Robert John Fontana1, Li Yi-Ju2, Elizabeth Phillips3, Naba Saeed4, Huiman Barnhart2, David Kleiner5, Jay Hoofnagle6. 1. Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI. 2. Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC. 3. Vanderbilt University Medical Center, Nashville, TN. 4. Department of Internal Medicine, University of Kentucky, Louisville, KY. 5. Laboratory of Pathology, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD. 6. Liver Disease Research Branch, Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD.
Abstract
BACKGROUND/ AIMS: Allopurinol can cause HLA class I associated life-threatening severe skin reactions. However, HLA risk and association with clinical features in allopurinol hepatotoxicity are unknown. METHODS: 11 of 17 patients with suspected allopurinol hepatotoxicity enrolled into the Drug Induced Liver Injury Network were adjudicated as definite, highly likely or probable. High resolution HLA sequencing was undertaken in cases and compared to population and other DILI controls. RESULTS: Median age was 60 years, 54% were male, and 63% African- American, 27% Caucasian, and 9% Hispanic. Patients presented at a median of 52 days after starting allopurinol, all were hospitalized and 6 were jaundiced. The median peak ALT, alkaline phosphatase, and total bilirubin were 525 U/L, 521 U/L, and 7.8 mg/dL, respectively, with a median R ratio of 2.7 at onset. During follow-up, 9 patients were treated with corticosteroids including 5 of the 6 with suspected DRESS. Three patients died including two from liver failure at 38 and 45 days after onset, and the remaining 8 recovered. Three HLA alleles were found to be overrepresented in allopurinol cases, particularly in African Americans: HLA- B * 58:01, which has been previously linked to severe skin reactions, and HLA-B*53:01 and HLA-A*34:02 all of which are more frequently found in African-Americans than European-Americans or Latinos. CONCLUSIONS: Allopurinol hepatotoxicity is associated with systemic hypersensitivity, a short latency to onset, African American race and 3 HLA risk alleles, HLA-B*58:01, HLA-B*53:01 and HLA-A*34:02. HLA- 58:01 testing may help confirm a diagnosis of hepatotoxicity in allopurinol treated patients. This article is protected by copyright. All rights reserved.
BACKGROUND/ AIMS: Allopurinol can cause HLA class I associated life-threatening severe skin reactions. However, HLA risk and association with clinical features in allopurinolhepatotoxicity are unknown. METHODS: 11 of 17 patients with suspected allopurinolhepatotoxicity enrolled into the Drug Induced Liver Injury Network were adjudicated as definite, highly likely or probable. High resolution HLA sequencing was undertaken in cases and compared to population and other DILI controls. RESULTS: Median age was 60 years, 54% were male, and 63% African- American, 27% Caucasian, and 9% Hispanic. Patients presented at a median of 52 days after starting allopurinol, all were hospitalized and 6 were jaundiced. The median peak ALT, alkaline phosphatase, and total bilirubin were 525 U/L, 521 U/L, and 7.8 mg/dL, respectively, with a median R ratio of 2.7 at onset. During follow-up, 9 patients were treated with corticosteroids including 5 of the 6 with suspected DRESS. Three patientsdied including two from liver failure at 38 and 45 days after onset, and the remaining 8 recovered. Three HLA alleles were found to be overrepresented in allopurinol cases, particularly in African Americans: HLA- B * 58:01, which has been previously linked to severe skin reactions, and HLA-B*53:01 and HLA-A*34:02 all of which are more frequently found in African-Americans than European-Americans or Latinos. CONCLUSIONS:Allopurinolhepatotoxicity is associated with systemic hypersensitivity, a short latency to onset, African American race and 3 HLA risk alleles, HLA-B*58:01, HLA-B*53:01 and HLA-A*34:02. HLA- 58:01 testing may help confirm a diagnosis of hepatotoxicity in allopurinol treated patients. This article is protected by copyright. All rights reserved.
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Keywords:
Hyperuricemia; genetic polymorphisms; gout; human leukocyte antigen; liver injury