Abstract
Background: The Roussel Uclaf Causality Assessment Method (RUCAM) is a validated tool for assessing causality in cases of suspected drug-induced liver injury (DILI). However, RUCAM cannot discriminate between concomitant hepatotoxic drugs with the same temporal sequence. Objective: To analyse the utility of the lymphocyte transformation test (LTT) for assisting updated RUCAM in 45 patients and 40 controls with a clinical diagnosis of DILI. Methods: Suspected DILI cases were detected through the Prospective Pharmacovigilance Program from Laboratory Signals in Hospital (PPLSH) or by consultations. The controls completed the drug therapy with no adverse reactions during the study period. A receiver operating characteristics (ROC) curve analysis was performed to calculate the optimal cut-off value for the stimulation index (SI), corresponding to the largest sum for the specificity and sensitivity values of LTT for true DILI cases. Results: Out of 45 patients diagnosed with DILI, 42 cases were detected by the PPLSH, two cases by consultation and one case by both methods. Most DILI cases (64.4%) arose during hospitalization. According to the biochemical parameters, 24 cases (53.3%) had the hepatocellular phenotype, 14 (31.1%) had the cholestatic phenotype, and 7 cases (15.6%) had the mixed phenotype. Considering the severity criteria, 7 (15.5%) cases were classified as moderate DILI, and 4 (8.9%) were severe DILI; there were no fatal cases. A total of 149 drugs (median/case, 3; IQR, 2–5) were suspected to be involved in the DILI cases (RUCAM score ≥3). In 8 cases, only one drug was suspected, and polypharmacy (≥5 drugs) was identified in 29% of the cases. Of all DILI cases, 46 (30.9%) of the 149 suspected drugs produced positive LTT results, and the LTT was positive in 34 (75.5%) of the 45 patients. No exposed controls produced positive LTT results. The optimal cut-off of 1.95 for the SI was obtained with a sensitivity of 77% and specificity of 100% (area under the curve, 0.91; 95% asymptotic confidence interval 0.84–0.97; p < 0.001). The sensitivity of the hepatocellular phenotype was 92%. Conclusion: Our results demonstrate that LTT is an add on strengthening causality in cases of suspected idiosyncratic DILI, especially for patients with several suspected drugs and a hepatocellular phenotype.
Highlights
Drug-induced liver injury (DILI) is an uncommon but potentially lethal adverse drug reaction, with an annual incidence ranging from 2.4 to 23.8 per 100,000 patients
For all patients initially categorised as having suspected DILI, a complete report was submitted to the pharmacovigilance centre in Madrid, Spain
Out of 45 patients diagnosed with DILI, 42 cases were detected by the Pharmacovigilance Program from Laboratory Signals in Hospital (PPLSH), two cases by consultation and one case by both methods
Summary
Drug-induced liver injury (DILI) is an uncommon but potentially lethal adverse drug reaction, with an annual incidence ranging from 2.4 to 23.8 per 100,000 patients. The diagnosis of DILI is complicated when it is a doseindependent or idiosyncratic adverse reaction (Andrade et al, 2019), especially when the patient has been exposed to more than one drug (García-Cortés et al, 2011; Weber et al, 2021). The diagnosis is based on ruling out other potential causes for the liver disorders and on applying causality algorithms to the suspected drugs when patients have been exposed to several drugs. The Roussel Uclaf Causality Assessment Method (RUCAM) is a validated tool for assessing causality in cases of suspected drug-induced liver injury (DILI). RUCAM cannot discriminate between concomitant hepatotoxic drugs with the same temporal sequence
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