Liver Toxicants Flashcards
what makes the liver a target?
vulnerable!!
- no protective barriers
- high perfusion
- dual circulation
- highest in biotransformation pathways
describe the regional differences in the 3 liver zones
zone 1/periportal:
-highest in oxygen
-rich in mitochondria: ATP
-high in glutathione
-high regenerative capacity
zone 2: midzonal (she’s just there)
zone 3:
-lowest in O2
-highest in cytP450 enzymes
-low in glutathione
describe the clinical response to liver toxicants
- acute liver failure
-anorexia, depression, weight loss
-abdominal pain, vomiting
-hepatomegaly, icterus
-coagulopathies, elevated liver enzymes and bilirubin - chronic liver failure:
-intermittent vomiting, icterus
-small, fibrotic or cirrhotic liver
-photosensitization
what pathology is caused by liver toxicants?
- hepatitis
- hepatomegaly
- fatty liver
- necrosis
- fibrosis, cirrhosis
describe cyanobacteria
- water contaminated with bacteria: mycrocystis sp and nodularia sp
- produce peptide hepatotoxins: mycrocystin and nodularin
- warm weather, stagnant water, high nutrient contents (nitrogen and phosphorous)
- algal blooms: late summer, early fall; winds concentrate the bacteria at shoreline
describe the toxicokinetics of microcystins and nodularins
- exposure: drink or swim, bacteria lysed in acidic stomach, release toxins
- absorption: rapid uptake by small intestine, enter liver cells using bile acids transporters
- MOA
-target cytoskeleton
-inhibit phosphatases
-hyper-phosphorylation of cytoskeletal proteins = collapse, apoptosis
describe clinical presentation and treatment of microcystins and nodularins
clinical presentation:
1. dogs and cattle, 1-4 hours post ingestion
2. lethargy, vomiting, diarrhea, GI stasis, weakness, pale MM
3. elevated liver enzymes
4. death within 24 hours
5. survivors experience photosensitization
treatment:
1. no specific antidote
2. standard GI decontamination
-dogs: bathe
3. supportive care
4. prognosis: poor to grave
describe mycotoxins/aflatoxins
- infect crops with high nutrient content:
-corn, peanuts, cottonseed, rice, sweet potato
-associated with Aspergillus FLavus - field or in storage: invades damaged or inactive plants
-with/at moisture content >15%, relative humidity >75% (sustained)
-warm temps - fungus does NOT = toxin
- fungal metabolites:
-B1!!! B2, G1, G2 - FDA regulates levels in food, feed (20-300ppb), milk (0.5 ppb)
describe the mechanism of aflatoxins
- biotransformed to reactive intermediate epoxides in LIVER and kidney
- epoxides bind macromolecules, DNA, RNA proteins
- inhibit protein synthesis, leading to hepatocyte cell death
- also immunosuppressive, mutagenic, and carcinogenic
describe clinical presentation and treatment of aflatoxins
clinical presentation:
1. birds, fish, dogs, swine > mature cattle
2. chronic toxicosis:
-reduced weight gain, rough haircoat
-anorexia, depression, jaundice, anemia
-gastroenteritis, ascites
-elevated liver enzymes (GGT) (bile duct epithelial cells hardest hit, so will see a disproportionate increase in GGT as a clue of aflatoxins)
- acute toxicosis:
-anorexia, depression, collapse, vomiting, diarrhea, seizures
-jaundice, bleeding
-elevated liver enzymes (GGT)
treatment:
1. no specific antidote
2. remove source
3. supportive care: fluids, good nutrition, antioxidants, P450 inhibitors (cimetidine)
4. activated charcoal: recent exposure
prevention:
1. mold retardants: proprionic acid, for storage only
2. ammoniation of feeds
*human and dog: urine biomarker DNA adduct formation, could be helpful for chronic toxicities
describe drug induced hepatopathy
- an adverse liver reaction to medication usually develops within 2 weeks of initial dosing
- most adverse liver drug reactions are idiosyncratic
- examples:
-acetaminophen (CATS)- can try ctyP450 inhibitors acutely
-phenobarbital to control epileptic seizures: dose can be reduced if combined with potassium bromide
-high doses of corticosteroids
-carprofen (rimadyl, an NSAID); liver damage is relatively rare - treatment:
-discontinue suspected medication
-fluid therapy
-diurectics
describe xylitol
- sugar alcohol:
-D-xylose
-in plants and fungi
-corn cobs: ethanol production
-carbohydrate metabolism - sugar substitute
-sweet as sucrose with 2/3 calories
-does not require insulin for uptake into cells
-does not stimulate insulin release in most species
-antimicrobial properties
describe the toxicokinetics and toxicity of xylitol
toxicokinetics:
1. oral absorption
-humans, rodents: slow, 49-95%
-dogs: fast and complete, peak levels in 30min
- biotransformation:
-liver
-d-xylulose, glucose, glycogen
toxicity:
1. rat LD50 >20g.kg
-humans: 130g/day, diarrhea
- dogs:
-100mg/kg: hypoglycemia; stimulates insulin release, 6x more potent than insulin, glucose drops 50mg/dl in 1 hour
-500mg/kg: acute liver failure; mech unknown but independent of hypoglycemia
describe xylitol toxicosis
- hypoglycemia:
-sudden onset of vomiting, lethargy
-ataxia, collapse, seizures
-profound hypoglycemia
-hypokalemia, hypophosphatemia - acute liver failure:
-vomiting, lethargy 9-72 hrs post ingestion
-elevated liver enzymes: ALT, AST, ALP, GGT, CK
-hyperbilirubinemia
-widespread petechial hemorrhage
-GI hemorrhage
-prolonged clotting times
-TCP
-altered mentation
-mild hypoglycemia
describe treatment and prognosis of xylitol toxicity
treatment:
1. emesis ONLY for asymptomatic animals
2. activate charcoal NOT beneficial
3. baseline glucose, K+, phosphorus
4. liver enzymes, clotting times monitor
5. fluids with dextrose for hypoglycemia, add K+ for hypokal
6. liver protectants: N-acetylcysteine (NAC), SAMe, vitamin E
7. blood/plasma transfusion
prognosis:
1. hypoglycemia, mild liver enzyme elevation: GOOD
2. severely elevated liver enzymes, prolonged clotting times: guarded to POOR
describe iron intoxication
sources: supplements, oral and injectable, multivitamins, fertilizers
species affected: dogs, cats, piglets
toxicokinetics:
1. Fe2+ (Fe3+) absorbed by SI
2. carrier mediated uptake by transferrin-like protein
3. transported by transferrin (Fe3+)
4. stored in liver bound to ferritin or hemosiderin
5. little to no excretion
mechanism:
1. excess Fe caustic to GI tract
2. Fe binding overwhelmed
3. excess free Fe in blood, accumulates in liver mitochondria
4. oxidative damage leads to hepatocyte necrosis
5. free Fe also damages vasculature and cardiac myocytes
acute toxicosis:
1. gastroenteritis, GI bleeding
2. lethargy, tachycardia, hypotension, acidosis
3. liver failure
treatment:
1. fluids
2. GI protectants
3. chelation: deferoxamine
describe copper intoxication
source: diet, supplements (foot baths, fungicides, algicides)
types of toxicosis:
1. ruminants (sheep): excess intake, excess absorption due to deficiencies
2. dogs: genetic defect in copper excretion (WHW, bedlington, skye terrier)
toxicokinetics:
1. gut absorption limited by dietary Mo, S, Fe, Zn
2. active transport across gut
3. blood transport bound to albumin, ceruloplasmin, transcuprein
4. stored in liver, kidney, bound to ceruloplasmin in lysosomes
mechanism:
1. liver storage overwhelmed: excess free copper leads to hepatocyte necrosis
2. then free copper in blood = oxidative damage to RBC, hemoglobin
clinical signs:
1. sheep: acute onset IV hemolysis, hemoglobinuria, icterus, anorexia, DEATH
2. dogs: chronic liver failure
treatment:
1. sheep: ammonium molybdate or sodium sulfate
-prevention: maintain dietary Cu:Mo ratio between 6:1 and 10:1
- dogs: D-penicillamine, increase dietary zinc
describe arsenic intoxication
source: organic and inorganic, pesticides (ant baits, herbicides), feed additives (arsanilic acid), treated lumber
species affected: dogs, CATS, ruminants
mechanism:
1. As5+ converted to As3+, which binds sulfhydryls
2. lipoic acid: cofactor TCA cycle, inhibits cellular respiration
3. As5+ substitutes for Pi in ox phos, decreasing ATP
4. targets tissue with high oxidative needs: GI, liver, lungs
5. unknown mech: GI epithelial cells
clinical signs:
1. high morbidity and mortality
2. intense abdominal pain, vomiting, staggering, watery or bloody diarrhea, sloughing of GI mucosa
3. DEATH
treament:
1. fluids, transfusions
2. chelation:
-ruminants: BAL
-dogs, cats: succimer, DMSA
describe pyrrolizidine alkaloids
- rattlebox (crotolaria), senecia (groundsel, tansy ragwort)
- mechanism:
-bioactivated to pyrrole metabolites
-bind covalently to macromolecules in hepatocytes, esp DNA, leading to impaired cell division and hepatocytomegaly (10-30x normal) - clinical presentation:
-chronic toxicosis:
–2-8 months after ingestion
–prolonged loss of condition
–jaundice
–neuro signs in horses (yawning, drowsiness, staggering, chew fences, wander aimlessly)
-secondary photosensitization in cattle: SQ edema, dry scaly muzzle, nervous signs late (mania)
describe lantadene alkaloids
- mech: unknown but causes hepatocytomegaly, biliary stasis, and apoptosis
- clinical presentation:
-subacute toxicosis: 1-2d post ingestion
-secondary photosensitization: ulceration of muzzle, mouth, nostrils, oral cavity, swelling and peeling of MM in nostrils, swelling and ulceration of ears
-anorexia, depression, dehydration, constipation
-death within 24hr or delayed several weeks
- treatment:
-no specific antidotes
-remove source
-GI decontamination
-supportive care
describe cycad palms/cyasin
- tropical/subtropical plants; common in florida and now in georgia
-japanese palm, sago palm
-contain heaptotoxin cyasin - species affected:
-dogs, ruminants, horses, swine
-multiple cases of intox dogs in south GA, often ingest seeds and chew on root
-cattle and sheep preferentially seek out the palms (young leaves = tasty) - hepatic/GI syndrome:
-onset: 12-24hr
-gastroenteritis: vomiting, diarrhea, anorexia
-elevated liver enzymes
-hyperbilirubinemia
-electrolyte disturbances
-seizures secondary to hepatoencephalopathy - treatment:
-activated charcoal: repeated
-supportive care: fluids with dextrose, electrolytes
describe GI caustics and corrosives-household cleaners
- caustics: alkalis (lyes)
-sodium hypochlorite, hydroxides, lime
-calcium, potassium, sodiu carbonates
-bleaches, drain cleaners, oven cleaners, laundry detergents, dishwasher detergents - corrosives: acids
-hydrochloric, phosphoric, sulfuric, nitric
-toilet bowl cleaners, metal cleaners, drain cleaners, antirust compounds - target organ: GI, respiratory, skin, eye
how do alkalis cause damage to GI?
liquefaction necrosis:
-deep penetrating lesions
-ulcers and perforations
-transmural necrosis within 1 second
-scars
how do acids cause damage to GI?
coagulation necrosis:
-severe burns
-denature proteins
-tissue dessication
-destruction of surface epithelium, submucosa
describe toxicosis of caustics and corrosives
oral exposure: severity depends on approx pH, amount, concentration, and duration
initial signs:
-dysphagia, polydipsia, excessive salivation, pawing at lips
-lesions/ulcers: lips, tongue, gums, esophagus
progress:
-GI tissues: burns, ulcerations, gastroenteritis
-oral pain (acids), abdominal pain, vomiting (bloody)
-respiratory distress: swelling or spasm of larynx
-alkalis: esophageal perforation, stricture
-acids: pyloric spasm, gastric perforation, peritonitis
-shock, death
describe treatment of caustics and corrosives
- standard decontamination CONTRAINDICATED
-emesis: increases exposure to toxicants
-activated charcoal: does not bind acids/alkalis - dilution: water or milk
- NPO: ulcers and perforations
-IV fluids, gastric feeding tube - corticosteroids: prevent stricture formation
- antibiotics: secondary bacterial infections
- pain management
describe cationic detergents
- quarternary ammonium
-benzalkonium chloride
-benzethonium chloride: fabric softeners, potpourri oils, hair conditioners, disinfectants, germicides - target: contact injury, CNS (unknown)
- CATS
- clinical features of oral exposure:
-corrosive burns of mouth, throat, esophagus
-hypersalivation, vomiting, diarrhea
-muscle weakness, tremors
-CNS and respiratory depression
-seizures, coma - treatment: similar to caustics/corrosives
