Abstract
Drug-induced liver injury (DILI) presentation varies biochemically and histologically. Certain drugs present quite consistent injury patterns, i.e., DILI signatures. In contrast, others are manifested as broader types of liver injury. The variety of DILI presentations by a single drug suggests that both drugs and host factors may contribute to the phenotype. However, factors determining the DILI types have not been yet elucidated. Identifying such factors may help to accurately predict the injury types based on drugs and host information and assist the clinical diagnosis of DILI. Using prospective DILI registry datasets, we sought to explore and validate the associations of biochemical injury types at the time of DILI recognition with comprehensive information on drug properties and host factors. Random forest models identified a set of drug properties and host factors that differentiate hepatocellular from cholestatic damage with reasonable accuracy (69–84%). A simplified logistic regression model developed for practical use, consisting of patient’s age, drug’s lipoaffinity, and hybridization ratio, achieved a fair prediction (68–74%), but suggested potential clinical usability, computing the likelihood of liver injury type based on two properties of drugs taken by a patient and patient’s age. In summary, considering both drug and host factors in evaluating DILI risk and phenotypes open an avenue for future DILI research and aid in the refinement of causality assessment.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Aithal GP, Watkins PB, Andrade RJ et al (2011) Case definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Rep 89:806–815. https://doi.org/10.1038/clpt.2011.58
Andrade RJ, Lucena MI, Fernández MC et al (2005) Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology 129:512–521. https://doi.org/10.1053/j.gastro.2005.05.006
Andrade RJ, Chalasani N, Björnsson ES et al (2019) Drug-induced liver injury. Nat Rev Dis Primers 5:58. https://doi.org/10.1038/s41572-019-0105-0
Benet LZ, Broccatelli F, Oprea TI (2011) BDDCS applied to over 900 drugs. AAPS J 13:519–547. https://doi.org/10.1208/s12248-011-9290-9
Bénichou C (1990) Criteria of drug-induced liver disorders. Report of an international consensus meeting. J Hepatol 11:272–276. https://doi.org/10.1016/0168-8278(90)90124-A
Bessone F, Hernandez N, Lucena MI et al (2016) The Latin American DILI Registry experience: a successful ongoing collaborative strategic initiative. Int J Mol Sci 17:313. https://doi.org/10.3390/ijms17030313
Broccatelli F, Cruciani G, Benet LZ, Oprea TI (2012) BDDCS class prediction for new molecular entities. Mol Pharm 9:570–580. https://doi.org/10.1021/mp2004302
Chen M, Hong H, Fang H et al (2013) Quantitative structure-activity relationship models for predicting drug-induced liver injury based on FDA-approved drug labeling annotation and using a large collection of drugs. Toxicol Sci 136:242–249. https://doi.org/10.1093/toxsci/kft189
Chen M, Suzuki A, Borlak J, Andrade RJ, Lucena MI (2015) Drug-induced liver injury: interactions between drug properties and host factors. J Hepatol 63:503–514. https://doi.org/10.1016/j.jhep.2015.04.016
Danan G, Benichou C (1993) Causality assessment of adverse reactions to drugs–I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries. J Clin Epidemiol 46:1323–1330. https://doi.org/10.1016/0895-4356(93)90101-6
European Association for the Study of the Liver (2019) EASL clinical practice guidelines: drug-induced liver injury. J Hepatol 70:1222–1261. https://doi.org/10.1016/j.jhep.2019.02.014
Garcia-Cortes M, Robles-Diaz M, Stephens C, Ortega-Alonso A, Lucena MI, Andrade RJ (2020) Drug induced liver injury: an update. Arch Toxicol 94:3381–3407. https://doi.org/10.1007/s00204-020-02885-1
Hayashi PH, Björnsson ES (2018) Long-term outcomes after drug-induced liver injury. Curr Hepatol Rep 17:292–299. https://doi.org/10.1007/s11901-018-0411-0
Hong H, Chen M, Ng HW, Tong W (2016) QSAR models at the US FDA/NCTR. Methods Mol Biol 1425:431–459. https://doi.org/10.1007/978-1-4939-3609-0_18
Kim WR, Flamm SL, Di Bisceglie AM, Bodenheimer HC, Public Policy Committee of the American Association for the Study of Liver Disease (2008) Serum activity of alanine aminotransferase (ALT) as an indicator of health and disease. Hepatology 47:1363–1370. https://doi.org/10.1002/hep.22109
Lammert C, Björnsson ES, Niklasson A, Chalasani N (2010) Oral medications with significant hepatic metabolism at higher risk for hepatic adverse events. Hepatology 51:615–620. https://doi.org/10.1002/hep.23317
Liu R, Sun H, So SS (2001) Development of quantitative structure-property relationship models for early ADME evaluation in drug discovery. 2. Blood-brain barrier penetration. J Chem Inf Comput Sci 41:1623–1632. https://doi.org/10.1021/ci010290i
Lowe D, Sanvictores T, John S (2020) Alkaline Phosphatase. In StatPearls [Internet]. StatPearls Publishing, 2020
Lucena MI, Sanabria J, García-Cortes M, Stephens C, Andrade RJ (2020) Drug-induced liver injury in older people. Lancet Gastroenterol Hepatol 5:862–874. https://doi.org/10.1016/S2468-1253(20)30006-6
Matsunaga N, Rogers DW, Zavitsas AA (2003) Pauling’s electronegativity equation and a new corollary accurately predict bond dissociation enthalpies and enhance current understanding of the nature of the chemical bond. J Org Chem 68:3158–3172. https://doi.org/10.1021/jo020650g
Medina-Caliz I, Robles-Diaz M, Garcia-Muñoz B et al (2016) Definition and risk factors for chronicity following acute idiosyncratic drug-induced liver injury. J Hepatol 65:532–542. https://doi.org/10.1016/j.jhep.2016.05.003
Suzuki A, Yuen N, Walsh J, Papay J, Hunt CM, Diehl AM (2009) Co-medications that modulate liver injury and repair influence clinical outcome of acetaminophen-associated liver injury. Clin Gastroenterol Hepatol 7:882–888. https://doi.org/10.1016/j.cgh.2009.03.034
Suzuki A, Yuen NA, Ilic K et al (2015) Comedications alter drug-induced liver injury reporting frequency: data mining in the WHO VigiBaseTM. Regul Toxicol Pharmacol 72:481–490. https://doi.org/10.1016/j.yrtph.2015.05.004
Warner DJ, Chen H, Cantin LD et al (2012) Mitigating the inhibition of human bile salt export pump by drugs: opportunities provided by physicochemical property modulation, in silico modeling, and structural modification. Drug Metab Dispos 40:2332–2341. https://doi.org/10.1124/dmd.112.047068
Weersink RA, Alvarez-Alvarez I, Medina-Cáliz I et al (2020) Clinical characteristics and outcome of drug-induced liver injury in the older patients: from the young-old to the oldest-old. Clin Pharmacol Ther. https://doi.org/10.1002/cpt.2108
WHO Collaborating Centre for Drug Statistics Methodology (2018) Guidelines for ATC classification and DDD assignment 2020, 23rd edn. Norwegian Institute of Public Health, Oslo
Wishart DS, Knox C, Guo AC et al (2006) DrugBank: a comprehensive resource for in silico drug discovery and exploration. Nucleic Acids Res 34(Database issue):D668–D672. https://doi.org/10.1093/nar/gkj067
Acknowledgements
This article/publication is based upon work from COST Action “CA17112—Prospective European Drug-Induced Liver Injury Network” supported by COST (European Cooperation in Science and Technology). www.cost.eu. The authors AG-J, AS, IA-A, RJA, and MIL are members of the Cost Action 17112.
Funding
The present study has been supported by grants of Instituto de Salud Carlos III cofounded by Fondo Europeo de Desarrollo Regional – FEDER (contract numbers: PI 18/01804; PT20/00127) and Agencia Española del Medicamento. Plataforma ISCiii de Investigación Clínica and CIBERehd are funded by Instituto de Salud Carlos III. IAA holds a Sara Borrell research contract from the National Health System, Instituto de Salud Carlos III (CD20/00083).
Author information
Authors and Affiliations
Contributions
AS, MC, RJA and MIL designed the study. AG-J, AS, MC and KA analyzed the data. AG-J, AS, MC, IA-A, RJA and MIL wrote the manuscript. All the authors critically revised the manuscript and approved the final version.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical standards
The study protocol was approved by the local Ethics Committee at the Virgen de la Victoria University Hospital in Málaga, Spain. All subjects gave informed consent.
Disclaimer
The views presented in this article do not necessarily reflect those of the U.S. Food and Drug Administration. Any mention of commercial products is for clarification and is not intended as an endorsement.
Participating clinical centers in the Spanish DILI Registry
Hospital Universitario Virgen de la Victoria, Málaga (coordinating center): RJ Andrade, MI Lucena, C Stephens, M García Cortés, M Robles-Díaz, A Ortega-Alonso, J Pinazo, B García Muñoz, R Alcántara, A Hernández, MD García Escaño, E del Campo, I Medina-Cáliz, J Sanabria-Cabrera, A González-Jiménez, R Sanjuán-Jiménez, A Cueto, I Álvarez-Álvarez, E Bonilla, D Di Zeo, H Niu, M Villanueva, A Papineau; Hospital Regional Universitario de Málaga: M Jiménez Pérez, R González Grande, S López Ortega, I Santaella, A Ocaña, P Palomino; Hospital Torrecárdenas, Almería: MC Fernández, G Peláez, A Porcel, M Casado, M González Sánchez; Hospital Universitario Virgen del Rocío, Sevilla: M Romero-Gómez, R Millán-Domínguez, B Fombuena, R Gallego, J Ampuero, JA del Campo, R Calle-Sanz, L Rojas, A Rojas, A Gil Gómez, E Vilar; Hospital Sant Pau, Barcelona: G Soriano, C Guarner, EM Román, MA Quijada Manuitt, RM Antonijoan Arbos; Hospital Parc Tauli, Barcelona: J Sánchez Delgado, M Vergara Gómez; Hospital Morales Meseguer, Murcia: H Hallal, E García Oltra, JC Titos Arcos, A Pérez Martínez, C Sánchez Cobarro, JM Egea Caparrós; Hospital Universitario de Donostia, San Sebastián: A Castiella, E Zapata, J Arenas, A Gómez García, FJ Esandi; Hospital de Basurto, Bilbao: S Blanco, P Martínez Odriozola; Hospital Marqués de Valdecilla, Santander: J Crespo, P Iruzubieta, J Cabezas; Hospital Virgen del Rocío, Sevilla: A Giráldez Gallego, E del P Rodríguez Seguel, M Cuaresma; Hospital de León, León: J González Gallego, F Jorquera, S Sánchez Campos; Hospital Alto Deba Mondragón, Guipúzcoa: P Otazua, A de Juan Gómez; Hospital La Fe, Valencia: M Prieto, I Conde Amiel, M Berenguer, M García-Eliz, Hospital de Laredo, Cantabria: M Carrascosa; Hospital 12 de Octubre, Madrid: E Gómez Domínguez, L Cuevas; Hospital Germans Trias i Pujol, Badalona, Barcelona: M Farré, E Montané, AM Barriocanal, AL Arellano, Y Sanz, RM Morillas, M Sala, H Masnou Ridaura; Hospital Clínic, Barcelona: M Bruguera, P Gines, S Lens, JC García, Z Mariño; Hospital Universitario de Canarias, La Laguna, Tenerife: M Hernández Guerra, JM Moreno Sanfiel, C Boada Fernández del Campo; Hospital Infanta Elena, Valdemoro, Madrid: M Tejedor, R González Ferrer; Hospital Miguel Servet, Zaragoza: J Fuentes Olmo, EM Fernández Bonilla; Complejo Hospitalario Universitario de Albacete, Albacete: JM Moreno, P Martínez-Rodenas, M Garrido, C Oliva; Hospital Puerta de Hierro, Madrid: JL Calleja, JL Martínez Porras; Hospital de Galdakao, Bizkaia: JL Cabriada.
Participating clinical centers in the LATINDILI Network:
Argentina: Hospital Provincial del Centenario: Rosario F Bessone, H Tanno, V Reggiardo, S Ferretti, F Tanno, L Arribillaga, M Amateis, Y Zambello, A Ferretti, J Vorobioff, A Galimberti, V Trevizan, M Chiaraviglio, P Caballini, J Montero, J Ortiz, A Rodil, M La Placa, L Zitelli, F Jaureguizahar, A Ferrari, N Tamagnone, S Bullati, J Pacual, M Tanno, G Carbonetti, G Piñero, L Muñoz, G Carnevale, Y Zambello, M Amateis, C Guerrina, A Wulfson, ML Arribillaga; Hospital Privado de Rosario: A Ruf, M Dirchwolf; Hospital de Córdoba: A Zerega; Hospital Universitario Austral: M Mendizábal, M Silva; Hospital Nacional Alejandro Posadas: G Gualano, E Fassio; Centro de Educación Médica e Investigaciones Clínicas (CEMIC), Buenos Aires: E Ridruejo; Hospital Italiano de Buenos Aires: N Sobenko, J Pizzala, L Haddad, A Villamil, A Gadano; Hospital Británico, Buenos Aires: J Benavidez, N Fernandez, L Colombato; Clínica de Nefrología, Santa Fe: L Gaite; Sanatorio de niños, Rosario: A Costaguta, A País; Hospital Alemán, CABA: M Anders; Hospital de infecciosas F.J. Muñiz, CABA: M Peralta, S Campuzano, S Paz, H Famboin; Hospital Italiano de La Plata, La Plata: F Gruz; Hospital Universitario Fundación Favaloro: V Descalzi; Hospital General de Agudos Dr. Cosme Argerich: G Tsariktsian, A Bruno, B Frider; Hospital Santojanni: NE Libaak; Hospital San Bernardo: C Facundo Zarbá; Hospital Aeronáutico Central: P Testa; Hospital Internacional General de Agudos: E Giraudo; Hospital Marcial Quiroga: R Romo; Nuevo Hospital Río Cuarto, Córdoba: C Mendoza; Centro de Hepatología La Plata: S Borzi; Hospital Español, Mendoza: O Galdame, M Paez; Hospital El Cruce, Buenos Aires: F Villamil; Hospital JM Penna: M Mesquida; Hospital Bonorino Udaondo, Buenos Aires: M Cartier; Hospital Presidente Perón de Avellaneda, Buenos Aires: S Chao; Sanatorio San Carlos, Bariloche: C Garcia Dans; Hospital Eva Perón, Buenos Aires: C Guma. Uruguay: Hospital de Clínicas, Montevideo: N Hernández, A Sanchéz, D Chiodi. Brazil: Hospital Universitário Prof. Edgard Santos-UFBA, Salvador: R Paraná, MI Schinoni, V Nunes, G Santos, A de Araujo, D Jamil, M Costa Silva; ICHC FMUSP Universidad de Sao Paulo: G Belchior, F Carrilho, SK Ono, N Lopes, G Dagostino, F Roberto, V Alves; Universidade Federal de Juiz de Fora, Juiz de Fora: A Meirelles; Oswaldo Cruz Foundation: H Perazzo. Peru: Hospital Nacional Daniel Alcides Carrion, Callao: P Montes; Clínica Anglo Americana, Lima: M Tagle; Hospital Rebagliati: M Dávalos-Moscol. Ecuador: Hospital de Especialidades Eugenio Espejo, Quito: E Carrera; Hospital Teodoro Maldonado Carbo, Guayaquil: L Campos. Chile: Pontificia Universidad Católica de Chile: M Arrese, A Ruíz, R Zapata, RM Mellado; Hospital Clínico de Chile: JR Brahm, J Arancibia. Venezuela: Hospital Universitario de Maracaibo: M Lizarzábal, E Megual; Hospital Universitario de Caracas: M Garassini. Paraguay: Hospital de Clínicas: M Girala, M Gadischesky. Santo Domingo: Centro de Gastroenterología Avanzada: F Contreras. Mexico: Hospital Médica Sur: N Méndez-Sánchez; Hospital General de Mexico: D Kerschenobich, A Loaeza.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Gonzalez-Jimenez, A., Suzuki, A., Chen, M. et al. Drug properties and host factors contribute to biochemical presentation of drug-induced liver injury: a prediction model from a machine learning approach. Arch Toxicol 95, 1793–1803 (2021). https://doi.org/10.1007/s00204-021-03013-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-021-03013-3