A case report of a drug‐induced liver injury (DILI) caused by multiple antidepressants with causality established by the updated Roussel Uclaf causality assessment method (RUCAM) and in vitro testing

González‐Muñoz, Miguel; Villatoro, Jaime Monserrat; Marín-Serrano, Eva; Stewart, Stefan; Rivera, Belén Bardón; Marı́n, Jesús; Soto, Lucía Martínez de; Meseguer, Enrique Seco; Ramírez, Elena

doi:10.1002/ccr3.3348

Cited by 10 publications

(17 citation statements)

References 20 publications

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“…The analysis of infiltrates in liver biopsy samples from patients with DILI ( Wuillemin et al, 2014 ) and the generation of drug-specific T-cell clones from patients with DILI indicate that T cells participate actively in liver injuries ( Kim et al, 2015 ). Consequently, the LTT, which measures the specific drug T-cell response, has been employed to support the DILI diagnosis ( Rotmensch et al, 1981 ; Takikawa et al, 2003 ; Pichler and Tilch, 2004 ; Kim et al, 2015 ; Whritenour et al, 2017 ; González‐Muñoz et al, 2020 ). The limitations of this test include the fact that the diagnostic performance depends on the clinical entity and drug involved in the adverse reaction and the lack of standardisation that contribute to the high variability between published studies regarding their accuracy ( Mayorga et al, 2016 ; Mayorga et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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“…In some cases, a lymphocyte transformation test (LTT) was performed with the suspected drugs, as previously described [ 13 ]. The test was considered positive if the stimulation index defined as the ratio between the mean value of counts per minute in cultures with the drug and those obtained without the drug was ≥2.…”

Section: Methodsmentioning

confidence: 99%

Characterisation of Drug-Induced Liver Injury in Patients with COVID-19 Detected by a Proactive Pharmacovigilance Program from Laboratory Signals

Delgado

Stewart

Urroz

et al. 2021

JCM

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Coronavirus disease 2019 (COVID-19) has a wide spectrum of clinical manifestations. An elevation of liver damage markers has been observed in numerous cases, which could be related to the empirical use of potentially hepatotoxic drugs. The aim of this study was to describe the clinical and analytical characteristics and perform a causality analysis from laboratory signals available of drug-induced liver injury (DILI) detected by a proactive pharmacovigilance program in patients hospitalised for COVID-19 at La Paz University Hospital in Madrid (Spain) from 1 March 2020 to 31 December 2020. The updated Roussel Uclaf Causality Assessment Method (RUCAM) was employed to assess DILI causality. A lymphocyte transformation test (LTT) was performed on 10 patients. Ultimately, 160 patients were included. The incidence of DILI (alanine aminotransferase >5, upper limit of normal) was 4.9%; of these, 60% had previous COVID-19 hepatitis, the stay was 8.1 days longer and 98.1% were being treated with more than 5 drugs. The most frequent mechanism was hepatocellular (57.5%), with mild severity (87.5%) and subsequent recovery (88.1%). The most commonly associated drugs were hydroxychloroquine, azithromycin, tocilizumab and ceftriaxone. The highest incidence rate of DILI per 10,000 defined daily doses (DDD) was with remdesivir (992.7/10,000 DDD). Some 80% of the LTTs performed were positive, with a RUCAM score of ≥4. The presence of DILI after COVID-19 was associated with longer hospital stays. An immune mechanism has been demonstrated in a small subset of DILI cases.

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“…Atypical or second-generation antipsychotics (SGAs), including aripiprazole (ARI) and olanzapine (OLA), are drugs of choice for schizophrenia treatment and are effective against delusions, hallucinations, and extrapyramidal adverse events [ 1 ]. SGAs also cause adverse metabolic side effects [ 2 ], among them drug-induced liver injury (DILI) [ 3 ]. DILI associated with antidepressant use is mostly hepatocellular, while the etiology is metabolic or immuno-allergic [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

“…SGAs also cause adverse metabolic side effects [ 2 ], among them drug-induced liver injury (DILI) [ 3 ]. DILI associated with antidepressant use is mostly hepatocellular, while the etiology is metabolic or immuno-allergic [ 3 ]. The Roussel Uclaf Causality Assessment Method (RUCAM) is a clinical scoring method reflecting the likelihood of hepatic injury due to a specific medication [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

“…Reports of RUCAM scores of SGAs are scarce; an RUCAM score of 7, indicating a probable cause of DILI, was recently reported for OLA [ 5 ]. Patients with schizophrenia and depression disorders are often treated with several antipsychotics successively or even at the same time [ 3 , 6 ]. This can hinder the unequivocal involvement of a particular drug in eliciting DILI.…”

Section: Introductionmentioning

confidence: 99%

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Antipsychotic Drug Aripiprazole Protects Liver Cells from Oxidative Stress

Kramar

Marolt

Monsalve

et al. 2022

IJMS

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Antipsychotics used to treat schizophrenia can cause drug-induced liver injury (DILI), according to the Roussel Uclaf Causality Assessment Method. The role of oxidative stress in triggering injury in these DILI cases is unknown. We repeatedly administrated two second-generation antipsychotics, aripiprazole and olanzapine, at laboratory alert levels to study underlying mechanisms in stress prevention upon acute oxidative stress. The drugs were administered continuously for up to 8 weeks. For this, hepatoma Fao cells, which are suitable for metabolic studies, were used, as the primary hepatocytes survive in the culture only for about 1 week. Four stress responses—the oxidative stress response, the DNA damage response and the unfolded protein responses in the endoplasmic reticulum and mitochondria—were examined in H2O2-treated cells by antioxidant enzyme activity measurements, gene expression and protein quantification. Oxidant conditions increased the activity of antioxidant enzymes and upregulated genes and proteins associated with oxidative stress response in aripiprazole-treated cells. While the genes associated with DNA damage response, Gadd45 and p21, were upregulated in both aripiprazole- and olanzapine-treated cells, only aripiprazole treatment was associated with upregulation in response to even more H2O2, which also coincided with better survival. Endoplasmic reticulum stress-induced Chop was also upregulated; however, neither endoplasmic reticulum nor mitochondrial unfolded protein response was activated. We conclude that only aripiprazole, but not olanzapine, protects liver cells against oxidative stress. This finding could be relevant for schizophrenia patients with high-oxidative-stress-risk lifestyles and needs to be validated in vivo.

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A case report of a drug‐induced liver injury (DILI) caused by multiple antidepressants with causality established by the updated Roussel Uclaf causality assessment method (RUCAM) and in vitro testing

Cited by 10 publications

References 20 publications

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

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

Characterisation of Drug-Induced Liver Injury in Patients with COVID-19 Detected by a Proactive Pharmacovigilance Program from Laboratory Signals

Antipsychotic Drug Aripiprazole Protects Liver Cells from Oxidative Stress

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