Yang Hongyi, Guo Daihong, Xu Yuanjie, Zhu Man, Yao Chong, Chen Chao, Jia Wangping
Department of Pharmaceutical Care, Chinese People's Liberation Army General Hospital, Beijing, China.
Front Pharmacol. 2019 Jul 19;10:816. doi: 10.3389/fphar.2019.00816. eCollection 2019.
According to the updated Roussel Uclaf Causality Assessment Method (RUCAM), drug-induced liver injury (DILI) is currently defined based on thresholds of alanine aminotransferase (ALT) levels above 5 × the upper limit of normal (ULN) and/or alkaline phosphatase (ALP) levels greater than 2 × the ULN. However, many parameters with different thresholds are also currently used in the clinic. We therefore performed a comparative analysis to evaluate which set of criteria was the most appropriate to detect DILI. We enrolled hospitalized patients who received fluoroquinolones to treat or prevent infections. Three liver test criteria were used to diagnose DILI in these patients. RUCAM criteria were defined as the gold standard, and the other two criteria were as follows: 1) ALT or aspartate aminotransferase (AST) levels greater than 5 × the ULN on two consecutive occasions and/or ALP levels greater than 2 × the ULN on two consecutive occasions [issued by DILI Network (DILIN)]; 2) ALT levels greater than 1 × the ULN on two consecutive occasions or ALT levels greater than 2 × the ULN [issued by the National Medical Products Administration (NMPA) of China]. We found that the RUCAM criteria resulted in 657 warnings, DILIN criteria resulted in 358, NMPA criteria resulted in 1,377, and the positive predictive value (PPV) were 9.74%, 10.89%, and 9.73% ( = 0.80), respectively. The levels of agreement of the DILIN and NMPA criteria with the RUCAM criteria were moderate, but the agreement between the DILIN criteria and NMPA criteria was poor. In conclusion, the NMPA criteria with relatively lax thresholds for the parameters require much more labor to determine the diagnosis, making them unsuitable for clinical practice. Conversely, the DILIN criteria employing stricter thresholds for the parameters were more effective but would miss some positive cases, and the cases it identified were usually quite serious, which is not conductive to early intervention. Therefore, we still recommend the use of the RUCAM criteria in clinical practice.
根据更新后的鲁塞尔·优克福因果关系评估方法（RUCAM），目前药物性肝损伤（DILI）是根据丙氨酸氨基转移酶（ALT）水平高于正常上限（ULN）的5倍和/或碱性磷酸酶（ALP）水平高于ULN的2倍来定义的。然而，目前临床中也使用许多具有不同阈值的参数。因此，我们进行了一项比较分析，以评估哪一套标准最适合检测DILI。我们纳入了接受氟喹诺酮类药物治疗或预防感染的住院患者。使用三种肝脏检测标准对这些患者进行DILI诊断。将RUCAM标准定义为金标准，另外两种标准如下：1）连续两次ALT或天冬氨酸氨基转移酶（AST）水平高于ULN的5倍和/或连续两次ALP水平高于ULN的2倍[由药物性肝损伤网络（DILIN）发布]；2）连续两次ALT水平高于ULN的1倍或ALT水平高于ULN的2倍[由中国国家药品监督管理局（NMPA）发布]。我们发现，RUCAM标准产生了657次警告，DILIN标准产生了358次，NMPA标准产生了1377次，阳性预测值（PPV）分别为9.74%、10.89%和9.73%（ = 0.80）。DILIN标准和NMPA标准与RUCAM标准的一致性水平为中等，但DILIN标准和NMPA标准之间的一致性较差。总之，NMPA标准对参数的阈值相对宽松，确定诊断需要更多的工作量，因此不适合临床实践。相反，DILIN标准对参数采用更严格的阈值更有效，但会遗漏一些阳性病例，并且它识别出的病例通常相当严重，不利于早期干预。因此，我们仍然建议在临床实践中使用RUCAM标准。
