DILI

Question 1

describe Metabolic DILI

Answer 1

Causes mitochondrial dysfunction due to an increase in reactive oxygen species and through the depletion of ATP. Done by inhibition of the mitochondrial respiratory chain.

Usually from phase 1 metabolites. Can occur when compounds conjugated with the substrate in phase 2 reactions have been all used.

Question 2

describe Immunologic DILI

Answer 2

The drug metabolite may bind to cellular proteins and its antigens will be recognised by major histocompatibility complex proteins (MHCs). This triggers immune response against hepatocytes. Further worsened by increased cytokine release and oxidative stress.

Question 3

Risk factors for DILI

Answer 3

Patient factors: age, alcohol and drug usage, disease state.

Question 4

Explain Paracetamol DILI

Answer 4

Metabolic

UGT and SULT conjugation account for the majority of the metabolism of paracetamol. Small amount metabolised by CYP to produce NAPQI, which is rapidly conjugated with glutathione by GST. When high doses are administered, the glutathione stores can become depleted, leading to build up of NAPQI.

NAPQI covalently binds to cysteine groups in proteins and nucleic acids, inducing liver toxicity.

Activated charcoal can prevent absorption from the GIT - can treat if early enough. N-acetylcysteine replenishes glutathione stores, preventing NAPQI build up - treatment more affective the earlier its done.

Question 5

Explain Halothane DILI

Answer 5

Immunologic

It is converted to CF3CO- which binds to hepatocyte proteins. It is recognised as an antigen, and immune response against it.

The immune response is sensitised, so consequent halothane administration leads to attack of hepatocytes again. This can cause halothane hepatitis.

Question 6

Explain Isoniazid DILI

Answer 6

Idiosyncratic

Predominantly metabolised by NAT2. Smaller amounts are metabolised to hydrazine, which is hepatotoxic.

Individuals with lower NAT2 functionality will result in higher [hydrazine]

Question 7

explain NSAID DILI

Answer 7

proposed as both metabolic and immunologic

4-OH-diclofenac and secondary metabolite arene oxide are reactive metabolites,

Other metabolite pathway produces diclofenac Acyl glucuronide induces immunologic response