Role of immune dysfunction in drug induced liver injury

Abstract

Drug-induced liver injury (DILI) is one of the leading causes of liver failure and withdrawal of drugs from the market. A poor understanding of the precipitating event aetiology and mechanisms of disease progression has rendered the prediction and subsequent treatment intractable. Recent literature suggests that some drugs can alter the liver's repair systems resulting in injury. The pathophysiology of DILI is complex, and immune dysfunction plays an important role in determining the course and severity of the disease. Immune dysfunction is influenced by the host response to drug toxicity. A deeper understanding of these processes may be beneficial in the management of DILI and aid in drug development. This review provides a structured framework presenting DILI in three progressive stages that summarize the interplay between drugs and the host defence networks.

Keywords: Drug-induced liver injury; Hepatotoxic drugs; High mobility group box 1; Immune dysfunction; Liver damage.

Figure 1

Initiation of drug-induced liver injury - Direct damage by drug and metabolite. Drugs and their metabolites damage organelles and cell membrane of liver cells causing damage. ER: Endoplasmic reticulum.

Figure 2

Initiation of drug-induced liver injury - Indirect damage by drugs. Drugs can modulate the functioning of enzymes and transporters involved in drug metabolism and elimination that may lead to toxicity.

Figure 3

Immune allergic drug-induced liver injury. A: Endoplasmic reticulum stress by drug, causes misfolded protein resulting in cell death and release of stress signals and drug-protein complex. Kupffer cells ingest the drug-protein complex to T-helper cells; B: T-helper cells process it and present it to B-cells; C: B-cells produce anti-drug antibodies; D: These antibodies target the tissues, where drug is accumulated. KC: Kupffer cell; HSC: Hepatic stellate cells.

Figure 4

Mechanism of autoimmune drug-induced liver injury. A: Drug causes mitochondrial dysfunction resulting in cell death and release of HMGB-1 and other stress signals; B: Kupffer cells and Stellate cells get activated. Release cytokines, chemokines and toxins; C: Chemokines attract monocytes; D: Amplification of injury and cell death. KC: Kupffer cell; HSC: Hepatic stellate cells; ROS: Reactive oxygen species.