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The Role of CYP2E1 IgG4 Subclass Autoantibodies in the Development of Anesthetic Sensitization
Dolores B. Njoku, M.D., Jenelle L. Mellerson, B.A., Nauder Faraday, M.D., Monica V. Talor, M.S., Noel R. Rose, M.D., Ph.D.
Anesthesiology and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland.
Elevated levels of cytochrome P450 2E1 (CYP2E1) IgG autoantibodies have been found in the sera of 45-70% of patients diagnosed with halothane hepatitis (Bourdi et al., 1996). These autoantibodies are believed to have a role in the development of sensitization to halogenated volatile anesthetics. However, these autoantibodies may be found in alcoholic liver disease (Vidali et al., 2003) and toxic liver injury by hydrochlorofluorocarbons (Hoet et al., 1997). Furthermore, CYP2E1 IgG autoantibodies may also be found in persons chronically exposed to halogenated volatile anesthetics in the absence of liver injury (Njoku et al., 2002). This latter finding suggests that the role of CYP2E1 IgG autoantibodies in halogenated volatile anesthetic-induced hepatitis (anesthetic hepatitis) is not clear.

Immunoglobulin subclasses are believed to have a role in several systemic and organ-specific autoimmune diseases. Elevated IgG1 and IgG3 restricted autoantibodies have been demonstrated in rheumatoid arthritis while elevated IgG4 restricted autoantibodies have been seen in idiopathic membranous nephropathy, pemphigus foliaceus, subclinical hypothyroidism and Graves disease. Since IgG4 restricted autoantibodies have been seen in organ-specific autoimmune disease we hypothesize that IgG4 autoantibodies to CYP2E1 are elevated in anesthetic hepatitis patients but not in persons exposed to anesthetics without clinical liver injury. IgG2 autoantibodies to CYP2E1 were tested for comparison.

Methods: Four experimental groups were studied: control persons (random selection of pre-employment sera, CON, N=43), persons with anesthetic hepatitis (AH, N=24), pediatric anesthesiologists (exposed to high levels of anesthetic gases, SPA, N=44) and general anesthesiologists (exposed to lower levels of anesthetic gases, JHU, N=44).One hundred microliters of human sera (1:100 dilution) were tested for CYP2E1 IgG4 or IgG2 subclasses using an enzyme–linked immunosorbent assay with a human CYP2E1 test antigen (0.5μg/100μl), as well as, an alkaline phosphatase-conjugated mouse anti-human IgG4 subclass (γ4 chain specific) or mouse anti-human IgG2 subclass (γ2 chain specific) secondary antibody (1:1000 dilutions). The plates were developed using an alkaline phosphatase substrate kit and read at 405 nm after 30, 60 and 90 minutes.

Results: There was no difference in absorbance for CYP2E1 IgG2 subclass autoantibodies in all of the experimental groups studied. Conversely, absorbance levels of CYP2E1 IgG4 autoantibodies were significantly higher in anesthetic hepatitis patients (0.120 ± 0.107) when compared to CON (0.066 ± 0.038, p < 0.001), SPA (0.016 ± 0.012, p<0.001), or JHU (0.014 ± 0.015, p < 0.001) groups.

Conclusions: Increases in IgG4 restricted autoantibodies have been associated with organ-specific autoimmune diseases. The particular role of this IgG subclass is not as clear as that of IgG1 and IgG3. However, IgG4 has been associated with IgE, IL-4 and Th-2 immune mechanisms. Thus, finding significantly elevated levels of CYP2E1 IgG4 autoantibodies may suggest that these and possibly other Th-2-mediated immune mechanisms may have a role in the pathophysiology of anesthetic hepatitis.

Anesthesiology 2004; 101: A1441