Causes, Clinical Features, and Outcomes From a Prospective Study of Drug-Induced Liver Injury in the United States

doi:10.1053/j.gastro.2008.09.011

Gastroenterology

Volume 135, Issue 6, December 2008, Pages 1924-1934.e4

https://doi.org/10.1053/j.gastro.2008.09.011 Get rights and content

Background & Aims

Idiosyncratic drug-induced liver injury (DILI) is among the most common causes of acute liver failure in the United States, accounting for approximately 13% of cases. A prospective study was begun in 2003 to recruit patients with suspected DILI and create a repository of biological samples for analysis. This report summarizes the causes, clinical features, and outcomes from the first 300 patients enrolled.

Methods

Patients with suspected DILI were enrolled based on predefined criteria and followed up for at least 6 months. Patients with acetaminophen liver injury were excluded.

Results

DILI was caused by a single prescription medication in 73% of the cases, by dietary supplements in 9%, and by multiple agents in 18%. More than 100 different agents were associated with DILI; antimicrobials (45.5%) and central nervous system agents (15%) were the most common. Causality was considered to be definite in 32%, highly likely in 41%, probable in 14%, possible in 10%, and unlikely in 3%. Acute hepatitis C virus (HCV) infection was the final diagnosis in 4 of 9 unlikely cases. Six months after enrollment, 14% of patients had persistent laboratory abnormalities and 8% had died; the cause of death was liver related in 44%.

Conclusions

DILI is caused by a wide array of medications, herbal supplements, and dietary supplements. Antibiotics are the single largest class of agents that cause DILI. Acute HCV infection should be excluded in patients with suspected DILI by HCV RNA testing. The overall 6-month mortality was 8%, but the majority of deaths were not liver related.

Section snippets

Patients and Methods

The DILIN prospective study is an ongoing multicenter observational study. The study design and procedures were approved by the institutional review board of each clinical center site, and all enrolled patients provided written, fully informed consent. The study design has been described in detail elsewhere.²¹ In brief, patients (2 years of age or older) were enrolled in this study if there was a strong clinical suspicion that a liver injury event was caused by a medication or an herbal agent

Presenting Features

The 300 patients included in this report were enrolled between September 2004 and December 2007. Selected demographic and clinical characteristics are shown in Table 1. Ninety-three percent were adults (≥18 years), 18% were older than 65 years, and 60% were women. Six percent of patients had known liver disease before the onset of DILI, and 3% had underlying human immunodeficiency virus infection. Sixty-nine percent had jaundice during the DILI episode, and 60% were hospitalized. The median

Discussion

This is an initial analysis of an ongoing prospective study of DILI being performed in the United States, the primary aim of which is to develop well-characterized cases of medication-related liver injury on which to conduct hypothesis-driven research aimed at developing means to diagnose, prevent, and treat DILI. Among the first 300 cases identified, more than 100 different medications, herbal supplements, and dietary supplements were implicated. Newly identified hepatotoxic drugs that had

References (39)

L.B. Seeff
Herbal hepatotoxicity
Clin Liver Dis
(2007)
D.B. Strader et al.
Hepatotoxicity of herbal preparation
E. Elinav et al.
Association between consumption of Herbalife® nutritional supplements and acute hepatotoxicity
J Hepatol
(2007)
A.M. Schoepfer et al.
Herbal does not mean innocuous: ten cases of severe hepatotoxicity associated with dietary supplements from Herbalife® products
J Hepatol
(2007)
G. Danan et al.
Causality assessment of adverse reactions to drugs - IA novel method based on the conclusions of international consensus meeting
J Clin Epidemiol
(1993)
C. Benichou et al.
Causality assessment of adverse reactions to drugs–IIAn original model for validation of drug causality assessment methods: case reports with positive rechallenge
J Clin Epidemiol
(1993)
R.J. Andrade et al.
Drug induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period
Gastroenterology
(2005)
P.E. Ganey et al.
Adverse hepatic drug reactions: inflammatory episodes as consequence and contributor
Chem Biol Interact
(2004)
H.B. El-Serag et al.
Diabetes increases the risk of acute hepatic failure
Gastroenterology
(2002)
C. Sgro et al.
Incidence of drug-induced hepatic injuries: a French population-based study
Hepatology
(2002)

P.B. Watkins et al.

Drug-induced liver injury: summary of a single topic clinical research conference

Hepatology

(2006)

V.J. Navarro et al.

Drug-related hepatotoxicity

N Engl J Med

(2006)

G. Abboud et al.

Drug-induced liver injury

Drug Saf

(2007)

G. Ostapowicz et al.

Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States

Ann Intern Med

(2002)

J. Uetrecht

Idiosyncratic drug reactions: current understanding

Annu Rev Pharmacol Toxicol

(2007)

R.A. Wilkes et al.

Identifying genetic risk factors for serious adverse drug reactions: current progress and challenges

Nat Rev Drug Discov

(2007)

C. Lammert et al.

Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: search for signals

Hepatology

(2008)

J.R. Senior

What is idiosyncratic hepatotoxicity?What is not?

Hepatology

(2008)

D.N. Sarma et al.

Safety of green tea extracts: a systematic review by the US Pharmacopeia

Drug Saf

(2008)

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Rifampicin induced a dose-dependent hepatotoxicity in HHL-17 cells (IC₅₀; 600 μM), and increased the serum levels of liver injury markers, e.g., alanine transaminase (ALT) and aspartate transaminase (AST) in rats. Rifampicin-induced cell death was non-apoptotic and non-necroptotic both in vitro and in vivo. Further, excessive cellular vacuolization and reduced expression of Alix protein confirmed the induction of paraptosis both in vitro and in vivo. In addition, a significant increase in the endoplasmic reticulum (ER) stress markers (e.g., BiP, CHOP, and total polyubiquitinated proteins) was detected, demonstrating the induction of ER stress and altered protein homeostasis. Interestingly, rifampicin-induced hepatotoxicity was associated with the inhibition of autophagy and enhanced reactive oxygen species (ROS) generation in HHL-17 cells. Furthermore, inhibition of protein synthesis by cycloheximide (CHX) suppressed paraptosis by alleviating rifampicin-induced ER stress and ROS generation.
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Drug-induced liver injury (DILI) represents a significant clinical problem for which no standard treatment currently exists. Most DILI mechanisms center on oxidative stress resulting from glutathione depletion, excessive ROS production, and subsequent cell death. Flavonoid-rich Cyclopia intermedia E. Mey (honeybush) is a commercially important African herbal tea and is traditionally promoted as a restorative treatment. Cytotoxicity evaluation of a fermented C. intermedia extract in C3A hepatocytes confirmed the absence of toxicity up to 200 µg/mL using quantitative fluorescence microscopy with Hoechst 33342-PI dual-labeling. DPPH, NO scavenging, and ORAC assays established a strong antioxidant potential. Antioxidant bioavailability, assessed using the CAPe assay, indicated significant uptake at 100 µg/mL (p < 0.005). C. intermedia extract decreased TBHP-induced oxidative stress in C3A cells and attenuated TBHP-induced changes in thiol group levels at 200 µg/mL (p < 0.005) as confirmed by CellROX® Orange and ThiolTracker™ Violet staining, respectively. Apoptotic cell death was significantly reduced by the extract from 50 µg/mL (p < 0.005) as determined by Annexin-V FITC staining. These results suggest that C. intermedia can function as a hepatoprotectant and has potential as a treatment against DILI.
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Lipopolysaccharides (LPS), the lipid component of gram-negative bacterial cell wall, is recognized as the key factor in acute lung inflammation and is found to exhibit severe immunologic reactions. Phosphodiesterase-4 (PDE-4) inhibitor: “apremilast (AP)” is an immune suppressant and anti-inflammatory drug which introduced to treat psoriatic arthritis. The contemporary experiment designed to study the protective influences of AP against LPS induced lung injury in rodents. Twenty-four (24) male experimental Wistar rats selected, acclimatized, and administered with normal saline, LPS, or AP + LPS respectively from 1 to 4 groups. The lung tissues were evaluated for biochemical parameters (MPO), Enzyme Linked Immunosorbent Assay (ELISA), flowcytometry assay, gene expressions, proteins expression and histopathological examination. AP ameliorates the lung injuries by attenuating immunomodulation and inflammation. LPS exposure upregulated IL-6, TNF-α, and MPO while downregulating IL-4 which were restored in AP pretreated rats. The changes in immunomodulation markers by LPS were reduced by AP treatment. Furthermore, results from the qPCR analysis represented an upregulation in IL-1β, MPO, TNF-α, and p38 whereas downregulated in IL-10 and p53 gene expressions in disease control animals while AP pretreated rats exhibited significant reversal in these expressions. Western blot analysis suggested an upregulation of MCP-1, and NOS-2, whereas HO-1, and Nrf-2 expression were suppressed in LPS exposed animals, while pretreatment with AP showed down regulation in the expression MCP-1, NOS-2, and upregulation of HO-1, and Nrf-2 expression of the mentioned intracellular proteins. Histological studies further affirmed the toxic influences of LPS on the pulmonary tissues. It is concluded that, LPS exposure causes pulmonary toxicities via up regulation of oxidative stress, inflammatory cytokines and stimulation of IL-1β, MPO, TNF-α, p38, MCP-1, and NOS-2 while downregulation of IL-4, IL-10, p53, HO-1, and Nrf-2 at different expression level. Pretreatment with AP controlled the toxic influences of LPS by modulating these signaling pathways.
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Nitrofurantoin (NTF) is widely used for the treatment (short-term) and prevention (long-term) of urinary tract infections. We aimed to describe the clinical characteristics, outcomes, and HLA risk factors for NTF-induced liver injury (NTF-DILI) among individuals enrolled in the Drug Induced Liver Injury Network (DILIN).
Seventy-eight individuals with definite, highly likely, or probable NTF-DILI were enrolled into DILIN studies between 2004–2020. HLA alleles were compared between NTF-DILI and three control groups: population (n = 14,001), idiopathic autoimmune hepatitis (n = 231), and non-NTF DILI (n = 661).
Liver injury was hepatocellular in 69% and icteric in 55%. AST > ALT was more common in the 44 long-exposure (≥1 year) NTF-DILI cases than in the 18 short (≤7 days) and 16 intermediate (>7 to <365 days) exposure cases (73% vs. 33% vs. 50%, respectively, p = 0.018), as was ANA or SMA positivity (91% vs. 44% vs. 50%, respectively, p <0.001), and corticosteroid use (61% vs. 27% vs. 44%, respectively, p = 0.06). In long-term NTF-DILI, bridging fibrosis, nodularity or cirrhosis, or clinical and imaging evidence for cirrhosis were present in 38%, with massive or sub-massive necrosis in 20%. No one in the short-term exposure group died or underwent transplantation, whereas 7 (12%) patients from the other groups died or underwent transplantation. After covariate adjustments, HLA-DRB1∗11:04 was significantly more frequent in NTF-DILI compared to population controls (odds ratio [OR] 4.29, p = 1.15 × 10⁻⁴), idiopathic autoimmune hepatitis (OR 11.77, p = 7.76 × 10⁻⁵), and non-NTF DILI (OR 3.34, p = 0.003).
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Nitrofurantoin is a recognized cause of drug-induced liver injury (DILI). In this study consisting of a large cohort of well-phenotyped individuals with nitrofurantoin-induced liver injury, two distinct patterns of liver injury were identified: liver injury associated with short-term exposure, which is generally self-limiting, and liver injury associated with long-term exposure, which can lead to advanced fibrosis, cirrhosis and liver failure. HLA DRB1∗11:04 is a risk factor for liver injury due to long-term nitrofurantoin exposure. Our findings are important for regulators as well as physicians prescribing and pharmacists dispensing nitrofurantoin.

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: DILIN is supported by the National Institute of Diabetes and Digestive and Kidney Diseases under the following cooperative agreements: 1U01DK065201, 1U01DK065193, 1U01DK065184, 1U01DK065211, 1U01DK065238, and 1U01DK065176.

: The authors disclose the following: N.C. served as a paid consultant in the preceding 12 months to Takeda Pharmaceuticals, AtheroGenics, Advanced Life Sciences, Kari Bio, Metabasis, Pfizer, and Eli Lilly. He received research grant support from Debiovision and Sanofi-Aventis. On his behalf, his institution has initiated contract negotiations with Gilead Sciences and Pfizer for conducting clinical trials unrelated to drug-induced liver injury. He served as an expert witness for a product liability litigation involving suspected drug-induced liver injury.

: R.J.F. has served on the speakers' bureau or as a paid consultant during the past 12 months to Roche, Bristol-Myers Squibb, Vertex Pharmaceuticals, and Gilead Sciences.

: H.L.B. served as a paid advisor to InfaCare Pharmaceuticals, Novartis Pharmaceuticals, and Ovation Pharmaceuticals. He is on the speakers' bureau of Ovation Pharmaceuticals. He receives support for research studies from the American Porphyria Foundation, Merck, Novartis, Roche, and Vertex. During the past 12 months, he has served as an expert witness for plaintiffs in litigation regarding suspected drug-induced liver injury.

: P.B.W. served as a paid consultant in the preceding 12 months to the following pharmaceutical companies: Actelion, Aldus, Astellas, Bristol-Myers Squibb, Boehringer-Ingleheim, Danube, Endo, FibroGen, GlaxoSmithKline, Hoffmann-La Roche, Imtech, King, Millennium, Merck, Novartis, Nuon, Orion, Pfizer, Pharmasset, Schering Plough, TAP, Valiant, VIA, and Wyeth. He served as both a plaintiff and a defense expert in litigation involving suspected drug-induced liver injury.

: T.D. served as a paid consultant to Entelos and FibroGen. He served as both a plaintiff and a defense expert in litigation involving suspected drug-induced liver injury.

: J.S., H.Y., and J.R. have no potential conflicts of interest to report.

: Members of DILIN include the following: Clinical Centers—Indiana University: Naga Chalasani, MD (primary investigator), Raj Vuppalanchi, MD (coinvestigator), Jean Molleston, MD (coinvestigator), Lawrence Lumeng, MD (coinvestigator), Audrey Corne (research coordinator), Angie Plummer (research coordinator); University of Connecticut: Herbert Bonkovsky, MD (primary investigator), Petr Protiva, MD (coinvestigator), James Freston, MD, PhD (coinvestigator), Robert Rosson, MD (coinvestigator), Robert A. Levine, MD (satellite site investigator), Benedict Maliakkal, MD (satellite site investigator), Paul Appleton, MD (research coordinator), Mariola Smialek, RN (research coordinator); University of Michigan: Robert J. Fontana, MD (primary investigator), Hari Conjeevaram, MD (coinvestigator), Stuart Gordon, MD (satellite site investigator), Suzanne Welch (research coordinator), Jessica Worley (research coordinator), Jordan Kridler (research coordinator); University of North Carolina: Paul Watkins, MD (primary investigator), Paul Hayashi, MD (coinvestigator), Mark Russo, MD (coinvestigator), the late Harry Guess, MD, PhD (coinvestigator), Kimberly Beaver, MD (satellite site investigator), Alastair Smith, MD (satellite site investigator), James Lewis, MD (satellite site investigator), Susan Pusek (research coordinator); University of California, San Francisco: Tim Davern, MD (primary investigator), Maurizo Bonacini, MD (coinvestigator), Kristine Partovi (research coordinator). Data Coordinating Center—Duke Clinical Research Institute: James Rochon, MD (primary investigator), John McHutchison, MD (coinvestigator), Don Rockey, MD (coinvestigator), Mary Maggio (project manager), Hongqiu Yang, PhD (biostatistician); National Institute of Diabetes and Digestive and Kidney Diseases Scientists: Jose Serrano, MD (project officer), Leonard Seeff, MD, Jay Hoofnagle, MD, Mark Avigan, MD, and John Senior, MD, employees of the US Food and Drug Administration, have participated in selected aspects of DILIN activities.

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Clinical Advances in Liver, Pancreas, and Biliary TractCauses, Clinical Features, and Outcomes From a Prospective Study of Drug-Induced Liver Injury in the United States

Background & Aims

Methods

Results

Conclusions

Section snippets

Patients and Methods

Presenting Features

Discussion

Clin Liver Dis

J Hepatol

J Hepatol

J Clin Epidemiol

J Clin Epidemiol

Gastroenterology

Chem Biol Interact

Gastroenterology

Hepatology

Drug-induced liver injury: summary of a single topic clinical research conference

Hepatology

Drug-related hepatotoxicity

N Engl J Med

Drug-induced liver injury

Drug Saf

Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States

Ann Intern Med

Idiosyncratic drug reactions: current understanding

Annu Rev Pharmacol Toxicol

Identifying genetic risk factors for serious adverse drug reactions: current progress and challenges

Nat Rev Drug Discov

Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: search for signals

Hepatology

What is idiosyncratic hepatotoxicity?What is not?

Hepatology

Safety of green tea extracts: a systematic review by the US Pharmacopeia

Drug Saf

Clinical Advances in Liver, Pancreas, and Biliary Tract
Causes, Clinical Features, and Outcomes From a Prospective Study of Drug-Induced Liver Injury in the United States