HISTOLOGICAL CHANGES DURING THE EVOLUTION OF CHRONIC REJECTION OF LIVER ALLOGRAFTS
Index
Desley Neil and Stefan Hubscher
Department of Pathology, University of Birmingham, UK
AIM
The progression of changes in the development of chronic rejection is poorly understood. It is the aim of this study to evaluate serial changes in biochemical and histological parameters during the evolution of chronic rejection.
METHODS
The serial biopsies and transplant hepatectomy specimens from 28 patients retransplanted due to chronic rejection of their first liver transplant were assessed, together with biochemical markers of liver function: aspartate transaminase (AST), alkaline phosphatase (Alk Phos) and bilirubin (bili). Both the actual values and the pattern of change: normal, static, slow rise, rapid rise, slow fall, or rapid fall were determined. Biochemistry was lost in one patient. The time of acute deterioration which led to graft failure was determined from the biochemical flowsheets. Biopsies were divided into groups relating to this acute event: 1 Time zero (to) reperfusion, 2. Prior, 3. Initial, 4. During, 5. Hepatectomy. The biopsies taken during the evolution were subgrouped according to time after the initial biopsy: 4a. Up to 7 days; 4b. 8-14 days; 4c. 15-31 days; 4d. More than 31 days). Time zero (to) reperfusion biopsies were available in 20 patients, 19 biopsies in 14 patients prior to the acute episode, 27 biopsies at the start of the process, 84 biopsies during the evolution of the process and 28 hepatectomy specimens. Portal tract foam cells, parenchymal foam cells, perivenular hepatocyte ballooning, perivenular congestion / haemorrhage and acinar zone 3 fibrosis were assessed for the presence or absence of the feature. Portal tract fibrosis was graded on a 0-3 scale with 0=none, 1=zonal, 2=bridging, 3=nodular/cirrhosis. Perivenular necrosis was graded on a 0-3 scale with 0=none, 1=small foci, 2=confluent necrosis, 3=bridging necrosis. Hepatocyte apoptosis and spotty lobular inflammation were graded on a 0-2 scale with 0=none, 1= present but not prominent, 2=prominent. Dysplastic bile ducts were graded on a 0-2 scale with 0=none, 1=minority, 2=majority of bile ducts being affected. Arteriopathy in the hepatectomy specimens was graded on a 0-3 scale with 0=none, 1=minority, 2=half and 3=majority of medium to large sized arteries affected. All other features were graded on a 0-3 scale with 0=none, 1=mild, 2=moderate and 3=severe. Nonparametric statistical analyses were performed.
RESULTS
The initial biopsies showed acute rejection, at least moderate in severity, with prominent parenchymal inflammation and zone 3 necrosis. This was associated with a rise in liver function tests, most notably an acute rise in AST (p=0.001), the rise in bilirubin was also significant (p=0.007). The length in the delay from the acute rise in LFTs until the time of initial biopsy, correlated with an increase in the percentage of remaining portal tracts missing bile ducts (p=0.015), an increased proportion of bile ducts having a dysplastic appearance (p=0.003), less identifiable portal tracts per biopsy (p=0.016), the development of acinar zone 3 fibrosis (p=0.000) and the Alk Phos level (p=0.005). Throughout the evolution of the process the AST tended to remain elevated and there was a progressive rise in the Alk Phos (p<0.05) and bilirubin (p,0.05). There was a progressive diminution of identifiable portal tracts (p<0.001), an increase in the percentage of portal tracts missing bile ducts (p<0.001), an increase in proportion of dysplastic bile ducts (p<0.001), an increase in parenchymal foam cells (p<0.001), an increase in acinar zone 3 fibrosis (p<0.002) and an increase in cholestasis (p<0.002).There was persistent mild perivenular inflammation, most prominent at the periphery of necrotic areas, apoptosis, spotty lobular inflammation, perivenular hepatocyte necrosis, and congestion / haemorrhage. The arteriopathy seen in the transplant hepatectomy specimens did not correlate with hepatocyte necrosis, congestion / haemorrhage, zone 3 fibrosis or the percent of portal tracts missing either hepatic artery branches or bile ducts at any time point. The histological features in the to biopsies and the mildly elevated day 1 AST median 436 IU/L (98-2992) are of mild preservation-reperfusion injury.
CONCLUSIONS
Chronic rejection of liver allografts appears to be an ongoing immune mediated process, probably cell-mediated, starting with an identifiable acute rejection episode. The intervening stages while still relating to immune mediated damage (rejection) can not however usually be graded as acute rejection based on the current diagnostic criteria. There is ongoing low-grade parenchymal inflammation relating to the persistent elevation in AST levels. Identifiable portal tracts, as well as bile ducts within remaining portal tracts, decrease. Remaining identifiable portal tracts have features diagnosable at most as borderline acute rejection. The foam cell arteriopathy appears to play no process in the evolution of changes relating to chronic rejection. Preservation-reperfusion injury would not appear to be a factor in the aetiology of chronic rejection. The inflammatory nature of the process suggests that modification of immunosuppression may prevent the progression of this process. Loss of identifiable portal tracts and bile ducts within portal tracts, parenchymal inflammation, hepatocyte necrosis and apoptosis and development of acinar zone 3 fibrosis and dysplastic bile ducts are the histological features of evolving chronic liver allograft rejection
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