Pathology of the Liver and Biliary Tract 4 Toxic and Idiopathic...
Transcript of Pathology of the Liver and Biliary Tract 4 Toxic and Idiopathic...
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Pathology of the Liver and Biliary Tract – 4 Toxic and Idiopathic diseases
Shannon Martinson, March 2017 http://people.upei.ca/smartinson/
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OUTLINE
Normal anatomy & function
Hepatobiliary injury and responses
Manifestations of hepatic failure
Developmental anomalies and miscellaneous lesions
Circulatory disturbances
Metabolic & nutritional disturbances
Infectious diseases of the liver (hepatitis)
Toxin-induced liver diseases
Diseases of uncertain cause
Proliferative lesions of the liver
Diseases of the gallbladder and bile ducts
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• Histomoniasis in turkeys*
• Coccidiosis (rabbits)*
• Leishmaniasis
• Toxoplasmosis
• Neosporosis
• Amoebiasis
INFECTIOUS DISEASES OF THE LIVER – PARASITIC INFECTIONS
Protozoa
Entamoeba invadens in a reticulated python
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• Turkeys > Chickens
• Typhlitis
• Target-like areas of Hepatic necrosis
• Transmitted in the ova of Heterakis gallinarum
INFECTIOUS DISEASES OF THE LIVER – PARASITIC INFECTIONS
Protozoa
Histomonas meleagridis
Histomoniasis
“Black head”
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INFECTIOUS DISEASES OF THE LIVER – PARASITIC INFECTIONS
Protozoa
Eimeria stiedae
Hepatic Coccidiosis • Disease of rabbits • Coccidia live in biliary epithelial cells • Proliferative cholangitis
www.askjpc.org/wsco/wsc/images/2008/080403-1
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• Liver is the most common site of toxic injury because:
• Ingested toxins GIT Liver
• Biotransformation of endogenous / exogenous substances for excretion
• Bioactivation more toxic
• Predictable or idiosyncratic
• Common Lesions:
• Acute: Hydropic degeneration, lipidosis & necrosis, often centrilobular
• Chronic: Fibrosis, biliary hyperplasia and nodular regeneration (= cirrhosis)
TOXIN INDUCED LIVER DISEASE
Acute toxic injury
Chronic toxic injury
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Classification of hepatotoxic liver injury
TOXIN INDUCED LIVER DISEASE
Biotransformation (most common)
• Cytochrome p450 system (in centrilobular area)
• Phase I: Bioactivation – reactive intermediates
• Phase II: Conjugation
• Phase III: Excretion (via bile)
Stimulation of autoimmunity
Stimulation of apoptosis
Disruption of calcium homeostasis
Canalicular injury causing cholestasis
Mitochondrial injury
Hepatoxic Agents
Toxic plants
Mycotoxins
Cyanobacteria
Chemicals
Therapeutic agents
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TOXIN INDUCED LIVER DISEASE – TOXIC PLANTS
• Pyrrolizidine Alkaloid Poisoning • Alsike Clover • Cycad palms
Image: Duane Hoffmann / msnbc.com
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• Occur worldwide
• Pigs > cattle > horses > goats and sheep
• Alkaloids cytochrome p450 system Toxic pyrrolic esters – Alkylating agents – react with nuclear and
cytosolic proteins and nucleic acid: antimitotic
– Prevent cell division but not DNA synthesis*
• Toxic compound in milk transferred to neonates
• Acute
• Chronic*
TOXIN INDUCED LIVER DISEASE – TOXIC PLANTS
Pyrrolizidine Alkaloid Poisoning
Senecio vulgaris (www.cals.ncsu.edu/plantbiology)
• Common genera: • Senecio, Crotalaria,
Heliotropium, etc
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TOXIN INDUCED LIVER DISEASE – TOXIC PLANTS
Pyrrolizidine Alkaloid Poisoning
Acute: (rare) • Centrilobular necrosis
Lesions
Chronic (common)* Gross • Small firm finely nodular liver
Histology • Megalocytosis (antimitotic effect) • Fibrosis • Biliary Hyperplasia • Minimal nodular hepatocyte regeneration
www.askjpc.org/wsco/wsc/images/2014/142302-1.jpg
Horse
Noah’s Arkive
Liver, Chronic PA toxicity
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• Palm like plants (sago palms) • Ornamental • Kept as yard plants
• Contain nontoxic glycoside (cycasin) • Deconjugated by intestinal bacteria
• Creates a toxin (methylazoxymethanol)
• Bioactivated in liver • Alkylating agent
• Also contain neurotoxins – ataxia / paralysis
• Lesions • Similar to pyrrolizidine alkaloid
poisoning • Cattle, sheep and goats • Dogs are also susceptible
TOXIN INDUCED LIVER DISEASE – TOXIC PLANTS
Cycads
www.thetutuguru.com.au/wp-content/uploads/2013/05/Cycad-cycas-revoluta.jpg
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• Horses – Chronic liver disease – Photosensitization (2⁰)
• Histo – Portal hepatitis and fibrosis – Biliary hyperplasia
• Toxic principle unknown – Possibly a mycotoxin
• “Sooty blotch”
TOXIN INDUCED LIVER DISEASE – TOXIC PLANTS
Alsike Clover
Photosensitization
http://extension.psu.edu
www.omafra.gov.on.ca/english/.../info_alsike_clover.htm
Noah’s Arkive
Fibrosis and Biliary hyperplasia
• Trifolium hybridum
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TOXIN INDUCED LIVER DISEASE - MYCOTOXINS
• Aflatoxins
• Sporidesmin
• Phomopsin
• Poisonous mushrooms
Image: Mike Tidd
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• Aspergillus flavus and A. parasiticus • 4 major aflatoxins : B1, B2, G1 , G2
• Aflatoxin B1* • Occur in mouldy feed
• Corn, peanuts, cottonseed • Pig, poultry/ducks, calves
• Commercial dog food • Dogs
• Most common in stored feed when temperatures are warm and humid
• Bioactivated (cytochrome p450) in liver • Toxic intermediates bind to DNA, RNA,
protein • Toxic • Carcinogenic
TOXIN INDUCED LIVER DISEASE - MYCOTOXINS
Aflatoxins
Cornell Veterinary Medicine
cdn.patch.com/users/2271668/stock/T800x600/20150555467e57f1c05.jpg
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Acute intoxication • Dogs
– Centrilobular to massive necrosis, hemorrhage and lipidosis
www.askjpc.org/wsco/wsc/images/2011/110303-2.jpg
TOXIN INDUCED LIVER DISEASE - MYCOTOXINS
Diagnosis: Submit food / stomach content / vomit for aflatoxin testing
Aflatoxins
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Chronic intoxication • Pigs, horses > cattle • Lipidosis • Fibrosis • Biliary hyperplasia • Mild megalocytosis
Images: Pathologic Basis of Veterinary Disease(2006), 5th ed., Mosby-Elsevier.
TOXIN INDUCED LIVER DISEASE - MYCOTOXINS
Aflatoxins
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• Occurs in dead ryegrass in warm climates (NZ/Australia) • Unconjugated sporidesmin excreted in bile toxic to biliary
epithelium cholestasis photosensitization • Facial eczema
http://luirig.altervista.org/schedeit/fo/lolium_perenne.htm www.mycology.adelaide.edu.au/images/pitho1.gif
TOXIN INDUCED LIVER DISEASE - MYCOTOXINS
Sporidesmin
Photosenstization
• Pithomyces chartarum
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TOXIN INDUCED LIVER DISEASE - MYCOTOXINS
Sporidesmin
Hepatic fibrosis
Images: Noah’s arkive
Lesions • Cholangiohepatitis and cholestasis
• Portal fibrosis and biliary hyperplasia • Atrophy of the left hepatic lobe • Photosensitization
Portal fibrosis and biliary hyperplasia
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• Grows on lupins
• Chronic damage in cattle, sheep, and horses:
• Small livers, finely nodular
• Mitotic abnormalities and fibrosis
• Photosensitization
TOXIN INDUCED LIVER DISEASE - MYCOTOXINS
Phomopsin
• Diaporthe toxica (Phomopsis leptostromiformis)
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• Amanita phalloides (Death Cap) • Produce toxic cyclopeptides:
• Amatoxin • Inhibits of RNA polymerase II
function • One mushroom is sufficient to kill
• Acute damage: • Shrunken hemorrhagic liver
• Centrilobular to massive lipidosis, necrosis and hemorrhage
TOXIN INDUCED LIVER DISEASE - MYCOTOXINS
Poisonous Mushrooms
Phase I – latent: 6-12 hrs Phase II – GI signs: 6-24 hrs Phase III – false recovery: 12 – 24 hrs Phase IV – hepatic failure: 36-48 hrs
Diagnosis: Test for α-amanitin in serum, urine, gastric content, liver
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• Cyanobacteria – more like bacteria than fungi
• Grows as blooms on lakes and ponds
• Late summer or early fall
• Microcystin (pre-formed toxin)
• Inhibits protein phosphatase and causes cytoskeletal damage and cell death
• Livestock, dogs, and cats
• Signs develop rapidly
• Diarrhea, Prostration and Death
TOXIN INDUCED LIVER DISEASE – CYANOBACTERIAL TOXINS
Blue-green algae http://dogtrekker.com/userfiles//GreenDogCCJillSiegrist.gif
• Microcystis • Ananbaena • Aphanizomenon • Nodularia
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Lesions • Acute hemorrhagic gastro-enteritis • Red swollen liver:
• Centrilobular to massive necrosis • Often die within a few hours • Chronic liver disease in survivors
TOXIN INDUCED LIVER DISEASE – CYANOBACTERIAL TOXINS
Blue-green algae
Diagnosis: Test gastrointestinal content /vomit or liver for
Microcystin
www.askjpc.org/wsco/wsc/images/2009/092304-1
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• Xylitol
• White Phosphorus
• CCL4
• Metals
– Iron
• Iron dextran in pigs
• Ferrous fumarate in foals
– Copper (already covered)
TOXIN INDUCED LIVER DISEASE – HEPATOXIC CHEMICALS
• Vomiting • Weakness • Incoordination • Tremors
• Depression or lethargy
• Seizures /Coma
• Artificial sweetener • Acute toxicity in dogs – 0.5 mg/kg • Hyperinsulinemia and marked hypoglycemia • Centrilobular to massive hepatic necrosis
Xylitol
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• Some are predictable – Acetaminophen – cats (↓ glucuronyltransferase activity)
• Idiosyncratic reactions – rare individuals affected – Usually centrilobular hepatocytes; often via unknown mechanisms – Species and individual variation
• Trimethoprim-sulfonamide - Doberman pinschers • Carprofen - Labrador retrievers • Anticonvulsants (primidone, phenytoin and phenobarbital) → end stage liver in some dogs • Diazepam – acute hepatic failure in some cats
TOXIN INDUCED LIVER DISEASE – HEPATOXIC THERAPEUTIC DRUGS
Noah’s Arkive
Cirrhosis, long term primidone therapy, Dog Centrilobular necrosis , Acetaminophen, cat
Noah’s Arkive
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Equine serum hepatitis
Canine chronic hepatitis
DISEASES OF UNCERTAIN ORIGIN
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Pathologic Basis of Veterinary Disease(2006), 4th ed.
Equine Serum Hepatitis (Theiler’s Disease)
DISEASES OF UNCERTAIN ORIGIN
• Typically occurs 1-2 months after injection with a biological of equine serum
• Etiology has long been unknown • Now thought to be a Flavivirus
• Clinical signs - Jaundice and encephalopathy
Gross
• Small, flabby and pale liver
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Noah’s arkive
DISEASES OF UNCERTAIN ORIGIN
Histology: • Centrilobular to massive necrosis • Fatty degeneration • Cholestasis • Mononuclear infiltration • Slight fibrosis and regeneration
Equine Serum Hepatitis (Theiler’s Disease)
www.askjpc.org/vspo/show_page.php?id=134
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Chronic-active hepatitis
• Descriptive term Etiology: • Idiopathic
• Copper associated (36%) • Leptospirosis • Infectious Canine Hepatitis • Progression from acute
hepatitis • Therapeutic drugs • Immune-mediated • Toxic injury
Noah’s arkive
Canine Chronic Hepatitis
DISEASES OF UNCERTAIN ORIGIN
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• Clinical features – Anorexia, lethargy, weakness, vomiting, diarrhea, weight loss – Icterus, coagulopathies, ascites, hepatic encephalopathy – ↑ALT ↑AST ↑ALP ↑GGT, ↓albumin
• Gross – Small liver, coarsely nodular
Images- Noah’s arkive
DISEASES OF UNCERTAIN ORIGIN
Canine Chronic Hepatitis
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Pathologic Basis of Veterinary Disease(2006), 4th ed.
DISEASES OF UNCERTAIN ORIGIN
• Histology • Portal + periportal mononuclear
inflammatory cells • Piecemeal necrosis (“interface hepatitis”) • Intrahepatic cholestasis • Bridging fibrosis • Regenerative nodules
Limiting plate
Canine Chronic Hepatitis
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