Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, D-63450 Hanau, Germany.
Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt/Main, D-60590 Frankfurt am Main, Germany.
Int J Mol Sci. 2023 Apr 3;24(7):6663. doi: 10.3390/ijms24076663.
Drug induced liver injury (DILI) occurs in patients exposed to drugs at recommended doses that leads to idiosyncratic DILI and provides an excellent human model with well described clinical features, liver injury pattern, and diagnostic criteria, based on patients assessed for causality using RUCAM (Roussel Uclaf Causality Assessment Method) as original method of 1993 or its update of 2016. Overall, 81,856 RUCAM based DILI cases have been published until mid of 2020, allowing now for an analysis of mechanistic issues of the disease. From selected DILI cases with verified diagnosis by using RUCAM, direct evidence was provided for the involvement of the innate and adapted immune system as well as genetic HLA (Human Leucocyte Antigen) genotypes. Direct evidence for a role of hepatic immune systems was substantiated by (1) the detection of anti-CYP (Cytochrome P450) isoforms in the plasma of affected patients, in line with the observation that 65% of the drugs most implicated in DILI are metabolized by a range of CYP isoforms, (2) the DIAIH (drug induced autoimmune hepatitis), a subgroup of idiosyncratic DILI, which is characterized by high RUCAM causality gradings and the detection of plasma antibodies such as positive serum anti-nuclear antibodies (ANA) and anti-smooth muscle antibodies (ASMA), rarely also anti-mitochondrial antibodies (AMA), (3) the effective treatment with glucocorticoids in part of an unselected RUCAM based DILI group, and (4) its rare association with the immune-triggered Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) caused by a small group of drugs. Direct evidence of a genetic basis of idiosyncratic DILI was shown by the association of several HLA genotypes for DILI caused by selected drugs. Finally, animal models of idiosyncratic DILI mimicking human immune and genetic features are not available and further search likely will be unsuccessful. In essence and based on cases of DILI with verified diagnosis using RUCAM for causality evaluation, there is now substantial direct evidence that immune mechanisms and genetics can account for idiosyncratic DILI by many but not all implicated drugs, which may help understand the mechanistic background of the disease and contribute to new approaches of therapy and prevention.
药物性肝损伤（DILI）发生于在推荐剂量下暴露于药物的患者中，导致特发性 DILI，并提供了一个极好的人类模型，具有良好描述的临床特征、肝损伤模式和诊断标准，这些标准基于使用 RUCAM（Roussel Uclaf Causality Assessment Method）对因果关系进行评估的患者，RUCAM 最初方法是 1993 年的方法，或其 2016 年的更新方法。总体而言，截至 2020 年年中，已经发表了 81856 例基于 RUCAM 的 DILI 病例，现在可以对该疾病的机制问题进行分析。从使用 RUCAM 验证诊断的选定 DILI 病例中，直接证据表明固有和适应性免疫系统以及遗传 HLA（人类白细胞抗原）基因型的参与。通过以下方式证实了肝免疫系统的作用：（1）在受影响患者的血浆中检测到抗 CYP（细胞色素 P450）同工型，这与观察到的 65%最易导致 DILI 的药物是由一系列 CYP 同工型代谢一致，（2）DIAIH（药物诱导的自身免疫性肝炎），特发性 DILI 的一个亚组，其特征是 RUCAM 因果关系评分高，并检测到血浆抗体，如阳性血清抗核抗体（ANA）和抗平滑肌抗体（ASMA），很少也检测到抗线粒体抗体（AMA），（3）部分未选择的基于 RUCAM 的 DILI 组用糖皮质激素有效治疗，以及（4）与免疫触发的史蒂文斯-约翰逊综合征（SJS）和中毒性表皮坏死松解症（TEN）罕见相关，由一小部分药物引起。通过与选定药物引起的 DILI 相关的几种 HLA 基因型的关联，显示了特发性 DILI 的遗传基础的直接证据。最后，模仿人类免疫和遗传特征的特发性 DILI 动物模型尚不可用，进一步的搜索可能不会成功。从本质上讲，基于使用 RUCAM 进行因果关系评估来诊断 DILI 的病例，现在有大量的直接证据表明，免疫机制和遗传学可以解释许多但不是所有涉及的药物引起的特发性 DILI，这有助于了解疾病的机制背景，并有助于治疗和预防的新方法。
