Hepatitis halothane-induced

Satoh, H. et al., Human anti-endoplasmic reticulum antibodies in sera of patients with halothane-induced hepatitis are directed against a trifluoroacetylated carboxylesterase, Proc. Nat. Acad. Sci. USA, 86, 322, 1989. 

Halothane-induced hepatitis seems to be mediated by both humoral and cell-mediated aspects of the immune system. Thus, both specific circulating antibodies and cytotoxic T lymphocytes are involved. One suggestion is that the mechanism involves antibody-dependent cell cytotoxicity (ADCC). 

The principal antigenic proteins seem to be associated with the smooth endoplasmic reticulum. This is not particularly surprising since it is the probable site of metabolite formation via P450. Trifluoroacyl adducts have also been detected on the outer surface of hepatocytes, although it is not clear how they arrive there. In halothane-induced hepatitis the number of exposures does seem to be important, with about four being optimum. 

Hasan F. Isoflurane hepatotoxicity in a patient with a previous history of halothane-induced hepatitis. Hepatogastroenterology 1998 45(20) 518-22. 

W12. Wood, M., Berman, M. L., and Harbison, R. D., Halothane-induced hepatic necrosis in triiodothyronine pre-treated rats. Anesthesiology 52, 470-476 (1980). 

Halothane-induced hepatitis that occurs in the postoperative period most often is due to transmission of hepatitis virus (e.g., in transfused blood), involvement of the liver by disease processes, or damage by known hepatotoxic drugs. Hepatic necrosis, although rare, does occur with halothane. 

Approximately 60-80% of halothane taken up by the body is eliminated unchanged via the lungs in the first 24 hours after its administration. A substantial amount of the halothane not eliminated in exhaled gas is biotransformed by hepatic CYPs. Trifiuoroacetylchloride, an intermediate in oxidative metabolism of halothane, can trifluoroacetylate several proteins in the liver. An immune reaction to these altered proteins may be responsible for the rare cases of fulminant halothane-induced hepatic necrosis. 

Satoh H, Martin BM, Schulick AH, Christ DD, Kenna JG, Pohl LR (1989) Human anti-endoplasmic reticulum antibodies in sera of patients with halothane-induced hepatitis are directed against a trifluoroacetylated carboxylesterase. Proc Natl Acad Sci USA 86 322-326 Saxon AJ, Sloan KL, Reoux J, Haver VM (1998) Disulfiiam use in patients with abnormal liver function test results. J Clin Psychiatry 59 313-316 Schnyder B, Mauri-Hellweg D, Zanni M, Bettens F, Pichler WJ (1997) Direct, MHC-dependent presentation of the drug sulfamethoxazole to human alphabeta T cell clones. J Clin Invest 100 136-141... 

In a study on halothane-induced hepatitis in the United States the incidence of fatal massive hepatic necrosis from any cause was 7.1 in 10,000 after multiple administrations of halothane and only 2.4 in 10,000 after multiple administrations of non-halothane anesthetics. However, this increased risk appeared to be more than offset by higher mortality for other reasons in the non-halothane group. The general enthusiasm for halothane is reflected by the fact that it is now used for more than 70% of all anesthetic procedures in the United Kingdom (Davies and Holmes 1972). 

Methoxyfluorane is another fluorinated compound which is structurally related to halothane, and which has also been reported to cause hepatic necrosis. The reaction produced closely mimics halothane-induced hepatitis. Furthermore crossreaction between these two compounds may occur (Judson et al. 1971). This is not surprising since they undergo similar metabolic processes. 

Although both metabolic and immune factors may be involved in the aetiology of severe hepatitis after halothane the aetiology of postanaesthetic/postsurgical hepatitis is far from clear. A recent study revealed that paediatric anaesthesiologists had high titres of serum autoantibodies which react with specific hepatic proteins. Since the vast majority of these individuals have not developed hepatitis the pathological role of autoantibodies in volatile anaesthetic-induced hepatitis remains questionable (Njoku and co-workers 2002). 

About 20% of halothane is metabolised and it induces hepatic enzymes, including those of anaesthetists and operating theatre staff. Hepatic damage occurs in a small proportion of exposed patients. Typically fever develops 2 or 3 days after anaesthesia accompanied by anorexia, nausea and vomiting. In more severe cases this is followed by transient jaundice or, very rarely, fatal hepatic necrosis. Severe hepatitis is a complication of repeatedly administered halothane anaesthesia and has an incidence of 1 50000. It follows immime sensitisation to an oxidative metabolite of halothane in susceptible individuals. This serious complication, along with the other disadvantages of halothane and the popularity of sevoflurane for inhalational induction, has almost eliminated its use in the developed world. It remains in common use other parts of the world because it is comparatively inexpensive. 

This patient had multiple risk factors for anesthesia-induced hepatitis, including obesity, middle age, female sex, a history of drug allergies, and multiple exposures to fluorinated anesthetic agents. Desflurane has a very low rate of hepatic oxidative metabolism (0.02 versus 20% for halothane), and is considered to be one of the safest volatile agents as far as hepatotoxicity is concerned. Nevertheless, this case shows that it can cause severe hepatotoxicity. 

The death rate due to halothane-induced liver damage was estimated in 1993 at one in 35 000 anesthetics (27), three times greater than the one in 110 000 incidence reported in 1976 (28). Both immune function and the metabolism of halothane play important roles in the pathophysiology of Uver damage (29). Human hepatic microsomal carboxyles-terase is a target antigen in halothane hepatitis, protein disulfide isomerase is an important factor in the mechanism of Uver impairment, and an associated immune response... 

Hepatic damage related to isoflurane anesthesia has very occasionally been described (9,10), including one report of hepatic necrosis and death (11). Hepatitis or hepatocellular injury has been described with all current volatile anesthetics. Among these, halothane-associated hepatitis has been best characterized and is probably caused by an immune reaction induced by hepatocyte proteins that have been covalently trifluoroacetylated by the trifluoro-acetyl metabolite of halothane. The reactive acyl-halide metabolite of trifluoroacetic acid can trifluoroacetylate liver proteins, resulting in immune-mediated hepatic necrosis (12). However, isoflurane biotransformation to trifluoroacetate is less than 0.2%, compared with 15-20% for halothane. 

Kenna, J. G., Neuberger, J., Williams, R. Evidence for expression in human liver of halothane-induced neoantigens recognized by antibodies in sera from patients with halothane hepatitis. Hepatology 1988, 8, 1635-1641. 

---