Drug-induced liver injury causality assessment data from a crosssectional study in Brazil: a call for the use of updated RUCAM in hospital Pharmacy

Abstract

Objective: to identify the frequency of DILI inpatients from abnormal liver enzyme levels using the updated Roussel Uclaf Causality Assessment Method (RUCAM) causality assessment algorithm, as well as to provide a descriptive analysis of DILI cases. Methods: we conducted a crosssectional study in a medium complexity hospital in southern Brazil. Data regarding DILI was collected retrospectively from electronic medical records (EMR) in 2015. Inclusion criteria were all adult patients (≥ 18 years old) who presented alanine aminotransferase (ALT) greater than twice the superior limit of normality (ALT > 60 UI/L) with concomitant change of aspartate aminotransferase (AST) or alkaline phosphatase (ALP) or change of ALP greater than twice the superior limit of normality (ALP > 250 UI/L) during hospitalization. The RUCAM was applied to all suspected DILI cases. Results: 84,134 inpatients in this period; 178 patients had abnormal liver tests, six patients had sufficient medical information to allow DILI causality assessment, and two patients had DILI described in EMR, although our group could not find suficient information to apply RUCAM retrospectively. Absence of information was mainly related to drug reconciliation at hospital admission, time of onset of suspected drug therapy and no description of previous clinical conditions in EMR. Four patients developed hepatic injury as a result of drug treatment initiated during hospitalization. Suspected drugs were antibiotics, nonsteroidal anti-inflammatory drugs, antiviral, tuberculostatics and platelet antiaggregant. Liver injury pattern was identified as hepatocellular and mixed. Conclusion: DILI appeared as a rare ADR, but absence of data in most EMR affected the application of RUCAM and underestimated DILI frequency. There is an urgency to develop DILI knowledge in Brazilian hospitals. Pharmacists must be aware of the use of the updated RUCAM to prospectively assess possible DILI cases. For future research, we suggest to combine cross-linking DILI tracers such as ICD-10 liver injury codes, abnormal liver biomarkers, search for trigger hepatotoxicity drugs and EMR text search tools, adding artificial intelligence to pharmacovigilance and hospital pharmacy.

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.…”

“…Cessation of all non-essential drugs is mandatory as soon as the idiosyncratic DILI is suspected [13,28,29,90,91]. This alone has a positive effect on LTs as shown in many reports on DILI with verified diagnosis based on the RUCAM [1][2][3][4][5][6][7][8][9]. In most cases, a complete resolution of the liver injury is achieved, while in a few others, a protracted course of LTs is observed.…”

“…In the past decade, much progress was recognizable in many segments of DILI research, with a focus on clinical characteristics [1][2][3][4][5][6][7][8][9][10]13,30,39,40,110], experimental studies on mechanistic steps [49,55,56,58,59,61,63,71,111], and drug development [25][26][27][28]. Despite these promising developments, DILI has been a treatment challenge nowadays as it was in the past, considering problems of previous therapeutic approaches as well as recent novel therapies [112].…”

“…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.…”

Advances in Idiosyncratic Drug-Induced Liver Injury Issues: New Clinical and Mechanistic Analysis Due to Roussel Uclaf Causality Assessment Method Use

“…Advances and breakthroughs in the RUCAM field were also noted because for drugs which are implicated in iDILI, the updated RUCAM was increasingly used and mentioned for reasons of transparency in the title of virtually all publications [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ]. Examples are case series with multiple drugs [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ] as well as individual drugs in alphabetical order: androgenic anabolic steroid drugs (updated RUCAM score 6, probable causality grading) [ 34 ], atezolizumab (score 7, probable) [ 35 ], fluoroquinolones (scores 6–8, probable, and scores ≥9, highly probable) [ 36 ], methotrexate (scores 6–8/≥9, probable and highly probable) [ 37 ], nevirapine (scores 6–8, probable) [ 38 ], para-aminobenzoate (score 10, highly probable) [ 39 ], rosuvastatin (score 9, highly probable) [ 40 ], pazopanib (score 8, probable) [ 41 ], teriflunomide (score and causality grading not reported) [ 42 ], and tigecycline (scores as mean ± SD: 6.8 ± 0.7, probable, and 9.1 ± 0.3, highly probable) [ 43 ]. Analysis of the nine reports above showed that iDILI cases with a possible causality grading have also been included in a few of these publications, which should not be carried out because it clouds the robust clinical features provided by iDILI cases, for which probable and highly probable causalities were found.…”