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Department of Anesthesia and Perioperative Care, University of California, San Francisco, California
Address correspondence to Dr. Edmond I Eger II, Department of Anesthesia, S-455, University of California, San Francisco, California 94143–0464. Address e-mail to egere{at}anesthesia.ucsf.edu
The report by Njoku et al. (1) in this issue of Anesthesia & Analgesia has good news and bad news. They examined the sera of 105 pediatric and 53 general anesthesiologists (including 3 nurse anesthetists), 20 halothane hepatitis patients, and 20 control individuals never exposed to inhaled anesthetics for hepatic protein autoantibodies (cytochrome P450 2E1 and Erp58). They found that pediatric anesthesiologists, particularly females, have increased serum autoantibody concentrations approximating those inpatients with known halothane hepatitis. The larger autoantibody concentrations in pediatric anesthesiologists was predicted from their increased occupational exposure to volatile anesthetics because of the more frequent use of nonrebreathing systems and the use of uncuffed endotracheal tubes. The good news is that despite having higher antibody levels, pediatric anesthesiologists did not have higher mean alanine aminotransferase (ALT) values than general anesthesiologists. This finding indicates that these antibodies may be insufficient to cause appreciable damage to normal cells in the liver. Add to that the finding that the pediatric anesthesiologists in their sample were older than the general anesthesiologists (42.7 ± 7.7 yr versus 37.9 ± 9.3 yr) and had a longer history of exposure to inhaled anesthetics (16.0 ± 8.1 yr versus 10.9 ± 9.8 yr), and thus might be subject to increased injury if chronic exposure correlates with injury. But the devil and the bad news are in the details.
Despite their shorter exposure to inhaled anesthetics, general anesthesiologists with higher levels of P450 2E1 autoantibodies had higher ALT levels (i.e., the two were correlated; P = 0.05). And one female anesthesiologist reported recurrent hepatitis after exposure to volatile anesthetics. This anesthesiologist no longer gave anesthesia but still had increased Erp58 and P450 2E1 antibody levels. Thus the conclusion that "autoantibodies may not have a pathological role in volatile anesthetic-induced hepatitis" may be premature.
Njoku et al. (1) took a snapshot, a single picture, of autoantibody and ALT values. This snapshot reveals neither the relationship between the time of sampling and the last exposure to inhaled anesthetic nor the anesthetics to which the anesthesiologists were exposed. Several factors may determine the production of injury to normal liver cells from autoantibodies. One might be the amount of (serum concentration of) autoantibodies. A second is that the antibody would need to react with normal hepatic proteins unconnected with anesthetic degradation products.
But both the particular anesthetic degradation hapten and the quantity of hepatic proteins connected with such haptens might be important. Covalent binding of the trifluoroacetyl moiety from halothane, isoflurane and desflurane metabolism to hepatic proteins may induce the production of antibodies which may attack the altered proteins and thereby injure the liver (2). If binding is a function of metabolism then it should be greatest for halothane (40% metabolized) (3), far less for isoflurane (0.2%) (3), and still less for desflurane (0.02%) (4). Although sevoflurane metabolism is relatively high (5%) (5), metabolism does not produce trifluoroacetyl moieties, and thus sevoflurane may not induce autoantibodies (although hepatic injury has been noted to follow anesthesia with sevoflurane) (6–9). Perhaps these observations explain one of the findings of Njoku et al. (1). Why should the data for general anesthesiologists, but not pediatric anes thesiologists, show a correlation of autoantibodies and ALT? The use of isoflurane is more prevalent in adults than in children. In children, sevoflurane has become the anesthetic of choice, largely displacing halothane. Unfortunately, Njoku et al. (1) did not collect data defining the exposure to anesthesiologists to specific anesthetics, although they indicate a belief that the use of sevoflurane was not widespread at the time of their sampling. Nor do we know when the samples were obtained relative to exposure; increase in ALT from anesthetic exposure is likely short-lived, and samples of sera from the pediatric anesthesiologists were collected at the 1998 Society for Pediatric Anesthesia meeting (i.e., not on a day of administering anesthesia). Thus, the ALT values for the pediatric anesthesiologists may underestimate the potential for hepatic injury from the autoantibodies. This, also, may explain why there was a correlation between ALT and autoantibodies for general, but not pediatric anesthesiologists; the samples may have been collected closer to the giving of anesthesia in the general anesthesiologists. Finally, the data collected by Njoku et al. (1) do not include the extent of exposure to the anesthetic (i.e., the amount as well as the type).
Sample size is a limitation of the study by Njoku et al. (1). They studied sera from 158 pediatric and general anesthesiologists. But the incidence of "halothane" hepatitis from halothane is perhaps one in several thousand (10). And the incidence is far less for anesthetics such as isoflurane or desflurane (or sevoflurane?). Thus, this study is not adequately powered to reveal either a subtle effect spread over a population or a rare event.
In summary, Njoku et al. (1) have done the anesthesia community a service in demonstrating that the presence of hepatic autoantibodies alone usually does not produce material hepatic injury. We need the information from such epidemiological-based studies. But we cannot tell from this study whether the unusual anesthesiologist might have injury. We do not know whether such antibodies in concert with anesthetic exposure might produce injury. We do not know whether the substitution of sevoflurane for halothane in pediatric practice will remove any concern regarding occupational exposure. Perhaps Njoku et al. (1) will soon supply data that address these concerns.
Acknowledgments
The author thanks Dr. Dennis Fisher for his several helpful comments.
Footnotes
Dr. Eger is a paid consultant to Baxter Healthcare Corp.
References
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