Chronic liver transplant rejection was described for the first time in four of Starzl's first 27 patients reported from Denver . Many of the small branches and some of the large branches of the hepatic artery were completely occluded by intimal thickening which included many foam cells. Porter called this process "late rejection with vascular change" and noted that it was similar to that seen in human renal grafts. The arterial narrowing was accompanied in all instances by fibrosis and cholestasis, and in two patients by cirrhosis, and occurred 68 to 186 days after transplantation. Similar changes were seen in two of the first 26 patients reported from the United Kingdom . A later report from Denver, reporting the first 93 patients , used the term "chronic rejection" to describe a very similar syndrome, although only three livers were then considered to be affected. No mention was made of bile duct damage in any Denver case and, indeed, one of the cases illustrated in the earlier report  (OT9) clearly shows a normal small bile duct. Nevertheless, it is of interest to note that one liver (case not identified), from an anencephalic monster, never cleared bilirubin and when it was removed 85 days later it had "the histopathological findings of intrahepatic biliary atresia". It is possible that this was the first, but unrecognized, description of the syndrome that was clearly defined in the next review from the Cambridge/King's College Hospital group, covering the first 64 patients . One of their patients showed complete absence of small bile ducts (Figure 1), a condition that was later called "vanishing bile duct syndrome" by Portmann [5, 6]. This term has since gained wide acceptance [7-19] and is frequently used interchangeably with "chronic rejection". Ludwig  prefers "ductopenic rejection" since the lesion can be found as early as three weeks after transplantation, and the term chronic is therefore, he argues, inappropriate. A recent study from Cambridge  suggests that, although in the majority of cases both vascular lesions and ductopenia are found together, in a significant minority of cases each can occur independently. The present study extends the latter series and assesses the role of biopsy in the diagnosis of chronic rejection.
FCE was found most often in medium-sized or hilar vessels, of a diameter not normally sampled in needle biopsies (Figure 2). In the 45 livers which showed VBD, this was not an all or none phenomenon. Only 18 (32%) showed 100% bile duct loss, with diminishing proportions of livers showing 75-100%, 50-75%, and four livers less than 50% loss (Figure 3). Perivenular dropout, cholestasis and fibrosis were common but did not correlate well with the other findings. For example, one liver with no VBD but extensive FCE, showed no dropout (Table 1), whilst another, with 100% VBD but no FCE showed neither dropout nor cholestasis (Table 2). Median graft survival was below average in those patients with FCE alone and above average in those with VBD alone (Figure 4).
Of the grafts in which both lesions were present, one or more of the prior biopsies was diagnostic in 71%. When only VBD was present, biopsy was positive in 6/7 (86%), whilst biopsy was positive in only 5 of the 11 livers (45%) with FCE only. Overall, biopsy was positive in 68% (38/56) of the livers subsequently removed for chronic rejection, (Figure 5).
The survival of grafts without arteriopathy is greater than when both lesions are present (Figure 4), and shorter than average when only arteriopathy is present, suggesting that FCE is the more important in determining survival. Furthermore, significant fibrosis was seen mainly in the longer surviving grafts (Tables 1 & 2), suggesting that this is mainly a function of the length of graft survival.
Needle biopsy can be expected to diagnose chronic rejection in about 68% of cases, but other parameters, such as high resolution arteriography, are necessary in the remaining patients. Following a number of reports where bile duct loss has apparently reversed , it has been suggested that a biopsy diagnosis of chronic rejection would be unsafe if less than 50% of bile ducts are without a bile duct. A retrospective study of this nature, where the end-point was hepatectomy for graft failure, clearly does not include any cases which have failed to progress. Nevertheless, four of our patients with less than 50% VBD did progress to graft failure with otherwise typical chronic rejection (Figure 3). Furthermore, the variability of the proportion of duct loss seen in the hepatectomy specimens in this series, all of which were removed for graft failure, suggests that any attempt to quantitate or grade chronic rejection on prior biopsies will be doomed to failure.
Foam cell endovasculitis
FCE - Distribution of lesions.
Portal tract bile duct loss
VBD - Distribution of lesions.
Relative survival of the 11 livers without VBD, and the 7 livers without arteriopathy, compared to that of the whole series of 56 livers.
Chronic Rejection - Summary
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