posted 09-14-2003 12:17 PM         

Cyanosis and pale-muddy mucous membranes develop from methemoglobinemia within 3-12 hours after ingestion of a toxic dose of acetaminophen. Hematuria and hemoglobinuria may appear when blood methemoglobin levels exceed 20%. Laboratory findings include anemia with a large number of Heinz bodies. Death can occur within 18 to 36 hours when methemoglobin concentrations exceed 50%.

Acetaminophen is metabolized to its highly reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI) in cells with P450 activity. In most species, excluding cats, a majority of administered acetaminophen is excreted in the urine as glucoronide and sulfate conjugates which are essentially non-toxic metabolites. A small amount of acetaminophen is normally metabolized to highly reactive intermediates which are scavenged by glutathione and excreted. Once glutathione stores are depleted, the reactive intermediates bind to intracellular macromolecules resulting in cell death. Cats are relatively deficient in activity of the enzyme glucuronyl transferase which conjugates acetaminophen to glucuronic acid for excretion. For a given dose of acetaminophen, less than 3% of acetaminophen glucuronide is excreted by cats, while humans and dogs eliminate 50-60% as the glucuronide conjugate. Therefore, in cats a relatively greater proportion of acetaminophen is available and metabolized to reactive intermediate compounds. Cellular stores of glutathione become rapidly depleted in the liver, erythrocytes, as well as in other cells throughout the body. Glutathione depletion leaves the cells unprotected from the oxidizing effect of the toxic acetaminophen metabolite NAPQI.

In the majority of animals, including dogs and humans, acetaminophen toxicity primarily causes damage to the liver. However, while cats can and do have liver damage associated with acetaminophen toxicosis, the primary manifestation of toxicosis is severe methemoglobinemia leading to hemolysis and methemoglobinuria.

Blood from animals with methemoglobinemia is darker and browner than normal. Heinz bodies are formed from the precipitation of damaged hemoglobin within the red blood cell, which leads to increased osmotic fragility of the erythrocyte and hemolysis.

Diagnosis is usually based on a history of ingestion, appropriate clinical signs, methe-moglobinemia, Heinz Body anemia, hemo-globinuria, and elevated serum activities of liver enzymes.