Cholangiocytic apoptosis in chronic ductopenic rejection

The significance of cholangiocytic apoptosis as a mechanism of ductopenia i n liver rejection remains controversial. In a previous study, the presence but not the extent of ductal apoptosis was assessed by electron microscopy. Other previously published studies using an in situ hybridization method ( in situ end labeling) produced conflicting results (no apoptosis upsilon ma ssive apoptosis). We studied 47 liver needle biopsies from 8 patients with chronic ductopenic rejection confirmed by pathologic examination of the fai led grafts. These biopsies were performed because of graft dysfunction, dur ing a period of several months before retransplantation, and they showed ch olangiocytic injury with progressive ductal paucity. Terminal deoxynucleoti dyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling (TUNEL) was used to detect apoptosis (tissue digestion with proteinase K 2 0 mug/mL for 20 minutes). The interlobular bile ducts did not show labeling , even in lymphocytic cholangitis with obvious epithelial injury. However, there was minimal staining of ductular nuclei. Lymphocytic nuclei were also labeled. Apoptosis was not detectable in the vanishing interlobular bile d ucts, even when more representative samples were studied and a more sensiti ve method was used. Unless apoptosis of cholangiocytes is an exceptionally rapid process escaping detection by conventional methods, ductopenia result s mainly from ordinary, nonprogrammed cholangiocytic death. Apoptosis could still be involved in the pathogenesis of ductopenia by depleting cholangio cytic precursors, generally presumed to reside in ductules. This is a possi ble mechanism suggested by the following: (I) the established role of apopt osis in the homeostatic control of immature/progenitor cells, (2) the pauci ty of ductular proliferation in chronic rejection, (3) the previously repor ted decrease of ductular bcl-2 expression in rejection, and (4) the sporadi c ductular TUNEL labeling seen in this study. Hunt PATROL 32:823-827. (C) 2 001 by W.B. Saunders Company.