Idiosyncratic liver injury

Critical Review Is There Sufficient Clinical, Pre-Clinical and In Vitro Data to Substantiate the Link Between Oxidative Stress and Idiosyncratic Liver Injury ... 

Zou W, Beggs KM, Sparkenbaugh EM, et al. Sulindac metabolism and synergy with tumor necrosis factor-alpha in a drug-inflammation interaction model of idiosyncratic liver injury. / Pharmacol Exp Ther. 2009 331(1) 114-121. 

Jaeschke, H. Troglitazone hepatotoxicity Are we getting closer to understanding idiosyncratic liver injury Toxicol. Sci. 2007, 97, 1-3. 

A number of experimental and clinical reports have suggested that a variety of factors unrelated to drug metabolism and direct hepatotoxicity may also influence susceptibility to DILL In addition, the nature of idiosyncratic liver injuries suggests that a majority of these reactions involve an immune mechanism. Hepatic cellular dysfunction and death have the ability to initiate immunological reactions, including both adaptive and innate immune responses. This inflammatory process has been implicated in the development of liver injury induced by such drugs as APAP, dihydralazine, and halothane (Laskin and Gardner 2003 Liu and Kaplowitz 2002 Luster et al. 2001). 

DILI is a term that describes a condition in which medical intake of a drag(s) causes an individual to have abnormalities in liver tests, often manifested by an increase in serum ALT levels. DILI can cause severe liver injury, with the most catastrophic consequence being acute liver failure leading to death or requiring a liver transplant (Ulrich 2007). It has been estimated that around 60% of all cases of acute liver failure are caused by drugs (Kaplowitz 2005 Ostapowicz et al. 2002). The clinical cases of acute liver failure due to DILI are primarily due to overdose of APAP ( 50% of acute liver failure due to drugs) and drugs that cause idiosyncratic liver injury (-10%). 

Waldhauser KM, Torok M, Ha HR, Thomet U, Konrad D, Brecht K, Follath F, Krahenbuhl S (2006) Hepatocellular toxicity and pharmacological effect of amiodarone and amiodarone derivatives. J Pharmacol Exp Ther 319(3) 1413-1423 Wang Y, Singh R, Lefkowitch JH, Rigoli RM, Czaja MJ (2006) Tumor necrosis factor-induced toxic liver injury results from JNK2-dependent activation of caspase-8 and the mitochondrial death pathway. J Biol Chem 281(22) 15258-15267 Watkins PB (2005) Idiosyncratic liver injury challenges and approaches. Toxicol Pathol 33 (l) l-5... 

Metushi, I. G., Hayes, M. A., Uetrecht, J. 2015. Treatment of PD-1(-/-) mice with amodiaquine and anti-CTLA4 leads to hver injury similar to idiosyncratic liver injury in patients. Hepatology, 61, 1332-42. 

Lammert, C., Einarsson, S., Saha, C Niklasson, A., Bjornsson, E. and Chalasani, N. (2008) Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury search for signals. Hepatology (Baltimore, Md), 47, 2003-2009. 

What are the key strategies in predicting DILI Most of the DILI are idiosyncratic, meaning that not all patients taking the drug will experience liver toxicity. In fact, only a small percentage of patients (typically fewer than 1 in 100) will experience elevated liver enzymes in their sera (a biomarker for liver injury), and even a smaller percentage (typically fewer than 1 in 1,000 patients) will go... 

Lucena MI, Andrade RJ, Martinez C, et al. Glutathione S-transferase ml and tl null genotypes increase susceptibility to idiosyncratic drug-induced liver injury. Hepatology. 2008 48(2) 588-596. 

Shaw PJ, Ditewig AC, Waring JF, et al. Coexposure of mice to trovafloxacin and lipopolysaccharide, a model of idiosyncratic hepatotoxicity, results in a unique gene expression profile and interferon gamma-dependent liver injury. Toxicol Sci. 2009 107(l) 270-280. 

Aithal GP. Diclofenac-induced liver injury A paradigm of idiosyncratic drug toxicity. Expert Opin Drug Saf. 2004 3(6) 519-523. 

Amacher DE (2012) The primary role of hepatic metabolism in idiosyncratic drug-induced liver injury. Expert Opin Drug Metab Toxicol 8(3) 335-347... 

For reasons that are unclear, drug-induced liver injury affects females more than males Females accounted for approximately 79% of all reactions to acetaminophen and 73% of all idiosyncratic drug-induced reactions (88). Females exhibit increased risk of hepatic injury from drugs such as atorvastatin, nitrofurantoin, methyidopa, and diclofenac. 

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