C13 pt 2 Flashcards

1
Q

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

A

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

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2
Q

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

A
  • 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
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3
Q
  • Different species have different detoxification enzyme activity levels
  • what is the issue with cats and acetaminophen?
A
  • 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
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4
Q
  • Mechanisms of toxic hepatic injury
A

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

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5
Q

Classifications of hepatotoxin and their properties

A

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

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6
Q

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

A

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

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7
Q

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

A
  • Clinical and gross presentation of acute toxicity is usually consistent across causes
    o Encephalopathy, zonal pattern, hemorrhages
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8
Q

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

A
  • Chronic toxicity is more variable (more helpful to differentiate causes)
    o Often a combination of lesions, clinical signs due to inadequate detoxification
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9
Q

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

A
  • Pretty much everything can cause hepatotoxicity (metals, drugs, plants, fungi, bacterial toxins, etc…)
    o Dose rate determines whether toxicity is acute or chronic
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10
Q
  • Adverse drug reactions: cause drug-induced liver injury (DILI)
  • definition
A

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

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11
Q

Drugs with known liver ADR

A

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
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12
Q

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

A

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

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13
Q

Fungi that are hepatoxic

A

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)

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14
Q

plant hepatotoxin? most common when? histo sign?

A
  • 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)
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15
Q

hepatotoxic metals?
- how?
- risks?
- pathogenesis

A
  • 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
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16
Q

species with bile duct separate from exocrine pancreas

A

cattle
pig
dos

17
Q

species with bile duct combined with exocrine pancreas

A

horse
sheep
goat
cat

18
Q

what tissue makes up the pancreas? what regulates it?

A
  • 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
19
Q

pancreas size and secretory activity are altered based on:

A

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

20
Q

pancreatic autolysis character

A

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

21
Q

pancreas regenerative and anti-injury capabilities

A
  • 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….
22
Q

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

A

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

23
Q

Developmental anomalies of the pancreas
- how common
- appearance

A

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

24
Q

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

A
  • 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
25
Q

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

A
  • 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
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  • Dogs: most commonly due to juvenile pancreatic atrophy
    o Second most common demographic is older females (probably necrosis?)
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  • Less common in cats, not strongly linked to chronic pancreatitis
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  • Confirm via reduced trypsin-like immunoreactivity in serum
26
Q

Exocrine pancreatic insufficiency
- consequences
- clinical signs

A
  • 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
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  • Risk of small intestinal bacterial overgrowth (SIBO)
    o Carbohydrate fermentation leads to osmotic diarrhea
    o Hard to prove due to overlap with normal flora
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  • 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
27
Q

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

A
  • 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
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  • 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
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  • familial or sporadic
28
Q

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

A
  • Clinically called ‘pancreatitis’ but different pathogenesis than true pancreatitis
    o Inflammation is not the primary issue
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  • 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
29
Q

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

A
  • 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?)
30
Q

Acute pancreatic necrosis
- pathogenesis

A

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

31
Q

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

A
  • 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
32
Q

Acute pancreatic necrosis in cats
- appearance
- signalment
- consequences

A
  • 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
33
Q

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

A

o Several mycotoxins, selenium toxicity
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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

34
Q

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

A

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)

35
Q

chronic pancreatitis
- species
- anatomical extent
- signalment, causes

A

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

36
Q

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

A

Exocrine hyperplasia
- Older dogs, cats, cattle
- multiple
- variable size
- discrete demarcation
- no compression
- Very common, grey-white and firm, usually incidental

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Exocrine adenoma
- single
- large
- discrete demarcation
- compression
- Rare, usually incidental, unlikely to progress to carcinoma
- Look more like normal parenchyma than nodular hyperplasia

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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

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  • Round cell tumours may metastasize to the pancreas, and liver and GI tumours may locally invade pancreatic tissue
37
Q

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

A

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