0304 - Acute Liver Injury Flashcards
What are the most common aetiologies of acute liver failure?
Paracetamol (39%), drugs 13%
What are the two mechanisms of drug toxicity?
1 - cellular accumulation leading to dysfunction
2 - Toxic metabolites produced, which enter cell and lead to toxicity
What is the difference between intrinsic and idiosyncratic hepatotoxicity
Intrinsic - if dose is high enough, toxicity is predictable (e.g. paracetamol)
Idiosyncratic - Hepatotoxicity results at therapeutic doses, in 1:1,000-1:100,000 people.
What are the 6+1 mechanisms of hepatocyte injury?
1 - Disrupted Ca homeostasis (gives blebbing and rupture)
2 - Disruption of actin next to canaliculi inhibits transporters (bile blocked in cell)
3 - Covalent binding of drug to CYP450, forming adduct - Prevents CYP450 function, stopping cell metabolism.
4 - Adduct migrates to plasma membrane - generating immune response.
5 - Apoptosis due to loss of nuclear chromatin
6 - Inhibit mitochondria, resulting in loss of ATP, rising ROS and FAs
+1 - Bile duct epithelium can be damaged by toxic metabolism.
What is the threshold for hepatic injury from paracetamol?
> 150mg/kg (10g for 67kg person)
What is the treatment for paracetamol overdose? How does it work?
N-acetylcysteine.
Replaces glutathione, allowing NAPQI to conjugate with glutathione and be excreted.
Briefly outline paracetamol metabolism
Can be metabolised into paracetamol glucuronide and paracetamol sulphate, however these become saturated at overdose, pushing it down a minor, CYP450 pathway to NAPQI. NAPQI is hepatotoxic, however can be conjugated with glutathione and excreted.
Toxicity results when glutathione is used up, and NAPQI builds up.
How is paracetamol/NAPQI toxic?
Multiple parallel events, rather than single mechanism. Inhibits glutathione synthesis Uncouples mitochondria Further depletes glutathione Disrupts Ca++ homeostasis.
Why does alcohol increase susceptibility to paracetamol toxicity?
Both Paracetamol and EtOH require CYP450 for metabolism, however EtOH bind preferentially, and so induces more CYP450 production (too much product around). Combination of EtOH metabolism and increased CYP450 for binding means more NAPQI produced, and greater hepatotoxicity.
