Venous Sclerosis and Fibrosis in Chronic Rejection of Liver Allografts
Index
Yuichi Nakazawa, Neal Walker, Stephen Lynch, Andrew Clouston
Departments of Pathology, Gastroenterology and Hepatology, and
Surgery, Princess Alexandra Hospital, Brisbane, Australia.
Fibrosis in liver allografts undergoing chronic rejection (CR) is a
variable
and poorly understood process. Suggested contributing causes include
the
prolonged cholestasis and ductular proliferation that can accompany
CR;
others have noted its occurrence in a proportion of allografts with
prolonged ischemia. The latter does not explain why foam-cell
arteriopathy
sufficient to cause severe ductopenia has unpredictable and sometimes
negligible changes on the hepatic parenchyma.
Recently, Wanless has suggested that fibrosis in liver disease may be
the
result of venous occlusion. He proposes that occlusion of both the
portal
and central hepatic veins results in parenchymal extinction followed
by
fibrosis. We studied the temporal and spatial relationships of venous
and
biliary lesions in an attempt to clarify their potential contributions
to
graft fibrosis.
Seventeen patients with explanted or postmortem grafts were available
for
study. Initially, venous lesions were assessed. Hepatic veins (HV,
including terminal hepatic venules) and portal veins (PV) were
segregated by
size, and almost 3000 vessels analyzed for severity, prevalence and
morphology of venous lesions. Then, fibrosis was scored in periportal
and
centrilobular regions and this was correlated with the presence of
ductular
proliferation and venous lesions.
Three groups were found; group 1 (n=5) with no HV lesions, group 2
(n=5)
with HV lesions only, and group 3 with lesions of both HV and PV. The
earliest and most common lesion to develop, in 71% of grafts, was
concentric
intimal thickening of small HV (central veins) which mimicked that
seen in
veno-occlusive disease. The lesions were significantly more severe and
more
frequent grafts from group 3 compared with group 2. With increasing
frequency and severity of small HV sclerosis there was a significant
correlation with the development of eccentric or mixed
eccentric/concentric
fibrosis in medium/large veins. The morphology of the lesions in
larger
vessels suggested organized thrombosis as the cause.
Scores for fibrosis varied. Centrilobular fibrosis was significantly
greater in group 3 (with dual HV and PV lesions). Conversely, portal
fibrosis scores were significantly higher in grafts with ductular
proliferation and did not show any correlation with the venous
lesions.
Portal fibrosis was slowly progressive, but centrilobular fibrosis
developed
unpredictably and sometimes rapidly.
This suggests a model of CR in which mild venoocclusive-like lesions
develop
commonly in terminal hepatic venules, probably due to immune-mediated
damage. In only a proportion, with increased frequency and severity of
the
lesions, there is stasis and thrombosis in larger veins (PV and HV)
resulting in parenchymal ischemia and fibrosis. This also helps to
explain
why ischemic changes in the acini may not be apparent despite
significant
foam-cell arteriopathy and bile duct loss, in those grafts with only
mild
venous sclerosis. The roles played by immunological mechanisms and
arterial
ischemia in this model remain to be determined.
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