Epidemiology and Genetic Risk Factors of Drug Hepatotoxicity

Abstract

Idiosyncratic drug-induced liver injury (DILI) from prescription medications and herbal and dietary supplements has an annual incidence rate of approximately 20 cases per 100,000 per year. However, the risk of DILI varies greatly according to the drug. In the United States and Europe, antimicrobials are the commonest implicated agents, with amoxicillin/clavulanate the most common, whereas in Asian countries, herbal and dietary supplements predominate. Genetic analysis of DILI is currently limited, but multiple polymorphisms of human leukocyte antigen genes and genes involved in drug metabolism and transport have been identified as risk factors for DILI.

Keywords: Drug-induced liver injury (DILI); Epidemiology; Genetics.

Figure 1:

World map illustrating countries with DILI incidence data. Most of the world lacks any reliable data on DILI incidence.

Figure 2:

Pattern of liver injury based on national data The higher percentage of hepatocellular injury in Korea reflects the implicated drugs as the vast majority of cases there are related to herbal and dietary supplements. (Data from references 2, 4, 8, 9)

Figure 3:

Candidate Gene Approach to DILI Genetics Discovery. The large number of hepatic proteins involved in drug metabolism can be placed in three broad categories: bioactivation and detoxification enzymes and transporters. Drug hepatotoxicity may be dose dependent and may be due to the parent drug or its metabolites. Therefore, the relative activity levels of proteins involved in drug metabolism are likely important determinants of susceptibility to DILI. The redox state of hepatocytes is also known to affect the activity of these proteins. The genes encoding hepatocyte bioactivation and detoxification enzymes as well as transporters involved in drug metabolism are highly polymorphic, which may lead to uncommon or rare idiosyncratic reactions that only cause liver injury in select individuals.

Figure 4:

DILI Genetic Study Alternatives. Abundant candidate gene studies have been performed to uncover genes and polymorphisms responsible for DILI but the scope of these studies is necessarily limited by preconceptions as to the cause of DILI. Genome-wide association studies and whole genome sequencing represent unbiased approaches to improving our understanding of DILI. To date few of the latter approaches have been applied to those with DILI, but there have been some preliminary results that show promise.

Figure 5:

Geographic Variability in Candidate Gene Analysis Results for DILI. The majority of studies focused on anti-tuberculosis treatment (AT) induced liver injury since it is very common. NAT2 polymorphisms, which lead to slow acetylation of AT drugs were the most commonly associated with AT. Most of the other polymorphisms or mutations associated with DILI were population specific. An x before a gene name indicates, no association was found. Some negative association results may have been due to the limited power of a smaller study to detect a weak or moderate association.