Lecture 18 Flashcards
What is important about the liver
Subject to more toxins than any other organ as it is the portal blood flow directly from GIT
What are the two toxic effects
- Intrinsic: predictable toxic effect is given species and dose range
- Idisyncraric: less dose dependent and only seen in a small number of individuals
What does the severty of hepatotoxicty depend on
- Age, sex, diet, genetics, endocrine
- Dose
What are most hepatotoxins
Predictable (intrinsic)
What are cats deficient in
Glucaronyl transferase
Where are idiosyncreatic reations seen
Small number of individual animals
What are 4 things to consider with idiosyncratic reactions
- Atypical metabolism due to genetic variation in enxymes
- Atypical immune response
- Interactions with other drugs
- Most drugs need bioactivation in liver
What are the categories of Hepatotoxic injury
- Injurious intermediary metabolites produced by cytochrome P450 enxymes - substances activated in liver
- Alteration of cells to become antigenic to immune system - Drugs and cellular constituents combine form neoantigens
- Stmulation of apoptosis - direcof toxins or immune mediated
- Membrane damage and disruption to calcium homeostasis - calcium activates damaging enzymes such as proteases
- Mitochondrial damage - disrupt energy supply to cells - disrupt energy supply to cell
- Disruption of bile secretion causing cholestasis - interupt molecular pumps that secrete bile
Explain acute hepatotoxic injury
Within 2-3 days
- Macrophages clear debris
- Remainig hepatocyes withn lobule proliferation
One week later
- Normalhistologic appearance
- Unless massive necrosis
Marked to massive coagulatice centrilobular necrosis with haemorrhage, possible acute hepatic failure
Acute hepatotoxic injury
How do animals get chronic hepatotoxic injury
Repeated bouts of exposure or daily ingestion
- Activation of stellate cells > fibrosis
- Disruption of architecture
- Nodules of regeneration
- > Cirrhosis
When severe enough there is signs of hepatic failure
Clincial signs of acute hepatoxicty
- Rapid death
- Anorexia
- Depressin
- Colic
- Seizures
Gross appearance of hepatotoxicity
- Swollen/enlarged
- Turgid/firable
- Red-yellow mottled to dark purple
Clinical signs of chronic hepatotoxicity
- Weight loss
- Jaundice
- Photosensitization
- Head pressing, wandering
Gross appearance of chronic hepatotoxicity
- Small
- Pale tan to yellow
- Firm
What do pyrrolizide alkaloids cause
- Toxins are metabolised to active form in liver
- Prevents cell division - but cells continue DNA synthesis
- Usually chronic toxicity
- Megalocytosis
- Fibrosis
- Biliary hyperplasia
Chronic Pyrroliidine alkaloid Hepatotoxicity: Fibrosis and Distortion
Chrinic Pyrrolizidine Alkaloid Hepatotoxicity: megalocytes, fibrosis, biliary hyperplasia
How is lantana toxic
- Subacute signs
- Signs of liver failure
- Damage bile canaliculi membrane -> Cholestasis
- Subacute signs: signs within a few days (depression, dehydration, constipation)
- Signs of liver failure
- Jaundice
- 2nd degree photosensitisation
- Death 1-4 weeks
Pathological changes seen with latana
- Photosensitisation
- Icterus
- Swollen liver and kidneys
- Distended gall bladder
- Constipation
What is the liver histopathology seen with lantana
- Often mild chnages
- Cholestasis
- Hepatocyte swelling with fine vacuolation
- Fibrosis and bile duct changes
How are cycads and zamia plants toxic
Seeds contain cyasin/microzamin
- Broken down in GIT by bacteria to MAM
- Converted to active form by enzymes in the liver
Where is acute intoxication with cycads and zamia seen and what does it cause
Sheep
- Swollen red liver and acities
- Centrolobular hepatic necrosis: GIT dysfunction
Where is chornic toxicity with cycads and zamia plams seen and what is the effect
Cattle
- Hepatic necrosis and dissecting fibrosis
What produces aflatoxin
Product of fungus: Aspergillis flavus, A. parasiticus, Penicillium puberulum
Where is acute aflatoxosis usually seen and what does it cause
Dogs
Haemorrhagic centrolobular to massive necrosis
What is seen with chronic alflatoxicosis
- Shrunken fibrotic liver
- Fatty change, biliary hyperplasia, centrilobular fibrosis, metalocytosis
Chronic hepatic aflatoxicosis: fatty change and biliary hyperplasia
What is sporidesmin and its cause
Facial eczema
- Product of fungus Pithomyces chartarum
- Grows in moistened dead rye grass
- Cause cholestasis and failure to ecvrete phylloerythrin
What is the gross pathology of Sporidesmin
- Secondary photosensitisation esp on face
- Bile stained liver
What is the histopathology fo sporidesmin
- Cholangitis and cholestasis
- Necrosis of biliary epithelium
- Dilatele ducts
Sporidesmin hepatotoxicity
- Facial Eczema
What is Phmopsin a product of
Fungus Diaporthe toxica - grows on lupin stubble
What animals does Phmopsin and what does it cause
- Sheep, cattle, occ. horses
- Subacute chronic toxicity
- Jaundice, secondary photosensitisation
Pathology of Phmopsin
Liver shrunken and fibrotic
Histopathology of Phmopsin
- Scattered hepatocyte necrosis
- Abronmal nitotic figures
- Diffuse fibrosis and biliary hyperplasia
Lupins infected with fungus Diaporthe toxica -> acute or chornic signs of liver failure
What is seen with blue-green alage acute intoxication
- Diarrhoea, prostration, death
- Can cause signs of liver failure if survive
Patholog changes with blue green algae
- Haemorrhagic gatro-enteritis
- Swollenhaemorrhagic liver
What does white phosphorus cause
- Directly toxic
- Jaundice
- Fattyliver
- Periportal fibrosis
What does carbon tetrachloride need and casue
- Activation to free radical CCl3- > causes lipid peroxidation of membranes
- Centrolobular necrosis
What does Xylitol cause
- Hyperinsulinaemia, hypoglycaemia, icterus
- Vomiting, lethargy and weakness
- Centrilobular to massive hepatocellular necrosis and periportal vacuolar change
What does the ingestion of copper cause
- Chronic hepatic intoxication and injury
- Acute haemolytic anaemia in ruminants
What does the ingestion of iron cause
- Iron dextran intoxication in piglets
- Ferrous fumarate intoxication in foals
What drugs are cats susceptible to
- Para-acetylaminophenol: deficient in glucaronyl transferase
- Diazepam
What drugs are dogs suceptible to
- Carprofen
- Long term anticonvulsants
