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Liver allograft fibrosis and minimization of immunosuppression

In this issue, Lin et al. evaluate whether low-dose maintenance immunosuppression with oncedaily calcineurin inhibitor is associated with progression of fibrosis, a feature of chronic allograft injury in a stable previously described cohort of 33 pediatric liver transplant recipients. This cohort did not have acute rejection or significant fibrosis on a baseline biopsy. Nineteen recipients provided serial biopsies for assessment. The authors’ observations are timely, because inflammation and fibrosis are frequently reported from surveillance biopsies performed in recipients with normal liver function tests. Whether such changes lead to chronic injury and are therefore actionable may depend on the time after transplantation, and the goal of minimization, whether daily dosing, “spaced” weaning, or complete withdrawal. In Feng et al.’s prospective immunosuppression withdrawal study, eight subjects in whom immunosuppression withdrawal demonstrated non-specific inflammation or acute rejection in nearly equal proportions were uniformly treated with an escalation in immunosuppression (1). A central review of these biopsies yielded a more uniform interpretation of acute rejection in all but one of eight such subjects. These findings suggest that the ultimate determinant of the validity of biopsy findings, that is, treatment decisions, remains open to debate and is in evolution. Illustrating these differences, no significance was assigned to the appearance of early portal inflammation because of the absence of elevated liver enzymes in the current study. At our center, portal inflammation in the absence of obvious biliary issues fosters a search for additional information. While late rejection frequently differs from early rejection with a more hepatitic pattern in some cases, evidence of any type of biliary injury in the absence of ductular reaction may indicate a low-grade rejection that may warrant treatment despite normal liver function tests. Another major problem in assessing late liver allograft biopsies is the measurement of degree of fibrosis. It is obvious that systems used to score fibrosis in native liver biopsies, for example, Ishak score, cannot be applied to liver allograft biopsies (2). This is so because of potential discordance in the degree of fibrosis between portal and pericentral areas which may not be captured by any single system. These limitations are recognized by Lin et al. and will need further study to create a classification system that assigns specific scores to portal, pericentral, and lobular/ sinusoidal fibrosis. In this regard, the fibrosis scoring system suggested by Venturi et al. (3) is better correlated with morphometric assessment of fibrosis. However, early reports suggest that the clinical validity of this novel system remains to be established. In a follow-up study, Venturi et al. (4) found that portal fibrosis was associated with prolonged ischemia time, deceased grafts, and lymphoproliferative disease. Further, sinusoidal fibrosis was associated with biliary complications, while centrilobular fibrosis was associated with vascular complications, and autoantibodies. In contrast, an independent evaluation of liver allograft fibrosis with the Venturi system by Bass et al. from Groningen demonstrated that portal fibrosis was associated with biliary complications and centrilobular fibrosis was associated with HLA mismatches (unpublished observations presented at the IPTA meeting, April 2015). Sinusoidal fibrosis was associated with acute cellular rejection in this study. These clinical associations are also illustrated by serial liver allograft biopsies in a child who received living donor liver transplantation at our center for biliary atresia during infancy. Tacrolimus was reduced gradually to three doses per week starting five yr after transplantation, when the first of two late surveillance biopsies shows no acute rejection or fibrosis. A second surveillance biopsy performed five yr later in the setting of normal liver function tests showed