Utility of Lymphocyte Transformation Test for Assisting Updated Roussel Uclaf Causality Assessment Method in Drug-Induced Liver Injury: A Case-Control Study

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.

Treatment of Drug-Induced Liver Injury

“…The top drugs causing RUCAM-based DILI worldwide have been assessed as to whether they were metabolized through CYP isoforms [62]. Literature provided highquality data on clinical features of DILI [1][2][3][4][5][6][7][8][9][10][16][17][18][19][20][21][22][23][24][25][26][27][28]39,64]. However, although most of the clinical features are well established, a variety of mechanistic steps remain unresolved in this complex disease.…”

“…Drug-induced liver injury (DILI) remains an important concern among scientists, physicians, regulators, and experts in the field, with a focus on general aspects [1][2][3][4][5][6] or more specifically on drugs such as multiple antidepressants [7], teriflunomide [8], tigecyc-line [9], or potassium para-aminobenzoate [10]. The last three decades have witnessed substantial efforts on the question of how best to ensure the diagnosis of DILI in patients with abnormal liver tests (LTs) under treatment with drugs.…”

Allergic Clinical Symptoms and Distribution of Stimulation Index of Drug Lymphocyte Stimulation Test for Local Anesthetics

“…Effectively employing DLST necessitates the meticulous determination of the cut-off Stimulation Index (SI). For diagnosing drug-induced liver injury, an optimized cut-off SI of 195% has been established, rendering DLST a reported utility [11,12]. Notably, in the context of sulfonamide allergy, DLST demonstrated usefulness by identifying 25 out of 34 cases when the cut-off SI was set at 220% [13].…”

Immune-Mediated Organ-Specific Reactions to COVID-19 Vaccines: A Retrospective Descriptive Study

“…However, they have low (not higher than 37.5%) specificity and negative predictive values [ 31 ]. Together with algorithms, the LTT constitutes a useful tool for assisting in the diagnosis of adverse drug reactions [ 34 ].…”

“…LTT was performed after event recovery and at least 1 month after steroid therapy was stopped, if applicable. Lymphocyte proliferation was measured as previously described [ 34 , 48 ]. Mononuclear cells were separated over a density gradient (Histopaque–1077, Sigma-Aldrich, Madrid, Spain) from fresh peripheral blood and were plated in flat bottom wells of microtiter plates at 2 × 10 5 cells/well.…”