Development and Validation of a Test to Identify Drugs That Cause Idiosyncratic Drug-Induced Liver Injury.

BACKGROUND & AIMS: Idiosyncratic drug-induced liver injury (iDILI) is one of the most challenging diagnoses in hepatology. It is frequently impossible to identify the agent that has caused iDILI in patients who take multiple medicines. We developed an in vitro method to identify drugs that cause liver injury in patients, based on drug toxicity to monocyte-derived hepatocyte-like (MH) cells from patient blood samples. We then collected data on patients who were re-exposed to drugs found to be toxic in the MH test to validate test performance. METHODS: We performed a prospective study of patients referred to the University Hospital in Munich, Germany, with acute liver injury believed to be caused by medications (300 patients were enrolled in the study and we present data from 40 patients with iDILI and re-exposure to implicated drugs). We collected data from patients on medical history, laboratory test and imaging results, findings from biopsy analyses, and medications taken. Blood samples were collected from all patients and MH cells were isolated and cultured for 10 days. MH cells were then incubated with drugs to which each patient had been exposed, and toxicity was measured based on release of lactate dehydrogenase. Agents found to be toxic to MH cells were considered as candidates for the cause of liver injury. Patients were followed up for up to 6 months after liver injury and data on drug re-exposures and subsequent liver damage within the following 3 to 24 months were associated with findings from MH tests. RESULTS: Our test identified 10 drugs that were toxic to MH cells from 13 patients (amoxicillin/clavulanate to cells from 2 patients; diclofenac to cells from 2 patients; methylprednisolone to cells from 2 patients; and atorvastatin, metamizole, pembrolizumab, piperacillin/tazobactam, moxifloxacin, duloxetine, or sertraline each to cells from 1 patient). Thirteen patients had a recurrence of liver injury after inadvertent re-exposure to a single drug, and the MH test correctly identified 12 of the 13 drugs that caused these liver re-injury events. All 86 drugs that were not toxic to MH cells in our assay were safely resumed by patients and were not associated with liver re-injury in 27 patients. Therefore, the MH test identifies drugs that cause liver injury with 92.3% sensitivity and 100% specificity (1 false-negative and 12 true-positive results). CONCLUSIONS: We developed a test to identify drugs that cause liver injury in patients based on their toxicity to MH cells isolated from patients with DILI. We validated results from the assay and found it to identify drugs that cause DILI with 92.3% sensitivity and 100% specificity. The MH cell test could be a tool to identify causes of iDILI, even in patients taking multiple medications. ClinicalTrials.gov no: NCT 02353455.

Monocyte-derived hepatocyte-like cells for causality assessment of idiosyncratic drug-induced liver injury.

BACKGROUND: Idiosyncratic drug-induced liver injury (iDILI) is a frequent cause of acute liver injury and a serious problem in late stage drug-development. Its diagnosis is one of the most challenging in hepatology, since it is done by exclusion and relies on expert opinion. Until now no reliable in vitro test exists to support the diagnosis of iDILI. In some instances it is impossible to determine the causative drug in polymedicated patients. AIM: To investigate if monocyte-derived hepatocyte-like (MH) cells might be a tool supporting clinical judgment for iDILI diagnosis and causality assessment. METHODS: This prospective study included 54 patients with acute liver injury and intake of at least one drug. Thirty-one patients were diagnosed with iDILI based on causality likelihood. MH cells were generated from every patient and in vitro toxicity of the respective drugs was assessed by lactate-dehydrogenase release. The results from MH cells and RUCAM, the most widely used scoring system as methods to support clinical judgement were compared. RESULTS: MH cells showed enhanced toxicity in 29 of the 31 patients with iDILI, similar to RUCAM score. MH cells exhibited negative results in the 23 non-DILI cases, whereas RUCAM indicated possible iDILI in six cases. Analysis of the comedications also showed superior specificity of MH cells. No MH cell toxicity of the drugs showing toxicity in patients with iDILI was observed in MH cells of healthy donors. CONCLUSIONS: In this pilot study in vitro testing using MH cells derived from patients with acute liver injury was able to identify patients with iDILI with an excellent sensitivity and a higher specificity than RUCAM, the most widely used current causality assessment score. Therefore, MH cells could be useful to identify the causative drugs even in polymedicated patients by adding objective data to causality assessment. TRIAL REGISTRATION NUMBER: NCT02353455.