Chronic liver allograft rejection - analysis of reversibility, implications for a staging schema and long-term follow-up 

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Blakolmer, K., Jain, A., Ruppert, K., Gray, E., Rakela, J., Fung J.J., Demetris, A.J.

Thomas E. Starzl Transplant Institute, Department of Pathology, Division of Transplantation, University of Pittsburgh Medical Center, Pittsburgh, PA 15213

Introduction: In contrast to all other vascularized organ allografts, chronic liver rejection (CR) is potentially reversible and its incidence is decreasing. Better control of acute rejection and the use of tacrolimus as an antirejection agent have been thought to be responsible for this.

Aims: To study demographic, perioperative, biochemical and histologic features associated with reversibility or progression to graft failure of CR, we used the National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database (LTD) patient population. Subsequently, applying the histological criteria for CR identified in the LTD population, we investigated the incidence, risk factors and outcome of CR in UPMC liver transplant patients who had been treated almost exclusively with tacrolimus as baseline immunosuppression.

Methods and Results: Using a combination of clinical and histological criteria, we identified a subgroup of 43/916 (4.7 %) primary liver allograft recipients from the LTD who developed CR. Of these 20 were excluded from analysis because of various co-morbid conditions, and 13 experienced graft failure due to CR while 10 patients recovered to normal histology and/or liver injury tests. Male-to-female sex mismatch (p=0.07), younger recipient age (p=0.09), younger donor age (p=0.06), white-to-white race match (p=0.09), primary diagnosis of biliary atresia (p=0.02) and cold ischemia time >12 hours (p=0.02) were associated with graft failure. Patients who eventually recovered from CR were more likely to have acute rejection within the first 2 weeks (p=0.04), had a higher number of acute rejection episodes (ACR) (p=0.08) and were more likely to have been treated with OKT3 (p=0.07). Although overlap existed in the histopathological findings between the patients whose grafts failed and those who recovered, bile duct loss in more than 50% of the portal tracts (p<0.01), severe perivenular fibrosis (p=0.05) and the presence of foam cell clusters (p=0.06) were associated with irreversible CR. These potential staging criteria were applied to the University of Pittsburgh Medical Center (UPMC) patients who underwent liver transplantation during a similar period of time, but were followed for a much longer period of time. In this patient population, 35/1057 (3.3%) patients developed CR. Donor age >40 years (p=0.03), number (p<0.01) and severity (p<0.01) of ACR were associated with the development of CR, but in contrast to the LTD study, a cold ischemic time of >14 hours was not significant. Of these 35 patients, 17 patients were excluded from the outcome analysis because of co-morbid conditions. Comparing the 8 patients whose grafts failed due to CR and the 10 patients who recovered from CR, findings similar to those seen in the LTD were significantly predictive of graft loss: the percentage bile duct loss (p=0.05) and the presence of foam cell clusters (p=0.01). Although greater centrilobular fibrosis was seen in the grafts that failed from CR, the difference did not reach statistical significance (p = 0.170). An additional finding of an association between arterial loss and failure from CR was also uncovered (p = 0.069). In both the LTD and UPMC studies, total bilirubin and ALT were significantly higher in the patients who went on to graft failure.

Conclusion: CR is relatively uncommon after liver transplantation, consistent with known tolerogenic influence of liver allografts. However, when CR does develop, it is potentially reversible and risk factors are similar to those seen in other vascularized organ allografts, such as number and severity of acute rejection episodes, and older donor age. A combination of histopathological findings (percent bile duct loss, foam cell clusters, bridging centrilobular fibrosis, and possibly arterial loss) and liver injury tests are associated with graft failure from CR and can be used to understand its evolution and to design a reproducible staging system.

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