HYPOTHYROIDISM MINIMIZES LIVER-DAMAGE AND IMPROVES SURVIVAL IN RATS WITH THIOACETAMIDE-INDUCED FULMINANT HEPATIC-FAILURE

Recent data from animal studies suggest that induced hypothyroidism pr events the hyperdynamic circulation in portal vein ligated rats, liver cirrhosis in rats chronically treated with thioacetamide (TAA), and i mmune-mediated acute liver injury induced in mice by concanavalin A, T herefore, the aim of this present study is to determine whether hypoth yroidism would likewise prevent fulminant hepatic failure (FHF) in rat s, FHF was induced by 3 consecutive ip injections of TAA (400 mg/kg) a t 24-hour intervals. Hypothyroidism was induced in rats by either meth imazole (MMI) or propylthiouracil (PTU) and surgical thyroidectomy and was confirmed by elevated serum thyroid stimulating hormone levels. S erum levels of liver enzymes, blood ammonia, and prothrombin time were significantly lower in all 3 groups of hypothyroid rats, The stage of hepatic encephalopathy (HE) and the survival rates were significantly improved in the hypothyroid rats (P < .01); the histologic examinatio n of their livers showed less necrosis and inflammation (P < .01). In the hypothyroid rats, the serum levels of malondialdehyde 48 hours aft er thioacetamide (TAA) administration were lower than in control rats (P < .01), Exogenous supplementation of hypothyroid rats with L-thyrox ine started 48 hours before TAA administration abrogated the protectiv e effects of hypothyroidism. The serum levels of tumor necrosis factor alfa (TNF-alpha), interleukin (IL) 2 and IL-6 after 24 hours were sli ghtly lower in the hypothyroid rats, but the administration of soluble receptor of TNF (10-1,000 mu g/rat) did not prevent the induction of fulminant liver failure by TAA, Oxygen extraction, studied in isolated perfused liver preparation, was significantly lower in livers of hypo thyroid rats (P < .01). These results suggest that induced hypothyroid ism decreases the development of liver injury in a rat model of FHF Th e mechanism may involve diminished oxidative cell injury caused by dec reased oxygen utilization and hypometabolism associated with hypothyro idism.