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Cited by 925Drug-Induced Hepatotoxicity and ProtectionPharmacovigilance and Adverse Drug ReactionsDrug-Induced Adverse Reactions

Features and outcomes of 899 patients with drug-induced liver injury: the DILIN Prospective Study

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Chalasani, Naga, Bonkovsky, Herbert L., Fontana, Robert, Lee, William, Stolz, Andrew, Talwalkar, Jayant, Reddy, K. Rajendar, Watkins, Paul B. +74 more·2015·Gastroenterology
DOI 10.1053/j.gastro.2015.03.006PMC PMC4446235
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Abstract

Background & aims The Drug-Induced Liver Injury Network is conducting a prospective study of patients with DILI in the United States. We present characteristics and subgroup analyses from the first 1257 patients enrolled in the study.Methods In an observational longitudinal study, we began collecting data on eligible individuals with suspected DILI in 2004, following them for 6 months or longer. Subjects were evaluated systematically for other etiologies, causes, and severity of DILI.Results Among 1257 enrolled subjects with suspected DILI, the causality was assessed in 1091 patients, and 899 were considered to have definite, highly likely, or probable DILI. Ten percent of patients died or underwent liver transplantation, and 17% had chronic liver injury. In the 89 patients (10%) with pre-existing liver disease, DILI appeared to be more severe than in those without (difference not statistically significant; P = .09) and mortality was significantly higher (16% vs 5.2%; P < .001). Azithromycin was the implicated agent in a higher proportion of patients with pre-existing liver disease compared with those without liver disease (6.7% vs 1.5%; P = .006). Forty-one cases with latency ≤7 days were caused predominantly by antimicrobial agents (71%). Two most common causes for 60 DILI cases with latency >365 days were nitrofurantoin (25%) or minocycline (17%). There were no differences in outcomes of patients with short vs long latency of DILI. Compared with individuals younger than 65 years, individuals 65 years or older (n = 149) were more likely to have cholestatic injury, although mortality and rate of liver transplantation did not differ. Nine patients (1%) had concomitant severe skin reactions; implicated agents were lamotrigine, azithromycin, carbamazepine, moxifloxacin, cephalexin, diclofenac, and nitrofurantoin. Four of these patients died.Conclusions Mortality from DILI is significantly higher in individuals with pre-existing liver disease or concomitant severe skin reactions compared with patients without. Additional studies are needed to confirm the association between azithromycin and increased DILI in patients with chronic liver disease. Older age and short or long latencies are not associated with DILI mortality.

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  • SMX-TMP is in the top five leading drugs implicated in idiosyncratic DILI in the United States.

    “Importantly, SMX-TMP is in the top five leading drugs implicated in idiosyncratic DILI in the United States.11”

    From N-Acetyltransferase (NAT) 1 and NAT2 Enzyme Activities Drive Interindividual Variability in Sulfamethoxazole N-Acetylation (2025) · cites this paper as [11]

    The Results section on comparisons among frequent agents discusses DILI due to trimethoprim-sulfamethoxazole in its analysis of the ten most frequent prescription drugs. The passages available from our copy do not establish that it ranked in the top five; they also describe a US study cohort rather than a nationwide ranking. (LLM, conf=0.82)

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Authors
Chalasani, N., Bonkovsky, H. L., Fontana, R., Lee, W., Stolz, A., Talwalkar, J., Reddy, K. R., Watkins, P. B., Navarro, V., Barnhart, H., Gu, J., Serrano, J., Ahmad, J., Bach, N., Bansal, M., Barnhart, H. X., Beavers, K., Bonkovsky, H., Calvo, F. O., Chalasani, N., Chang, C., Conjeevaram, H., Conner, G., Darling, J., de Boer, Y., Dieterich, D., DiPaola, F., Durazo, F. A., (Jay) Everhart, J. E., Fontana, R. J., Ghabril, M. S., Goldstein, D., Gopalreddy, V., Grewal, P., Hayashi, P. H., Hoofnagle, J., Kaplowitz, N., Liangpunsakul, S., Lichtman, S., Liu, L., Navarro, V. J., Odin, J., Rossi, S., Russo, M., Schiano, T., Serrano, J., Sherker, A. H., Stolz, A., Vuppalanchi, R., Watkins, P., Zacks, S., Balasco, A., Chesney, K., Corne, A., Cummings, S., Groseclose, G., Hammett, A., Hooker, J., Kesar, V., Mao, S., Marks, K., McFadden, R., Melgoza, Y., Mikhail, S., Milstein, S., Morlan, W., Peacock, V., Rosado, N., Russell, T., Vega, M., Verma, M., Walker, P., Yalamanchili, R., McClanahan-Crowder, M., Galan, K., (Sherry) Gu, J., Chau, T., Ragavan, K., Rostami, H., Puglisi-Scharenbroich, C., Torrance, R. J., & Van Raaphorst, R.
Affiliations
  • The University of Texas at Austin (US)
  • Mayo Clinic (US)
  • University of Pennsylvania (US)
  • Indiana University Indianapolis (US)
ORCID
Venue
Gastroenterology
Publisher
Elsevier BV
Published
2015-06
Volume
148
Issue
7
Pages
1340-1352.e7
ISSN
0016-5085 (ISSN-L)
DOI
10.1053/j.gastro.2015.03.006
PMC
PMC4446235
OpenAlex
W2075352120
Cited by
925
References
35
Citations by year
2026: 62 · 2025: 92 · 2024: 92 · 2023: 90 · 2022: 82 · 2021: 118 · 2020: 104 · 2019: 81 · 2018: 69 · 2017: 74 · 2016: 44 · 2015: 15 · 2014: 1
FWCI
78.31
Type
journal article
Language
en
Open access
Licence
Locations
  • Gastroenterology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion)
  • Purdue University Indianapolis (Indiana University) (submittedVersion)
Funders
  • University of Southern California
  • Purdue University
  • University of Pennsylvania
  • University of Texas Southwestern Medical Center
  • Georgia Clinical and Translational Science Alliance (UL1RR024986, UL1 RR025747, UL1RR024982, UL1 RR024150, UL1 RR025761, UL1 RR024134)
  • National Institutes of Health (5u01dk065211-22, UL1TR001105, UL1TR001108, 5u01dk065238-11, 5u01dk065193-05, 5u01dk065184-22, RR024150, RR025747, RR025761, RR024982)
  • University of California, Los Angeles
  • University of California, San Francisco
  • National Cancer Institute (RR025761)
  • National Institute of Diabetes and Digestive and Kidney Diseases (U01 DK-065238, U01‐DK065193, U01 DK-065184, DK065211, DK082992, U01DK083023, DK065184, U01 DK-065211, U01DK082992, DK083020, DK065238, DK083023, RR024986, U01DK100928, DK 065201, DK083027, U01DK083027, U01DK065201, U01DK083020, U01DK065176)
  • National Center for Research Resources (UL1RR024986, UL1RR024982, UL1RR025761, UL1RR024134, UL1RR025747, UL1RR024150)
  • National Center for Advancing Translational Sciences
  • Duke Clinical Research Institute
  • School of Medicine, University of North Carolina at Chapel Hill
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
  • Health Sciences › Medicine › Pharmacology › Drug-Induced Adverse Reactions
Keywords
drug-induced liver injury, Drug-Induced Liver Injury Network, mortality, liver transplantation, chronic liver injury, pre-existing liver disease, azithromycin, nitrofurantoin, minocycline, antimicrobial agents, cholestatic liver injury, severe cutaneous adverse reactions, age and mortality
MeSH terms
Adult, Age Factors, Aged, Drug Eruptions, Female, Humans, Longitudinal Studies, Male, Middle Aged, Prognosis, Prospective Studies, Risk Factors, Severity of Illness Index, Time Factors, United States, Comorbidity, Chemical and Drug Induced Liver Injury, Chemical and Drug Induced Liver Injury, Chronic

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