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      A Challenge for Diagnosing Acute Liver Injury with Concomitant/Sequential Exposure to Multiple Drugs: Can Causality Assessment Scales Be Utilized to Identify the Offending Drug?

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          Abstract

          Drug-induced hepatotoxicity most commonly manifests as an acute hepatitis syndrome and remains the leading cause of drug-induced death/mortality and the primary reason for withdrawal of drugs from the pharmaceutical market. We report a case of acute liver injury in a 12-year-old Hispanic boy, who received a series of five antibiotics (amoxicillin, ceftriaxone, vancomycin, ampicillin/sulbactam, and clindamycin) for cervical lymphadenitis/retropharyngeal cellulitis. Histopathology of the liver biopsy specimen revealed acute cholestatic hepatitis. All known causes of acute liver injury were appropriately excluded and (only) drug-induced liver injury was left as a cause of his cholestasis. Liver-specific causality assessment scales such as Council for the International Organization of Medical Sciences/Roussel Uclaf Causality Assessment Method scoring system (CIOMS/RUCAM), Maria and Victorino scale, and Digestive Disease Week-Japan were applied to seek the most likely offending drug. Although clindamycin is the most likely cause by clinical diagnosis, none of causality assessment scales aid in the diagnosis.

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          Drug-induced hepatotoxicity.

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            Causality assessment of adverse reactions to drugs--II. An original model for validation of drug causality assessment methods: case reports with positive rechallenge.

            Standards are lacking for validation of drug causality assessment methods. An original model is proposed using a positive rechallenge as an external standard. This model was used to validate the novel causality assessment method (RUCAM) described in the previous article (Part I; J Clin Epidemiol 1993; 46: 1323). Seventy seven reports of drug-induced acute liver injuries with positive rechallenge were collected from the medical literature and divided into 49 cases and 28 controls. The RUCAM was applied to information obtained prior to readministration. The score was significantly higher (p < 10(-4)) in cases than in controls with high levels of sensitivity, specificity and predictive values. It is concluded that (1) adverse drug reaction reports with a positive rechallenge can provide a standard for validation of causality assessment methods, (2) RUCAM applied to drug-induced liver injuries has been validated.
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              Standardization of nomenclature and causality assessment in drug-induced liver injury: summary of a clinical research workshop.

              Idiosyncratic drug-induced liver injury (DILI) is an important but relatively infrequent cause of potentially severe acute and chronic liver injury. The aim of this clinical research workshop was to review and attempt to standardize the current nomenclature and terminology used in DILI research. Because DILI is a diagnosis of exclusion, selected elements of the medical history, laboratory tests, and previous reports were proposed to improve causality assessment. Definitions and diagnostic criteria regarding the onset of DILI, evolution of liver injury, risk factors, and mandatory testing versus optional testing for competing causes were reviewed. In addition, the role of intentional and inadvertent rechallenge, liver histology, and host genetic polymorphisms in establishing the diagnosis and prognosis of DILI were reviewed. Consensus was established regarding the need to develop a web-of-knowledge database that provides concise, reliable, and updated information on cases of liver injury due to drugs and herbal and dietary supplements. In addition, the need to develop drug-specific computerized causality assessment methods that are derived from prospectively phenotyped cases was a high priority. Proposed scales for grading DILI severity and assessing the likelihood of an agent causing DILI and written criteria for improving the reliability, accuracy, and reproducibility of expert opinion were reviewed. Finally, the unique challenges of assessing causality in children, patients with underlying liver disease, and subjects taking herbal and dietary supplements were discussed. Workshop participants concluded that multicenter referral networks enrolling patients with suspected DILI according to standardized methodologies are needed. These networks should also collect biological samples that may provide crucial insights into the mechanism(s) of DILI with the ultimate aim of preventing future cases of DILI.
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                Author and article information

                Journal
                Case Rep Pediatr
                Case Rep Pediatr
                CRIPE
                Case Reports in Pediatrics
                Hindawi Publishing Corporation
                2090-6803
                2090-6811
                2014
                24 November 2014
                : 2014
                : 156389
                Affiliations
                Division of Pediatric Gastroenterology and Nutrition, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
                Author notes
                *Wikrom Karnsakul: wkarnsa1@ 123456jhmi.edu

                Academic Editor: Nan-Chang Chiu

                Author information
                http://orcid.org/0000-0001-6720-724X
                Article
                10.1155/2014/156389
                4260426
                25506455
                30b8dc13-a53e-4a03-9c9c-94f2826ef508
                Copyright © 2014 Roxanne Lim et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 25 August 2014
                : 1 November 2014
                : 2 November 2014
                Categories
                Case Report

                Pediatrics
                Pediatrics

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