Idiosyncratic DILI and RUCAM under One Hat: The Global View
Abstract
:1. Introduction
2. Search Terms and Strategy
3. RUCAM, Its Global Use and High Appreciation
4. RUCAM Qualities with Strengths, Challenges and Limitations
4.1. Advantages of RUCAM
4.2. Challenges and Limitations of RUCAM
5. Validation
6. Liver Injury Criteria
7. Liver Injury Pattern
8. Top Drugs
8.1. Global Analysis
8.2. National Data
9. New RUCAM-Based iDILI Cases
10. Updated RUCAM in iDILI Cases with New Drugs
11. RUCAM and DILI in COVID-19
12. RUCAM and DILI Related to Immune Checkpoint Inhibitors
13. RUCAM in Search for Alternative Causes
14. RUCAM in Search for Pharmacotherapy Options of iDILI
15. RUCAM in Genetic iDILI
16. RUCAM, iDILI, and the Microbiome Dysbiosis
17. RUCAM and Metabolomics in iDILI
18. RUCAM-Based iDILI Features
19. Epidemiology of iDILI and RUCAM Use
20. Pharmaceutical Firms, DILI Registries, Regulators, and LiverTox
20.1. Pharmaceutical Firms
20.2. Regulatory Agencies
20.3. DILI Registries
20.4. LiverTox
21. Guidelines
22. Getting All under One Hat
23. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Country | Cases, n | Country | Cases, n | Country | Cases, n |
---|---|---|---|---|---|
1. China | 35,825 | 12. Iceland | 367 | 23. Singapore | 1 |
2. United States | 20,311 | 13. Pakistan | 264 | 24. Brazil | 4 |
3. Germany | 10,907 | 14. UK | 263 | 25. Canada | 4 |
4. Korea | 6528 | 15. France | 170 | 26. Israel | 1 |
5. Italy | 1562 | 16. Australia | 106 | 27. Malaysia | 1 |
6. Sweden | 1508 | 17. Serbia | 99 | 28. Mexico | 1 |
7. Spain | 1181 | 18. Egypt | 75 | 29. Morocco | 1 |
8. Japan | 939 | 19. Switzerland | 68 | 30. Saudi Arabia | 1 |
9. Argentina | 625 | 20. Portugal | 53 | 31. Turkey | 1 |
10. Thailand | 509 | 21. Bahrain | 25 | ||
11. India | 424 | 22. Colombia | 19 |
First Author | Number of RUCAM Based DILI Cases | Drugs | Comments on Cases |
---|---|---|---|
Fontana, 2005 [25] | 2 | Amoxicillin ± Clavulanate | Well-described features of DILI |
Lee, 2005 [26] | 6448 | Ximelagatran | Well-described features of DILI |
Stojanovski, 2007 [27] | 1 | Atomoxetine | Well-described features of DILI |
Lammert, 2008 [28] | 598 | Various drugs | No feature presentation of DILI by individual drugs |
Singla, 2010 [29] | 1 | Cephalexin | DILI features of a single case |
Nabha, 2012 [30] | 1 | Etravirine | Well-described features of DILI |
Sprague, 2012 [31] | 1 | Varenicline | Well-described features of DILI |
Markova, 2013 [32] | 56 | Bosentan | Well-described features of DILI |
Marumoto, 2013 [33] | 4 | NSAID | Limited feature details of DILI cases |
Bohm, 2014 [34] | 1 | Daptomycin | Well-described features of DILI |
Cheetham, 2014 [35] | 11,109 | Various drugs | No feature description of DILI associated with any suspected drug |
Lim, 2014 [36] | 1 | Various drugs | No presentation of specific features of DILI by 4 drugs used concomitantly or sequentially |
Russo, 2014 [37] | 22 | Statins | No individual feature description for DILI caused by various statins |
Veluswamy, 2014 [38] | 1 | Pomalidomide | Well-described features of DILI |
Baig, 2015 [39] | 1 | Rivaroxaban | Well-described features of DILI |
Hammerstrom, 2015 [40] | 1 | Amlodipine | Well-described features of DILI |
Stine, 2015 [41] | 2 | Simeprevir | Well-described features of DILI |
Tang, 2015 [42] | 1 | Bupropion, Doxycycline | Complex feature presentation of DILI due to comedication |
Unger, 2016 [43] | 1 | Ciprofloxacin | Well-described features of DILI |
Gharia, 2017 [44] | 1 | Letrozole | Well-described features of DILI |
Nicoletti, 2017 [45] | 339 | Various drugs | No specific feature details of DILI caused by individual drugs |
Gayam, 2018 [46] | 3 | Various drugs | Well-described features of DILI |
Hayashi, 2018 [47] | 493 | Various drugs | No specific feature details of DILI caused by individual drugs |
Patel, 2018 [48] | 1 | Everolimus | Well-described features of DILI |
Shamberg, 2018 [49] | 34 | Various drugs | No specific features of DILI |
Cirulli, 2019 [50] | 268 | Various drugs | No specific feature details of DILI |
Nicoletti, 2019 [51] | 197 | Flucloxacillin | No specific feature details of DILI |
Sandritter, 2019 [52] | 1 | Various drugs | No specific feature details of DILI caused by individual drugs |
Shumar, 2019 [53] | 1 | Memantine | Well-described features of DILI |
Tsung, 2019 [54] | 70 | Pembrolizumab | Well-described features of DILI |
Xie, 2019 [55] | 1 | Anastrozole | Well-described features of DILI |
Ghabril, 2020 [56] | 551 | Various drugs | No specific feature details of DILI caused by individual drugs |
Mullins, 2020 [57] | 99 | Micafungin | Well-described features of DILI |
Experiences and Weaknesses of the US DILI Network Method [58] |
---|
● Cases were enrolled in the registry within 6 months of DILI onset and underwent global introspection with so-called expert opinion |
● Causality assessment in real time for clinicians’ use was not feasible |
● There was no accepted definition provided for an expert in DILI |
● For each case, consensus must be achieved excluding minority votes |
● Consensus is still a subjective opinion |
● The network process restricts the naming of offending agents to 3 |
● Strong opinions or biases of a single experts were reported |
● Lengthy and lively conversations often occurred during the processes |
● The network process is described as cumbersome, time-consuming, and costly, needing data exchanges, monthly meetings, and logistics with administrative, organizational, and technological expertise |
● Each case received a final likelihood range as percentage, arbitrarily given by the assessors not based on individually scored elements |
● Total bilirubin was one of the inclusion criteria if >2.5 mg/dl without ruling out unconjugated hyperbilirubinemia due to, e.g., Gilbert syndrome |
● Network experts missed the diagnosis of HEV in wrongly diagnosed DILI cases needing a downgrading of percentage DILI likelihood |
● Not using a gold standard, a good method reliability was assumed |
● External validation of the method with a different group of experts is explicitly discouraged as labor is considered intensive and expensive |
● The network method was used only in US centers |
● Despite the weaknesses, the network method is assumed as best standard for the time being, but it was imperfect in 2016, asking for mandatory improvements |
● Finally, the original RUCAM was surprisingly quoted and described with 11 plain words: “RUCAM requires decline in liver enzymes to get a high score”. |
RUCAM with Its Basic Features and Specifics |
---|
● Fully validated method based on cases with positive reexposure test results (gold standard), providing thereby a robust CAM [1,18] |
● External validation by interrater reliability in 3 studies [59,60,61] |
● Worldwide use with 81,856 DILI cases assessed by RUCAM published up to mid-2020, outperforming thereby any other CAM in terms of number of cases published [20] |
● Valid and reproducible assessment of DILI and HILI cases [19] |
● A typical intelligent diagnostic algorithm in line with concepts of AI (artificial intelligence) to solve complex processes by scored items [62] |
● A diagnostic algorithm for objective, standardized, and quantitative causality assessment [1,13,14,15,19]. Summing up the individual scores derived from each key element provides final causality gradings: score ≤ 0, excluded causality; 1–2, unlikely; 3–5, possible; 6–8, probable; and ≥9, highly probable [19]. |
● Assessment is user friendly, cost effective with results available in time, and without need of expert rounds to provide arbitrary opinions [1,19,21,23,63] |
● Transparency of case data and clear result presentation [1,19,21] |
● Suitable for reevaluation by peers [1] and regional registries, national or international regulatory agencies, and pharma firms [1,19,64] |
● Mandatory use to validate future diagnostic biomarkers [65,66] and HLA association |
● Encourages prospective case data collection to obtain best results; however, RUCAM is also prepared for studies with a retrospective study protocol [19] |
● Real-time evaluation of the DILI case at the bed side [19] |
Clearly defined and scored key elements [19] |
● Time frame of latency period |
● Time frame of dechallenge |
● Recurrent ALT or ALP increase after drug cessation |
● Risk factors |
● Individual comedications |
● Exclusion of alternative competing causes |
● Markers of HAV, HBV, HCV, and HEV |
● Markers of CMV, EBV, HSV, and VZV |
● Cardiac hepatopathy and other alternative causes |
● Liver and biliary tract imaging |
● Doppler sonography of liver vessels |
● Prior known hepatotoxicity of drugs or herbs |
● Unintentional reexposure |
Other important specifics [19] |
● Laboratory-based liver injury criteria |
● Laboratory-based liver injury pattern |
● Liver-injury-specific method |
● Structured, liver-related method |
● Quantitative method, based on scored key elements |
Reexposure Test Result | Hepatocellular Injury | Cholestatic or Mixed Liver Injury | ||
---|---|---|---|---|
ALTb | ALTr | ALPb | ALPr | |
● Positive | <5 times ULN | ≥2 times ALTb | <2 times ULN | ≥2 times ALPb |
● Negative | <5 times ULN | <2 times ALTb | <2 times ULN | <2 times ALPb |
● Negative | ≥5 times ULN | ≥2 times ALTb | ≥2 times ULN | ≥2 times ALPb |
● Negative | ≥5 times ULN | <2 times ALTb | ≥2 times ULN | <2 times ALPb |
● Uninterpretable | <5 times ULN | n.a. | <2 times ULN | n.a. |
● Uninterpretable | n.a. | ≥2 times ALTb | n.a. | ≥2 times ALPb |
● Uninterpretable | n.a. | n.a. | n.a. | n.a. |
Challenges and Limitations of RUCAM |
---|
● The quality of published RUCAM-based case data depends strongly on the qualification and experience of the submitting physician |
● RUCAM cannot compensate for inadequate quality data and case providers not familiar with liver diseases; quality problems also remain on the side of the reviewers and journal management [67,68,69,70] |
● Intentional upgrading of causality levels from possible to probable in cases initially assessed by the objective updated RUCAM and subsequently reassessed by the global introspection in a report with western co-authors remain debatable [66] as substantiated in three Letters to the Editor, presented by authors from India and Iceland [68], and China [69,70] |
● Fraudulent upgrading from possible to probable RUCAM gradings of published cases with the intention to provide more power on risky liver injury, uncovered in court, is outside of any ethics standard [71] |
● Challenging are reports entitled as DILI, but in fact several cohorts were lumped together with non-drugs like herbs or so-called dietary supplements as causatives of HILI, providing biased results for drugs and the other causatives due to cohort heterogeneity |
● Publications occasionally report on RUCAM-based DILI cohorts that include cases with a possible causality grading, which confounds good data with a probable or highly probable causality level [66]. This problem must be solved prior to submission by deleting all cases with a possible or lower causality grading from the analysis to be published |
● Challenging for RUCAM are mixed cohorts of DILI caused by multiple medicinal products without providing individual RUCAM scores for each product, or giving causality gradings as means ± SEM or ± SD for drug groups [20] |
● Misuse of RUCAM by using reports on DILI without values of ALT and ALP, preventing both, verification of criteria characterizing the liver injury as well as calculation of the R (ratio) and selection of the appropriate RUCAM subtype for correct causality assessment [19] |
● Misuse of RUCAM by attempting including results of positive unintentional reexposure without adherence to the specific criteria [19] |
Reports on Validation of RUCAM |
---|
● RUCAM was internally validated using published DILI reports with positive test results of reexposure, also named positive rechallenge, which demonstrated without incorporation of the rechallenge test into the score, a sensitivity of 86%, specificity of 89%, positive predictive value of 93%, and negative predictive value of 78% [18], providing results that were commonly appreciated [1] and underlined the value of the original RUCAM as robust diagnostic algorithm [17]. Positive unintentional reexposure tests are considered as gold standard among DILI experts [1,18], as erroneous reexposure of a suspected drug provides in retrospect the strongest evidence for DILI [1] if strict criteria were fulfilled [19]. The good validation data were confirmed by subsequent studies [59,60,61]. |
● A good reliability based on interrater agreement by using the original RUCAM for DILI cases was reported as first external study [59]. |
● A second external study reported that there were no discrepancies in assessment by the two hepatologists who used the original RUCAM in suspected iDILI cases due to sevoflurane and desflurane [61]. This was a prospective incidence study of fifteen patients that provided RUCAM-based causality gradings of highly probable in 3 cases, probable gradings in 5 cases, and possible gradings in 7 patients. |
● A third external validation study used the updated RUCAM for determination of causality described in 72 patients with COVID-19 and suspected DILI [60]. Two independent rating pairs (consisting of two clinical pharmacologists plus 2 general physicians), who had received a short training program for pilot testing just prior to the actual RUCAM use, determined the likelihood of DILI using the RUCAM scale in these DILI patients. As a result, the overall Krippendorf kappa was 0.52, with an intraclass correlation coefficient (ICC) of 0.79 and viewed as excellent reliability for using the updated RUCAM [60]. Whether this is achieved through the prior training remains to be verified by assessors without prior training. Confirming previous reports [18,59], this good reliability result was remarkable as it was based on a retrospective study design [60]. |
Drugs | Total RUCAM Based DILI Cases | References with First Author Reporting Individual RUCAM Based DILI Cases, n |
---|---|---|
1. Amoxicillin-clavulanate | 333 | Andrade [74], 59 cases; Björnsson [59], 4; Andrade [75], 4; [García-Cortés [76], 34; Devarbhavi [77], 3; Lucena [78], 187; Stephens [79], 26; Björnsson [80], 16. |
2. Flucloxacilllin | 130 | Björnsson [59], 129; Douros [81], 1. |
3. Atorvastatin | 50 | Björnsson [59], 4; Andrade [75], 2; Devarbhavi [77], 5; Björnsson [82], 30; Björnsson [80], 2; Zhu [83], 5; Rathi [84], 2. |
4. Erythromycin | 48 | Björnsson [59], 42; Andrade [74], 6 |
5. Diclofenac | 46 | Björnsson [59], 20; Andrade [74], 12; Andrade [75], 1; Devarbhavi [77], 1; Björnsson [80], 2; Douros [81], 8; Rathi [84], 2. |
6. Simvastatin | 41 | Björnsson [59], 4; Björnsson [82], 28; Douros [81], 7; Zhu [83], 2. |
7. Carbamazepine | 38 | Björnsson [59], 17; Andrade [74], 8; Devarbhavi [77], 9; Douros [81], 4. |
8. Ibuprofen | 37 | Björnsson [59], 4; Andrade [74], 18; Devarbhavi [77], 2; Douros [81], 11; Zhu [83], 2. |
9. Disulfiram | 27 | Björnsson [59], 27 |
10. Anabolic steroids | 26 | Robles-Diaz [85], 25; Zhu [83], 1. |
11. Phenytoin | 22 | Andrade [75], 1; Lucena [78], 21. |
12. Sulfamethoxazole/Trimethoprim | 21 | Björnsson [59], 21. |
13. Isoniazid | 19 | Björnsson [59], 7; Andrade [74], 9; Douros [81], 3. |
14. Ticlopidine | 19 | Björnsson [59], 5; Andrade [74], 13; Wai [86], 1. |
15. Azathioprine/6-Mercaptopurine | 17 | Björnsson [59], 4; Andrade [74], 6; Devarbhavi [77],1; Björnsson [80], 4; Douros [81], 2. |
16. Contraceptives | 17 | Björnsson [59], 6; Wai [86], 1; Devarbhavi [77], 1; Douros [81], 9. |
17. Flutamide | 17 | Andrade [74], 17. |
18. Halothane | 15 | Björnsson [59], 15 |
19. Nimesulide | 13 | Andrade [74], 9; Devarbhavi [77], 2; Zhu [83], 1; Rathi [84],1. |
20. Valproate | 13 | Andrade [74], 5; Andrade [75], 1; Devarbhavi [77] 3; Douros [81], 3; Zhu [83], 1. |
21. Chlorpromazine | 11 | Björnsson [59], 9; Zhu [83], 2. |
22. Nitrofurantoin | 11 | Björnsson [59], 3; Björnsson [80], 4; Douros [81], 1; Zhu [83], 3. |
23. Methotrexate | 8 | Devarbhavi [77], 3; Zhu [83], 2; Rathi [84], 3. |
24. Rifampicin | 7 | Björnsson [59], 3; Douros [81], 4. |
25. Sulfazalazine | 7 | Björnsson [59], 7. |
26. Pyrazinamide | 5 | Björnsson [59], 5. |
27. Natriumaurothiolate | 4 | Douros [81], 4. |
28. Sulindac | 5 | Douros [81], 5. |
29. Amiodarone | 4 | Douros [81], 4. |
30. Interferon beta | 3 | Björnsson [80], 1; Douros [81], 2. |
31. Propylthiouracil | 2 | Wai [86], 1; Zhu [83], 1 |
32. Allopurinol | 1 | Douros [81], 1. |
33. Hdralazin | 1 | Douros [81], 1. |
34. Infliximab | 1 | Douros [81], 1. |
35. Interferon alpha/Peginterferon | 1 | Rathi [84], 1. |
36. Ketoconazole | 1 | Zhu [83], 1. |
Top Drugs/Drug Classes Causing iDILI Assessed by RUCAM in Various Regions/Countries | |||||
---|---|---|---|---|---|
Region/ Country | Ranking #1 | Ranking #2 | Ranking #3 | Ranking #4 | Ranking #5 |
Global, 2020 [87] | Amoxicillin-Clavulanate | Flucloxacilllin | Atorvastatin | Disulfiram | Diclofenac |
Spain, 2021 [88] | Amoxicillin- Clavulanate | Atorvastatin | Cefazoline | Levofloxacin | Metamizole |
Egypt, 2020 [89] | Diclofenac | Amoxicillin-clavulanate | Halothane | Ibuprofen | Tramadol |
Korea, 2020 [90] | Piperacillin- Tazobactam | Methotrexate | Ceftriaxone | Vancomycin | Meropenem |
China, 2016 [83] | Atorvastatin | Simvastatin + Aspirin | Azithromycin | Prednisone | INH-RIP-PIZ |
Germany, 2015 [81] | Phenprocoumon | Flupirtine | Pyrazinamide | Diclofenac | Simvastatin |
US, 2014 [35] | Ciprofloxacin | Trimethoprim- Sulfamethoxazole | Phenytoin | Nitrofurantoin | Isoniazid |
Iceland, 2013 [80] | Amoxicillin- Clavulanate | Diclofenac | Azathioprine | Infliximab | Nitrofurantoin |
India, 2010 [77] | Antituberculous drugs | Phenytoin | Dapsone | Olanzapine | Carbamazepine |
Sweden, 2005 [59] | Flucloxacillin | Erythromycin | Trimethoprim-Sulfamethoxazole | Disulfiram | Diclofenac |
Spain, 2005 [74] | Amoxicillin-Clavulanate | Ebrotidine | INH-RIP-PIZ | Ibuprofen | Flutamide |
Japan, 2023 [91] | Antiinfectives | NSAIDs | Psychiatric-neuro- logical drugs | Cardiovascular drugs | Gastrointestinal drugs |
Spain, 2022 [92] | Antibiotics | NSAIDs | Analgesics | Psychotropics | Statins |
China, 2021 [93] | Antitumor drugs | Antimicrobial drugs | Cardiovascular drugs | Analgesics-Antipyretics | Hormones |
Korea, 2020 [90] | Antibiotics | Chemotherapeutic drugs | Anticoagulation drugs | NSAIDs | Gastrointestinal drugs |
Qatar, 2020 [94] | Antimicrobial drugs | Anticonvulsants | Statins | Analgesics | Antihyperten-sives |
Colombia, 2019 [95] | Antiinfectives | Anticonvulsants | Antiparasitic drugs | Antithrombotic drugs | Antidiabetics |
India, 2017 [84] | Antituberculotic drugs | Antiepileptic drugs | Antiretroviral drugs | NSAIDs | Methotrexate |
Italy, 2017 [96] | Antibiotics | NSAIDs | Immuno-suppressants | Statins | Anti-platelets drugs |
China, 2016 [83] | Antibiotics | Antituberculotics | Antithyroid drugs | Antineoplastic drugs | Hypolipidemic drugs |
China, 2015 [97] | Antithyroid drugs | Antituberculotics | Antibiotics | Chemotherapy drugs | Immuno- suppressants |
Drug | RUCAM Score/Grading | First Author |
---|---|---|
● Amlodipine | score 6, probable | Varghese, 2020 [98] |
● Anastrozole | score 6, probable | Potmešil, 2020 [99] |
● Atorvastatin | score 9, highly probable | Khan, 2020 [100] |
● Atovaquone | score 9, highly probable | Abbass, 2021 [101] |
● Candesartan | score 8, probable | Hermida Pérez, 2020 [102] |
● Ciprofloxacin | score 11, highly probable | Napier, 2020 [103] |
● Fenofibrate | score 10, highly probable | Ma, 2020 [104] |
● Flucloxacillin | score 8, probable | Teixeira, 2020 [105] |
● Gemcitabine | score 10, highly probable | Mascherona, 2020 [106] |
● Infliximab | score 10, highly probable | Worland, 2020 [107] |
● Metamizole | score 7, probable | Sebode, 2020 [108] |
● Teriflunomide | score 8, probable | LeSaint, 2020 [109] |
Drugs/Drug Classes | RUCAM Scores/Causality Gradings | First Author |
---|---|---|
● Androgenics | score 6, probable | Abeles, 2020 [110] |
● Atezolizumab | score 7, probable | Tzadok, 2022 [111] |
● Durvalumab | score 6 or 7, probable | Swanson, 2022 [112] |
● Ceftriaxone | score 6, probable | Asif, 2023 [113] |
● Enoxaparin | score 8, probable | Eze, 2023 [114] |
● Favipiravir | score 6, probable | Yamazaki, 2021 [115] |
● Fluoroquinolones | scores 6–8, probable; score ≥9, highly probable | Yang, 2019 [116] |
● Girosivan | score 8, probable | Ma, 2023 [117] |
● Ibuprofen | score 8, probable | Deng, 2022 [118] |
● Iguratimod | Score 9, highly probable | Li, 2018 [119] |
● Ipragliflozin | score 7, probable | Niijima, 2017 [120] |
● Liraglutide | score 8, probable | Inayat, 2023 [121] |
● Metformin | score 10, highly probable | Mian, 2023 [122] |
● Methotrexate | scores 6–8, probable; ≥9, highly probable | Qin, 2022 [123] |
● Nevirapine | scores 6–8, probable | Giacomelli, 2018 [124] |
● Para-aminoben- zoate | score 10, highly probable | Plüß, 2022 [125] |
● Pazopanib | score 8, probable | Studentova, 2022 [126] |
● Propylthiouracil | score 7, probable | Salsabila, 2023 [127] |
● Rosuvastatin | score 9, highly probable | Díaz-Orozco, 2022 [128] |
● Teriflunomide | scores/causality gradings not reported | Wurzburger, 2022 [129] |
● Tigecycline | score 6, probable | Althomali, 2022 [130] |
● Tigecycline | score 7, probable | Shi, 2022 [131] |
● Tigecycline | scores ≥6, probable and highly probable | Yu, 2022 [132] |
● Antidepressants | scores up to 9–10, highly probable | Gonzáles-Muñoz, 2020 [133] |
● Antituberculotics | scores >6, probable/highly probable | Huang, 2023 [134] |
● Antituberculotics | scores ≥6, probable/highly probable | Wang, 2022 [135] |
● Various | scores 4–9, possible-highly probable | Cano-Paniagua, 2019 [95] |
● Various | scores >3, possible, probable, highly probable. | Chen, 2021 [136] |
● Various | highly probable, 38%; probable, 53%; possible, 2%; unlikely, 0%; excluded, 7%. | Danjuma, 2020 [94] |
● Various | scores ≥6, probable; scores ≥3, possible. | Delago, 2021 [137] |
● Various | highly probable, 10%; probable, 54%; possible, 36%. | Li, 2022 [138] |
●Various | scores 9/10, highly probable; scores 6–8, probable; score 4, possible. | Lunardelli, 2022 [139] |
● Various | highly probable, 3%; probable, 35%; possible, 46%; unlikely, 12%; excluded, 4%. | Nassarallah, 2022 [60] |
First Author | Case Details of RUCAM-Based iDILI in COVID-19 Patients |
---|---|
Muhović, 2020 [140] Montenegro (cases, n = 1) (drugs, n = 4) | Reported is a case of DILI by tocilizumab (TCZ) in a male patient with COVID-19 infection that caused a cytokine storm [140]. Using the original RUCAM [17,18] instead of the commonly preferred updated RUCAM [19], causality for TCZ was probable based on a RUCAM score of 8. Such high causality grading is commonly achieved with complete data sets collected prospectively during the clinical course. TCZ is a humanized recombinant monoclonal antibody that acts as an IL-6 receptor antagonist by specific binding to IL-6 receptors. Preexisting liver disease was excluded as well as anoxia leading to liver hypoxia. It was noted that slightly elevated transaminases were detected before TCZ administration. Comedication included azithromycin, ceftriaxone, chloroquine, lopinavir, methylprednisolone, and ritonavir, but none of these drugs were considered causative for the liver injury, although a contributory role of the previously used antiviral drugs (lopinavir/ritonavir) is possible. |
Chen, 2021 [136] China (cases, n = 830) (discussed drugs, n = 4) | This study analyzed 830 COVID-19 cases with liver injury. This is the largest study cohort evaluated for causality [136], using the updated RUCAM [17]. Among 74/830 cases, the RUCAM score was >3, corresponding to a possible, probable, or highly probable causality. To achieve a homogeneous cohort, a good approach would have been to include only cases with a probable or highly probable causality. The concomitant drugs abidol, acetaminophen, oseltamivir, and ribavirin were discussed. For this retrospective study, all data were retrieved from the digital medical records during hospitalization. Important note is when multiple drugs in combination are used in COVID-19 patients, the RUCAM score is required to evaluate the risk of DILI of each drug. |
Delgado, 2021 [137] Spain (cases, n = 160) (drugs, n = 18) | The updated RUCAM [19] was used in 124 males and 36 female patients [137], providing in 82 patients a probable causality grading based on a RUCAM score of ≥6 and in 78 cases a possible causality ranking based on a RUCAM score of ≥3. The high number of cases with a possible causality grading could have been avoided by using a prospective and proactive study protocol. The mean number of drugs per patient was 14.7 (SD 7.6), whereby 98.1% received more than 5 drugs. Among the used drugs were acetaminophen, azithromycin, ceftriaxone, dexketoprofen, doxycycline, enoxaparin, hydroxychloroquine, interferon, levofloxacin, lopinavir, metamizole, omeprazole, pantoprazole, piperacillin/tazobactam, remdesivir, ritonavir, and tocilizumab. |
Jothimani, 2021 [141] India (cases, n = 1) (drugs, n = 4) | RUCAM was used without clear definition of the version applied [17,19] in a male COVID-19 patient [141], who suffered from DILI after using the oral anticoagulant dabigatran, for which a RUCAM score of 7 corresponding to a probable causality was provided. Additional medications included enoxaparin, esomeprazole, and methylprednisolone. It was outlined that the cause of liver injury is multifactorial in COVID-19. |
Kumar, 2021 [142] India (cases, n = 3) (drugs, n = 3) | In this study of three patients (2 females, one male) with COVID-19, each treated with favipiravir that caused DILI, RUCAM was used without specifying the RUCAM version applied [142]. The updated RUCAM was likely used, which requires the exclusion of hepatitis E virus (HEV) infection [19], a parameter considered in the present study [142] that was not an element of the original RUCAM [17]. For all three patients, a RUCAM score of 7 was found consistent with a probable causality level [142]. Of note, the second patient also used acetaminophen, and the third patient was treated with entecavir for his hepatitis B-related cirrhosis, currently with absence of serum hepatitis B virus (HBV) DNA. |
Yamazaki, 2021 [115] Japan (cases, n = 1) (drugs, n = 8) | The updated RUCAM [19] was used for a male COVID-19 patient experiencing DILI by favipiravir, providing a RUCAM score of 6 in line with a probable causality and not a possible level as erroneously published [115]. The patient also received interferon-β, lopinavir, meropenem, micafungin, ritonavir, trimethoprim-sulfamethoxazole, and vancomycin. A contributory role of vancomycin and meropenem was discussed. |
Deng, 2022 [118] China (cases, n = 2) (drugs 2) | In 2 COVID-19 patients [55], the updated RUCAM was used [19], leading to a score of 8 for a probable causality for the male patient treated with ibuprofen and with a score of 9 for a highly probable causality for the female patient, who used acetaminophen [118]. In 3 other COVID-19 patients, the LT abnormalities were related to the COVID-19 infection. Of note, many other COVID-19 patients were not treated by antiviral drugs. |
Naseralallah, 2022 [60] Qatar (cases, n = 72) (drugs, n = 8) | This study analyzed 72 COVID-19 patients with DILI due to the use of acetaminophen, amoxicillin-clavulanate, azithromycin, ceftriaxone, cefuroxime, favipiravir, hydroxychloroquine, and lopinavir [60]. Using the updated RUCAM [17], drug causality was excluded in 4.17% of the cases, unlikely in 12.5%, possible in 45.83%, probable in 34.72%, and highly probable in 2.78% of the cases [60]. Azithromycin was the most used drug implicated in causing DILI. |
Sigurdason, 2023 [143] Iceland (cases, n = 3) (drugs, n.a.) | In a 2020 retrospective population-based study of Iceland on liver injury, 3/225 hospitalized patients with COVID-19 met the criteria of RUCAM-based DILI but achieved only a possible causality grading, leading to a conclusion of vague clinical features except that the affected population hospitalized in Iceland is not large enough to detect iDILI (between 1/10,000 and 20,000 inhabitants). |
RUCAM-Based DILI Characteristics in COVID-19 Patients |
---|
● The male gender prevailed, and age was in a range of 45 and 57 years |
● Hepatocellular injury was more commonly observed than cholestatic or mixed injury |
● Multi-medication is likely a risk factor for liver injury |
● The list of used drugs is impressive but co-medication was evaluated smoothly |
● RUCAM can be well used in retrospective studies, although the better approach is using a prospective design |
● High RUCAM-based causality gradings can be well achieved in retrospective studies |
● One study provided excellent external validation results of the updated RUCAM |
● The large number of RUCAM-based iDILI cases can certainly foster the global use of RUCAM in addition to the 81,856 cases published so far |
● The high quality of RUCAM based iDILI cases cannot compensate the low quality of abundant published reports on COVID-19 patients with non-RUCAM based cases because these were, at best, only narratives describing the multiplicity of drugs patients were using |
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Teschke, R.; Danan, G. Idiosyncratic DILI and RUCAM under One Hat: The Global View. Livers 2023, 3, 397-433. https://doi.org/10.3390/livers3030030
Teschke R, Danan G. Idiosyncratic DILI and RUCAM under One Hat: The Global View. Livers. 2023; 3(3):397-433. https://doi.org/10.3390/livers3030030
Chicago/Turabian StyleTeschke, Rolf, and Gaby Danan. 2023. "Idiosyncratic DILI and RUCAM under One Hat: The Global View" Livers 3, no. 3: 397-433. https://doi.org/10.3390/livers3030030