Mechanisms of adaptation and progression in idiosyncratic drug induced liver injury, clinical implications

Abstract

In the past decade our understanding of idiosyncratic drug induced liver injury (IDILI) and the contribution of genetic susceptibility and the adaptive immune system to the pathogenesis of this disease process has grown tremendously. One of the characteristics of IDILI is that it occurs rarely and only in a subset of individuals with a presumed susceptibility to the drug. Despite a clear association between single nucleotide polymorphisms in human leukocyte antigen (HLA) genes and certain drugs that cause IDILI, not all individuals with susceptible HLA genotypes develop clinically significant liver injury when exposed to drugs. The adaptation hypothesis has been put forth as an explanation for why only a small percentage of susceptible individuals develop overt IDILI and severe injury, while the majority with susceptible genotypes develop only mild abnormalities that resolve spontaneously upon continuation of the drug. This spontaneous resolution is referred to as clinical adaptation. Failure to adapt or defective adaptation leads to clinically significant liver injury. In this review we explore the immuno-tolerant microenvironment of the liver and the mechanisms of clinical adaptation in IDILI with a focus on the role of immune-tolerance and cellular adaptive responses.

Keywords: T cells; drug induced liver injury; hepatotoxicity; human leukocyte antigen; immune-tolerance.

Figure 1

Clinical Adaptation to INH. Aspartate Aminotransferase (AST) levels of eight patients described in the original paper by Mitchell et al (Ref. 34) as plotted by Dr. John Senior (FDA). A) Data from cases with AST > 60 and bilirubin >1.2 mg/dl are included. Three patients with elevated bilirubin >2 times upper limit of normal (Hy’s law cases) are noted with an *. Notice the early rise in AST in the first few weeks on the drug followed by normalization of serum AST despite continued INH therapy. B) AST and Bilirubin trends of the three Hy’s Law cases. AST: Aspartate amino transferase.

Figure 1

Clinical Adaptation to INH. Aspartate Aminotransferase (AST) levels of eight patients described in the original paper by Mitchell et al (Ref. 34) as plotted by Dr. John Senior (FDA). A) Data from cases with AST > 60 and bilirubin >1.2 mg/dl are included. Three patients with elevated bilirubin >2 times upper limit of normal (Hy’s law cases) are noted with an *. Notice the early rise in AST in the first few weeks on the drug followed by normalization of serum AST despite continued INH therapy. B) AST and Bilirubin trends of the three Hy’s Law cases. AST: Aspartate amino transferase.

Figure 2

Role of Adaptation in IDILI. Certain drugs produce reactive metabolites, which can act as haptens or antigenic peptides. When subjects with susceptible HLA haplotypes are exposed to these antigenic peptides some immediately become tolerant and others develop mild injury, which can resolve with continued exposure to the drug, a phenomenon known as adaptation. In rare instances due to defective adaptation, mild liver injury can progress to severe IDILI and acute liver failure. SNP: Single Nucleotide Polymorphism, HLA: Human Leukocyte Antigen, IDILI: Idiosyncratic Drug Induced Liver Injury, ALF: Acute Liver Failure.