Drug-induced liver injury: the dawn of biomarkers?

Abstract

Drug-induced liver injury (DILI) is a potentially fatal adverse event with significant medical and economic impact. Many drugs, especially anti-infective, neurologic or pain-modifying substances, act as hepatotoxins. With cardiovascular toxicity, liver toxicity is one of the two leading causes for drug withdrawal from the market. The liver can be affected directly, in a predictable and dose-dependent manner, or idiosyncratically, independent of the dose and therefore unpredictable.Currently DILI is a diagnosis of exclusion that physicians have to bear in mind in patients with an unexplained increase of liver enzymes. The type of injury is categorized into hepatocellular, cholestatic, or mixed by the respective enzyme pattern of injury. Symptoms of affected patients can mimic any other liver disease.Therefore, new diagnostic and prognostic biomarkers for early liver injury are currently being evaluated in multi-centre clinical trials that are conducted by international consortia and other initiatives. Pharmacogenetic testing, next-generation sequencing, proteomics, metabolomics and mechanistic markers can help to preselect susceptible patient populations and tailor drug therapy to individual patients. Proposed DILI indicators that are under investigation include microRNAs, cytokeratin-18 (CK18), high mobility group box protein 1 (HMGB-1), and several other biomarkers. These developments can change clinical practice, and improve patients' safety and management. However, they have not been translated into clinical practice or approved for routine use yet. Management of DILI usually consists of initial withdrawal of the suspected drug and—if applicable—administration of specific antidotes, such as N-acetylcysteine. However, the overall management of DILI could change in the near future with the advent of novel diagnostic and prognostic DILI markers.

Clinical decision support for drug related events: Moving towards better prevention

“…Research continues to find biomarkers to indicate drug injury such as microRNAs and serum metabolites presenting as better indicators than ALT[58]. Biomarkers, such as the ones discussed above, can be employed in the future to guide clinicians in making early interventions with CDS alerts.…”

Metabolômica: Definições, Estado-Da-Arte E Aplicações Representativas

“…A metabolômica tem sido aplicada na toxicologia forense e trabalhos nessa área têm sido revisados frequentemente, [258][259][260][261][262] mostrando que o estudo comparativo do perfil metabólico pode desempenhar um papel importante na descoberta e validação de novos biomarcadores, além de contribuir para o entendimento e consequente interpretação dos mecanismos de ação tóxica de xenobióticos. 263 A dependência de drogas como cocaína, anfetaminas, opióides e etanol é um grave problema de saúde pública e, recentemente, estudos de metabolômica vem sendo conduzidos para [264][265][266][267][268] na busca por biomarcadores para hepatotoxicidade e nefrotoxicidade induzida pela ação de drogas 269,270 e, ainda, métodos de quantificação de drogas e seus metabólitos vêm sendo desenvolvidos para aplicação em diversas matrizes biológicas. 271 No que tange às ciências forenses, a metabolômica tem sido utilizada em diferentes aplicações, com análise em diversos biofluidos como urina, plasma, cabelo, unha, saliva, etc., 272 abordagem metabolômica alvo, os autores determinaram a presença de diversos neurotransmissores e seus metabólitos, tais como noradrenalina, serotonina, ácido 5-hidroxi-indolacético, dopamina, e ácido 3,4-dihidroxifenilacético, no córtex frontal, estriado e tálamo de ratos controle e tratados com cocaína.…”

Bile acids in drug induced liver injury: Key players and surrogate markers

“…In addition, conjugated BAs were higher than unconjugated BAs in the patient group. The portion of free and conjugated CA in serum was also higher in subjects with liver injury compared to healthy controls The IMI SAFE-T consortium, a public-private partnership between industry, health authorities and academia, is currently evaluating BA profiles as potential markers for drug-induced BA transporter inhibition and liver injury [101]. The complexity of this endeavor lies in the fact that different mechanisms can lead to changes in BA profiles with overlapping effects.…”