since it may ultimately compromise graft and patient survival.
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