Liver & biliary system (+pancreas) pathology 4

What are the different sources of toxins?

• Plants —> phytotoxins

• Fungi —> mycotoxins

• Inorganic chemicals —> drugs, metals

What are the different forms of a toxin that can cause an effect?

• Uptake as toxic substances

• Toxic after biotransformation

• Toxic after metabolisation by GI microbes

What is the difference between obligate and idosyncratic toxin?

Obligate —> predictable toxic effects, dose dependent, direct or indirect effect on hepatocytes

• E.g. paracetamol

Idiosyncratic —> only in some individuals, unpredictable, dose-indenpendent, usually immunologic (hypersens against hepatocytes)

What are the two modes of actions of obligate toxic substances?

Direct effect

• oxidation of membrane lipids (cell, organelle, mitochondria)

• Denaturing of structural proteins

• Inhibition of enzymes

Indirect effect

• Blocking of receptor or transport proteins

• Modification of proteins

• Binding to nuclear proteins, DNA, RNA or ribosomes

What is the most common entry of exogenous poisons to liver?

• Via portal blood (intestine)

  • Because most ingested

What are the roles of hepatocytes in detoxification?

• Biotransformation —> hydroxylation & conjugation of lipophilic substances → excretion via bile

  • Mainly centrolobular hepatocytes

• Carrier systems for uptake of water-soluble substances from blood & secretion via bile

• Activation of Kupffer cells (macropahges) via receptors (e.g. by endotoxins)

  • Release of free radicals & inflam mediators → damage to surrounding tissue

What are the phases of biotransformation?

• Phase I —> oxidation (CytP450 oxidase enzyme)

• Phase II —> conjugation of metabolic product with water

Damage occurs to hepatocytes during biotransformation

What zone dominates when damage occurs to hepatocytes during biotransformation?

Zone 3

• Zone 1 much less common but dominates with direct acting toxicants such as metal satls

What gross findings are associated with acute toxic hepatosis?

• ascites

• oedema of gall bladder wall

• petechial haemorrhages in serosa (DIC)

What histological findings are associted with acute toxic hepatosis?

• usually centrolobular (periacinar) to massive necrosis, often with fatty / hydropic change of adjacent hepatocytes

  

• early stage —> degenerate/necrotic hepatocytes still orderly arranged

• later stage —> dilated, blood-filled sinusoids due to loss of hepatocytes

What are the overall toxin effects on the liver?

• One-time submassive necrosis —> regeneration of liver possible

• One-time massive necrosis with destruction of the reticular framework → fibrosis (repair)

• Chronic or recurrent toxin application —> chronic active hepatitis → cirrhosis

• Some toxins → hepatic neoplasms

What effects do toxic substances have on the hepatocytes?

• diffuse or zonal metabolic derangement → hydropic degeneration (swelling + vacuolation = reversible)

• lipidosis or necrosis

List some examples of specific hepatotoxins

• Copper toxicosis

• Pyrrolizidine alkaloidosis (seneciosis, ragwort poisoning)

• Aflatoxicosis

• Blue-green algae poisoning

What does copper deficiency cause in sheep and cattle?

Sheep = swayback

Cattle = coat & pigment abnormalities

What can cause copper toxicity?

• High intake

• Reduced biliary excretions

• Familial predisposition (bedlingtons, WHWT, North Ronaldsay sheep)

What are the causes of copper toxicosis in sheep?

• Low tolerance of dietary coopper

  • Inadvertent feeding of high Cu diet

• Pasture contam (slurry from other species e.g. pigs / poultry)

• Nutritional imbalance —> Cu & Molybdenum/Sulfur form complexes and reduce uptake and increase Cu excretion

• Consumption of hepatotoxic plants containing puyrrolizine alkaloids

• Breed susceptibility —> Merino most resistant; Texels and North Ronaldsay most susceptible

• Stress e.g. transport, movement, altered environ

How does copper toxicosis present?

• Haemolytic crisis

  • Release of Cu from necrotic hepatocytes into blood → inapp, jaundice, haemoglobinuria, death

  • May be precipitated by ingestion of hepatotoxin / stress

What histological changes are associated with copper toxicosis?

• liver necrosis (zone 3)

• renal tubular Hb casts

What has caused these lesions?

Copper toxicosis —> haemolytic crisis, acute chromoproteinaemic, nephrosis, liver degen, icterus

How is copper toxicosis diagnosed?

liver copper 500-1000µg/g

(normal = <400)

What dog breed is associated with copper toxicosis?

Bedlington terriers

• Autosomal recessive mutation

• Can lead to progressive hepatitis & ultimately cirrhosis

What is being shown in these images?

Familial copper toxicosis in dogs (progression)

What can copper retention occur secondary to in dogs?

Chronic liver disease where there is failure / obstruction to bile flow as in:

• Chronic active hepatitis in Dobermann Pinschers

• Skye terrier hepatitis

(Not as strong association as Bedlington, predisposition?)

In what breed of sheep does familial copper toxicosis occur?

North Ronaldsay sheep

• Sheep adapted to Cu deficient environment now have sensitivity to Cu

What is pyrrolizidine alkaloidosis?

Hepatotoxic plant toxins (pyrrolizidine alkaloids) found in different plant genera —> hepatotoxic substances

What plant genera can cause pyrrolizidine alkaloidosis?

• Senecio

  • Ragwort —> normally unpalatable but bigger risk when contaminated other feed stuff e.g. dry in hay / silage

• Crotolaria

• Heliotropium

What toxic mechanisms causes pyrrolizidine alkaloidosis

• Chronic hepatotoxicity

• Alkaloids themselves not toxic —> undergoes biotransformation to become toxic:

  • Cytochrome P450 produce toxic pyrrolic esters —> bind to DNA & RNA —> stop cell & protein replication

What animals are most sensitive to Pyrrolizidine alkaloidosis?

• Pig (greatest)

• Cattle, horse

• Sheep (least sensitive)

What pathological findings are associated with Pyrrolizidine alkaloidosis?

• hepatic cirrhosis, with:

  • single cell necrosis

  • megalocytes (INDICATIVE OF FINDING) —> regenerative attempt due to inhibition of mitosis but not protein syntehsis

    

• inflammatory infiltration, fibrosis [cattle]

  

• bile duct prolif

• hepatoencephalopathy

What is being shown here?

Hepatic cirrhosis due to Pyrrolizidine alkaloidosis

What is aflatoxicosis due to?

• Consumption of mouldy feedstuffs

  • Aspergillus flavus

  • A. parasiticus

  • Penicillum puberculum

What are the dangerous features of aflatoxins?

• toxic

• carcinogenic

• teratogenic (effect on unborn fetuses)

• mitosis inhibiting

• immunosuppressive

What does aflatoxicosis cause?

• Chronic hepatotoxicity

• Liver changes very similar to seneciosis

Sensitivity —> dog, cat, pig, calf [cattle & horses less sensitive]

In what animals is blue-green algae poisoning seen?

cattle, sheep, horse, pig, dog

What causes blue-green algae poisoning?

Microcystis aeruginosa

How does blue-green algae poisoning present?

Acute hepatotoxicity

• hepatotoxin (polypeptide) released when algae disintegrate (in water, in rumen or stomach)

Centrolobular to massive necrosis w/ haemorrhage

What are the two ducts of the pancreas?

Major pancreatic duct —> into duodenum at duodenal papilla

Minor pancreatic duct —> into duodenum at accessory duodenal papilla

What are the histological features of the exocrine pancreas?

• tubulo-acinar gland

• secretion of digestive enzymes

• regeneration —> by proliferation of differentiated cells

What are the anomalies of development of the pancreas?

• Aplasia —> rare, incompatible with life, no exocrine or endocrine tissue

• Hypoplasia —> sporadically in calves, clinically = EPI (exocrine pancreatic insuffiency)

• Juvenile atrophy

In what age dogs does juvenile atrophy occur?

young dogs esp. german sheperds

How does juvenile atrophy present histologically?

• exocrine pancreatic tissue almost absent

• islets usually unaffected

What are the clinical signs of juvenile atrophy?

Chronic exocrine pancreatic insufficiency

What is being shown here?

Juvenile atrophy

• Severe diffuse atrophy, no fat in mesentery

• Steatthorhea

  • Cannot digest food properly → high fat content in faeces (lipases not synthesised to breakdown & absorb fat ingested)

What ciruclatory disorder can be seen in the pancreas?

haemorrhage

List the reasons you may see pancreatic haemorrahge?

with coagulation disorders

a) infectious diseases [canine infectious hepatitis]

b) intoxications [dicumarol]

c) DIC

What are the differences between acute and chronic pancreatitis?

Acute pancreatitis

• Necrotising

• Painful

Chronic pancreatitis

• Fibrosis

• Insufficiency

What are the causes of pancreatitis?

• Most idiopathic

• Systemic infections (canine infectious hepatitis, FIP, FMD)

• Migrating parasite (strongyles in horses)

• Zinc poisoning (sheep, calves, dogs)

• Trauma, obstruction of pancreatic duct

What is being shown here?

Acute necrotising pancreatitis

What is the physioloigcal cause of acute necrotising pancreatitis?

Release & activation of pancreatic enzymes within the pancreas

What lesions are associated with acute necrotising pancreatitis?

focal necrosis, haemorrhage, thrombosis, oedema

followed by inflammatory infiltration & fat necrosis

What are the clinical signs of acute necrotising pancreatitis?

• suddenly decreased appetite

• dullness, vomiting, diarrhoea, thirst

• abdo pain

What are these lesions associated with?

Acute necrotising pancreatitis

• Necrotising pancreatitis w/ fat necrosis

• Reddened, haemorrhage

• Necrosis of adjacent tissue (adjacent to stomach) = R image

What is being shown here?

Acute necrotising pancreatitis with fat necrosis

fibrin accum + inflam

What is being shown?

What are the outcomes of acute necrotising pancreaitis?

• Death within a few days

  • Consumption of plasma protease inhibitors →

  • Activation of kinin, coagulation, fibrinolysis, complement cascades →

  • DIC, shock →

• Animals survive & develop repeated acute episodes

  • chronic fibrosing pancreatitis

  • exocrine pancreatic insufficiency, diabetes mellitus

What is chronic fibrosing pancreatitis?

• sequel of acute necrotising pancreatitis or w/o signs of acute pancreatitis [cats]

• pancreatic tissue replaced by fibrous tissue

How does chronic fibrosing pancreatitis present in cats?

chronic interstitial pancreatitis w/ chronic cholangitis / cholangiohepatitis (& IBD) —> “triaditis”

What are the clinical signs of chronic firbosing pancreatitis?

EPI +/- endocrine deficiency

What is being shown here?

Chronic fibrosing pancreatitis

What is being shown here

Chronic fibrosing pancreatitis with severe interstitial fibrosis

some islands of exocrine tissue left + fibrosis

What are the causes of exocrine pancreatic insufficiency?

• Juvenile atrophy (dogs)

• Chronic pancreatitis (cats)

• Exocrine pancreatic neoplasia

• Hypoplasia (calves)

What are the signs associated with exocrine pancreatic insuffiency?

• Diarrhoea and chronic weight loss

• pale, soft, voluminous, malodorous faeces (pancreatogenic maldigestion)

  

• +/- steatorrhoea

• bacterial overgrowth (SIBO)

• malabsorption of vitamins → hypovitaminosis

• +/- diabetes mellitus (depending on underlying aeitiology)

How do you differentiate a nodular hyperplasia from a neoplasia?

• nodular hyperplasia = not neoplasm

• seen in old dogs, cats and cattle

• multiple

• no encapsulation

• no compression of adjacent tissue

List the neoplasms of the exocrine pancreas

• Adenoma

  • Very rare

  • Usually solitary

• Adenocarcinoma

What are the features of adenocarcinomas

• Often arising within centre of pancreas

• Cellular origin = acini / ducts

• Gross = greyish, scirrhous tissue

• V. agressive (early metastases)

  • implantation metastases (peritoneum, diaphragm → thorax)

  • Haematogenous (portal vein → liver)

  • Lymphogenic spread (local LNs)

  • Local invasion (into duodenal wall)

What is being shown here?

Pancreatic carcinoma (Ddx: duodenal carcinoma)

mass highly infiltrative

What is being shown here?

metastases of pancreatic carcinoma:

liver, omentum (spread across abdo cavity), parietal pleura

How can adenocarcinoma of the exocrine pancreas metastasise?

• Implantation metastases [peritoneum, diaphragm to thorax]

• Haematogenous spread [portal vein to liver]

• Lymphogenic spread [local lymph nodes]

• Local invasion into duodenal wall