Lecture 17 Liver Toxicology Flashcards
What anatomy characteristics makes the liver uniquely susceptible to toxins?
High blood flow
Unusual capillaries with big gaps (sinusoids)
Portal recirculation
What processes does zone 3 (centrolobular) liver entail?
CYP450 mediated metabolism
How does xenobiotics move in the liver?
Portal triad to central vein
How does bile move in the liver?
Central vein to bile duct
What are the two classes of hepatoxins?
Intrinsic (predictable): dependent on agent.
Idiosyncratic (unpredictable): dependent on individual.
What are some food sources of liver toxicology?
Aflatoxin in grains
Death cap mushrooms
What are some industrial sources of liver toxicology?
Copper
Manganese
What are some drug sources of liver toxicology?
Indinavir
Inhibits OATP1B1 and 1B3, which uptakes bilirubin (haem breakdown product) as part of metabolism of bilirubin
What is steatosis?
Accumulation of lipids (TAG) in liver.
Macrovesicular or microvesicular
Commonly in conjunction with necrosis but can also occur without.
What is cholestasis?
Inhibition of bile salt secretion by blockade of transporters on canalicular side.
Decreases bile flow –> accumulates in hepatocytes –> rise of bile excretory products in blood.
May occur with or without necrosis.
What is necrosis?
Focal: randomly distributed dead cells
Zonal: entire zones
Panacinar: massive hepatocyte death
What occurs in Zone 3 necrosis?
Zone 3 closest to hepatic vein (central vein).
High conc of drug metabolising enzymes and lowest O2.
Toxicants often involve alkylating metabolites and free radicals
What occurs in Zone 1 necrosis?
Zone 1 is near central vein with hepatic artery so has high O2 conc. Lowest CYP conc.
Toxicants include phosphorous, ferrous sulphate
What are the phases of chronic hepatic toxicity?
Inflammation (hepatitis) –> necrosis –> proliferation (cirrhosis) –> malignancy
What is cirrhosis?
Connective tissue scarring, liver becomes nodular.
Arises from necrosis + deficient repair + proliferation of CT cells
