Halothane-Associated Liver Damage

The first well-documented case (Klatskin and Kimberg 1969) was that of an anaesthetist who developed hepatitis seven times in 5 years. Each of these attacks followed his return to work and re-exposure to halothane. Jaundice was preceded by systemic manifestations which could all be explained by, or interpreted as, manifestations of an immunologically mediated reaction. These included pyrexia, myalgia and eosinophilia. Serial liver biopsies which were carried out showed hepatic cell necrosis, followed by the development of post-necrotic cirrhosis. It had to be established whether that patient was sensitive to halothane, because of the nature of his occupation. Thus, he was exposed to subanaesthetic doses of that agent. 

These challenge tests were followed each time be fever, rigors and myalgia, which developed after 4 h. Hepatitis was shown by biopsy after 24 h. 

Several other cases of hepatitis resulting from occupational exposure to halo-thane have been reported. Thus, there is little doubt that hepatitis may follow the inhalation of this anaesthetic. Extensive surveys of post-operative jaundice have also been carried out. A summary of the findings will be given here. Despite numerous reports in the literature of liver damage in patients who had halothane anaesthesia, there is still considerable controversy between anaesthetists and pathologists as to whether the hepatitis and halothane are causally related. 

The case of the anaesthetist just mentioned points to one of the underlying factors. This patient suffered from asthma and hay fever. That this was not a mere coincidence was subsequently suggested by the high incidence of personal or family history of allergy, e.g. in the series of Carney and van Dyke (1972) 46% of all patients developing this affliction gave a history of previous allergy. 

According to a number of surveys of post-operative jaundice, the majority of patients who developed jaundice after halothane administration had received that agent more than once within a short period (a few weeks). 

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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... 

Two patterns of liver damage associated with halothane have been observed (45). One pattern is a mild derangement of liver enzymes, which occurs in about one in four anesthetics. The other pattern is rare but is associated with severe hepatitis, often resulting in fulminant Uver failure. This severe form occurs more often in middle-aged, obese women, usually after multiple anesthetics, and is known as halothane hepatitis. It is defined as unexplained severe liver damage occurring within 28 days of halothane exposure in a person with a previously normal... 

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. 

Centrolobular necrosis is often a dose-related, predictable reaction secondary to drugs such as acetaminophen however, it also can be associated with idiosyncratic reactions, such as those caused by halothane. Also called direct or metabolite-related hepatotoxic-ity, centrolobular necrosis is usually the result of the production of a toxic metabolite (see Fig. 38-1). The damage spreads outward from the middle of a lobe of the liver. 

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