Causes of Methemoglobinemia
Methemoglobinemia results from either acquired exposures to oxidizing substances (most common) or inherited genetic defects affecting hemoglobin reduction pathways. 1, 2
Acquired Causes (Most Common)
Acquired methemoglobinemia occurs when oxidant stressors convert ferrous iron (Fe2+) to ferric iron (Fe3+) in hemoglobin, rendering it unable to carry oxygen. 1 The following categories represent the major culprits:
Medications and Anesthetics
- Local anesthetics: Benzocaine and lidocaine are well-documented triggers 2
- Antimalarials: Chloroquine and primaquine 2
- Antibiotics: Sulfonamides, trimethoprim, and dapsone 2, 3
- Other pharmaceuticals: Phenazopyridine, metoclopramide, phenacetin, and cyclophosphamide 1, 2
Environmental and Chemical Exposures
- Nitrates and nitrites: Contaminated well water or food with excessive nitrates, particularly dangerous for infants and pregnant women 2, 4
- Industrial chemicals: Aniline exposure through inhalation 5
- Herbicides: Urea-substituted compounds containing linuron 5
High-Risk Populations for Acquired Forms
Infants face substantially greater risk due to three physiologic vulnerabilities: 4
- Lower erythrocyte cytochrome b5 reductase (CYB5R) enzyme activity
- Higher fetal hemoglobin levels (more easily oxidized to methemoglobin)
- Greater water consumption per body weight, increasing exposure to waterborne nitrates
Inherited Causes
Cytochrome b5 Reductase Deficiency
- Genetic basis: Biallelic mutations in the CYB5R3 gene cause NADH cytochrome b5 reductase deficiency, with over 80 disease-causing variants reported 2
- Type I presentation: Methemoglobin levels typically exceed 25%, causing cyanosis, headache, fatigue, and dyspnea 2
- Inheritance pattern: Autosomal recessive 1
Hemoglobin M Disease
- Genetic basis: Autosomal dominant variants in globin genes create structural hemoglobin abnormalities 1, 2
- Typical methemoglobin levels: Range from 12.5% to 25% 2
- Inheritance pattern: Autosomal dominant 1
Secondary Associations
Elevated methemoglobin can occur secondarily in patients with: 2
- Unstable hemoglobins: Particularly after exposure to oxidant drugs
- Glucose-6-phosphate dehydrogenase (G6PD) deficiency: Especially when exposed to oxidizing medications
Critical Clinical Pitfall
Never rely solely on pulse oximetry in suspected methemoglobinemia—it systematically overestimates true oxygen saturation and can plateau around 85% regardless of actual oxygenation status. 6 The classic presentation includes chocolate-brown blood, cyanosis unresponsive to oxygen therapy, and a discrepancy between pulse oximetry readings and arterial blood gas measurements. 7, 8 Co-oximetry is the only reliable diagnostic method, as it directly measures methemoglobin fraction using multiple wavelengths of light. 6