Supplementary Material for: LKM immunofluorescence is associated with DILI, especially after metamizole intake

Background & Aims: Drug induced liver injury (DILI) is a rare but potentially serious clinical condition. One phenotype of DILI is termed drug-induced autoimmune like hepatitis (DI-ALH) that presents with laboratory and histological features indistinguishable from autoimmune hepatitis. Liver kidney microsomal antibodies (LKM-antibodies) are common in the diagnosis of AIH but were also described to be associated with halothane-induced DILI. Also, the antigens of anti-LKM-1 and anti-LKM-2 belong to the cytochrome P450 enzyme family that is involved in metabolism various drugs. Therefore, we aimed to study the impact of LKM-antibodies in the diagnostic work-up of suspected DILI in a large cohort of patients with liver injury in a tertiary care centre. Methods: We screened a large single centre hospital data base and retrospectively identified 63.300 cases with liver injury as defined: AST or ALT > 3 ULN or AP or TBI > 2 ULN. Of those, 82 cases with LKM immunofluorescence positivity (titre ≥ 1: 160) were identified, of which 64 patients fulfilled the inclusion criteria for this study. Results: Positive LKM immunofluorescence was associated with drug-induced autoimmune-like hepatitis (DI-ALH). Metamizole association was identified in half of the patients (n=33, 52%). Eight patients with metamizole associated DI-ALHs required liver transplantation and one patient died. Conclusion: DI-ALH, especially after metamizole administration, can be a reason for a positivity in LKM immunofluorescence tests. Metamizole DI-ALH has a high liver-related mortality.背景与目的：药物性肝损伤（Drug Induced Liver Injury, DILI）是一类罕见但具有潜在致死风险的临床病症。其一种表型被称为药物诱导的自身免疫样肝炎（Drug-induced Autoimmune-like Hepatitis, DI-ALH），该病症的实验室检测与组织病理学特征与自身免疫性肝炎（Autoimmune Hepatitis, AIH）无法区分。肝肾微粒体抗体（Liver Kidney Microsomal Antibodies, LKM-antibodies）是AIH诊断中的常见标志物，但也有研究报道其与氟烷诱导的DILI存在关联。此外，抗LKM-1与抗LKM-2的靶抗原均属于参与多种药物代谢的细胞色素P450酶家族。因此，本研究旨在某三级医疗中心的大规模肝损伤患者队列中，探讨LKM抗体在疑似DILI的诊断评估中的作用。方法：我们检索了一家大型单中心医院的数据库，回顾性筛选出63300例符合下述肝损伤定义的病例：天门冬氨酸氨基转移酶（Aspartate Aminotransferase, AST）或丙氨酸氨基转移酶（Alanine Aminotransferase, ALT）大于3倍正常上限（Upper Limit of Normal, ULN），或碱性磷酸酶（Alkaline Phosphatase, AP）或总胆红素（Total Bilirubin, TBI）大于2倍正常上限（ULN）。在此类病例中，共筛选出82例LKM免疫荧光检测呈阳性（滴度≥1:160）的患者，其中64例符合本研究的纳入标准。结果：LKM免疫荧光阳性与药物诱导的自身免疫样肝炎（DI-ALH）显著相关。近半数患者（n=33，占比52%）的发病与安乃近相关。其中8例安乃近相关DI-ALH患者需接受肝移植，1例患者死亡。结论：DI-ALH，尤其是安乃近给药后诱发的DI-ALH，可导致LKM免疫荧光检测呈阳性。安乃近相关DI-ALH的肝相关死亡率较高。