Beyond Hy's Law: Importance of Markedly Elevated Aminotransferases without Hyperbilirubinemia

Elevated aminotransferases with concomitant jaundice in drug-induced liver injury (DILI) are associated with adverse outcomes, but the prognostic significance of very high aminotransferases without jaundice is unclear. We examined selected outcomes of patients with DILI and markedly elevated aminotransferases but normal or near-normal total bilirubin (TBL). We analyzed the data from the prospective Drug-Induced Liver Injury Network (DILIN) and the Spanish DILI registries. Patients were categorized based on peak alanine or aspartate aminotransferase (ALT/AST) levels-very high (500-1,000 U/L) or towering (>1,000 U/L)-and concomitant normal (≤1.0 mg/dL) or near-normal (1.1-2.5 mg/dL) TBL levels. Primary outcome was subsequent development of nR-based Hy's Law (nR ≥5 with TBL >2.5 mg/dL). A total of 964 patients were analyzed (692 DILIN; 272 Spanish DILI). In both cohorts, very high aminotransferases with normal TBL were rarely followed by nR-based Hy's Law. In DILIN, only 1.3% of patients with very high ALT and normal TBL developed nR-based Hy's Law, whereas risk increased markedly with minimally elevated TBL (odds ratio (OR) 7.8). Towering aminotransferases conferred increased risk regardless of TBL, with the highest risk observed when accompanied by minimally elevated TBL (OR 23.6). Similar inflection points were observed in the Spanish DILI Registry, in patients with very high aminotransferases and minimally elevated TBL or towering aminotransferases with or without elevated TBL. In conclusion, patients with DILI and very high aminotransferases may tolerate liver injury well when bilirubin is normal, but even minimal bilirubin elevation or towering aminotransferases signal increased risk for poor outcomes.