What causes methemoglobinemia?

Causes of Methemoglobinemia

Methemoglobinemia is primarily caused by either acquired exposure to oxidizing substances or inherited genetic mutations, with acquired forms being the most common.1

Primary Causes

1. Acquired Methemoglobinemia

Acquired methemoglobinemia is the most prevalent form and results from exposure to substances that oxidize hemoglobin:

• Medications:

  • Dapsone - the most frequent cause in both pediatric (73.3%) and adult (65.3%) populations 2
  • Local anesthetics (particularly benzocaine) 2
  • Nitroglycerin - can cause methemoglobinemia in overdose 3
  • Antimalarials (primaquine) 4
  • Sulfonamides 4

• Chemical Agents:

  • Nitrites (including sodium nitrite, amyl nitrite, isobutyl nitrite) 2
  • Nitrates in contaminated food 2
  • Aniline dyes 4
  • Naphthalene 4
  • Nitrofurantoin 4

• Other Conditions:

  • Sepsis 2
  • Inhaled nitric oxide therapy 2

2. Inherited Methemoglobinemia

Inherited forms are less common and occur through two main mechanisms:

• NADH Cytochrome b5 Reductase Deficiency:

  • Autosomal recessive condition caused by mutations in the CYB5R3 gene 1
  • Two clinical subtypes:
    • Type I: Enzyme deficiency restricted to red blood cells, causing cyanosis, headache, fatigue, and dyspnea 1
    • Type II: Generalized enzyme deficiency affecting all cells, with early onset and more severe manifestations 5

• Hemoglobin M Disease:

  • Autosomal dominant variants in globin genes (HBA1, HBA2, HBB, HBG1, HBG2) 1
  • Structural abnormalities in the globin portion cause heme iron to auto-oxidize 1
  • Typically presents with cyanosis but patients are otherwise asymptomatic 1

Pathophysiology

Methemoglobinemia occurs when the iron in hemoglobin is oxidized from the ferrous (Fe²⁺) to the ferric (Fe³⁺) state. This oxidation:

1. Results in irreversible binding of oxygen to hemoglobin 1
2. Shifts the oxygen-dissociation curve to the left 1
3. Impairs oxygen release to tissues, causing functional anemia despite normal hemoglobin levels 1
4. Produces the characteristic chocolate-brown colored blood that doesn't change color when exposed to air 3, 6

Risk Factors

• Age: Infants are at higher risk due to:

  • Lower levels of erythrocyte CYB5R activity 1
  • Fetal hemoglobin being more easily oxidized to methemoglobin 7

• Genetic Factors:

  • Glucose-6-phosphate dehydrogenase (G6PD) deficiency 4
  • Methemoglobin reductase deficiency 4
  • Hemoglobin M variants 4

• Comorbidities that worsen symptoms:

  • Anemia 1
  • Heart failure 1
  • Chronic obstructive pulmonary disease 1
  • Any condition impairing oxygen delivery 1

Clinical Presentation

Symptoms correlate with methemoglobin levels and range from:

• Cyanosis (appears at levels >1.5 g/dL of MetHb)
• Fatigue, weakness, headache
• Central nervous system depression
• Metabolic acidosis
• Seizures, dysrhythmias
• Coma and death (at levels >70%) 1

Diagnostic Considerations

Methemoglobinemia should be suspected in patients with:

• Unexplained cyanosis unresponsive to oxygen therapy
• Chocolate-brown colored blood
• Oxygen saturation gap between pulse oximetry and blood gas analysis
• History of exposure to oxidizing agents 1, 6

Diagnosis is confirmed by measuring methemoglobin levels using co-oximetry and can be further characterized by enzyme activity testing and genetic analysis when inherited forms are suspected 1.