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Drug Induced Immune Mediated Hepatotoxicity / Liver Damage -



Role of the innate immune system
NAPQI induce liver damage trigger activation and inflammatory responses of the innate immune system causing the production of inflammatory mediators, including cytokines, chemokines, and reactive oxygen and nitrogen species that contribute to the progression of liver injury. Some of these mediators, such as IFN-, Fas, or Fas ligand, are directly involved in causing liver damage. Mutant mice lacking these factors are resistant to APAP hepatotoxicity.APAP hepatotoxicity leads to the activation of KC.KC activation results in the release of pro-inflammatory mediators which are TNF( directly induce tissue damage), IL-12 and IL-18, activators of NK and NKT cells. KC may also play a protective role. They are a source of IL-10 and IL-6, important in counteracting inflammatory responses and stimulating liver regeneration.

Role Of Adaptive Immune System

Clinical Signs:
Following are the clinical characteristics which show involvement of the adaptive immune system in drug-induced hepatotoxicity

(1)The concurrence of rash, fever, and eosinophilia;
(1) Delay of the initial reaction
(2) Rapid recurrence of toxicity on reexposure to the drug
(4) Presence of antibodies specific for native or drug-modified hepatic proteins.

Drugs inducing these types of reactions are Halothane, Tienilic Acid, Dihydralazine, Diclofenac, Phenytoin, Carbamazepine


Drug-induced adaptive immune responses are largely based on the hapten hypothesis and the p-i concept. The hapten hypothesis proposes that drugs, or more often reactive metabolites of the drugs, act as haptens and covalently bind to endogenous proteins to form immunogenic drug-protein adducts. These immunogenic adducts elicit either antibody or cytotoxic T-cell responses. The hapten hypothesis is supported by the detection of antibodies that recognize drug-modified hepatic proteins in the sera of DILI patients. For example, antibodies that recognize trifluoroacetate-altered hepatic proteins have been detected in the sera of patients with halothane-induced hepatitis. Such drug-specific antibodies or autoantibodies that recognize native liver proteins have also been found in patients with the liver injury caused by other drugs, such as tienilic acid, dihydralazine, and diclofenac. The p-i concept suggests that certain drugs can bind to T-cell receptors, mimicking a ligand and its receptor interaction, and cause T-cell activation in an MHC-dependent fashion. In patients who developed drug-induced systemic reactions of the liver and other organs, drug-specific T cells have been detected, and in some cases, T-cell clones were generated. Despite the detection of drug-specific antibodies and T cells, it has been difficult to directly prove the pathogenic role of the adaptive immune system in DILI, in part because of the lack of animal models. An important reason for the difficulty in developing animal models is that the default response of the liver to antigens is immunological tolerance. This tolerogenic response could also explain the low occurrence of this type of DILI in humans. As described in the above section, the anatomy, cellular composition, and microenvironment of the liver favour tolerance rather than pathogenic immunity. Therefore, DILI mediated by adaptive immune reactions against a drug can occur only when the tolerance mechanism is deficient or abrogated in susceptible individuals. As such, animal models of this type of DILI can be developed only after the barrier of such tolerance is overcome.
Drugs Causing Hepatotoxicity

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