PATHOLOGY OF LIVER & BILIARY TRACT

Lecture 4 Bacterial & parasitic infections; toxininduced liver diseases

Enrique Aburto

Winter 2015

7.2 Bacterial infections of the liver Morphological patterns  Multifocal necrotizing/suppurative hepatitis • Fetuses and neonates • • • •

Salmonella sp Listeria monocytogenes Campylobacter spp Actinobacillus sp

 Abscesses  Granulomas

Multifocal necrosuppurative hepatitis, tularemia, beaver.

From Noah’s arkive

Salmonellosis, liver, pig (right, bottom). The necrotic foci are infiltrated by macrophages (paratyphoid nodules). Pathologic Basis of Veterinary Disease , 4th ed.

Multifocal necrotizing hepatitis, necrobacillosis, sheep

7.2.1 Liver abscesses  Chemical rumenitis & traumatic reticulitis (cattle)  Single or multiple  Commonly involved agents: • • • • •

Fusobacterium necrophorum infection, liver, lamb.

Fusobacterium necrophorum Corynebacterium pseudotuberculosis Trueperella (Arcanobacterium) pyogenes Streptococci and Staphylococci Rhodococcus equi

Pathologic Basis of Veterinary Disease , 5thed., Mosby-Elsevier

Rhodococcus equi infection, liver, goat.

Trueperella pyogenes infection, liver, cow,

Liver abscesses

Outcome • • • •

Incidental finding Become encapsulated and sterile Cause fibrous adhesions Break into hepatic vein or vena cava    

• •

Thrombophlebitis Endocarditis Pulmonary aneurisms Lung abscesses

Pathologic Basis of Veterinary Disease, 5th ed., Mosby-Elsevier

V

A

Generalized infection in young Rupture and toxemia

Liver abscess (A) with rupture into an hepatic vein (v), cow

T

Vena cava thrombophlebitis (left, T) and pulmonary emboli (right, arrows), secondary to liver abscessation, cow

Pathologic Basis of Veterinary Disease, 5thed., Mosby-Elsevier

 Hepatic granulomas Mycobacteriosis (Tuberculosis)

M

V

Epithelioid macrophages laden with Mycobacterium avium (M) around a blood vessel (V), dog Hepatic granulomas, bovine tuberculosis (left, top and bottom)

7.2.2 Bacillary hemoglobinuria  Etio: Clostridium hemolyticum  Cattle & sheep  Pathogenesis: Liver injury by migrating flukes  anaerobiosis  spore germination  exotoxins  liver necrosis / intravascular hemolysis  hemoglobinuria

 Lesion • Single large area of necrosis • Rapid autolysis

7.2.3 Black disease of sheep  Syn: Infectious necrotic hepatitis  Etio: Clostridium novyi  Multifocal necrosis  Subcutaneous congestion Downloaded from Noah’s arkive

Single large area of necrosis due to C. hemolyticum (top). Focal hepatic necrosis, black disease, sheep (bottom).

7.2.4 Tyzzer's disease 





Downloaded from Noah’s arkive

Etio: Clostridium piliforme • Rodents, • Immunocompromised or young foals, calves, kittens, puppies Lesions • Multifocal necrotizing hepatitis • Necrotizing colitis Diagnosis • Bundles of long bacilli in hepatocytes • Silver stain (Warthin-Starry) Multifocal hepatitis, foal. Cl. piliforme infection

Tyzzer’s disease (Clostridium piliforme). Liver, horse. Disseminated gray-white 1- to 2-mm foci of necrosis and by suppurative inflammation. Pathologic Basis of Veterinary Disease, 5thed., Mosby-Elsevier

C. Foal. Clostridium piliforme can be readily seen with special stains such as Warthin-Starry (arrows)

B. Tyzzer’s disease (Clostridium piliforme), liver, foal. Note the haphazard distribution of filamentous bacteria in the cytoplasm of hepatocytes (arrow). Giemsa stain. Pathologic Basis of Veterinary Disease, 5thed., Mosby-Elsevier

Other bacterial and mycotic diseases 7.2.5 Leptospirosis 7.3 Mycotic hepatitis • Hemorrhagic infarcts • Granulomatous hepatitis • Blastomyces spp • Histoplasma spp

Dissociation of hepatic cords, leptospirosis, dog

Yeasts of Histoplasma in the cytoplasm of Kupffer cells and macrophages Liver infarcts, mycotic infection, cow

Pathologic Basis of Veterinary Disease (2006), 4th ed., Mosby-Elsevier.

7.4 Parasitic diseases of liver 7.4.1 Nematodes  Ascaris suum • “Milk spots" in pigs • Multifocal fibrosis • Tunnel  hemorrhage  eosinophilic infiltration/coagulative necrosis  fibrosis

 Stephanurus dentatus – pigs Adult forms of Ascaris suum in bile ducts, pig

Milk spots, liver, pig

Strongylus vulgaris - horses

Granulomatous hepatitis, Capillaria hepatica, pen-tail bettong (rat-kangaroo). From Noah’s arkive

•Migration of larvae •Associated with perihepatitis filamentosa??

Calodium (Capillaria) hepatica dogs, rodents (adults and eggs in liver) Dirofilaria immitis (heartworm)

•Fatal vena caval syndrome in heavy infections

Larval migration, liver, equine

Dirofilariasis, vena caval syndrome, dog. Several adult forms of Dirofilaria immitis are present in the caudal vena cava.

7.4.2 Cestodes

Hydatidosis, pig

 Ecchinonoccus granulosus (Hydatidosis) • Cysts in multiple species • Adults in carnivores • Uncommon in Canada

 Stilesia hepatica  Thysanosoma actinoides  Cysticercus tenuicollis.

Thysanosoma, sheep

C. tenuicollis (T. hydatigena), liver, pig

7.4.3 Trematodes 

Species • •



Chronic cholangitis due to Fasciola hepatica, liver, cow.

Fasciola hepatica, F. gigantica, Fascioloides magna and Dicrocoelium - ruminants Opisthorchis and Platynosomun dogs and cats

Most significant • •

F. hepatica & F. gigantica – in bile ducts Fascioloides magna - cavitations within liver parenchyma

Fasciola hepatica Chronic cholangitohepatitis and severe parenchymal fibrosis due to Fasciola hepatica, liver, ox.

Liver flukes 

LESIONS: • •



Immature flukes: trauma during migration (clostridial infections) Adults: mechanical and chemical irritation; physical obstruction  fibrosing cholangitis / hepatitis  pipestem liver  Black pigment with F. magna

Blood loss

Migratory tracts of Fasciola hepatica, liver, sheep

Parenchymal, encapsulated, cavitated lesions , Fascioloides magna, liver, caribou. Note the black excretory pigment (hematin) deposited by the fluke.

Pipestem liver, Fasciola hepatica, cow

7.4.4 Protozoa     

Coccidiosis (rabbits) Leishmaniasis Toxoplasmosis Neosporosis Histomoniasis in turkeys Proliferative cholangitis, gross (top) and histo (bottom), Eimeria stiedae (arrows), rabbit

Histomoniasis, liver, turkey. Well-defined rounded areas of necrosis

VIII. Toxic-induced liver disease Centrilobular coagulative necrosis (N), liver, marmoset. P = normal parenchyma (P), central vein (c)

 Liver, most common site of toxic injury • Toxic agents  GIT  liver • Biotransformation of endogenous and exogenous substances for excretion. • Bioactivation  more toxic

c

P

N

 Most agents are predictable, a few are idiosyncratic  Lesions: • Acute: Hydropic degeneration, steatosis & necrosis, often centrilobular • Chronic: Fibrosis, biliary hyperplasia and nodular regeneration

Images from Noah’s arkive

Diffuse fibrosis and nodular regeneration, primidone toxicity, liver, dog

Classification of hepatotoxic liver injury  Biotransformation  cytochrome p450 system (in centrilobular area)  Stimulation of autoimmunity  Stimulation of apoptosis  Disruption of calcium homeostasis  Canalicular injury  Mitochondrial injury

Hepatotoxic agents  Numerous • • • •

Phytotoxins Mycotoxins Chemicals Some therapeutic agents

Centrilobular necrosis (red areas), liver, bovine

From Noah’s arkive

8.1 Toxic plants 8.1.1 Pyrrolizidine alkaloid poisoning  Common genera: Senecio and Crotalaria  Worldwide (pigs, cattle, horses, goats & sheep)

 Alkaloids  cytochrome p450 system  pyrrolic esters.  Milk  sucklings  Lesions • Acute - centrilobular necrosis • Chronic - fibrosis (Hepatic veno-occlusive disease)

• Megalocytosis (antimitotic effects)

Senecio vulgaris (Downloaded from Wikimedia Commons)

Pyrrolizidine alkaloid poisoning – liver

Finely nodular liver (minimal parenchymal regeneration)

Robbins and Cotran Pathologic Basis of Disease (2010), 8th ed., Elsevier, Inc. chaper 18

Veno-occlusive disease. A reticulin stain reveals the marked deposition of collagen within the lumen of the central vein.

Giant hypertrophy of hepatocytes (Megalocytosis) (arrow) and hyperplasia of biliary epithelium (arrowhead) Downloaded from Noah’s arkive

Pathologic Basis of Veterinary Disease, 4 and 5th eds., Mosby-Elsevier

8.1.2 Cycads  Contain nontoxic glycoside (cycasin) • Deconjugated by intestinal bacteria • Bioactivated in liver Dioon mejiae

 Lesions • similar to pyrrolizidine alkaloid poisoning (cattle, sheep and goats)

Ceratozamia kuesteriana

8.1.3 Alsike clover www.omafra.gov.on.ca/english/.../info_alsike_clover.htm

 Trifolium hybridum in North America  Horses - chronic liver disease  Histo • Portal hepatitis and fibrosis, bile duct hyperplasia • Photodynamic dermatitis

Trifolium hybridum

 Toxic principle unknown (likely a mycotoxin) F

Alsike clover toxicosis, liver, horse. Extensive fibrosis (F) and marked bile duct hyperplasia (arrows) replacing the liver parenchyma (P)

P Noah’s arkive

8.2 Mycotoxins Secondary metabolites of fungi    

Aflatoxins Sporidesmin Phomopsin Poisonous mushrooms

8.2.1 Aflatoxins  Aspergillus flavus  4 major : B1, B2, G1 & G2  B1 - most common & potent (also a carcinogen)

http://w3.vet.cornell.edu/nst/nst.asp

 In mouldy feed  Become toxic in hepatocytes  Occurrence • Warm humid temperatures • Not a major problem in Canada

 Pigs, poultry, cattle and dogs

Colonies of Aspergillus flavus (yellow) and Penicillium (green)

www.mycolog.com/chapter21.htm

Aflatoxins

Hepatic steatosis, aflatoxicosis (aflatoxin B1), dog

 Acute intoxication (dogs & ducklings) • Lipidosis/necrosis centrilobular to massive • Ducklings - periportal necrosis

 Chronic intoxication • • • •

Steatosis Fibrosis Biliary hyperplasia Megalocytosis

http://www.askjpc.org/wsco/wsc/images/2011/110303-2.jpg

 Aflatoxins are carcinogenic

Chronic aflatoxicosis, pig. The liver is shrunken and fibrotic from collapse of areas of massive necrosis and condensation of the fibrous stroma. Pathologic Basis of Veterinary Disease(2006), 4th ed., Mosby-Elsevier.

8.2.2 Sporidesmin www.mycology.adelaide.edu.au/images/pitho1.gif

 Pithomyces chartarum  Dead rye grass; warm climates (New Zealand & Australia)

Conidiophores and conidia of Pithomyces chartarum

 Unconjugated sporidesmin in bile  toxic to biliary epithelium  Lesions • Cholangiohepatitis and cholestasis • Atrophy of the left hepatic lobe • Photosensitization in sheep

Lolium perenne http://luirig.altervista.org/schedeit/fo/lolium_perenne.htm

Sporidesmin toxicity in sheep. Locally extensive areas of hepatic fibrosis (* top, left) zonal, diffuse hepatocellular necrosis on cut surface (bottom left); photosensitization (facial eczema); fibrosis and bile duct hyperplasia (histo). Images from Noah’s arkive.

More mycotoxins www.mooseyscountrygarden.com/garden-journal-0...

8.2.3 Phomopsin • Phomopsis leptostromiformis • Grows on lupins • Chronic damage :  Small livers, finely nodular (mitotic inhibition and fibrosis)  Photosensitization

Lupins

8.2.4 Poisonous mushrooms • Amanita phalloides • Acute damage: •

Lipidosis, hemorrhage, necrosis (centrilobular to massive )

• Toxic cyclopeptides (amatoxin & phalloidin)  Inhibition of RNA polymerase II function Amanita phalloides

8.3 Blue-green algae Microcystis bloom

 Microcystis aeruginosa (microalga; cyanobacteria)

 Grows as blooms on lakes and ponds  Late summer or early fall  Microcystin (preformed toxin)  Lesions • Acute hemorrhagic gastro-enteritis • Centrilobular to massive necrosis • Chronic liver disease in survivors

Light micrograph of Microcystis http://research.myfwc.com/features/view_article.asp

8.4 Hepatotoxic chemicals  Phosphorus • Vermin control; rodenticide • Lipidosis and periportal necrosis (no metabolic transformation)

 Carbon tetrachloride (CCl4) • Fire extinguishers; refrigerants; cleaning solvents; pesticide; anthelmintic • Centrilobular lipidosis and necrosis

*

 Cresols • Asphalt shingles; clay pigeons • Massive hepatic hemorrhage and necrosis in pigs

 Metals (Iron, copper) • Iron-dextran injection in piglets – massive hepatic necrosis

CCL4 toxicosis, liver cirrhosis (left*) and acquired portosystemic shunts (tortuous vascular channels), dog

8.5 Hepatotoxic therapeutic drugs  Idiosyncratic reactions in a minority of individuals  Species and individual variation • • • • •

Trimethoprim-sulfonamide - Doberman pinschers Carprofen - Labrador retrievers Ivermectin - Collies and Shelties Acetaminophen – cats (↓ glucuronyltransferase activity) Anticonvulsants (primidone, phenytoin and phenobarbital) – endstage liver. • Diazepam – acute hepatic failure in cats

 Usually centrilobular hepatocytes; unknown mechanisms

Downloaded from Noah’s arkive

Hepatocellular necrosis (N), centrilobular, acetaminophen toxicosis. P = normal parenchyma

P N

P

N

http://w3.vet.cornell.edu/nst/nst.asp

BF PF

RN BF

Drug-induced cirrhotic livers, dogs (left top &bottom) and cat (right bottom) due to prolonged primidone therapy. RG = regenerative nodule, PF = portal fibrosis, BF = bridging fibrosis