The first modern halogenated volatile anesthetic, halothane, was introduced in 1955. Clinical exposure to halothane is associated with two distinct types of hepatic injury. Subclinical hepatotoxicity occurs in 20% of adults who receive halothane. It is characterized by mild postoperative elevations in alanine aminotransferase and aspaate aminotransferase, but is reversible and innocuous. Anaerobic halothane reduction by CYP2A6 to a 2-chloro-1,1,1-trifluoroethyl radical is thought to mediate this mild hepatic injury. The fulminant form of hepatotoxicity, commonly known as halothane hepatitis, is characterized by elevated alanine aminotransferase, aspaate aminotransferase, bilirubin, and alkaline phosphatase levels, massive hepatic necrosis following the administration of halothane. Halothane hepatitis is rare (1 in 5000 to 35,000 administrations in adults), but is fatal in 50% to 75% of these cases. Because of the potential for fatal hepatitis, halothane is no longer used in adult patients in many countries. Halothane hepatitis is caused by a hypersensitivity reaction associated with the oxidative metabolism of halothane. The highly reactive trifluoroacetyl chloride metabolite of halothane oxidation can react with nearby liver proteins. In most patients who developed hepatic necrosis after halothane anesthesia, antibodies against TFA-modified proteins were detected, suggesting that the hepatic damage is linked to an immune response against the modified protein, which acts as a neoantigen. Accordingly, patients who develop halothane hepatitis often have a history of prior exposures to halothane or other volatile anesthetics, together with symptoms suggestive of immune reactivity, such as fever, rash, ahralgia, and eosinophilia. A current hypothesis is that TFA-protein adducts induce a cytotoxic T cell reaction in sensitized individuals, which leads to liver damage. However, the immune responses observed in halothane hepatitis might not mediate liver injury. Ref: Miller's anesthesia 8th edition Ref: Morgan & Mikhail's clinical anesthesiology 6e