Toxic and Metabolic Diseases of the Liver Flashcards
why does the liver receive a lot of absorbed toxins, bacterial by-products, and orally administered drugs?
first-pass clearance
what is the major site of bioactivation (biotransformation)?
liver
what is bioactivation/biotransformation?
rendering drugs more water-soluble to increase their secretion by kidney or gall bladder
how does conversion to more polar metabolites often occur?
via cytochrome P450 system
what is the most common site of hepatotoxicity?
centrilobular necrosis
what causes periportal necrosis?
toxins that do not require bioactivation
when can chronic hepatic injury occur?
repeated exposures: long term grazing toxic plants, long term drug use
what is jaundice?
hyperbilirubinemia
what is edema and ascites from?
hypoproteinemia and portal hypertension
what are some hepatotoxins?
xylitol
blue-green algae/microcytin
fungal: alfatoxins
plants: pyrrolizidine alkaloids
mushrooms
what does microcystin LR do?
disorganization hepatocytes and endothelial cytoskeletal proteins
disruption shape/integrity: necrosis
massive hepatic necrosis
what does 8,9-epoxide do?
binds to DNA and proteins of hepatocytes
what may be the most common cause of liver disease in general equine practice and cattle?
plants: pyrrolizidine alkaloid toxicity
what is phase II of hepatic metabolism?
conjugation: UDP glucuronyl transferase and glutathione
what are the differential diagnoses for centrilobular necrosis?
toxin that undergoes bioactivation by cytochrome P450
hypoxic injury: anemia
what causes periportal necrosis?
toxins that do not require bioactivation: metal salts
what describes an intrinsic hepatotoxin?
predictable, dose related, reproducible
high incidence of injury in expose individuals
what describes an idiosyncratic hepatotoxin?
non-predictable, less dose related, may be delayed
occur in very small proportion of exposed individuals
what does xylitol cause in the liver?
acute, centrilobular to massive hepatic necrosis
widespread hemorrhage
what produces microcystin LR?
Microcystis aeruginosa (cyanobacteria)
what do Aspergillus sp and Penicilium sp produce?
alfatoxin B1
what is alfatoxin B1 converted to?
8,9-epoxide
this binds to DNA and proteins of hepatocytes
what is megalocytosis?
increase in nuclear and cytoplasmic size
what does dehydropyrrolizidine alkaloid from pyrrolizidine alkaloids do?
inhibits mitosis in hepatocytes: replacement by fibrosis and bile duct hyperplasia
how does pyrrolizidine alkaloid toxicosis present?
acute manifestation of chronic disease
what do amanitins (from some mushrooms) do?
inhibit mRNA synthesis: inhibits protein synthesis
massive hepatocellular necrosis
what type of necrosis does vitamin E/selenium deficiency cause?
hepatosis dietetica
centrilobular to massive hepatic necrosis
what are the three possible causes of copper toxicity in sheep?
high copper ingestion
low molybdenum
impaired copper excretion
what is the most common presentation for lysosomal storage diseases?
neurological disease
what can amyloidosis lead to?
liver rupture and hemoabdomen
why is biotransformation sometimes bad?
can lead to bioactivation: free radicals
which phase of hepatic metabolism may result in highly reactive intermediates?
phase 1: conversion to more polar metabolite
what leads to massive necrosis?
higher dose or highly toxic
mushroom
blue-green algae
what are the outcomes of acute hepatotoxicity?
cell death, hemorrhage, fatty degeneration
may be rapid regeneration if stromal framework survives
what happens in chronic hepatic injury?
hepatocellular loss, fibrosis, nodular regeneration
usually with inflammation
what is the mechanism of intrinsic hepatotoxins?
conversion to reactive metabolites: free radicals
what are the mechanisms of idiosyncratic toxins?
hypersensitivity related
toxic metabolite-dependent: phase I metabolism excessive generation
what does NAPQI (highly toxic metabolite of acetaminophen) binding to hemoglobin lead to?
methemoglobinemia
how do animals get exposed to alpha toxins?
contaminated food or waste
what is seen in subacute/chronic cases of alpha toxin?
fatty degeneration
bile duct hyperplasia
fibrosis
what are some plants with pyrrolizidine alkaloid toxicity?
Senecio jacobaea and vulgaris
Crotalaria spp
Heliotropium spp
what can be seen in the blood with pyrrolizidine alkaloid toxicity?
hyperammonemia (hepatic encephalopathy)
hypoproteinemia (generalized edema)
