PATHOLOGY OF LIVER & BILIARY TRACT

Enrique Aburto Winter 2015

Lecture 4

Bacterial &

parasitic

infections;

toxin-

induced

liver

diseases

7.2 Bacterial infections of the liver

Multifocal necrotizing/suppurative hepatitis

• Fetuses and neonates • Salmonella sp

• Listeria monocytogenes

• Campylobacter spp

• Actinobacillus sp

Abscesses

Granulomas

Morphological patterns

Multifocal

necrosuppurative

hepatitis, tularemia,

beaver.

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

From Noah’s arkive

7.2.1 Liver abscesses

Chemical rumenitis & traumatic reticulitis (cattle)

Single or multiple

Commonly involved agents: • Fusobacterium necrophorum

• Corynebacterium pseudotuberculosis

• Trueperella (Arcanobacterium) pyogenes

• Streptococci and Staphylococci

• Rhodococcus equi

Trueperella pyogenes infection, liver, cow, Rhodococcus equi infection, liver, goat.

Fusobacterium necrophorum infection, liver, lamb.

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

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

• Generalized infection in young

• Rupture and toxemia

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

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

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

A

V

T

Hepatic granulomas

Mycobacteriosis (Tuberculosis)

Epithelioid macrophages laden with Mycobacterium

avium (M) around a blood vessel (V), dog

Hepatic granulomas, bovine tuberculosis (left, top and bottom)

M

V

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

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

Single large area of necrosis due to C. hemolyticum (top).

Focal hepatic necrosis, black disease, sheep (bottom).

7.2.3 Black disease of sheep

Syn: Infectious necrotic hepatitis

Etio: Clostridium novyi

Multifocal necrosis

Subcutaneous congestion

Downloaded from Noah’s arkive

7.2.4 Tyzzer's disease

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

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

Tyzzer’s disease (Clostridium piliforme). Liver,

horse. Disseminated gray-white 1- to 2-mm foci of

necrosis and by suppurative inflammation.

Downloaded from Noah’s arkive

B. Tyzzer’s disease (Clostridium piliforme),

liver, foal. Note the haphazard distribution

of filamentous bacteria in the cytoplasm of

hepatocytes (arrow). Giemsa stain.

C. Foal. Clostridium piliforme can be

readily seen with special stains such as

Warthin-Starry (arrows)

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

Pathologic Basis of Veterinary Disease (2006), 4th ed., Mosby-Elsevier. Liver infarcts, mycotic infection, cow

7.4.1 Nematodes Ascaris suum

• “Milk spots" in pigs

• Multifocal fibrosis

• Tunnel hemorrhage eosinophilic infiltration/coagulative necrosis fibrosis

Stephanurus dentatus – pigs

7.4 Parasitic diseases of liver

Milk spots, liver, pig Adult forms of Ascaris suum in bile ducts, pig

Dirofilariasis, vena caval syndrome, dog. Several

adult forms of Dirofilaria immitis are present in the

caudal vena cava. Larval migration, liver, equine

Strongylus vulgaris - horses •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

Granulomatous hepatitis, Capillaria hepatica,

pen-tail bettong (rat-kangaroo). From Noah’s arkive

7.4.2 Cestodes

Ecchinonoccus granulosus

(Hydatidosis)

• Cysts in multiple species

• Adults in carnivores

• Uncommon in Canada

Stilesia hepatica

Thysanosoma actinoides

Cysticercus tenuicollis.

Hydatidosis, pig

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

Thysanosoma,

sheep

7.4.3 Trematodes

Species • 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

Chronic cholangitis due to Fasciola hepatica, liver, cow.

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

Pipestem liver, Fasciola hepatica, cow

Parenchymal, encapsulated, cavitated lesions , Fascioloides

magna, liver, caribou. Note the black excretory pigment

(hematin) deposited by the fluke.

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

Liver, most common site of toxic

injury

• Toxic agents GIT liver

• Biotransformation of endogenous and

exogenous substances for excretion.

• Bioactivation more toxic

Most agents are predictable, a few

are idiosyncratic

Lesions:

• Acute: Hydropic degeneration,

steatosis & necrosis, often

centrilobular

• Chronic: Fibrosis, biliary hyperplasia

and nodular regeneration

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

Centrilobular coagulative necrosis (N), liver, marmoset.

P = normal parenchyma (P), central vein (c)

Images from Noah’s arkive

P

N

c

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

Giant hypertrophy of hepatocytes (Megalocytosis) (arrow) and hyperplasia of biliary epithelium (arrowhead)

Finely nodular liver (minimal parenchymal regeneration)

Veno-occlusive disease. A reticulin stain reveals the marked

deposition of collagen within the lumen of the central vein.

Robbins and Cotran Pathologic Basis of Disease

(2010), 8th ed., Elsevier, Inc. chaper 18

Pathologic Basis of Veterinary Disease, 4 and 5th eds., Mosby-Elsevier Downloaded from Noah’s arkive

8.1.2 Cycads

Contain nontoxic

glycoside (cycasin)

• Deconjugated by intestinal

bacteria

• Bioactivated in liver

Lesions

• similar to pyrrolizidine

alkaloid poisoning (cattle,

sheep and goats)

Dioon mejiae

Ceratozamia kuesteriana

8.1.3 Alsike clover

Trifolium hybridum in

North America

Horses - chronic liver

disease

Histo

• Portal hepatitis and

fibrosis, bile duct

hyperplasia

• Photodynamic dermatitis

Toxic principle unknown (likely a mycotoxin)

www.omafra.gov.on.ca/english/.../info_alsike_clover.htm

Trifolium hybridum

Alsike clover toxicosis, liver, horse.

Extensive fibrosis (F) and marked

bile duct hyperplasia (arrows)

replacing the liver parenchyma (P)

F

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)

In mouldy feed

Become toxic in hepatocytes

Occurrence • Warm humid temperatures

• Not a major problem in Canada

Pigs, poultry, cattle and dogs

www.mycolog.com/chapter21.htm

Colonies of Aspergillus flavus (yellow)

and Penicillium (green)

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

Aflatoxins

Acute intoxication (dogs & ducklings)

• Lipidosis/necrosis - centrilobular to massive

• Ducklings - periportal necrosis

Chronic intoxication • Steatosis

• Fibrosis

• Biliary hyperplasia

• Megalocytosis

Aflatoxins are carcinogenic

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

Chronic aflatoxicosis, pig. The liver is shrunken

and fibrotic from collapse of areas of massive

necrosis and condensation of the fibrous stroma.

Hepatic steatosis, aflatoxicosis (aflatoxin B1), dog

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

8.2.2 Sporidesmin

Pithomyces chartarum

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

Unconjugated sporidesmin in bile toxic to biliary epithelium

Lesions • Cholangiohepatitis and cholestasis

• Atrophy of the left hepatic lobe

• Photosensitization in sheep

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

Lolium perenne

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

Conidiophores and conidia of

Pithomyces chartarum

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.

8.2.3 Phomopsin • Phomopsis leptostromiformis

• Grows on lupins

• Chronic damage :

Small livers, finely nodular (mitotic inhibition and fibrosis)

Photosensitization

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

Lupins

Amanita phalloides

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

8.3 Blue-green algae

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

Microcystis bloom

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) – end-stage liver.

• Diazepam – acute hepatic failure in cats

Usually centrilobular hepatocytes; unknown mechanisms

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

Hepatocellular necrosis (N), centrilobular,

acetaminophen toxicosis. P = normal parenchyma

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

N

N

P

P

RN

PF

BF

BF

Downloaded from Noah’s arkive