Methemoglobinemia

Learning objectives

Methemoglobin is the form of the hemoglobin molecule where the iron moiety is oxidized (Fe3+)
It is formed in the presence of an oxidizing substrate and does not carry oxygen
It shifts the oxygen-hemoglobin dissociation curve to the left, hindering the unloading of oxygen to the tissues
These effects are proportional to the concentration of methemoglobin and reversible
Normal methemoglobin levels: 1-2 %
Methemoglobinemia refers to an abnormally high concentration of methemoglobin and results in functional anemia
Methemoglobinemia can be a life-threatening condition

Congenital (rare)
- Autosomal recessive defects in cytochrome b5 reductase (CYB5R)
  - Congenital methemoglobinemia type I: CYB5R defect only in erythrocytes
  - Congenital methemoglobinemia type II: CYB5R defect in all cells
- Autosomal dominant mutations in hemoglobins M (hemoglobin M disease)
Acquired
- Exposure to oxidizing agents leading to methemoglobin production that exceeds the body’s reduction capacity
- Oxidizing agents:
  - Direct
    - Benzocaine
    - Prilocaine
    - Lidocaine
    - Tetracaine
  - Indirect
    - Nitrates, nitrites
  - Metabolic activation
    - Aniline
    - Dapsone

Reduction of methemoglobin by cytochrome b5 reductase:

Hemoglobin M disease:
- Mutation in globin protein allows for stabilization of iron in the ferric state (Fe3+)
- Most patients have methemoglobin levels between 15-30% and remain asymptomatic
Congenital methemoglobinemia: Defect in CYB5R function raising methemoglobin levels
Acquired methemoglobinemia: CYB5R is overwhelmed by oxidative stress resulting in raised methemoglobin levels

Pulse oximetry measurements of oxygen saturation (SpO2): Refractory hypoxemia
Refractory hypoxemia is usually not detected using blood gas analysis using the partial oxygen pressure (SaO2)
Saturation gap: Difference between depressed SpO2 measurement and falsely normal SaO2 calculation
A saturation gap >5% indicates the presence of abnormal forms of hemoglobin