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Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspectives.

ABSTRACT: Idiosyncratic drug-induced liver injury (DILI) is a rare disease that develops independently of drug dose, route, or duration of administration. Furthermore, idiosyncratic DILI is not a single disease entity but rather a spectrum of rare diseases with varying clinical, histological, and laboratory features. The pathogenesis of DILI is not fully understood. Standardization of the DILI nomenclature and methods to assess causality, along with the information provided by the LiverTox Web site, will harmonize and accelerate research on DILI. Studies of new serum biomarkers such as glutamate dehydrogenase, high mobility group box protein 1, and microRNA-122 could provide information for use in diagnosis and prognosis and provide important insights into the mechanisms of the pathogenesis of DILI. Single nucleotide polymorphisms in the HLA region have been associated with idiosyncratic hepatotoxicity attributed to flucloxacillin, ximelagatran, lapatinib, and amoxicillin-clavulanate. However, genome-wide association studies of pooled cases have not associated any genetic factors with idiosyncratic DILI. Whole genome and whole exome sequencing analyses are under way to study cases of DILI attributed to a single medication. Serum proteomic, transcriptome, and metabolome as well as intestinal microbiome analyses will increase our understanding of the mechanisms of this disorder. Further improvements to in vitro and in vivo test systems should advance our understanding of the causes, risk factors, and mechanisms of idiosyncratic DILI.

SUBMITTER: Fontana RJ

PROVIDER: S-EPMC4031195 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspectives.

Fontana Robert J RJ

Gastroenterology 20131231 4

Idiosyncratic drug-induced liver injury (DILI) is a rare disease that develops independently of drug dose, route, or duration of administration. Furthermore, idiosyncratic DILI is not a single disease entity but rather a spectrum of rare diseases with varying clinical, histological, and laboratory features. The pathogenesis of DILI is not fully understood. Standardization of the DILI nomenclature and methods to assess causality, along with the information provided by the LiverTox Web site, will ...[more]

PMID: 24389305

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Project description:Background & aimsChronic outcome following acute idiosyncratic drug-induced liver injury (DILI) is not yet defined. This prospective, long-term follow-up study aimed to analyze time to liver enzyme resolutions to establish the best definition and risk factors of DILI chronicity.Methods298 out of 850 patients in the Spanish DILI registry with no pre-existing disease affecting the liver and follow-up to resolution or ⩾1year were analyzed. Chronicity was defined as abnormal liver biochemistry, imaging test or histology one year after DILI recognition.ResultsOut of 298 patients enrolled 273 (92%) resolved ⩽1year from DILI recognition and 25 patients (8%) were chronic. Independent risk factors for chronicity were older age [OR: 1.06, p=0.011], dyslipidemia [OR: 4.26, p=0.04] and severe DILI [OR: 14.22, p=0.005]. Alanine aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin (TB) median values were higher in the chronic group during follow-up. Values of ALP and TB >1.1 x upper limit of normal (xULN) and 2.8 xULN respectively, in the second month from DILI onset, were found to predict chronic DILI (p<0.001). Main drug classes involved in chronicity were statins (24%) and anti-infectives (24%). Histological examination in chronic patients demonstrated two cases with ductal lesion and seven with cirrhosis.ConclusionsOne year is the best cut-off point to define chronic DILI or prolonged recovery, with risk factors being older age, dyslipidemia and severity of the acute episode. Statins are distinctly related to chronicity. ALP and TB values in the second month could help predict chronicity or very prolonged recovery.Lay summaryDrug-induced liver injury (DILI) patients who do not resolve their liver damage during the first year should be considered chronic DILI patients. Risk factors for DILI chronicity are older age, dyslipidemia and severity of the acute episode. Chronic DILI is not a very common condition; normally featuring mild liver profile abnormalities and not being an important clinical problem, with the exception of a small number of cases of early onset cirrhosis.

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Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspectives.

Publications

Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspectives.

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