Personalized Medicine for HLA-associated Drug-hypersensitivity Reactions

Mandvi Bharadwaj; Patricia Illing; Lyudmila Kostenko

Disclosures

Personalized Medicine. 2010;7(5):495-516. 

In This Article

Flucloxacillin-induced Liver Injury & HLA-B*5701

Flucloxacillin is a penicillinase-resistant antibiotic widely used in the treatment of Staphylococcus aureus infections. Approximately 8.5 of every 100,000 Europeans, on first time treatment with flucloxacillin for an average of 7 days, develop a potentially fatal cholestatic hepatitis within 45 days (median diagnosis 25.5 days).[58] In various studies female sex and age greater than 60 years, have been named as risk factors for flucloxacillin-induced liver damage.[58,59] More recently, a genome-wide SNP analysis study of a European population found the rs2395029 polymorphism of the HCP5 gene to be present in approximately 84% of sufferers of flucloxacillin-associated cholestatic hepatitis, compared with 5% of the general population.[60] The previously mentioned LD between this SNP and HLA-B*5701[37] prompted sequencing of the HLA-B locus in these patients. All patients with the rs2395029 polymorphism were positive for HLA-B*5701, which was present in approximately 6% of the controls.[60] It was, however, estimated that only 1 in 500 to 1 in 1000 individuals positive for HLA-B*5701 would experience liver damage when exposed to flucloxacillin,[60] and no flucloxacillin-tolerant cohort was tested for HLA-B*5701. Not only does this suggest the involvement of other factors in disease etiology, but that a very high number of individuals would be inappropriately precluded from flucloxacillin treatment if HLA-B*5701 screening was used preventatively.

There is limited evidence of the involvement of T cells in this reaction although flucloxacillin-induced lymphocyte proliferation has been observed in peripheral blood mononuclear cells isolated from a patient with flucloxacillin-induced liver injury.[61] Whilst this does suggest involvement of the HLA, more data is necessary to analyze a possible role for HLA-B*5701.

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