BACKGROUND Hyman Zimmerman observed that hepatocellular (HC) drug-induced liver injury (DILI) with jaundice had a mortality rate of ≥10% (Hy's Law). Hy's Law does not specify the timing of liver tests nor the definition of HC DILI versus cholestatic or mixed (C/M) DILI. We aimed to assess the validity of Hy's Law in the prospective Drug-Induced Liver Injury Network (DILIN) cohort. METHODS Drugs with ≥10 confirmed DILI cases with jaundice were analyzed. Four permutations of Hy's Law were applied: R≥ 5 using initial (1) or peak (2) ALT, AST and Alk P levels, and the FDA associated criteria of ALT or AST ≥ 3x ULN with Alk P ≤ 2x ULN using initial (3) or peak values (4). Mortality was death or liver transplant adjudicated to be due to DILI. RESULTS Using initial R values, mortality was 11.1% for HC vs 2.0% for C/M (p<0.001); using peak R values, mortality was 10.3% vs 1.6% (p<0.001). Using FDA associated definition, mortality was 7.9% vs 3.9% (p=0.04) using initial values and 7.9% vs 3.0% (p=0.01) using peak values. Using initial R values, drugs that frequently caused HC injury generally had mortality rates ≥ 10%; while drugs that typically caused C/M injury all had rates <10%. Occasional agents that caused HC injury with jaundice were associated with low mortality. CONCLUSIONS Initial R values were the most reliable means of identifying Hy's Law cases. There were some drugs that caused HC injury with jaundice but with mortality rates <10%. Refinement of Hy's Law is warranted.

中文翻译：

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使用药物诱导肝损伤网络数据库改进 Hy 定律。


背景 Hyman Zimmerman 观察到肝细胞 （HC） 药物诱导的肝损伤 （DILI） 伴黄疸的死亡率为 ≥10% （Hy's Law）。Hy 定律没有具体说明肝脏检查的时间，也没有规定 HC DILI 与胆汁淤积或混合 （C/M） DILI 的定义。我们旨在评估 Hy 定律在前瞻性药物诱导肝损伤网络 （DILIN） 队列中的有效性。方法 分析 ≥10 例确诊 DILI 黄疸病例的药物。应用了 Hy 定律的四种排列：R≥ 5 使用初始 （1） 或峰值 （2） ALT、AST 和 Alk P 水平，以及 FDA 的 ALT 或 AST ≥ 3x ULN 与 Alk P ≤ 2x ULN 使用初始 （3） 或峰值 （4）。死亡率是死亡或肝移植被判定为 DILI 所致。结果 使用初始 R 值，HC 的死亡率为 11.1%，C/M 为 2.0% （p<0.001）;使用峰值 R 值，死亡率为 10.3% 和 1.6% （p<0.001）。使用 FDA 相关定义，使用初始值的死亡率为 7.9% vs 3.9% （p=0.04），使用峰值的死亡率为 7.9% vs 3.0% （p=0.01）。使用初始 R 值，经常导致 HC 损伤的药物的死亡率通常≥ 10%;而通常导致 C/M 损伤的药物的发生率均为 <10%。偶尔导致 HC 损伤伴黄疸的药物与低死亡率相关。结论 初始 R 值是识别 Hy 定律案例的最可靠方法。有一些药物导致 HC 损伤伴有黄疸，但死亡率为 <10%。对 Hy 定律的改进是有道理的。