Liver 4 and Exocrine pancreas Flashcards
Where do toxic substances come from?
- Plants (phytotoxins)
- Fungi (Mycotoxins)
- Chemicals
In what ways do toxins have an effect on the body?
- Uptake as toxic substances
- Toxic after biotransformation
- Toxic after metabolisation by gastrointestinal microbes
Describe obligate toxic substances
Lead to predictable toxic effects in numerous species, dose-dependent, direct or indirect effect on hepatocytes
Describe the direct effect mode of action of obligate toxic substances
- Oxidation of membrane lipids (cell, organelle, mitochondria)
- Denaturing of structural proteins
- Inhibition of enzymes
Describe the indirect effect mode of action of obligate toxic substances
- Blocking of receptor or transport proteins
- Modification of proteins
- Binding to nuclear proteins, DNA, RNA or ribosomes
What are the 3 roles of Hepatocytes in detoxification
- Biotransformation: hydroxylation and subsequent conjugation of lipophilic substances → excretion
- Carrier systems for uptake of water-soluble substances from blood and secretion via bile (bilirubin)
- Activation of Kupffer cells via receptors (e.g. by endotoxins)
Biotransformation is mainly performed by which cells?
Centrolobular (periacinar) hepatocytes
What is the idiosyncratic toxic effect?
Only in some individuals of some species; unpredictable, dose-independent, usually immunologic (hypersensitivity against hepatocytes)
- Drug binds to hepatocellular carrier proteins which induces immune response
Describe the gross findings of acute toxic hepatosis
- Ascites
- Oedema of gall bladder wall
- Petechial haemorrhages in serosa (DIC)
Describe the histological findings of acute toxic hepatosis, compare early and late stage findings
- Usually centrolobular (periacinar) to massive necrosis, often with fatty or 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 effects of toxic substances on hepatocytes?
- Diffuse or zonal metabolic derangement → hydropic degeneration (swelling), lipidosis or necrosis
- one-time submassive necrosis: regeneration 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
Name the copper deficiency syndromes in sheep and cattle
Sheep = swayback (neurological immaturity) Cattle = coat and pigment abnormalities
What are the 3 methods of copper toxicity?
- High intake
- Reduced biliary excretion
- Familial predisposition
What are the causes of copper toxicosis in sheep?
- Sheep have a low tolerance of dietary copper excess due to a reduced biliary excretion of copper
- Pasture contamination
- Inadvertent feeding of high Cu diet
- Nutritional imbalance of Mo (S)
- Consumption of hepatotoxic plants
- Breed susceptibility
- Stress: Transport, movement, altered environment
Describe a haemolytic crisis
- Release of Cu from necrotic hepatocytes into blood (characterised by inappetance, jaundice, haemoglobinuria and death)
- May be precipitated by ingestion of hepatotoxin (plant, mycotoxin) or stress
What are the histological changes in copper toxicosis in sheep
- Liver necrosis (zone 3)
- Renal tubular Hb casts
Familial copper toxicosis affects which breed/spp?
Dog - Bedlington terrier
due to an autosomal recessive mutation in the breed
Describe Familial copper toxicosis
- Cu accumulates in liver (zone 3) to >1000µg/g (ppm) with progressive hepatitis and ultimately cirrhosis
- Normal Cu levels in liver: <400 ppm
What are the clinical signs of Familial copper toxicosis?
Gradual onset of liver dysfunction, with elevated liver specific enzymes, and progressing inexorably to liver failure
Name some Copper-associated liver diseases in other breeds of dog
- Chronic active hepatitis in Doberman Pinschers
- Skye terrier hepatitis
Which sheep breed are affected by Familial copper toxicosis?
North Ronaldsay sheep
What is the name of the Ragwort plant?
Senecio jacobea
Describe the features of ragworm
- Common weed in waste ground and roadside verges
- Biennial: during the first year the plant produces only roots, a short stem and leaves as a flat rosette (not damaged by mowing or cutting)
- Second year: plant develops tall stem and has characteristic small yellow flowers
- Long flowering period (May to Sept)
- Plant can be removed from fields by broadleaf herbicides or by pulling them up and burning
- Will take a number of years to eliminate the plant
Describe the toxic mechanism of ragwort
- Cumulative effect; chronic hepatotoxicity
- Alkaloids themselves are not toxic
- Cytochrome P450 produce toxic pyrrolic esters (acylating, interact with purine and pyrimidine bases of DNA and RNA)
Which spp are most to least sensitive to ragwort?
pig > cattle, horse > sheep
What pathological findings will be seen with ragwort toxicity?
- Hepatic cirrhosis, with: • Single cell necrosis, megalocytes • Inflammatory infiltration, fibrosis [cattle] • Bile duct proliferation • Hepatoencephalopathy - Megalocytosis • = regenerative attempt • Due to inhibition of mitosis, but not of protein synthesis
How will ragwort toxicity affect the liver grossly?
Jaundice, ascites, oedema of the abomasal wall and characteristically a small hard liver
How will ragwort toxicity affect the liver histologically?
-Lobular atrophy with enlargement or hypertrophy of surviving hepatocytes - megalocytes - these cells show nuclear enlargement (karyomegaly) and are frequently degenerate and undergoing necrosis. Additionally there may be fibrosis and biliary proliferation
What occurs following consumption of mouldy feedstuffs?
Aflatoxicosis
What is the primary cause of Aflatoxicosis?
Aspergillus flavus
Describe the features/changes of aflatoxicosis
- Toxic, carcinogenic, teratogenic, mitosis inhibiting, immunosuppressive
- Chronic hepatotoxicity
- Liver changes very similar to seneciosis
Describe the effects of blue-green algae poisoning
Acute hepatotoxicity;
• Hepatotoxin (polypeptide) is released when algae disintegrate (in water, in rumen or stomach)
- Liver changes: centrilobular to massive necrosis with haemorrhage
Describe the pancreas and its blood supply
Compound glandular organ: exocrine / endocrine
• Arterial blood: from cranial mesenteric and celiac arteries
• Venous blood: into portal vein
Describe secretion of the pancreas via the major duct
Into duodenum at duodenal papilla
- Only duct present in sheep, goats and most cats always present in horses
Describe secretion of the pancreas via the minor duct
Into duodenum at accessory duodenal papilla
- Only duct in swine and cattle often the only duct in dogs always present in horses present in 20% cats
What is secreted from the exocrine pancreas?
Digestive enzymes
How is auto-digestion prevented in the exocrine pancreas?
- Synthesis/storage of inactive proenzymes
- Storage of enzymes in zymogen granules separated from lysosomes
- Activation of enzymes distant from pancreas
- Protection of ductal epithelial cells by mucus layer
- Secretion of specific inhibitors of trypsin and nucleases
- Circulating protease inhibitors
Name the 3 groups of digestive enzymes secreted from the exocrine pancreas
- Proteases
- Lipase
- Amylase
Which proteases are secreted from the exocrine pancreas?
- Trypsin
- Chymotrypsin
What is the action of amylase?
Hydrolysis of starch into maltose
Name the substances that control exocrine pancreatic secretion
Cholecystokinin
Secretin
Gastrin
Describe the secretion and action of Cholecystokinin
- Secreted by endocrine cells in duodenum [secretion stimulated by partially digested proteins and fats]
- Secreted into blood
- Stimulates release of digestive enzymes
Describe the secretion and action of Secretin
- Secreted by endocrine cells in cranial small intestine in response to acid in intestinal lumen
- Stimulates secretion of water and bicarbonate in pancreas
Describe the secretion and action of gastrin
- Secreted by stomach in response to gastric distension
- Stimulates release of digestive enzymes
islets of Langerhans (pancreatic islands) are composed of?
- Beta cells: 60-70% secrete insulin concentrated in central part of islets
- Alpha cells: 20% secrete glucagon located peripherally in islets
Which spp/breed are affected by juvenile atrophy of the exocrine pancreas
Young dogs (<13 mo); esp. German shepherds
Describe the clinical signs of juvenile atrophy
Chronic exocrine pancreatic insufficiency e.g. fat rich faeces
Describe the histology of juvenile atrophy
- Exocrine pancreatic tissue almost absent
* Islets usually unaffected
When does haemorrhage of the pancreas occur?
With coagulation disorders
a) infectious diseases e.g. canine infectious hepatitis
b) intoxications [dicumarol]
What are the causes of pancreatitis?
- Systemic infections: • Canine infectious hepatitis • FIP • FMD - Migrating parasites: strongyles [horse] - Zinc poisoning: sheep, calves, dogs - Alcoholism [humans] - Trauma, obstruction of pancreatic duct
What are the two most frequent forms of pancreatitis?
- acute necrotising pancreatitis
- chronic fibrosing pancreatitis
Which spp are affected by acute necrotising pancreatitis?
Dogs
What is the cause of acute necrotising pancreatitis?
Due to release and activation of pancreatic enzymes within the pancreas - usually accompanied by fat necrosis
Describe the histology of acute necrotising pancreatitis
- Focal necrosis, haemorrhage, thrombosis, oedema
- Followed by inflammatory infiltration and fat necrosis
What are the clinical signs of acute necrotising pancreatitis?
- Suddenly decreased appetite
- Dullness, vomiting, diarrhoea, thirst
- Abdominal pain
What are the two outcomes of acute necrotising pancreatitis?
- Death within few days
- Animals survive and develop repeated acute episodes
How does death due to acute necrotising pancreatitis occur?
Consumption of plasma protease inhibitors -> Activation of kinin, coagulation, fibrinolysis, complement cascade -> DIC, shock
When does chronic fibrosing pancreatitis occur?
Sequel of acute necrotising pancreatitis or: without signs of acute pancreatitis [cats]
Describe the histological appearance of chronic fibrosing pancreatitis
Pancreatic tissue is replaced by fibrous tissue
Describe chronic fibrosing pancreatitis in cats
Chronic interstitial pancreatitis with chronic cholangitis/cholangiohepatitis (and inflammatory bowel disease)
(In cats, bile duct and pancreatic duct fuse before entering the duodenum)
When do clinical signs of exocrine Pancreatic Insufficiency occur?
Clinical signs with loss of >80% of tissue
What are the causes of exocrine pancreatic insufficiency?
- Juvenile atrophy (dogs)
- Chronic pancreatitis (cats)
- Exocrine pancreatic neoplasia
- Hypoplasia (calves)
What are the clinical signs of exocrine pancreatic insufficiency?
- Diarrhoea and chronic weight loss
- Pancreatogenic maldigestion: pale, soft, voluminous, malodorous faeces + steatorrhoea (excess fat in stools)
- Bacterial overgrowth (SIBO)
- Malabsorption of vitamins
- Diabetes mellitus [if EPI is 2ry to chronic pancreatitis, not common in pancreatic atrophy]
Name 2 neoplasms of the exocrine pancreas
- Adenoma
- Adenocarcinoma
What is the differential for an exocrine pancreas neoplasia?
Nodular hyperplasia
What are the features of nodular hyperplasia of the exocrine pancreas
- Seen in old dogs, cats and cattle
- Multiple, no encapsulation, no compression of adjacent tissue
- Not a neoplasm
Describe adenocarcinomas of the exocrine pancreas
- Dogs, cats
- Often arising within the centre of the pancreas
- Cellular origin: acini or ducts
Describe the gross appearance of an adenocarcinoma of the exocrine pancreas
Greyish, scirrhous tissue
Describe metastasis of an adenocarcinoma of the exocrine pancreas
- Implantation metastases [peritoneum, diaphragm -> thorax] - Haematogenous spread [portal vein -> liver] - Lymphogenic spread [local lymph nodes] - Local invasion into duodenal wall
