Definition

• Methemoglobin content in blood >1.5% of total hemoglobin.
• Methemoglobin differs from hemoglobin in that the iron moiety of heme groups has been oxidized from the ferrous (+2) to the ferric (+3) state.

Pathophysiology

• About 3% of hemoglobin is oxidized to methemoglobin each day in normal animals as a result of autoxidation of hemoglobin or secondary to oxidants produced in normal metabolic reactions.
• Methemoglobin usually accounts for <1% of total hemoglobin, because it is constantly reduced back to hemoglobin by an NADH-dependent cytochrome b₅ reductase (methemoglobin reductase) enzyme reaction within RBCs.
• Caused by either increased production of methemoglobin by oxidants or decreased reduction of methemoglobin associated with a deficiency of the RBC cytochrome b₅ reductase enzyme.

Systems Affected

• Hemic/Lymphatic/Immune-reduced oxygen-carrying capacity of blood, because methemoglobin cannot bind oxygen; if methemoglobin content reaches high values (e.g., >50% of total hemoglobin), various organs may suffer hypoxic injury.
• Hepatobiliary-in addition to hypoxic injury, the liver may be damaged directly by oxidant drugs that it metabolizes.
• Renal/Urologic-in addition to hypoxic injury, the kidneys may be damaged if intravascular hemolysis occurs.

Signalment

• Dogs and cats.
• Deficiency in RBC cytochrome b₅ reductase has been recognized in Chihuahuas, borzois, English setters, terrier mixes, cockapoos, coonhounds, poodles, corgis, Pomeranians, pit bull mixes, and toy Eskimo dogs and in domestic shorthair cats.

Signs

Causes

• Toxicity-acetaminophen, benzocaine, phenazopyridine, and skunk musk also cause Heinz body hemolytic anemia; excess nitrite in pet food and hydroxycarbamide toxicity are reported to cause methemoglobinemia without Heinz body hemolytic anemia.
• Deficiency in RBC cytochrome b₅ reductase.

Risk Factors

• Application of benzocaine to traumatized skin or mucous membranes increases the likelihood of systemic absorption and methemoglobinemia.
• Cats are much more likely to develop clinically significant methemoglobinemia than are dogs after acetaminophen administration; this drug is not recommended for use in cats.
• Methemoglobinemia secondary to cytochrome b₅ reductase deficiency is an inherited disorder.

Differential Diagnosis

• Both low blood oxygen tension and methemoglobinemia can cause cyanotic-appearing mucous membranes and dark-colored blood samples.
• Hypoxemia is documented by measuring low Po₂ in an arterial blood sample.
• Methemoglobinemia is suspected when arterial blood with normal or high Po₂ is dark-colored.

Laboratory Findings

CBC/Biochemistry/Urinalysis

• Chronic methemoglobinemia secondary to cytochrome b₅ reductase deficiency can result in a slightly high HCT; in contrast, anemia may accompany methemoglobinemia caused by oxidant drugs.
• If severe or induced by oxidant drugs, evidence of injury to various organs (e.g., high BUN and ALT) may be seen.

Other Laboratory Tests

• Spot test-determine if the patient's methemoglobin content is clinically important: one drop of blood from the patient is placed on a piece of absorbent white paper and a drop of normal control blood is placed next to it. If the methemoglobin content is 10%, the patient's blood will be noticeably browner than the bright red of the control blood.
• Co-oximetry is the method of choice for accurate measurement of methemoglobin content in whole blood samples.
• Methemoglobin content in dogs with cytochrome b₅ reductase deficiency varies from 13 to 51%; the methemoglobin content in six deficient cats was 44–52%.
• A definitive diagnosis of cytochrome b₅ reductase deficiency is made by measuring enzyme activity in RBCs; this assay is done in a few research laboratories and requires that arrangements be made before blood samples are submitted.

Imaging

N/A

Diagnostic Procedures

• Blood should be stained for Heinz bodies if evidence of toxicity is present.
• The presence of Heinz bodies indicates exposure to an oxidant drug that may also cause hemolytic anemia.

Drug(s) Of Choice

• Methylene blue-given slowly over several minutes as a 1% solution (1 mg/kg IV), may be administered in patients with severe methemoglobinemia; a dramatic response should occur during the first 30 minutes of treatment; caution: although this dose can be repeated if necessary, methylene blue can cause Heinz body hemolytic anemia in cats and dogs.
• N-acetylcysteine is efficacious in the treatment of acetaminophen toxicity in cats if given within a few hours after exposure; recommended dosage is 140 mg/kg PO followed by 70 mg/kg q6h for seven treatments.

Contraindications

None

Precautions

In patients that have been given drugs that cause substantial Heinz body formation and methemoglobinemia, methylene blue treatment can potentiate the formation of Heinz bodies and anemia; consequently, it is prudent to measure the HCT for 3 days after methylene blue treatment to ensure that clinically important anemia does not develop.

Possible Interactions

None

Alternative Drug(s)

None

Patient Monitoring

• The cyanotic appearance of skin and mucous membranes should disappear after reduction of methemoglobin to an amount that does not produce clinical signs.
• Blood on the spot test should appear bright red after reduction of methemoglobin to values <10% of total hemoglobin.
• If methylene blue treatment is given or Heinz bodies are present within RBCs, the HCT should be monitored closely, because it usually does not reach its lowest point until approximately 3 days after initial oxidant exposure.

Possible Complications

Coma and death can occur if methemoglobin content reaches 80% of total hemoglobin.

Associated Conditions

Heinz body anemia

Zoonotic Potential

None

Pregnancy/Fertility/Breeding

N/A

See Also

• Acetaminophen (APAP) Toxicosis
• Anemia, Heinz Body

Abbreviations

• ALT = alanine aminotransferase
• HCT = hematocrit
• RBC = red blood cell