Hepatotoxicology Flashcards
What are the 4 reasons that the liver is especially vulnerable to toxicants?
- key organ for nutrient homeostasis
- primary detoxication and toxication center
- downstream of the GIT = orally exposed toxicants reach the liver before any biotransformation
- passive entry of toxicants into hepatocytes = no required specialized transporters
What facilitates liver toxicity?
enterohepatic recirculation —> slows toxicant clearance and facilitates hepatocyte re-exposure
What are the 2 mechanisms of hepatotoxicity?
- INTRINSIC = predictable, reproducible, dose-dependent response accounting for a majority of toxic liver injuries
- IDIOSYNCRATIC = unpredictable response that is rare and not dose-dependent; can be associated with extrahepatic lesions
What are the 9 most common toxic hepatobiliary injuries?
- fatty degeneration (steatosis) - increased fat in hepatocytes
- hepatocyte death - increased ALT, AST
- hepatic melanocytosis - increased hepatocyte size
- cholestasis - increased bilirubin and bile salts, yellow-green liver
- bile duct damage - increased ALP, GGT, bilirubin, bile salts
- sinusoidal damage - dilation or blockade
- fibrosis - fibrin/scar tissue
- cirrhosis - incredibly increased fibrin/scar tissue, firm liver, loss of function
- neoplasia - hepatocyte, bile ducts, sinusoid tumors
What are the main signs of acute liver failure, subacute liver failure, and chronic liver failure?
ALF - abdominal pain, liver enlargement, vomiting, hypovolemic shock, hypoglycemia, icterus, secondary hepatoencephalopathy
SALF - intermittent GI upset, reduced appetite, poor condition, icterus, liver pain and enlargement
CLF - recurrent GI upset, chronic weight loss, hypoproteinemia, shrunken liver, cirrhosis, icterus, secondary photosensitization
What plants are the main sources of pyrrolizidine alkaloids? What are the 3 most common causes of exposure?
- Boraginaceae
- Copositae (Senecio)
- Leguminosae
- contaminated feed
- young plants indistinguishable from grasses
- favorable forage is not available
What affects susceptibility to pyrrolizidine alkaloids? What animals are most sensitive?
species, age, sex, nutrition, and biochemical/physiological factors
pigs > cattle > horses
What animals are resistant to pyrrolizidine alkaloids? What are the differences in species susceptibility likely due to?
sheep and goats —> used to graze pastures that are unsafe for cattle and horses
species-specific differences in enzymatic activation of PAs and rumen metabolism
How are pyrrolizidine alkaloids metabolized? How is it detoxified? Excreted?
bioactivated by mixed function oxidase (MFO) in the liver into toxic dehydropyrrolizidine alkaloids (pyrroles)
binds to GSH and by hydrolysis/oxidation
nontoxic metabolites are excreted and toxic metabolites damage the liver
What is the mechanism of toxicity of pyrrolizidine alkaloids?
pyrroles are potent electrophiles and powerful alkylating agents that cross-link dsDNA, proteins, and amino acids causing antimitotic and cytotoxic effects and the formation and death of megalocytes with fibrous tissue replacement
What are clinical signs of acute/chronic toxicosis with pyrrolizidine alkaloids?
ACUTE = acute liver failure - anorexia, depression, icterus, diarrhea, rectal prolapse, visceral edema/ascites, head pressing, walking in straight lines regardless of obstacles (ammonia elevation in blood)
CHRONIC = photosensitivity, icterus, increased susceptibility to other liver disease (lipidosis, ketosis) = “hepatic cripples”
What clinical pathology is used to diagnose acute/chronic toxicosis with pyrrolizidine alkaloids?
ACUTE = marked elevations of AST, GGT, ALP, SDH, and bilirubin/bile acids
CHRONIC = transient elevations of AST, GGT, ALP, and SDH with mild elevations of serum bilirubin and bile acids
What histological lesion is characteristic of pyrrolizidine alkaloid toxicosis?
continued synthesis of new cells to replace hepatocytes that have undergone necrosis when mitosis is inhibited results in megalocytosis (nuclear and cytoplasmic gigantism) and bile duct hyperplasia/fibrosis
What 3 treatments are recommended for pyrrolizidine alkaloid toxicosis?
not usually successful
- remove animals from plants source
- give diets high in carbohydrates and low in proteins
- treat dehydration and photosensitization
What toxic principles are found in Lantana spp. (yellow/red sage, white brush)?
triterpene acids - lantadene, icterogenin, dihydrolantadene
How are lantadenes absrobed and metabolized?
slow absorption in the small intestine, stomach, and rumen
biotransformed in the liver where they damage bile canalicular epithelium and hepatocytes and are secreted into the bile
What are the 3 mechanisms of toxicity with Lantana toxicosis?
- obstructive cholangitis and hepatotoxicity - reduction in canaliculi ATPase activity, collapse/blockage of canaliculi, loss of secretory function of hepatocytes
- hepatogenic photosensitization
- GIT irritation and cytotoxicity
What are the 2 major clinical signs of acute Lantana toxicosis? What else is seen?
- prominent jaundice
- photosensitization within 1-2 days of exposure
- depression, anorexia, transient diarrhea
- decreased GIT motility and constipation
- sluggishness, weakness
What is the most common presentation of chronic Lantana toxicosis? What 4 clinical signs appear?
photosensitization
- lesions on muzzle, mouth, and nostrils
- swelling, hardening, and peeling of nostril mucous membranes
- ulceration of cheeks, tongue, and gums
- invasion of photosensitized areas by blowfly maggots and bacteria
How can Lantana toxicosis be prevented?
destruction of plants —> clearing, grubbing, herbicide
What is Kochia? What is the major toxic principle found in it? What else?
poor man’s alfalfa - fireweed, belvedere, fireball, red sage —> drought resistant and tolerates high soil Na
saponins
- thiaminase-like substances, hepatotoxins, nephrotoxins, sulfates, nitrates, soluble oxalates
What is the major cause of toxicity with Kochia toxicity? What are the 4 mechanisms based on toxic principle?
hepatotoxicity with an occasional photosensitization
- SULFATES = laxative, CNS effects (H2S)
- THIAMINASE = CNS derangement
- NITRATES = methemoglobinemia
- OXALATES = nephrotoxicity
What 2 species are most susceptible to Kochia toxicity? What clinical signs are associated?
cattle, sheep
- loss of appetite, poor weight gain, diarrhea
- icterus, oral ulcerations, abdominal pain
- photosensitization, elevated liver enzymes and bilirubin
- CNS: ataxia, circling, head pressing, convulsions, blindness
What must be ruled out before diagnosing Kochia toxicity? What are 3 possible treatments?
other causes of liver failure
- remove animals from source
- reduce stress and keep photosensitized animals away from sunlight
- treat polioencephalomalacia with thiamine
How is xylitol absorbed? What are the 3 steps of its metabolism?
absorbed readily from the canine GIT
- oxidized in the liver by NAD-xylitol dehydrogenase into D-xylulose
- D-X is then phosphorylated by xylulose kinase to D-xylulose-5-phosphate (an intermediate of the PPP)
- DX5P is metabolized into fructose-6-phosphate and glyceraldehyde phosphate, which are converted to glucose then glycogen or lactate
How does the dose of xylitol affect clinical signs?
75-100 mg/kg = hypoglycemia
> 500 mg/kg = hepatic failure
(50 mg/kg warrants decontamination and blood glucose monitoring)
How does xylitol cause hypoglycemia?
the pentose phosphate pathways is thought to control insulin release —> PPP is a major source of NADPH, which reduces oxidized glutathione to GSH, which stimulates insulin release
- metabolism of xylitol through PPP in dogs causes rapid release of insulin
- direct stimulation of insulin secretion by beta cells in the pancreas
What are the 2 proposed mechanisms of hepatotoxicity by xylitol?
- depletion of ATP during xylitol metabolism
- production of ROS
What clinical signs are associated with xylitol toxicosis?
- hypoglycemia: vomiting, lethargy, weakness, ataxia, disorientation, depression, hypokalemia, seizures, collapse, coma
- hepatic dysfunction: elevated liver enzymes, hyperbilirubinemia, coagulopathy
- GI: diarrhea, intestinal gas production
- thrombocytopenia, hyperphosphatemia (poor prognosis)
Why is activated charcoal not indicated for xylitol toxicity? What must be monitored during treatment?
binds poorly to xylitol because it is absorbed rapidly
- blood glucose
- chemistry
- electrolytes
- liver enzymes
- coagulation
What 5 symptomatic treatments are recommended for xylitol toxicity?
- IV fluids with dextrose followed by parenteral fluids
- addition of fiber to diet to aid in elimination of wrappers
- potassium supplementation
- heptatoprotectants: SAMe, Silymarin, NAC
- treat coagulopathy with vitamin K1 or plasma transfusions
How should dogs be hospitalized for xylitol toxicity?
at least 12-24 hr after ingestion due to risk of delayed onset of hypoglycemia
What are the main 3 sources of Aflatoxins? Where are they found?
- Aspergillus flavus
- A. parasiticus - B1 and B2
- A. nominua - G1 and G2
crops with high energy content (almost any feedstuffs can support fungal growth - grains, potatoes)
What conditions support Aflatoxin-producing mold growth?
- warm temperatures
- high moisture
- high humidity
- sufficient oxygen
- damage to corn kernel
(not all moldy grain is toxic)
What species are the most susceptible to aflatoxin toxicity? What are the least susceptible?
ducklings and trout
adult ruminants —> detoxified by rumen microbes
(cause of mysterious turkey X disease in Great Britain in the 1950s and 1960s)
What are the 5 major risk factors for developing aflatoxin toxicity?
- nutrition status and feed quality
- low protein diets
- dietary amino acids - increased lysine, arginine, casein, decreased choline and methionine
- vitamin A and carotene
- antioxidants and Se reduce toxicity and promote repair macromolecules
How are aflatoxins absorbed? Where does it become most concentrated? How is it metabolized?
passive diffusion from small intestine (AFB1 is the most lipophilic = increased absorption)
liver
AFB1 is activated to reactive AFB1-8,9-epoxide by CYP450 and hydroxylated to AFM1 or bound to GSH
What is the main excretory product of aflatoxins? Where is it excreted?
aflatoxin M1
bile, urine, feces, milk, eggs, semen —> within 24 hours after exposure
What is the mechanism of toxicity of aflatoxins?
reactive metabolites (AFB1-8,9-E) binds with DNA/RNA, proteins, and organelles causing disruption of anabolism and catabolism
- loss of organelle function, carcinogenesis, mutagenesis, teratogenesis, decreased protein synthesis, immunosuppression
- impair reproductive performance
What are signs of acute aflatoxin toxicosis?
- anorexia, depression, weakness
- prostration, dyspnea, emesis
- diarrhea, epistaxis
- fever followed by subnormal temperature
- convulsions, hemorrhage, icterus
What are signs of chronic aflatoxin toxicosis?
- anorexia, reduced protein and feed conversion
- rough hair coat
- anemia, icterus, depression
- bleeding disorders, ascites (dogs)
- high mortality in young birds
What clincal pathology is associated with aflatoxin toxicosis?
- increased AST, ALT, ALP, GGST* (bile duct hyperplasia)
- increased serum bilirubin
- decreased serum proteins (albumin, beta-globulins)
- increased gamma globulin
- prolonged prothrombin and activated partial thromboplastin times, thrombocytopenia
What 3 hepatic lesions are associated with aflatoxin toxicosis?
- swelling, friable, congestion
- chronic = firm, fibrous, pale
- bile duct proliferation, fibrosis, icterus, megalocytosis, and periportal/centrilobular necrosis
What special diagnostic test is used to diagnose aflatoxin toxicosis? What is a major disadvantage? How can this be avoided?
black light test on feeds
significant number of false positives
followed by reliable analysis of aflatoxins by ELISA, HPLC, TLC and demonstration of fungus and toxins in lesions
How can the diet be optimized to treat aflatoxicosis? What 2 other treatments help the liver?
add proteins, amino acids (choline, methionine), vitamins B12 and K1, and trace elements
- liver protectants - SAMe, selenium, vitamine E
- reduce hepatic mortality - Oxytetracycline
What are 5 major ways of controlling aflatoxicosis?
- avoid contaminated feeds by monitoring batches for aflatoxin levels
- monitor local crop conditions as predictors for aflatoxin formation
- prevent crop damage with insecticides to decrease fungal invasion
- ammoniation of feeds hydrolyses AFB1
- use absorbents, like sodium calcium aluminosilicate, to bind aflatoxins
What 2 blue green algae (cyanobacteria) produce hepatotoxins? What do they produce? In what environments are they most likely found?
- Microcystis spp. - microcystin; stagnant freshwater
- Nodularia spp. - nodularin; brackish water
What conditions favor blue green algae growth? When are toxicoses most common?
sunny and windy weather, water high in nutrients
late summer to early winter
What is the pathophysiology of blue green algae toxicosis? What are 2 other target organs?
- algae ingested with water are broken down in GIT to release toxins
- toxins are rapidly absorbed in the small intestine, transported to the liver, and enter the hepatocytes through bile acid transported (unable to passively permeate)
kidney, gonads
What are the 3 mechanisms of blue green algae hepatotoxicity?
- disruption of hepatocyte cytoskeleton by inhibiting protein phosphatase 1 and 2A, which impairs phosphorylation of regulatory intracellular protein (microtubules, intermediate filaments, microfilaments)
- induction of apoptosis via ROS formation and mitochondrial dysfunction
- MICROCYSTIN = tumor promoter
What clinical signs are associated with blue green algae hepatotoxicity?
- lethargy, vomiting, diarrhea, GI atony, weakness, pale MM, shock
- hyperkalemia, hypoglycemia
- nervousness, recumbency, convulsions
- secondary photosensitization in animals that do not die acutely
- elevated hepatic enzyme activity
What are the gross and microscopic hepatic lesions associated with blue green algae hepatotoxicosis?
GROSS - enlarged, congested, hemorrhagic liver
MICRO - centrilobular/midzonal necrosis, breakdown of sinusoidal endothelium, intrahepatic hemorrhage
What 6 symptomatic treatments are recommended for blue green algae hepatotoxicosis?
- IV fluids
- blood transfusion
- vitamin K
- hepatoprotectants
- corticosteroids
- shock therapy
