A Prospective Nationwide Study of Drug-Induced Liver Injury in Korea
ABSTRACT To address a growing concern about drug-induced liver injury (DILI), a nationwide study was performed to investigate the significance of DILI in Korea.
From May 2005 to May 2007, cases of DILI (alanine transferase >3 × upper normal limit or total bilirubin >2 × upper normal limit) from 17 referral university hospitals were prospectively enrolled. Adjudication by the seven review boards was considered for the confirmation of causality and the Roussel Uclaf Causality Assessment Method (RUCAM) scale was used.
A total of 371 cases were diagnosed with DILI. The extrapolated incidence of hospitalization at university hospital in Korea was 12/100,000 persons/year. The causes included "herbal medications" (102, 27.5%), "prescription or non-prescription medications" (101, 27.3%), "health foods or dietary supplements" (51, 13.7%), "medicinal herbs or plants" (35, 9.4%), "folk remedies" (32, 8.6%), "combined" (30, 8.2%), "herbal preparations" (12, 3.2%), and others (8, 2.2%). Nine cases were linked to acetaminophen. The frequencies of hepatocellular, mixed, and cholestatic types were 76.3, 14.8, and 8.9%, respectively. A total of 234 cases met the criteria for Hy's law. Five patients died or underwent transplantation. Twenty-five cases (21 herbs and 4 medications) did not meet the time-to-onset criteria of the RUCAM.
DILI appears to be a highly relevant health problem in Korea. "Herbal medications" are the principal cause of DILI. A more objective and reproducible causality assessment tool is strongly desired as the RUCAM scale frequently undercounts the cases caused by herbs owing to a lack of previous information and incompatible time criteria.
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ABSTRACT: Herbal medicines have been generally believed to be safe. With the increasing use of herbal medicine worldwide, however the safety of traditional herbal drugs frequently becomes a medical issue. This study was aimed to characterize the safe dose of herbal medicines via the systematic review for "human equivalent dose (HED)" from animal-based toxicity studies. A literature search for animal-based toxicity studies of herbal medicines in eight databases, including PubMed and Embase, was performed without language restriction. From the "no observed adverse effect level (NOAEL)" of each animal study, HED values were then calculated according to the composition (single or multiple herbs) and indication of the medicines. Among 729 relevant articles identified in the initial screening, 112 (233 studies comprising 107 single-herb and 126 multiple-herb studies) that met our inclusion criteria were finally reviewed. The total average HED value (from mouse, rat, rabbit and dog) was 278.1±358.0mg/kg, and the values for single- and multiple-herb studies were 322.7±488.4mg/kg and 241.5±189.2mg/kg, respectively. When the studies were analyzed according to herbal drug indication, drugs used for revitalization had the highest HED value (433.0±265.2mg/kg), while those for infectious diseases had the lowest (120.3±124.3mg/kg). Our results provide important information regarding the safe dose of herbal medicines; thus, these data offer researchers and practitioners information critical for drug development or clinical application. Copyright © 2014. Published by Elsevier Ireland Ltd.Journal of Ethnopharmacology 12/2014; 162. DOI:10.1016/j.jep.2014.12.023 · 2.94 Impact Factor
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ABSTRACT: Background and AimsWe aimed to explore the effectiveness of preventive usage of hepatoprotectors in patients with tuberculosis (TB) receiving anti-TB treatment.Methods With stratified cluster sampling strategy, a prospective cohort with 4488 sputum smears positive pulmonary TB patients was established from 52 counties of four regions in China. During anti-TB treatment, prescriptions of hepatoprotectors were documented in detail, and liver enzymes were routinely monitored. Anti-TB drug-induced liver injury (ATLI) was assessed based on liver enzymes following the criteria of American Thoracic Society. The incidence of ATLI between the preventive usage group and reference group was compared by propensity score adjusted Cox proportional hazard analysis. Preexisting diseases, history of liver disease, hepatitis B surface antigen status, primary/re-treatment of TB, income per year, and liver enzymes before anti-TB treatment were included in the propensity score model.ResultsAfter 6-9 months of follow-up and monitoring, 4304 patients sustained in our cohort. Two thousand seven hundred fifty-two (63.9%) patients preventively took hepatoprotectors with a median course of 183 days. Most frequently used drugs were Hu Gan Pian, silymarin, glucurone, and inosine. Two thousand one hundred forty-four (77.9%) patients took those drugs more than 6 months. Sixty-nine (2.4%) patients of preventive usage group and 37 (2.5%) of reference group experienced ATLI, respectively. Statistical significances were not found by propensity score analysis for the association between using hepatoprotectors (hazard ratio[HR] = 0.99, 95% confidence interval [CI]: 0.65-1.52), using hepatoprotectors in the whole course (HR = 0.94, 95% CI: 0.60-1.48), using Hu Gan Pians, silymarin, glucurone, and inosine with ATLI occurrence.Conclusions No preventive effect of hepatoprotectors was observed in patients receiving anti-TB treatment.Journal of Gastroenterology and Hepatology 08/2014; 30(3). DOI:10.1111/jgh.12717 · 3.63 Impact Factor
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ABSTRACT: Abstract Objectives. The purposes of this study were to investigate the clinical presentation, cause and outcome of drug-induced liver injury (DILI) and to evaluate the predictive value of the model for end-stage liver disease (MELD) score in DILI. Methods. Patients diagnosed with DILI between January 1, 2010 and December 31, 2012 in the Emergency Department at Asan Medical Center in Seoul, Korea were analyzed retrospectively. The primary end point was poor outcome, defined as liver transplantation or death within 30 days of the initial hospital visit. Results. Of 213 patients, 13.1% had a 30-day poor outcome. Folk remedies were the most common cause of DILI in 147 patients (69%). Univariate logistic regression analysis showed that multiple drugs (odds ratio [OR] 2.30, 95% confidence interval [CI]: 1.03-5.15), concurrent alcohol consumption (OR 3.69, 95% CI: 1.03-13.18), white blood cell (WBC) count (OR 1.17, 95% CI: 1.07-1.28), hemoglobin (Hb) (OR 0.60, 95% CI: 0.49-0.74), platelet count (OR 0.993, 95% CI: 0.987-0.998), total bilirubin (OR 1.09, 95% CI: 1.06-1.13) and MELD (OR 1.23, 95% CI: 1.15-1.32) were significantly associated with 30-day poor outcomes. Multivariate analysis showed that the MELD (OR 1.21, 95% CI: 1.12-1.30) and Hb (OR 0.77, 95% CI: 0.61-0.98) were independent predictors of poor outcome. For 30-day mortality, the c-statistics for MELD alone and for combination of MELD and Hb were 0.93 (95% CI: 0.89-0.97) and 0.94 (95% CI: 0.90-0.97), respectively. Conclusion. The outcome of patients with DILI was poor. MELD score and Hb were reliable predictors of short-term outcome in patients with DILI.Scandinavian Journal of Gastroenterology 02/2015; 50(4):1-8. DOI:10.3109/00365521.2014.958094 · 2.33 Impact Factor