C13 pt 2

Question 1

why is the liver prone to toxic damage?
what can increase toxicity?

Answer 1

The liver is very prone to toxic damage because it sees everything that is ingested, and is a major site of metabolism of xenobiotics (ingested foreign chemicals)
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* Metabolism often occurs in multiple stages, and sometimes the toxicity of a substance can be higher at an intermediate stage
o Substances can compete for the same metabolic pathway, increasing risk of toxicity of any of the competing substances

Question 2

what liver zone most prone to toxic injury by metabolites? what about direct toxicity?

Answer 2

• Recall centrilobular (zone 3) hepatocytes are most prone to toxic injury by metabolites because they are most metabolically active
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• Periportal (zone 1) on the other hand, are prone to immediately toxic substances because they are closest to incoming portal blood

Question 3

• Different species have different detoxification enzyme activity levels
• what is the issue with cats and acetaminophen?

Answer 3

• Cats have reduced uridine diphosphate-glucuronosyl transferase
  o Reduced metabolism of acetaminophen leads to accumulation of its toxic
  metabolite, NAPQI (more sensitive than dogs)
  o This causes cell death and methemoglobinaemia

Question 4

• Mechanisms of toxic hepatic injury

Answer 4

o Binding cell proteins and causing cellular dysfunction
o Disruption of canalicular bile transport (cholestasis)
o Inhibition of cell enzyme pathways
o Binding cellular proteins and prompting immune cell attack
o Activation of programmed cell death
o Inhibition of mitochondrial function

Question 5

Classifications of hepatotoxin and their properties

Answer 5

Intrinsic:
- Dose-related, predictable, reproducible
- Usually involves conversion to reactive metabolites
- Ex: acetaminophen in cats and dogs
> In toxic metabolite dependent reactions, there is either excess metabolite
generated or an unusual toxic metabolite is formed

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Idiosyncratic:
- Less dose-related, unpredictable
- Occur in a small proportion of animals (related to individual susceptibility)
- Mechanisms often unknown, suspected genetic component
- Hypersensitivity related (drug allergy) or toxic metabolite dependent
> Drug ‘allergy’ has a latent period before toxicity and is often due to protein binding

Question 6

liver toxic diseases - cytotoxic injury lesions, when we see them

Answer 6

hepatocyte degeneration, zonal necrosis, apoptosis, lipidosis
o Lipidosis and centrilobular necrosis especially common in acute toxic injury

Question 7

Clinical and gross presentation of acute toxicity
- can we tell the cause by the signs?

Answer 7

• Clinical and gross presentation of acute toxicity is usually consistent across causes
  o Encephalopathy, zonal pattern, hemorrhages

Question 8

Clinical and gross presentation of chronic toxicity
- can we tell the cause by the signs?

Answer 8

• Chronic toxicity is more variable (more helpful to differentiate causes)
  o Often a combination of lesions, clinical signs due to inadequate detoxification

Question 9

what can cause hepatotoxicity? what determines if it is acute or chronic?

Answer 9

• Pretty much everything can cause hepatotoxicity (metals, drugs, plants, fungi, bacterial toxins, etc…)
  o Dose rate determines whether toxicity is acute or chronic

Question 10

• Adverse drug reactions: cause drug-induced liver injury (DILI)
• definition

Answer 10

o ‘An injurious or unintended response that occurs at a normal dose’

Question 11

Drugs with known liver ADR

Answer 11

TMS - Massive to submassive necrosis and cholestasis (dog)

Diazepam - Repeated administration: lobular to massive necrosis (cat)

Xylitol - Acute severe hepatic necrosis (dog)

Carprofen - Vacuolar degeneration, bridging necrosis (dog)

Phenobarbital - Cirrhosis (uncommon), hepatocutaneous syndrome (dog)

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• Others: SQ injection of intranasal Bordetella vaccine in dogs, halothane

Question 12

Cyanobacteria (blue-green algae)
- effects on liver?
- where its found
- species
- effects

Answer 12

Cyanobacteria (blue-green algae): primarily Microcystis aeruginosa
o Seasonal blooms in water bodies contaminated with agricultural runoff
o Microcystin-LR toxin disrupts the cytoskeleton and causes necrosis
o Most common in ruminants but all species at risk
o Other toxins can cause rapid death by interfering with nervous function

Question 13

Fungi that are hepatoxic

Answer 13

o Amanita sp. mushrooms: toxin interferes with protein synthesis (necrosis)
o Aflatoxin: Aspergillus sp., chronic exposure is carcinogenic
§ Midzonal necrosis
o Fumonisin: Fusarium sp. on mouldy corn (pigs and horses)
o Sporidesmin: Pithomyces chartarum on ryegrass (ruminants, causes
photosensitization and liver fibrosis)

Question 14

plant hepatotoxin? most common when? histo sign?

Answer 14

• Plant toxicity is most common when animals are grazing poor pastures
• Pyrrolizidine alkaloids: Senecio sp., Crotalaria sp., heliotrope, others
  o Damage cell proteins, antimitotic (DNA replicates but nuclei can’t divide)
  o Huge nuclei form (megalocytes)

Question 15

hepatotoxic metals?
- how?
- risks?
- pathogenesis

Answer 15

• Iron can cause hepatotoxicity in young pigs if accidentally overdosed
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• Copper: sheep are very sensitive to copper toxicity (low biliary excretion)
  o Vitamin E or molybdenum deficiency increases risk of copper toxicity
  o Toxicity is usually chronic (levels build up in liver over time)
  o Eventually the liver can’t cope and plasma copper quickly rises to levels that
  damage red blood cells (intravascular haemolysis) > Mix of hemoglobin and methemoglobin
  o Anemia makes hepatocyte necrosis worse, so more copper is released
  o Can be precipitated by stress, death occurs within a few hours

Question 16

species with bile duct separate from exocrine pancreas

Answer 16

cattle
pig
dos

Question 17

species with bile duct combined with exocrine pancreas

Answer 17

horse
sheep
goat
cat

Question 18

what tissue makes up the pancreas? what regulates it?

Answer 18

• 98-99% is exocrine tissue, but it is still regulated by the endocrine part
  o Insulin and pancreatic polypeptide are stimulatory
  o Somatostatin and glucagon are inhibitory

Question 19

pancreas size and secretory activity are altered based on:

Answer 19

Organ size and secretory activity are altered based on diet
o Hypertrophy with rich protein/energy, atrophy if insufficient

Question 20

pancreatic autolysis character

Answer 20

Autolysis is rapid due to release and activation of enzymes, and can look hemorrhagic even in postmortem change

Question 21

pancreas regenerative and anti-injury capabilities

Answer 21

• All cells within the pancreas can regenerate, and exocrine acini are repaired rapidly
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• Resident stellate cells mediate fibrosis in persistent injury
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  similar to liver….

Question 22

pancreatic atrophy
- common when?
- how fast
- extent
- mechanisms

Answer 22

o Common in animals with insufficient nutrition of any cause, especially fast-growing
o Rapid reduction in mass (>75% within 4 days) by protein catabolism without cell death o Can decrease to <10% normal mass in prolonged starvation
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* Two mechanisms involved
o Inability to synthesize proteins (normally a high number are produced)
o Lack of stimulation from the GI tract
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* Ductal obstruction can also cause rapid atrophy
o Look for dilation above the obstruction

Question 23

Developmental anomalies of the pancreas
- how common
- appearance

Answer 23

Uncommon and largely incidental
o Ectopic tissue in GI wall or spleen
o Formation of a ring around the duodenum in dogs, pigs (may cause stenosis)
o Cysts in lambs, associated with PKD in cats, pigs, goats

Question 24

exocrine pancreas main job, output?
other roles?
generates what that can cause injury?

Answer 24

• The exocrine pancreas’ main job is producing and secreting digestive enzymes o Highest protein production by weight of any tissue
  o Proenzymes (activated in gut) ex. trypsin, phospholipase
  o Active enzymes ex. amylase, lipase
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• Other roles
  o Intrinsic factor allows absorption of vitamin B12 (cobalamin)
  o Secretions inhibit bacterial proliferation
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• Lots of free radicals are generated via normal metabolism, so exogenous free radicals can cause injury

Question 25

Exocrine pancreatic insufficiency - etiology - when do clinical signs show - common cause in dogs, demographics - occurence in cats - Dx

Answer 25

* Congenital or acquired loss of exocrine tissue activity o Must lose at least 90% of secretory ability to show clinical signs o Acquired loss can be due to anything that destroys tissue or interferes with signals <><><><> * Dogs: most commonly due to juvenile pancreatic atrophy o Second most common demographic is older females (probably necrosis?) <><><><> * Less common in cats, not strongly linked to chronic pancreatitis <><><><> * Confirm via reduced trypsin-like immunoreactivity in serum

Question 26

Exocrine pancreatic insufficiency - consequences - clinical signs

Answer 26

* Reduced enzymes cause maldigestion and malabsorption o Also reduced cleavage of proenzymes – makes maldigestion worse o Antigenic proteins are not broken down – prone to dietary sensitivity <><><><> * Risk of small intestinal bacterial overgrowth (SIBO) o Carbohydrate fermentation leads to osmotic diarrhea o Hard to prove due to overlap with normal flora <><><><> * Clinical signs o Pot belly due to bulky GI contents o May develop hepatic lipidosis o Dogs more prone to mesenteric torsion o Cats may have greasy fecal soiling of hind end

Question 27

Juvenile pancreatic atrophy - disease course, precipitation - early stage - late stage - clinical signs, anatomic signs

Answer 27

* Most are normal until 6-12 months old, often precipitated by GI illness or a change to diet or environment * Early stages: T cell infiltrate without fibrosis (autoimmune?) * Late stage (clinical signs): advanced atrophy with no inflammation, normal islets <><><><> - Weight loss despite normal to voracious appetite - Poor hair coat, muscle atrophy - Pale (often greyish), soft, voluminous, malodourous feces - Minimal abdominal fat - Small pancreatic remnants surround normal ducts <><><><> - familial or sporadic

Question 28

Acute pancreatic necrosis - is it pancreatitis? why? - associations, causes - risk factors, predispositions

Answer 28

* Clinically called ‘pancreatitis’ but different pathogenesis than true pancreatitis o Inflammation is not the primary issue <><><><> * Associated with high fat, low protein diets but the inciting cause is often unclear o May develop after hypotension, abdominal surgery, GDV, trauma, some drugs o Middle aged to older, overweight, female dogs at higher risk o Miniature schnauzers with idiopathic hyperlipidemia especially at risk o Hyperadrenocorticism, hypothyroidism, uremia, hypercalcemia predispose

Question 29

Acute pancreatic necrosis - disease course - mortality, prognosis - consequences

Answer 29

* Acute, life threatening condition or intermittent relapsing disease o Either can progress to exocrine pancreatic insufficiency and/or diabetes o Mortality reported at 27-42%, though most mild cases recover within days o Can cause systemic problems, ex. cytokine storm and SIRS, endothelial damage and DIC o Some dogs develop multifocal necrotizing panniculitis (systemic enzyme release?)

Question 30

Acute pancreatic necrosis - pathogenesis

Answer 30

Pathogenesis incompletely understood o Acinar necrosis leads to increased calcium o Sustained increase in calcium leads to fusion of lysosomes and zymogen granules o Protective zymogen degradation mechanisms are overwhelmed o Enzymes are activated, leak, and damage nearby tissue including vessels and adipose o Damaged cells attract leukocytes, which worsen the enzymatic damage o Vessel damage leads to hemorrhage

Question 31

Acute pancreatic necrosis in dogs - early lesions - chronic appearance - resolution? - consequences

Answer 31

* The earliest lesion is peripancreatic adipose saponification (yellow flecks) accompanied by swelling and edema, hemorrhages in and around the pancreas, fibrin * In chronic cases, the pancreas is irregular to shrunken * Complete resolution is unlikely o Necrosis continues slowly and asymptomatically until the entire pancreas is destroyed o Common cause of diabetes in dogs

Question 32

Acute pancreatic necrosis in cats - appearance - signalment - consequences

Answer 32

* In cats, acute necrosis looks like chronic pancreatitis o Older DSH, no sex predilection o Consequences similar to dogs but often also develop severe hepatic lipidosis

Question 33

toxic causes of pancreatic necrosis - toxins - susceptibility - early lesions - late lesions

Answer 33

o Several mycotoxins, selenium toxicity <><><><> Zinc toxicity: o Susceptible due to role in zinc excretion o Early lesions: enlarged, pale, with interstitial edema, diffuse microvesicular degeneration of acini o Later: shrunken, nodular, with interstitial fibrosis, acinar atrophy

Question 34

acute pancreatitis - similarities to acute necrosis - species - cause in dogs?

Answer 34

Acute o More intense hemorrhage but otherwise similar to acute necrosis o Occasionally seen in cats, horses o In dogs, cause unclear but may be due to reflux of duodenal contents during increased abdominal pressure (ex. vomiting)

Question 35

chronic pancreatitis - species - anatomical extent - signalment, causes

Answer 35

o The most common pattern of pancreatic injury in species other than dogs o Usually extends from the ducts into the acini o Most common in adult cats (triaditis, FIP, toxoplasmosis) o Occasional in horses (ascending bacteria, strongyle migration), rare in others

Question 36

Hyperplasia and neoplasia of the pancreas - types - species - number - size - demarcation - compression - notes

Answer 36

Exocrine hyperplasia - Older dogs, cats, cattle - multiple - variable size - discrete demarcation - no compression - Very common, grey-white and firm, usually incidental <><><><> Exocrine adenoma - single - large - discrete demarcation - compression - Rare, usually incidental, unlikely to progress to carcinoma - Look more like normal parenchyma than nodular hyperplasia <><><><> Exocrine adenocarcinoma - Older dogs, cats - Single or multiple - Large - poor demarcation - invasive - Rare in all species, female > male - May be scirrhous, often contain necrosis - Poor prognosis – metastasize quickly and everywhere <><><><> * Round cell tumours may metastasize to the pancreas, and liver and GI tumours may locally invade pancreatic tissue

Question 37

Exocrine adenocarcinoma of the pancreas - predispositions - when diagnosed? - consequences - possible sequelae - rare presentation in cats

Answer 37

o Nitrosamines, concurrent pancreatic disease, and chronic pancreatitis predispose o Usually diagnosed late in disease course, nonspecific signs (anorexia, vomiting, etc) o Destruction of normal tissue can lead to EPI o Often invade duodenum, may block pancreatic and biliary ducts o Like pancreatic necrosis, can cause panniculitis in dogs o Rarely causes paraneoplastic alopecia in cats – characteristic shiny skin