Abstract
Drug-induced liver injury (DILI) is a potentially fatal adverse event and the leading cause of acute liver failure in the US and in the majority of Europe. The liver can be affected directly, in a dose-dependent manner, or idiosyncratically, independently of the dose, and therefore unpredictably. Currently, DILI is a diagnosis of exclusion that physicians should suspect in patients with unexplained elevated liver enzymes. Therefore, new diagnostic and prognostic biomarkers are necessary to achieve an early and reliable diagnosis of DILI and thus improve the prognosis. Although several DILI biomarkers have been found through analytical and genetic tests and pharmacokinetic approaches, none of them have been able to display enough specificity and sensitivity, so new approaches are needed. In this sense, metabolomics is a strongly and promising emerging field that, from biofluids collected through minimally invasive procedures, can obtain early biomarkers of toxicity, which may constitute specific indicators of liver damage.
Highlights
Liver injury due to both prescription and over-the-counter drugs is a growing public health problem
We have developed two animal models for studying this type of druginduced liver injury (DILI): lipopolysaccharide (LPS) Costimulation, consisting in the administration of potentially hepatotoxic drug after nontoxic doses of LPS [31] and Mn-SOD (+/−) heterozygous mice, which possess a decreased activity of the superoxide dismutase 2 (SOD2, the mitochondrial form of superoxide dismutase which protects against reactive oxygen species (ROS)) [32, 33]
Urine metabolomic profiles obtained 2 days prior to treatment were not sufficient to predict the development of mild liver damage, but the profiles obtained after a short period of administration of APAP were able to predict it. These results suggest that, before the drug administration, the differences in metabotypes are too small to be detected beyond the inherent variation of the population and that, after administration of the drug, changes in the endogenous metabolites can allow us to distinguish between those individuals who will adapt to the initial mild liver damage from those susceptible to developing a more severe liver damage [45]
Summary
Liver injury due to both prescription and over-the-counter drugs is a growing public health problem. Even though different genetic variants and biomarkers have been associated with the risk of developing DILI, hepatotoxicity remains a very common side effect. These variants include different HLA alleles [9,10,11] and various serum biomarkers, such as miRNA-122, high-mobility group box-1 (HMGB-1), full length and caspase-cleaved keratin-18 (K-18), and glutamate dehydrogenase (GLDH) [12]. Since DILI is associated with increased morbidity and can lead to ALF, liver transplant, and death, it would be desirable that physicians could and early establish the diagnosis. BioMed Research International of DILI identifying those patients with a poor prognosis.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
