How, why, and when does primary biliary cirrhosis recur after liver transplantation?

The questions posed in the title of this editorial remain difficult to answer, despite considerable clinical data and much detailed experimental study of the auto immune destruction of the bile ducts of primary biliary cirrhosis (PBC). At least one no longer has to argue over whether the disease does truly recur after transplantation as was the case when the Cambridge/King’s Transplant Programme first reported it in 1982. The 3 patients described in that New England Journal of Medicine article had been investigated at 3.5 to 4.5 yr after transplantation because of the reappearance of pruritus and jaundice. Mitochondrial antibody was present in high titer in the serum and typical histological changes were found on liver biopsy. Further cases were described in 1989, but Starzl et al., with the largest experience of liver transplantation in the world at that time, was far from convinced, as indeed were other centers for some years thereafter. Reappearance of the disease in the “new” liver would provide a wonderful opportunity to learn about the immunological processes involved in the development of the disease. In this respect we may not be much further on, although the pattern and clinical significance of recurrent PBC is now well established. In the latest long-term follow-up study published in this issue of Liver Transplantation, 74 of 154 PBC patients transplanted in the Mayo Clinic had histological evidence of recurrent disease on liver biopsy. Comparison with the nonrecurrent disease group showed that survival duration—free of death or transplantation— was not significantly altered when adjusted for age and gender. This is not to deny that a few cases will have progressive disease ultimately requiring retransplantation. Overall cross-sectional rates for recurrence based on the findings in serial protocol biopsies, increased from 18% at 3-5 yr to 23-32% at 10 yr with cumulative incidence rates of 22, 37, and 43% at 5, 10, and 15 yr, respectively. It might be anticipated that if the underlying immunological processes of the host are unaffected by removal of the diseased organ, its graft replacement will inevitably become affected. But even if cumulative incidence rates with longer follow-up get nearer to 100%, the severity of recurrent disease overall is significantly less than that of the primary condition. It is clear too that if a liver biopsy is carried out only when clinical features appear, the frequency of recurrence will be considerably underestimated. Currently, we have little knowledge of factors determining disease progression in the posttransplantation situation. The patients in the Mayo Clinic series were significantly older, more often male, had received grafts from older donors, were more likely to be on tacrolimus than cyclosporin and to have had a shorter duration of maintenance corticosteroid. But in multiple logistic regression mode the only significant predictors were tacrolimus immunosuppression and, surprisingly, male gender. That disease recurrence is more likely with tacrolimus as compared with cyclosporin-based immunosuppression was first noted in 2 patients in 1993. The 2 cases described had florid histological changes by 12 months after transplantation with return of pruritus