Comparison of Different Liver Test Thresholds for Drug-Induced Liver Injury: Updated RUCAM versus Other Methods.

Hongyi Yang,Chao Chen,Man Zhu,Daihong Guo,Chong Yao,Wangping Jia,Yuanjie Xu

doi:10.3389/fphar.2019.00816

Abstract

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% (P = 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.

Highlights

Drug-induced liver injury (DILI) is a frequent adverse drug reaction (ADR) that may present multiple clinical manifestations and is one of the most frequent reasons for drug nonapproval or withdrawal from market, as it leads to acute liver failure and even death (Iorga et al, 2017; Donato and Tolosa, 2019; Shen et al, 2019)
We mainly aimed to obtain the incidence, clinical features, and to find out the risk factors of fluoroquinolone-induced liver injury, and we found out that many sets of criteria for diagnosis of DILI were used in various researches, and it makes sense to compare the differences among them
We identified 17,822 patients who received fluoroquinolones to prevent or treat infections, 4,144 of whom were excluded due to abnormal or a lack of baseline laboratory data or were diagnosed with liver injury or liver failure before treatment, and 13,678 patients were eventually enrolled

Summary

Introduction

Drug-induced liver injury (DILI) is a frequent adverse drug reaction (ADR) that may present multiple clinical manifestations and is one of the most frequent reasons for drug nonapproval or withdrawal from market, as it leads to acute liver failure and even death (Iorga et al, 2017; Donato and Tolosa, 2019; Shen et al, 2019). Patients may not be provided the appropriate specific therapies in a timely manner (Teschke et al, 2013; Teschke et al, 2014). These problems have prompted the development of a new causality assessment method that is widely known as the Roussel Uclaf Causality Assessment Method (RUCAM) (Danan and Teschke, 2016). Based on data from the Adverse Drug Events Active Surveillance and Assessment System (ADE-ASAS) developed by the People’s Liberation Army ADR Monitoring Center, we compared different liver test criteria in the same population to determine which one is the most appropriate and to encourage health care providers to closely monitor this ADR

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