Methemoglobin

An assessment of methemoglobin levels is indicated as part of numerous tests used when methemoglobinemia is clinically suspected.

Normal findings ^[1] :

• 0.06-0.24 g/dL or 9.3-37.2 μmol/L (SI units)
• 0.4-1.5% of total hemoglobin

Possible critical values > 40% of total hemoglobin ^[1]

High values of methemoglobin indicate methemoglobinemia, which can be hereditary or acquired. Hereditary methemoglobinemias, in which methemoglobin values typically range from 15%-20% or more ^[2] fall into two groups, as follows: ^[3]

• Enzymic deficiencies that do not allow red blood cells to reduce methemoglobin (ferric [Fe³⁺]) back into normal hemoglobin (ferrous [Fe²⁺]), (eg, congenital adenine dinucleotide [NADH]-cytochrome-b5 reductase deficiency, inherited in an autosomal-recessive pattern

• Abnormal hemoglobin molecules (eg, hemoglobin M), inherited in an autosomal-dominant pattern

Acquired methemoglobinemia, which is far more common, results from overproduction of methemoglobin due to drug, toxin, and chemical substance exposures. These exposures include inorganic nitrates (eg, found in fertilizers, preservatives), organic nitrites and nitrates (eg, nitroglycerin, nitric oxide, nitrogen dioxide), household and industrial substances (eg, aniline dyes, naphthalene, nitrobenzene), and several pharmacological agents (eg, lidocaine, sulfonamide antibiotics). ^[4]

A methemoglobin concentration beyond 70% is usually fatal. ^[5]

Specimen type: Whole blood

Specimen container: Lavender top (EDTA)

Specimen volume: Two 5-mL tubes (2 mL minimum)

Specimen rejection: Mild hemolysis is acceptable, reject if gross

Special instructions include the following:

• Information regarding recent blood product transfusions must be provided

• The specimen must be received within 72 hours

Specimen storage/transport conditions: Refrigerated for up to 72 hours

Related tests/panels: The methemoglobin level is tested as part of a series of tests in the evaluation of methemoglobinemia. Additional tests include hemoglobin A2 and F, hemoglobin electrophoresis, sulfhemoglobin, and methemoglobin reductase.

Description

Methemoglobin is an oxidized form of hemoglobin in which iron exists in the ferric (Fe³⁺) state as opposed to ferrous (Fe²⁺). This state of oxidation decreases the ability of the molecule to bind reversibly with oxygen and therefore disallows it from being able to carry and deliver oxygen to the tissues.

Owing to oxidative stresses, methemoglobin is always being produced within red blood cells, but its levels are kept low by enzymic pathways that work to reduce the molecule. The pathway responsible for reducing most methemoglobin (95%-99%) back to hemoglobin is the NADH-dependant methemoglobin reductase system, in which the enzyme cytochrome-b5 reductase plays a crucial role in a transfer of electrons from NADH to methemoglobin. ^[4]

Alternative pathways by which methemoglobin can be reduced, which become more important in deficiencies of the primary pathway, involve the NADPH-methemoglobin reductase system, reducing agents such as ascorbic acid, and reduced glutathione. ^[3] As discussed in Interpretation, methemoglobinemia results from either an overproduction of methemoglobin that exceeds these protective pathways or a defect in the pathways themselves.

Indications/Applications

An assessment of methemoglobin levels is indicated as part of numerous tests used when methemoglobinemia is clinically suspected. Methemoglobinemia is usually asymptomatic when methemoglobin levels are less than 15% of total hemoglobin. ^[5] Signs and symptoms, which tend to progressively increase in severity as methemoglobin concentrations rise beyond 15%, include the following: ^[4]

• Cyanosis

• Anxiety

• Headache

• Dyspnea on exertion

• Fatigue

• Confusion

• Dizziness

• Tachypnea and palpitations

• Coma

• Seizures

• Arrhythmias

• Acidosis

Considerations

Given that methemoglobinemia is most commonly acquired and its associated symptoms are highly nonspecific, the patient history is the most important differentiating feature of the disease. This is particularly true for exposure to drugs and toxins, as discussed in Interpretation, most commonly through inhalation, ^[5] skin contact, or ingestion. ^[4]