Drug-induced liver injury: the dawn of biomarkers?
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.
Department of Clinical Pharmacology and Toxicology, University Hospital Zurich Raemistrasse 100, CH-8091 Zurich Switzerland.
Stefan
S
Weiler
Discovery and Investigative Safety, Novartis Institutes for BioMedical Research Klybeckstrasse 141, 4057 Basel Switzerland.
Michael
M
Merz
Department of Clinical Pharmacology and Toxicology, University Hospital Zurich Raemistrasse 100, CH-8091 Zurich Switzerland ; Discovery and Investigative Safety, Novartis Institutes for BioMedical Research Klybeckstrasse 141, 4057 Basel Switzerland.
Gerd A
GA
Kullak-Ublick