Drug‐induced liver injury: Advances in mechanistic understanding that will inform risk management

Abstract

Drug-induced liver injury (DILI) is a major public health problem. Intrinsic (dose-dependent) DILI associated with acetaminophen overdose is the number one cause of acute liver failure in the US. However the most problematic type of DILI impacting drug development is idiosyncratic, occurring only very rarely among treated patients and often only after several weeks or months of treatment with the offending drug. Recent advances in our understanding of the pathogenesis of DILI suggest that three mechanisms may underlie most hepatocyte effects in response to both intrinsic and idiosyncratic DILI drugs: mitochondrial dysfunction, oxidative stress, and alterations in bile acid homeostasis. However, in some cases, hepatocyte stress promotes an immune response that results in clinically important idiosyncratic DILI. This review discusses recent advances in our understanding of the pathogenesis of both intrinsic and idiosyncratic DILI as well as emerging tools and techniques that will likely improve DILI risk identification and management.

The diagnosis and management of idiosyncratic drug‐induced liver injury

“…Serum AST and ALT elevations do not reliably correlate with the degree of hepatic impairment, while increases in the INR are more indicative of loss of hepatic functional mass. Nonetheless, the degree of ALT elevation, as well as the serum AST/ALT ratio, was associated with the development of ALF and chronic liver injury in some DILI patients …”

“…Early discontinuation of the offending agent may help prevent the development and progression of further liver injury. However, the liver damage in many DILI patients is perpetuated after drug cessation via activation of the innate immune system and the development of a cytokine‐driven acquired immune response . Therefore, avoidance of exposure to other potentially hepatotoxic medications and substances, including alcohol, is also recommended for all DILI patients.…”

The transformation in biomarker detection and management of drug‐induced liver injury

“…This is believed to require activation of innate immune cells, particularly Kupffer cells within the liver. This calls for drug‐induced release of damage associated molecular patterns, or DAMPs, that initiate activation of the innate immune cells . If this is the case, elevations in serum ALT in the absence of release of DAMPs, and/or the absence of activation of innate immune cells should mean that an adaptive immune attack on the liver will not occur.…”

Improving Interpretation of New and Old Serum Biomarkers of Drug‐Induced Liver Injury Through Mechanistic Modeling

“…However, this is only the beginning. The delayed drug‐induced liver injuries seem to generally result from an adaptive immune attack on the liver . It is believed that there exist a series of necessary but not sufficient steps that must happen in the liver before an immune attack can occur.…”

“…As noted in Figure , this involves drug‐induced stress to the hepatocyte (but not necessarily hepatocyte death), release from the hepatocyte of “danger signals,” and activation of innate immune cells in the liver. Novel biomarkers, including HMBG1, have been proposed to be danger signals that can be measured in serum, and various cytokines, microRNAs, and acetylated HMGB1 have been proposed as serum biomarkers of immune cell activation . Identification of new and mechanistic biomarkers of drug‐induced liver injury has been a major focus of international research efforts, including a major new effort to start in 2019 .…”