Bruck R, Oren R, Shirin H, Aeed H, Papa M, Matas Z, Zaidel L, Avni Y, Halpern Z
Department of Gastroenterology, The E. Wolfson Medical Center, Holon, Israel.
Hepatology. 1998 Apr;27(4):1013-20. doi: 10.1002/hep.510270417.
Recent data from animal studies suggest that induced hypothyroidism prevents the hyperdynamic circulation in portal vein ligated rats, liver cirrhosis in rats chronically treated with thioacetamide (TAA), and immune-mediated acute liver injury induced in mice by concanavalin A. Therefore, the aim of this present study is to determine whether hypothyroidism would likewise prevent fulminant hepatic failure (FHF) in rats. FHF was induced by 3 consecutive ip injections of TAA (400 mg/kg) at 24-hour intervals. Hypothyroidism was induced in rats by either methimazole (MMI) or propylthiouracil (PTU) and surgical thyroidectomy and was confirmed by elevated serum thyroid stimulating hormone levels. Serum 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 examination of their livers showed less necrosis and inflammation (P < .01). In the hypothyroid rats, the serum levels of malondialdehyde 48 hours after thioacetamide (TAA) administration were lower than in control rats (P < .01). Exogenous supplementation of hypothyroid rats with L-thyroxine started 48 hours before TAA administration abrogated the protective effects of hypothyroidism. The serum levels of tumor necrosis factor alfa (TNF-alpha), interleukin (IL) 2 and IL-6 after 24 hours were slightly lower in the hypothyroid rats, but the administration of soluble receptor of TNF (10-1,000 microg/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 hypothyroid rats (P < .01). These results suggest that induced hypothyroidism decreases the development of liver injury in a rat model of FHF. The mechanism may involve diminished oxidative cell injury caused by decreased oxygen utilization and hypometabolism associated with hypothyroidism.
近期动物研究数据表明，诱导性甲状腺功能减退可预防门静脉结扎大鼠的高动力循环、硫代乙酰胺（TAA）长期治疗大鼠的肝硬化以及伴刀豆球蛋白A诱导的小鼠免疫介导性急性肝损伤。因此，本研究旨在确定甲状腺功能减退是否同样能预防大鼠暴发性肝衰竭（FHF）。通过每隔24小时连续3次腹腔注射TAA（400 mg/kg）诱导FHF。通过甲巯咪唑（MMI）或丙硫氧嘧啶（PTU）及手术甲状腺切除术诱导大鼠甲状腺功能减退，并通过血清促甲状腺激素水平升高得以证实。所有3组甲状腺功能减退大鼠的血清肝酶、血氨和凝血酶原时间水平均显著降低。甲状腺功能减退大鼠的肝性脑病（HE）分期和生存率显著改善（P <.01）；肝脏组织学检查显示坏死和炎症较少（P <.01）。在甲状腺功能减退大鼠中，硫代乙酰胺（TAA）给药48小时后丙二醛血清水平低于对照大鼠（P <.01）。在TAA给药前48小时开始对外源性补充甲状腺素的甲状腺功能减退大鼠消除了甲状腺功能减退的保护作用。24小时后甲状腺功能减退大鼠的肿瘤坏死因子α（TNF-α）、白细胞介素（IL）2和IL-6血清水平略低，但给予TNF可溶性受体（10 - 1000 μg/大鼠）并不能预防TAA诱导的暴发性肝衰竭。在离体灌注肝制备中研究的氧摄取在甲状腺功能减退大鼠的肝脏中显著降低（P <.01）。这些结果表明，诱导性甲状腺功能减退可减少FHF大鼠模型中肝损伤的发生。其机制可能涉及因氧利用减少和与甲状腺功能减退相关的代谢减退导致的氧化细胞损伤减轻。
