Drug-induced idiosyncratic liver disease (DIILD) depends largely on host susceptibility factors. Small studies support the genetic influence of human leukocyte antigen (HLA) class II molecules on the predisposition to DIILD. We sought associations between HLA-DRB and -DQB alleles and DIILD considered collectively or according to the biochemical expression of liver damage. We studied a total of 140 patients with a definitive or probable diagnosis of DIILD, as assessed with the Council for International Organizations of Medical Sciences scale, with 635 volunteer bone marrow and blood donors serving as controls. HLA-DRB1* and -DQB1* genotyping was performed by hybridization with sequencespecific oligonucleotides after genomic amplification. The group with DIILD did not differ from control subjects with regard to the distribution of HLA-DRB and -DQB antigens. The frequencies of alleles DRB1*15 (35.4% vs. 18.6% of controls; P ؍ .002; odds ratio [OR] 2.31) and DQB1*06 (61.5% vs. 40.8%; P ؍ .001; OR 2.32) were significantly increased in patients with the cholestatic/mixed type of liver damage in comparison to healthy subjects. By contrast, frequencies of alleles DRB1*07 (16.9% vs. 35.4%; P ؍ .003; OR 0.37) and DQB1*02 (32.3% vs. 55.8%; P ؍ .0003; OR 0.39) were significantly decreased. In conclusion, there is no association between any specific HLA allele and the propensity to develop DIILD. However, the genetic influence associated with HLA class II alleles appears to play a role in the biochemical expression of liver injury in cholestatic/mixed hepatotoxicity and may explain why a given drug may cause different patterns of liver damage. (HEPATOLOGY 2004;39:1603-1612.)
D rug-induced idiosyncratic liver disease (DIILD) accounts for most hepatic reactions attributable to drugs. 1 Although the pathogenesis of DIILD is, in general, poorly understood, 2 underlying (and not mutually exclusive) mechanisms have gained acceptance. 2 Most cases appear to be related to genetic polymorphism of cytochrome P-450 (CYP), which may lead to the formation of toxic derivatives of the parent drug that bind covalently to hepatic constituents. Alternatively, the protective mechanism involved in the inactivation of reactive metabolites may fail. In some cases, an immune response may be directed against neoantigens formed through the interaction of toxic intermediates with liver proteins. 3 An issue that awaits elucidation in DIILD is the hypothesized existence of factors that could predispose patients to the development of liver damage. Human leukocyte antigen (HLA) molecules play a critical role in the host immune response because they are involved in antigen presentation. Specifically, class II antigens present foreign antigens to both the CD4 ϩ helper-T lymphocytes (Th1 and Th2), leading to both humoral and cell-mediated immune responses. 4 Because of the occurrence of Abbreviations: DIILD, drug-induced idiosyncratic liver disease; CYP, cytochrome P-450; HLA, human leukocyte antigen; PCR, polymerase chain reaction.