Venoocclusive disease of the liver after marrow transplantation: Histological correlates of clinical signs and symptoms

Abstract

We evaluated the relationship between the signs and symptoms of the clinical syndrome called veno-occlusive disease of the liver after bone marrow transplantation and the histological findings in 76 patients who later came to autopsy. Coded necropsy liver was scored for individual histological features that were correlated with prospectively assessed clinical features that the patients had exhibited during life. Patients were stratified into two groups: those with severe clinical veno-occlusive disease (n = 32) and those without. Clinically severe veno-occlusive disease was statistically correlated with several zone 3 acinar changes: occluded hepatic venules, the frequency of occluded hepatic venules x degree of occlusion, eccentric luminal narrowing/phlebosclerosis, zone 3 sinusoidal fibrosis and zone 3 hepatocyte necrosis (all p < or = 0.03). There was a significant relationship between the number of these histological abnormalities in zone 3 of the liver acinus and a clinical diagnosis of severe veno-occlusive disease (p = 0.003). The presence of ascites was significantly correlated with occluded venules, zone 3 sinusoidal fibrosis and zone 3 hepatocyte necrosis (p = 0.001). Maximum serum bilirubin in the first 20 days after transplant was significantly correlated with sinusoidal fibrosis, hepatocyte necrosis and eccentric luminal sclerosis/phlebosclerosis (p < 0.01) but not with venular occlusion. The clinical syndrome of liver toxicity (commonly called veno-occlusive disease) that results from cytoreductive therapy before bone marrow transplant is strongly correlated with a constellation of histological lesions involving structures in zone 3 of the liver acinus and the hepatic venules into which sinusoidal blood flows. This study suggests that there is no single diagnostic histological feature. The severity of clinical veno-occlusive disease appears to be proportional to the number of such histological changes and is not due solely to occlusion of small hepatic venules.

Vascular liver diseases

“…Involvement of the hepatic veins by subendothelial edema occurs in more severe disease and compounds the obstruction of the microcirculation. Indeed, involvement of the hepatic veins is correlated with more severe disease [14]. In late SOS, the nature of the circulatory obstruction changes from hemorrhage and edema to sinusoidal fibrosis and phlebosclerotic and periadventitial fibrosis of the hepatic veins.…”

“…The easily recognizable occlusion of the central veins inspired the name hepatic veno-occlusive disease [13]. However, involvement of the central veins is not essential to the disease [14], and the disease process originates in the sinusoids [15]. Consequently, sinusoidal obstruction syndrome (SOS) has been proposed as more appropriate for the full range of disease, with or without involvement of the veins [16•].…”

“…Risk factors for nodular regenerative hyperplasiaLiver tion patients or myeloablative therapy for stem cell transplantation[14,18,41,42].…”

Life-threatening veno-occlusive disease after living-related liver transplantation

“…The diagnosis of VOD can be confirmed histologically on the basis of fibrous obliterative lesions in the hepatic veins (HVs), which are accompanied by centrilobular necrosis (CLN) and congestion (2,4).…”

Allogeneic hematopoietic cell transplant in HCV-infected patients

“…SOS is a liver toxicity syndrome after BMT caused by occlusion of centrilobular venules and damage to the surrounding hepatocytes and sinusoids, after myeloablative conditioning regimen [36,37]. SOS of the liver is characterized by hyperbilirubinemia, fluid retention, and painful hepatomegaly appearing soon after BMT [36,38]. Individual variability in cyclophosphamide metabolism, total body irradiation (TBI) dose, use of gentuzumab ozogamicin and pre-existing liver inflammation and fibrosis are risk factors [12,[39][40][41].…”