Liver Document - Toxins

What are the two main mechanisms of hepatotoxic injury?

Intrinsic (dose-dependent) and idiosyncratic (unpredictable).

Define intrinsic hepatotoxin.

Causes predictable, dose-related liver injury in all individuals once threshold exposure is reached (e.g., acetaminophen, aflatoxin).

Define idiosyncratic hepatotoxin.

Causes unpredictable liver injury in a small subset of individuals, usually due to metabolic or immune hypersensitivity differences (e.g., carprofen, phenobarbital).

What are the three functional patterns of hepatotoxicity?

Hepatocellular, cholestatic, and mixed injury.

What is a classic example of a hepatocellular toxin?

Acetaminophen or aflatoxin.

What is a classic example of a cholestatic toxin?

Anabolic steroids or azathioprine.

Why is the liver so vulnerable to toxins?

It receives high blood flow, has extensive metabolic activity (CYP450 system), and is the first organ exposed to absorbed xenobiotics.

What are the main cellular targets in hepatic injury?

Mitochondria, endoplasmic reticulum, plasma membrane, and canalicular transporters.

Concept: Toxin → ___ → ____ → ____ → ____

Reactive metabolite → Oxidative stress → Mitochondrial failure → Necrosis or apoptosis

Which species are most susceptible to acetaminophen toxicity?

Cats (extremely sensitive) > dogs.

Why are cats more sensitive to acetaminophen?

Deficient in glucuronyl transferase, leading to accumulation of the toxic metabolite NAPQI (N-acetyl-p-benzoquinone imine).

What is the toxic dose of acetaminophen in cats?

As little as 50–100 mg/kg can be fatal

What are the key clinical signs of acetaminophen toxicity in cats?

Cyanosis, facial/paw edema, dyspnea, brown mucous membranes, depression, and icterus.

What causes cyanosis in acetaminophen toxicity?

Methemoglobinemia — iron in hemoglobin oxidized to ferric form (Fe³⁺)

What are the main laboratory abnormalities with acetaminophen toxicity?

Marked ALT/AST increase, Heinz bodies, methemoglobinemia, hemolysis.

What is the antidote for acetaminophen toxicity?

N-acetylcysteine (NAC) — replenishes glutathione and detoxifies NAPQI.

NAC dosing regimen (IV or PO)?

Loading: 140 mg/kg, then 50–70 mg/kg q6h × 7 doses.

What adjunct therapies may help with acetaminophen toxicity?

S-adenosylmethionine (SAMe), vitamin C, and oxygen therapy

With acetaminophen toxicity, cats diet from ___, dogs from ___, both treated with __.

methemoglobinemia, hepatic necrosis, NAC

What is aflatoxin and what produces it?

A mycotoxin produced by Aspergillus flavus and A. parasiticus

What feed sources are most commonly contaminated with alfatoxin?

Moldy corn, peanuts, rice, wheat, soy, or pet food.

What is the mechanism of aflatoxin toxicity?

Bioactivated by CYP450 to aflatoxin B1-epoxide, which binds DNA and proteins → oxidative injury and impaired RNA/protein synthesis.

What species are most sensitive to alfatoxins?

Dogs (especially young ones), ducks, pigs.

What are the acute clinical signs of alfatoxins?

Vomiting, anorexia, icterus, coagulopathy, hepatic encephalopathy.

What are lab abnormalities of alfatoxicosis?

Markedly elevated ALT, ALP, prolonged PT/PTT, low albumin, high bilirubin.

What histologic lesion is characteristic of alfatoxicosis?

Centrilobular necrosis and bile duct proliferation.

What is the treatment for alfatoxicosis?

Remove contaminated feed, antioxidants (vitamin E, SAMe, silybin), low-protein diet, and lactulose for HE.

What feed additive can help prevent aflatoxicosis?

Toxin binders (bentonite clay, activated charcoal).

What is xylitol and in which species is it highly toxic?

A sugar alcohol toxic to dogs.

What is the mechanism of toxicity of xylitol?

Causes rapid insulin release → severe hypoglycemia and hepatic necrosis.

What is the toxic dose of xylitol for dogs?

As low as 75–100 mg/kg can cause hypoglycemia; >500 mg/kg causes hepatic necrosis

What are clinical signs of xylitol toxicity?

Vomiting, ataxia, weakness, seizures, icterus.

What are lab findings of xylitol toxicity?

Severe hypoglycemia, elevated ALT, sometimes hyperbilirubinemia.

What is the treatment of xylitol toxicity?

IV dextrose, liver protectants (SAMe, NAC), and supportive care.

Early ___ support can prevent hepatic necrosis in xylitol toxicity.

glucose

What cyanobacteria species cause hepatotoxicity?

Microcystis, Anabaena, Oscillatoria.

What toxins are produced from cyanobacteria?

Microcystins and nodularins.

What is the mechanism of hepatotoxic cyanobacteria?

Inhibit protein phosphatases 1 and 2A, leading to cytoskeletal collapse and massive hepatic necrosis

What are clinical signs of hepatotoxic cyanobacteria?

Rapid onset vomiting, diarrhea, shock, icterus, seizures, death.

What are lab findings of hepatotoxic cyanobacteria?

Massive ALT/AST increase, prolonged PT/PTT, hypoglycemia

What is the treatment of hepatotoxic cyanobacteria?

Activated charcoal, IV fluids, NAC, SAMe, vitamin E, and shock management.

What is the prognosis of hepatotoxic cyanobacteria?

Poor to grave once hepatic failure develops.

What part of the sago palm (Cycas) is toxic?

All parts, especially seeds.

What is the toxic compound in sago palm?

Cycasin, converted to methylazoxymethanol (MAM) in the liver.

What is the mechanism of toxicity of sago palm?

Alkylates DNA → hepatocellular necrosis and GI irritation.

What are the clinical signs of sago palm toxicity in dogs?

Vomiting, melena, icterus, coagulopathy, neurologic signs (HE).

What are lab abnormalities with sago palm?

Severe ALT/AST increase, elevated bilirubin, prolonged PT.

What is the treatment for sago palm toxicity?

Aggressive decontamination (emesis, activated charcoal), NAC, SAMe, vitamin E, fluids, plasma transfusion if coagulopathy.

What is the prognosis of sago palm toxicity?

Guarded to poor; mortality 30-50%

What species are affected by Amanita phalloides (death cap mushroom)?

Dogs, cats, humans.

What are the main toxins in Amanita?

Amatoxins (α-amanitin, β-amanitin).

What is the mechanism of Amanita?

Inhibit RNA polymerase II, halting protein synthesis → massive hepatic necrosis.

What are the clinical stages of amanita toxicity?

(1) GI phase (6–12h), (2) latent phase (12–24h), (3) hepatic failure (36–72h).

What are lab findings of amanita toxicity?

ALT/AST > 5000 IU/L, hyperbilirubinemia, coagulopathy, hypoglycemia

What is the treatment for amanita?

NAC, silybin (milk thistle extract), penicillin G, supportive therapy, possibly plasma exchange

What is the prognosis for amanita toxicity?

Grave; most die within 3–5 days without early intensive care.

What anticonvulsant can cause chronic hepatopathy in dogs?

Phenobarbital.

What is the mechanism of phenobarbitol toxicity?

Induction of CYP450 → oxidative injury and accumulation of toxic metabolit

What lab pattern occurs with phenobarbital toxicity?

Moderate ALT/ALP increase with or without clinical signs.

What should be done if ALT continues rising with phenobarbital?

Discontinue phenobarbital, switch to potassium bromide or levetiracetam.

What NSAIDs have been associated with idiosyncratic hepatotoxicity?

Carprofen, Deracoxib, and Etodolac.

What is the mechanism of carprofen-induced hepatopathy?

Idiosyncratic immune-mediated reaction, often in Labrador Retrievers.

What is the clinical presentation of carprofen-induced hepatopathy?

Acute onset anorexia, vomiting, jaundice within 2–4 weeks of starting the drug.

What antibiotic may cause hepatopathy with prolonged use?

Trimethoprim-sulfa or potentiated sulfonamides.

What chemotherapy agents are hepatotoxic?

CCNU (lomustine) and azathioprine.

How is azathioprine hepatotoxicity prevented?

Monitor liver enzymes every 2–4 weeks during therapy.

What drug commonly causes hepatic lipidosis in cats?

Glucocorticoids (steroid hepatopathy).

What metal causes hepatic and renal injury in large animals?

Copper (in sheep) and iron (in piglets, birds).

What plant causes pyrrolizidine alkaloid toxicity?

Senecio (ragwort), Crotalaria, Heliotropium.

What is the mechanism of pyrrolizidine alkaloids?

Form DNA adducts → hepatocyte megalocytosis, fibrosis, and cirrhosis.

What histologic hallmark identifies pyrrolizidine alkaloid toxicity?

Megalocytosis (enlarged hepatocytes with large nuclei).

What are clinical signs of chronic PA toxicity?

Weight loss, photosensitization, hepatic encephalopathy (esp. cattle, horses).

What mycotoxin causes hepatic lipidosis in dogs/cats?

Sterigmatocystin or ochratoxin (rare).