Sevelamer Ameliorates Early Cirrhosis and Inhibits Its Progression towards Hepatocellular Carcinoma in a Diethylnitrosamine-induced Rat Model.

Abstract

Cirrhosis has a very high morbidity and mortality and partially progressed into hepatocellular carcinoma (HCC). Sevelamer is an oral phosphate binder to treat hyperphosphatemia. Here, we investigated the contribution of sevelamer to the remission of cirrhosis, and further the prevention of HCC. Diethylnitrosamine (DEN)-treated rats, developing the sequential stage of cirrhosis to HCC, were used to identify the therapeutic and preventive effects via transient elastography, hematological biochemistry, and pathological examination. Ultrasound image and transient elastography are indicative of the occurrence of cirrhosis characterized by the pseudolobular formation and higher stiffness after DEN exposure, and few nodules and lower stiffness values were observed in the control and sevelamer treated group. Hematological biochemistry showed that indicators of liver fibrosis (serum hyaluronic acid and type III precollagen) and serum tumor biomarkers (VEGF-α, α-L-fucosidase) were also simultaneously reversed. Pathological examination showed that hepatic steatosis, inflammation, and fibrotic deposits were remarkably alleviated after sevelamer administration. The pharmacology of sevelamer might be attributable to rebalance of oxidative stress as assessed by determination of the total reactive oxygen specie, malondialdehyde and antioxidant enzymes, to modulation of inflammation as evidenced by decreased interleukin (IL)-1β, IL-4, IL-6 and TNFα levels, and to inhibition of angiogenesis as measured by microvessel density. Our findings confirm that sevelamer reverses cirrhosis and prevents its deterioration to in the DEN-induced rat HCC model.