The Immunological Mechanisms and Immune-Based Biomarkers of Drug-Induced Liver Injury

Abstract

Drug-induced liver injury (DILI) has become one of the major challenges of drug safety all over the word. So far, about 1,100 commonly used drugs including the medications used regularly, herbal and/or dietary supplements, have been reported to induce liver injury. Moreover, DILI is the main cause of the interruption of new drugs development and drugs withdrawn from the pharmaceutical market. Acute DILI may evolve into chronic DILI or even worse, commonly lead to life-threatening acute liver failure in Western countries. It is generally considered to have a close relationship to genetic factors, environmental risk factors, and host immunity, through the drug itself or its metabolites, leading to a series of cellular events, such as haptenization and immune response activation. Despite many researches on DILI, the specific biomarkers about it are not applicable to clinical diagnosis, which still relies on the exclusion of other causes of liver disease in clinical practice as before. Additionally, circumstantial evidence has suggested that DILI is mediated by the immune system. Here, we review the underlying mechanisms of the immune response to DILI and provide guidance for the future development of biomarkers for the early detection, prediction, and diagnosis of DILI.

The Hepatoprotective and Hepatotoxic Roles of Sex and Sex-Related Hormones

“…A relatively rare but important cause of cirrhosis is drug-induced liver injury (DILI), which rapidly provokes cell death, severe inflammation, oxidative stress, lipid peroxidation, and alterations in bile acid dysfunction of the liver. Some cases even have loss of immune tolerance, as well as the abnormalities of both innate and adaptive immunity ( 7 ). Even after drug cessation, a non-negligible proportion of DILI patients may progress into chronic DILI.…”

Toxic hepatitis-associated aplastic anaemia after dual homeopathic remedies and Gymnema sylvestre use

“…These include increased activation and a broad skewing pattern of T cell fractions such as circulating cytotoxic T cells which infiltrate and accumulate in the liver (with notable inflammation on liver biopsy), defective monocyte to macrophage differentiation, CD8+ Kupffer cell-mediated liver and bone marrow toxicity, increase in interferon-gamma and interleukin-2-mediated organ damage in liver and bone marrow—all of which are driven by hapten/antibody-mediated inflammatory cascade after the initial insult 16 17. Similar immune mechanisms, immune dysfunction and adaptive and innate immune changes (direct or indirect toxicity due to antibody or secondary metabolite generation) have been described in DILI, possibly explaining common pathophysiological mechanisms that result in HAAA syndrome development 18–20. In conclusion, CAMs such as ayurvedic herbals and homeopathic remedies have the potential to cause acute severe hepatitis that can be associated with secondary aplastic anaemia which may result in poor clinical outcomes.…”

The Dual Role of Innate Immune Response in Acetaminophen-Induced Liver Injury

“…Innate lymphocytes, such as NK cells, NKT cells, and γδT cells, as well as adaptive lymphocytes, such as αβT cells and B cells, are stored in the liver. NK cells, NKT cells, and T cells are up to 65% of all hepatic lymphocytes in humans [ 99 ], with NK cells accounting for 30–50% [ 100 ]. The liver NK cells can divide into two subsets, CD49a − DX5 + (conventional NK cells, cNK cells) and CD49a + DX5 − (the liver-resident NK cells) [ 101 ].…”