HLA-B*5801 Genotype, Allopurinol Hypersensitivity, Blood
Predicting increased risk of hypersensitivity reactions to allopurinol
Excluding patients at an elevated risk for allopurinol hypersensitivity syndrome from receiving allopurinol
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Allopurinol is widely used for hyperuricemia-related diseases such as gout, Lesch-Nyhan syndrome, and recurrent urate kidney stones. Allopurinol hypersensitivity syndrome is a spectrum of reactions that includes not only Stevens-Johnson syndrome and toxic epidermal necrolysis, but also systemic disease with a clinical constellation of features such as eosinophilia, vasculitis, rash, and major end-organ disease. There is a reported mortality rate of 20% to 25% for allopurinol hypersensitivity syndrome (AHS).
Studies in Han Chinese residing in Taiwan showed that the HLA-B*5801 allele was present in 100% of the patients with allopurinol-induced skin reactions, but in only 15% of allopurinol-tolerant controls. Data obtained from recombinant mapping further concluded that HLA-B*5801 itself is the major susceptibility gene for allopurinol-induced skin reactions in the Han Chinese population. In the Thai population, 100% of patients with allopurinol-induced skin reactions carried the allele, but only 13% of allopurinol-tolerant individuals tested positive for the HLA-B*5801 allele. A similar but more modest 80% of Korean cases compared to 12% of healthy controls and 56% of Japanese cases compared to 0.61% of healthy controls were positive for the HLA-B*5801 allele. Two studies of Europeans have been reported. In the first study, 55% of European cases compared to 1.5% of controls tested positive for the allele and, in the second study, 100% of cases compared to a population frequency of 1.5% were positive for the HLA-B*5801 allele. A meta-analysis that considered all published studies as of the date of the analysis gave the odds ratios for allopurinol-induced severe skin reactions in HLA-B*5801 carriers as 73 and 165 compared to healthy controls and allopurinol-tolerant controls, respectively. The frequency of the HLA-B*5801 allele is widely distributed among other populations: (eg, 2%-4% in Africans, 3%-15% in Asian Indians). Further studies are needed to determine if individuals from these populations with this allele are at similar risk for allopurinol hypersensitivity reaction.
Guidelines have been developed by the Clinical Pharmacogenomics Implementation Consortium that recommends that HLA-B*5801 genotyping be performed and that allopurinol should not be prescribed to patients who test positive for the allele. Also, guidelines developed by the 2012 American College of Rheumatology for Management of Gout recommend that HLA-B*5801 testing should be considered in select patient subpopulations at an elevated risk for AHS. Those of Korean descent, especially those with stage 3 or higher chronic kidney disease, or of Han Chinese or Thai extraction irrespective of renal function should be tested. However, given the literature as reviewed above, consideration should be given to testing all patients who will be given allopurinol.
Positivity for HLA-B*5801 confers risk for hypersensitivity to allopurinol
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
Patients who have received a heterologous blood transfusion within the preceding 6 weeks, or who have received an allogeneic blood or marrow transplant, can have inaccurate genetic test results due to presence of donor DNA.
Rare, unreported HLA-B58 alleles may occur and may or may not interfere with this assay. This assay also detects closely related, but rare, alleles including HLA-B*5705, *5804, *5805, *5809, *5810, *5811, *5812, *5813, *5815, *5817, *5819, *5821, *5822, *5823, *5824, and *5828. There are, as yet, no data indicating whether these subtypes are associated with hypersensitivity.
Clinical Reference Provides recommendations for further in-depth reading of a clinical nature
1. Chung WH, Hung SI, Chen YT: Human leukocyte antigens and drug hypersensitivity. Curr Opin Allergy Clin Immunol 2007;7:317-323
2. Khanna D, Fitzgerald J, Khanna P, et al: 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res 2012;64:1431-1446
3. Hershfield MS, Callaghan JT, Tassaneeyakul W, et al: Clinical Pharmacogenetics Implementation Consortium guidelines for human leukocyte antigen-B genotype and allopurinol dosing. Clin Pharmacol Ther 2013 Feb;93(2):153-158