Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt/Main, Leimenstrasse 20, D-63450 Hanau, Germany.
Pharmacovigilance Consultancy, Rue des Ormeaux, 75020 Paris, France.
Int J Mol Sci. 2023 Jun 29;24(13):10855. doi: 10.3390/ijms241310855.
Clinical and mechanistic considerations in idiosyncratic drug-induced liver injury (iDILI) remain challenging topics when they are derived from mere case narratives or iDILI cases without valid diagnosis. To overcome these issues, attempts should be made on pathogenetic aspects based on published clinical iDILI cases firmly diagnosed by the original RUCAM (Roussel Uclaf Causality Assessment Method) or the RUCAM version updated in 2016. Analysis of RUCAM-based iDILI cases allowed for evaluating immune and genetic data obtained from the serum and the liver of affected patients. For instance, strong evidence for immune reactions in the liver of patients with RUCAM-based iDILI was provided by the detection of serum anti-CYP 2E1 due to drugs like volatile anesthetics sevoflurane and desflurane, partially associated with the formation of trifluoroacetyl (TFA) halide as toxic intermediates that form protein adducts and may generate reactive oxygen species (ROS). This is accompanied by production of anti-TFA antibodies detected in the serum of these patients. Other RUCAM-based studies on serum ANA (anti-nuclear antibodies) and SMA (anti-smooth muscle antibodies) associated with AIDILI (autoimmune DILI) syn DIAIH (drug-induced autoimmune hepatitis) provide additional evidence of immunological reactions with monocytes as one of several promoting immune cells. In addition, in the blood plasma of patients, mediators like the cytokines IL-22, IL-22 binding protein (IL-22BP), IL-6, IL-10, IL 12p70, IL-17A, IL-23, IP-10, or chemokines such as CD206 and sCD163 were found in DILI due to anti-tuberculosis drugs as ascertained by the prospective updated RUCAM, which scored a high causality. RUCAM-based analysis also provided compelling evidence of genetic factors such as HLA (human leucocyte antigen) alleles contributing to initiate iDILI by a few drugs. In conclusion, analysis of published RUCAM-based iDILI cases provided firm evidence of immune and genetic processes involved in iDILI caused by specific drugs.
当涉及到仅仅是个案叙述或未经有效诊断的 iDILI 病例时，特发性药物性肝损伤 (iDILI) 的临床和机制考虑仍然是具有挑战性的话题。为了克服这些问题，应该基于已发表的临床 iDILI 病例，尝试从发病机制方面进行研究，这些病例是通过原始的 Roussel Uclaf Causality Assessment Method (RUCAM) 或 2016 年更新的 RUCAM 版本明确诊断的。基于 RUCAM 的 iDILI 病例分析可用于评估从受影响患者的血清和肝脏中获得的免疫和遗传数据。例如，通过检测基于 RUCAM 的 iDILI 患者血清中的药物引起的 CYP2E1 抗体，提供了有力证据表明肝脏中存在免疫反应，这些药物如挥发性麻醉剂七氟烷和地氟烷，部分与形成三氟乙酰基 (TFA) 卤化物有关，后者是有毒的中间产物，可形成蛋白质加合物，并可能产生活性氧 (ROS)。这伴随着在这些患者的血清中检测到抗 TFA 抗体。其他基于 RUCAM 的研究涉及与 AIDILI（自身免疫性 DILI）和 DIAIH（药物诱导的自身免疫性肝炎）相关的血清抗核抗体 (ANA) 和抗平滑肌抗体 (SMA)，为免疫反应提供了额外的证据，其中单核细胞是促进免疫细胞之一。此外，在患者的血浆中，细胞因子如白细胞介素 22 (IL-22)、白细胞介素 22 结合蛋白 (IL-22BP)、白细胞介素 6 (IL-6)、白细胞介素 10 (IL-10)、白细胞介素 12p70 (IL-12p70)、白细胞介素 17A (IL-17A)、白细胞介素 23 (IL-23)、干扰素诱导蛋白 10 (IP-10) 或趋化因子如 CD206 和 sCD163 等介质，在由抗结核药物引起的 DILI 中被发现，这是通过前瞻性更新的 RUCAM 确定的，该方法的因果关系评分很高。基于 RUCAM 的分析还提供了令人信服的证据，证明遗传因素如人类白细胞抗原 (HLA) 等位基因参与了少数药物引起的 iDILI 的发生。总之，对已发表的基于 RUCAM 的 iDILI 病例的分析提供了明确的证据，证明了特定药物引起的 iDILI 中涉及的免疫和遗传过程。
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