Lecture 17 - Copper Part 2, Alfatoxin

required reading: list of liver protectants

What criteria is part of diagnosis for copper toxicity? hint: signalment, lesions, tests

• appropriate source, species (sheep!)

• GIT, liver, RBC, kidney

• consider liver enzymes, liver biopsy, copper concentration in liver, NOT serum copper

• histologic lesions PM to differentiate primary vs secondary

• Cu analysis: liver, kidney, feed

Prognosis for Cu toxicity is ___ for clinically affected LA and SA.

guarded to poor

Cu toxicity in production animals are typically ____.

not treated due to cost

With SA, what can be used a treatment for Cu toxicity?

liver protectants, fluids-blood transfusion, corticosteroids, analgesics

The best treatment and prevention of copper toxicity is to ___ ____ ____ via what methods?

enhance copper excretion

Mo-S source to enhance excretion, Zn which competes for GI absorption, chelators to decrease body burden

What is the purpose of a Mo-S source?

Enhance fecal, urinary, biliary excretion AND slows down absorption

What element(s) will compete for GI absorption with copper?

Zn, Fe, Se

What chelators are used in SA copper toxicities? LA copper toxicities?

SA: D-penicillamine
LA: tetrathiomolybdate

others: trientine, BAL

Copper storage disease is __ on the top 5 liver conditions in dogs!

3rd

Copper storage disease was previously called ___.

chronic active hepatitis

Copper storage disease will present around ___ ages and will have signs of what

>2-4 years of age
chronic, intermittent heaptitis: anorexia, vomiting, weakness, lethargy, weight loss

Copper storage disease is historically considered a hereditary disease, inherited ___ in ____ and also seen in ____.

autosomal recessive, Bedlington terrier

West Highland white terriers

Other than the breeds classically associated with copper storage disease, other breeds such as ____ have been affected so other than genetics, secondary problem due to ___ or ____.

dobermans, Skye terriers, labs, mixed etc

hepatitis, too much copper in diet

The best diagnostic indicator for copper storage disease is ____ and ____ at the time of clinical disease and _____.

liver enzyme elevations, elevated bilirubin concentrations

liver biopsy histology lesions + copper levels

How do you treat a dog with copper storage disease?

chronic administration of chelator to reduce body burden → D-penicillamine, or trientine, tetrathiomolybdate as alternative

reduce absorption long term → zinc acetate

List common options for liver protectants

*required reading

S-adenosylmethione (SAMe)

silymarin: extract from milk thistle, silybin active component

Denamarin: SAMe & silybin

Denosyl: SAMe & glutathione

HepatoAdvanced: SAMe & silbyin & Vit E

N-acteylcysteine

Ursodiol

Vitamin E and/or selenium

What are mycotoxins?

secondary metabolites of fungi or mold that is harmful

The synthesis of mycotoxin is determined by ____ and the mold growth is determined by what factors?

• mold genetics

• substrate composition and texture, temperature, oxygen tension, moisture-humidity, pre-existing damage to feed

NOT ALL MOLDY FEEDS CONTAINS ____

mycotoxins - feed does not need to be moldy to have toxin present

NOT ALL FEEDS THAT CONTAIN MYCOTOXINS ARE ____.

toxic (dose dependent, species dependent, sex age dependent)

lots of fed have ___, to some degree

mold

Never say “I think it may be a ___” because why?

mycotoxin; each mycotoxin causes distinct clinical disease

There is considerable ___ and ___ variation with mycotoxin production

regional, seasonal

True or False? Alfatoxin is NOT a big problem in the PNW

True

What is alfatoxin?

a bisfuranocoumarin compound produced by some strains of Aspergillus flavus, nomius, parasiticus

___ is the precursor in synthesis of alfatoxin. We care about this because?

sterigmatocystin
less toxic than alfatoxin but can cause similar toxicosis

Name the four predominant forms of alfatoxin

alfatoxin B1, B2, G1, G2

What is the predominant form and metabolite of alfatoxin?

aflatoxin B1, and M1 (a primary metabolite and major excretion product in urine and milk)

What are common sources of alfatoxin?

Contaminated cereal grain: especially corn, cottonseed that has been damaged or broken

True or False? Alfatoxin only occurs as storage fungi and develops only when grain is in a storage environment.

False. Alfatoxin occurs as both a field fungi and storage fungi.

True or False? Proper feed processing practices routinely destroy alfatoxins.

False. Alfatoxins are very stable and are not routinely destroyed by most feed processing practices.

Sensitivity to alfatoxins depends on ___, ___, and ___.

species, age, sex

younger, males more sensitive

Aflatoxin toxicity most commonly reported in ___, ___, ___ however many outbreaks occurred in dogs via ____.

cattle, swine, birds
contaminated commercial pet food

What is the mechanism of action of alfatoxins?

potent hepatotoxin, nephrotoxin, immunosupressant, hepatic carcinogen

True or False? Hepatic carcinogens from aflatoxin are more of an issues in residues (milk, meat) and not in humans.

False. Risk is minimal in milk and meat, tightly regulated in production animals due to hepatic carcinogen in humans

Clinical signs of alfatoxin toxicity is related to ___ and is very ___. Acute/chronic signs are more common.

liver, dose-dependent, acute

What are acute clinical signs seen with alfatoxins? Is it more or less common than chronic signs?

vomiting, lethargy, anorexia, weakness, abdominal pain, icterus, if liver failure: petechiation, ascities

more common than chronic signs

What are chronic clinical signs seen with alfatoxins? Is it more common than acute signs?

drop body weight, unthriftiness, drop in production, poor fertility, increase incidence of disease, secondary photosensitization

less common than acute signs

What clinical pathology signs do you see with alfatoxin?

liver damage: elevated ALT, AST, AP, bile acids, hyperbilirubinemia/uria

liver failure: hypocholesteremia, increased PT/PTT, hypoalbuminemia, decreased protein C

renal changes also possible: isothenuria, granular casts, azotemia, glucosuria

What gross lesions are seen with alfatoxin toxicity? Acute vs chronic changes?

acute: enlarged, friable, heavy, congested, hemorrhagic, icteric liver

chronic: cirrhotic, shrunken

What histologic lesions are seen with alfatoxin toxicity? Acute vs chronic changes?

acute: necrosis

chronic: hepatocytomegaly, biliary hyperplasia, fibrosis

How do you diagnose alfatoxin toxicity? Hint: history, signs, tests

• signalment and appropriate feedstuffs (grain)

• liver lesions

• alfatoxin analysis via chromatography of a representative sample of feed is the best way

What are different methods of alfatoxin analysis? Which is ideal?

liver, kidney, lung - difficult

nonspecific black light screening or ELISA kit screening

chromatography of representative sample of feed is ideal

Remember with regards to chromatography testing of feed, that you may get a “false” negative if:

did not take a representative sample of feed, or

feed containing alfatoxin already consumed/gone by time sampling was done

Dr T says to be careful with what labs?

labs that run feed analysis and also sell binders (conflict of interest)

What is the treatment for alfatoxin toxicity? For LA vs SA?

symptomatic and supportive

LA: not cost effective

SA: liver protectants and supportive

Prognosis for alfatoxin toxicity is ___ however liver has tremendous regenerative capabilities.

guarded

What do you do with all the contaminated feed for livestock?

depends on state, aluminosicilate binders etc

The key for treatment of alfatoxin toxicity is ____.

prevention of mold growth