A Mouse Model of Severe Halothane Hepatitis Based on Human Risk Factors

Abstract

Halothane (2-bromo-2-chloro-1,1,1-trifluoro-ethane) is an inhaled anesthetic that induces severe, idiosyncratic liver injury, i.e., "halothane hepatitis," in approximately 1 in 20,000 human patients. We used known human risk factors (female sex, adult age, and genetics) as well as probable risk factors (fasting and inflammatory stress) to develop a murine model with characteristics of human halothane hepatitis. Female and male BALB/cJ mice treated with halothane developed dose-dependent liver injury within 24 h; however, the liver injury was severe only in females. Livers had extensive centrilobular necrosis, inflammatory cell infiltrate, and steatosis. Fasting rendered mice more sensitive to halothane hepatotoxicity, and 8-week-old female mice were more sensitive than males of the same age or than younger (4-week-old) females. C57BL/6 mice were insensitive to halothane, suggesting a strong genetic predisposition. In halothane-treated females, plasma concentration of tumor necrosis factor-alpha was greater than in males, and neutrophils were recruited to liver more rapidly and to a greater extent. Anti-CD18 serum attenuated halothane-induced liver injury in female mice, suggesting that neutrophil migration, activation, or both are required for injury. Coexposure of halothane-treated male mice to lipopolysaccharide to induce modest inflammatory stress converted their mild hepatotoxic response to a pronounced, female-like response. This is the first animal model of an idiosyncratic adverse drug reaction that is based on human risk factors and produces reproducible, severe hepatitis from halothane exposure with lesions characteristic of human halothane hepatitis. Moreover, these results suggest that a more robust innate immune response underlies the predisposition of female mice to halothane hepatitis.