Serum hyaluronic acid in patients with veno-occlusive disease following bone marrow transplantation

Abstract

Summary:The development of hepatic veno-occlusive disease following bone marrow transplantation is associated with high-dose combination cytoreductive therapy. Experimental models have suggested that drug-induced injury to hepatic sinusoidal endothelial cells is involved in the pathogenesis of this syndrome. Hyaluronic acid is a polysaccharide that is metabolized, almost exclusively, by hepatic sinusoidal endothelial cells. The aim of the present study was to evaluate serum hyaluronic acid as a marker for endothelial cell injury in patients with veno-occlusive disease following bone marrow transplantation. Hyaluronic acid was measured in sera from patients with and without veno-occlusive disease using an enzyme-linked protein binding assay. Mean peak serum hyaluronic acid levels were significantly greater in patients who had a diagnosis of VOD compared to those transplant patients who did not, 1173.4 ± 982.9 vs 444.9 ± 735.6 ng/ml (P = 0.01). Serial serum samples obtained from a separate cohort of patients also demonstrated that serum hyaluronic acid levels were higher in patients with moderate or severe veno-occlusive disease compared to those with none or mild disease at days 7, 17 and 25 following transplantation (greatest difference at day 25: 366 ± 327 vs 126 ± 151, P = 0.01). Serum hyaluronic acid levels are increased in veno-occlusive disease and increase over time in patients with severe disease. Further studies are required to determine if elevated serum hyaluronic acid levels are due to decreased clearance by injured hepatic sinusoidal endothelial cells or increased production from early hepatic fibrogenesis associated with the acute liver injury. Hepatic veno-occlusive disease (VOD) is a life-threatening complication of bone marrow transplantation (BMT) that is defined by the appearance of jaundice, tender hepatomegaly, and ascites. 1-3 Clinical manifestations of VOD usually occur within 3 weeks of transplant and vary in their severity. Mild VOD may be self-limited and resolve with supportive care, while severe VOD causes progressive hepatic synthetic dysfunction and complications of portal hypertension that culminate in multi-organ failure and death. 2 The histologic changes of VOD occur predominantly in the centrizonal region of the hepatic lobule and are characterized by subendothelial edema, occlusion of terminal hepatic venules, hepatocyte necrosis, and sinusoidal fibrosis. 4 The incidence of VOD following transplantation ranges between 10% and 54% depending on the cytoreductive regimen and the criteria used to define the syndrome. 2,3,5 The development of VOD has been strongly associated with high-dose combination cytoreductive therapy, particularly regimens that contain cyclophosphamide coupled with total body irradiation, busulfan, carmustine, or etoposide. 2,3 Several studies have provided evidence that injury to hepatic sinusoidal endothelial cells by chemotherapeutic agents is an early event in the pathogensis of VOD. 6,7 In cell culture, isolated sinusoidal endothelial cells were more susc...

Expression of MMP-9 in hepatic sinusoidal obstruction syndrome induced by Gynura segetum

“…The level of serum HA reflects damage to the SECs. Serum HA levels are increased in patients with HSOS, and correlate with the severity of the disease (Petaja et al, 2000;Fried et al, 2001). In addition, levels of N-terminal propeptide for type III procollagen (P-III-P), a sensitive index of hepatic fibrosis, increase in patients with HSOS.…”

Proinflammatory cytokines and their role in the development of major transplant-related complications in the early phase after allogeneic bone marrow transplantation

“…VOD is characterized by a systemic hypercoagulability state as evidenced by a decrease in naturally occurring anticoagulants including protein C and antithrombin III. 21,22 Also, high plasma levels of factors associated with fibrinogenesis such as N-terminal propeptide for type III procollagen 23,24 and hyaluronic acid 25 have been observed in VOD. Our findings are consistent with both processes involved in the pathogenesis of VOD, since it is known that a hypercoagulable status can be induced and maintained by proinflammatory cytokines.…”

Veno-occlusive disease of the liver in children with solid tumors undergoing autologous hematopoietic progenitor cell transplantation: a high incidence in patients with neuroblastoma

“…Many risk factors for the development of VOD are described in the literature and include surrogate markers of pre-existing liver damage and indicators of liver function prior to conditioning, such as baseline hepatitis seropositivity, transaminase levels, pseudocholinesterase and albumin levels; 3,17,18 and markers of liver damage during conditioning by drugs or cytokines, such as intensity of cytoreductive therapy, use of methotrexate and cyclosporine during transplantation, use of antimicrobials during conditioning or hyalurinic acid levels. 3,19 Our study did not have sufficient power to confirm the significance of factors such as baseline albumin, AST/ALT levels, or hepatitis seropositivity. Factors identified as significant on univariate analysis, such as age р7 years, surgery and radiation to the abdomen were strongly linked to the diagnosis of neuroblastoma and therefore not informative when added to the multivariate model.…”