0041-1337/01/7111-1566/0 TRANSPLANTATION Vol. 71, 1566–1572, No. 11, June 15, 2001 Copyright © 2001 by Lippincott Williams & Wilkins, Inc. Printed in U.S.A. ARE PARENCHYMAL CHANGES IN EARLY POST-TRANSPLANT BIOPSIES RELATED TO PRESERVATION-REPERFUSION INJURY OR REJECTION? DESLEY A.H. NEIL 1 AND STEFAN G. HUBSCHER Department of Pathology, Medical School, University of Birmingham, Edgbaston, Birmingham, UK B15 2TT Background. The progression of parenchymal changes in liver allograft biopsies due to preservation- reperfusion injury (PRI) and their differentiation from rejection related changes is poorly understood. The aim of this study was to determine which changes in a 1-week posttransplant biopsy could be attributed to PRI and which to acute rejection. Methods. One week protocol liver transplant biop- sies from patients with mild PRI (day 1 AST<400 IU/L) were compared with those from patients with severe PRI (day 1 AST>2000 IU/L). Parenchymal changes (cholestasis, ballooning, steatosis, necrosis) and rejec- tion-related inflammatory features (portal tract in- flammation, bile duct inflammation, portal vein endo- thelial inflammation, hepatic vein endothelial inflammation, and centrilobular inflammation) were blindly assessed semiquantitatively. Results. Fat, cholestasis, and hepatocyte ballooning were significantly worse in the severe PRI group, and these features showed no correlation with histological features related to acute rejection. Centrilobular he- patocyte necrosis correlated with hepatic venular en- dothelial inflammation and centrilobular inflamma- tion but not with rejection related features in portal tracts or with PRI. These findings suggest that centri- lobular necrosis is a manifestation of a rejection-re- lated parenchymal injury and may involve different pathogenetic mechanisms to rejection-related fea- tures in portal tracts. Conclusions. This study indicates that in early post- transplant biopsies, fat, cholestasis, and ballooning can largely be attributed to PRI. By contrast, centri- lobular hepatocyte loss should be suspected as a rejec- tion related phenomenon, even if typical portal tract changes are not prominent, and augmentation of im- munosuppression should be considered. INTRODUCTION Preservation-reperfusion injury (PRI) is characterized bio- chemically by high serum aspartate transaminase (AST) lev- els in the early postoperative period. A number of histological features have also been attributed to preservation-reperfu- sion injury. These include microvesicular steatosis, foci of parenchymal neutrophilic infiltration, cholestasis, hepato- cyte ballooning, necrosis, and apoptosis. These changes are commonly seen, usually to a minor degree, in biopsies taken from the transplanted liver after a short period of reperfusion (1–5) and are generally most prominent in centrilobular re- gions (acinar zone 3). Given that it takes several hours for morphological signs of tissue injury to become manifest, it has been assumed that the minor changes seen in time-zero biopsies are the precursors of more severe parenchymal dam- age, which is commonly seen in the early postoperative pe- riod. A number of studies have shown that the presence and/or severity of changes seen in time-zero biopsies may predict subsequent graft function (1, 6, 7). Sinusoidal endo- thelial cell damage resulting from PRI (1, 8, 9) can compro- mise microcirculatory flow, producing further ischemic dam- age (6, 7, 9, 10). This feature is not recognizable on routine light microscopy (1, 9). The time for which PRI related changes persist after transplantation is not clear. However, some studies suggest that certain features, including cho- lestasis and ballooning, may persist for several weeks (1, 4, 6, 11–13). Macrovesicular steatosis indicates preexisting donor abnormalities and is seen in preharvest biopsies, it predis- poses to PRI (14 –16), and is sometimes included in the spec- trum of PRI changes. Acute rejection of the liver allograft is characterized histo- logically by predominantly portal-based lesions, including a classical triad of a mixed inflammatory cell infiltrate, venous endothelial inflammation, and inflammatory infiltration of bile ducts (17–19). Varying degrees of parenchymal inflam- mation can also be seen. Typically, this predominantly af- fects centrilobular regions (acinar zone 3) and in more severe cases, may be associated with hepatocyte necrosis (17, 20– 23). Until recently, centrilobular necroinflammation was only considered of diagnostic importance if accompanied by the typical portal triad. However, it has now been recognized that centrilobular necroinflammation can occur as part of acute rejection in the absence of the portal features (24), and this feature is incorporated into the new Banff classification (25). In addition to direct immune mediated damage, bile duct inflammation may be an indirect cause for centrilobular cholestasis (26). It can thus be seen that a number of the features attributed to PRI overlap with parenchymal changes attributed to acute rejection. Because most acute rejection episodes occur during the first month after transplantation, a time when persistent changes due to PRI may still be present, there may be some difficulty in determining which changes are due to which factor. In addition, zone 3 parenchymal changes may be produced by a number of other factors (Table 1), including drugs, hepatic artery insufficiency, and viruses (19, 27). It is the aim of this study to determine which centrilobular fea- tures can still be attributed to PRI or preharvest donor injury in day 7, protocol liver biopsies and which correlate with acute rejection. 1 Address correspondence to: Dr. Desley Neil, Department of Pa- thology, Medical School, University of Birmingham, Edgbaston, Bir- mingham, UK B15 2TT. E-mail: d.neil@bham.ac.uk. 1566