What are the causes of methemoglobinemia, particularly in infants and individuals with underlying medical conditions such as glucose-6-phosphate dehydrogenase deficiency?

Causes of Methemoglobinemia

Methemoglobinemia results from either inherited genetic defects in hemoglobin reduction enzymes or acquired exposure to oxidizing substances, with acquired forms being far more common and primarily caused by medications like dapsone and benzocaine, while hereditary forms stem from NADH cytochrome b5 reductase deficiency or hemoglobin M variants. 1

Acquired Causes (Most Common)

Medications

The most frequent culprits of acquired methemoglobinemia include:

• Dapsone accounts for 42-73% of all medication-induced cases, representing the single most common cause in both pediatric and adult populations 2, 3
• Benzocaine (particularly 20% topical spray) causes severe methemoglobinemia with mean peak levels of 43.8%, accounting for up to 45% of cases when combined with dapsone 2, 3
• Local anesthetics including lidocaine and prilocaine are common triggers 1, 4
• Other medications include phenazopyridine, sulfonamides (including hydrochlorothiazide), and nitrate-containing drugs 5, 6

Environmental and Chemical Exposures

• Nitrate-contaminated well water poses particular risk to infants, as their higher intestinal pH promotes growth of Gram-negative organisms (E. coli, Campylobacter jejuni) that convert dietary nitrates to nitrites 1, 4
• Recreational drugs including amyl nitrite and isobutyl nitrite cause severe methemoglobinemia requiring methylene blue treatment 2
• Sodium nitrite used in suicide attempts has shown increasing incidence in recent years, with documented fatalities 2
• Industrial chemicals including aniline dyes, naphthalene, aminophenols, and pesticides 5

Clinical Conditions

• Infections with metabolic acidosis particularly in infants with sepsis or severe diarrhea and dehydration can trigger methemoglobinemia 1, 4
• Inhaled nitric oxide therapy for pulmonary hypertension represents the second most common cause (13-18%) in hospitalized patients, necessitating regular monitoring 1, 2

Inherited Causes (Rare)

Type I: NADH Cytochrome b5 Reductase Deficiency

• Autosomal recessive inheritance due to biallelic mutations in the CYB5R3 gene, with over 80 different disease-causing variants reported 1
• Enzyme activity <20% of normal with residual activity confined to red blood cells 1
• MetHb levels typically 20-30% presenting with intense cyanosis (lavender or slate-gray appearance) from birth, but patients are otherwise well without neurological impairment 1
• Frequency up to 1:1000 in some isolated populations with founder mutations 1

Type II: Severe Enzyme Deficiency with Neurological Involvement

• Systemic enzyme deficiency affecting all tissues, not just erythrocytes 1
• Severe neurological features including microcephaly (nearly always present), axial hypotonia, dystonia, choreo-athetoid movements, opisthotonos, cognitive impairment, and growth retardation emerging by 9 months of age 1
• Life expectancy reduced with death typically occurring in the first decade due to swallowing difficulties and respiratory complications 1

Hemoglobin M Disease

• Autosomal dominant inheritance (though many cases are de novo mutations) affecting alpha-globin (HBA1, HBA2), beta-globin (HBB), or gamma-globin (HBG1, HBG2) genes 1
• At least 13 different HbM variants including HbM Boston, Saskatoon, Iwate, and Hyde Park, where tyrosine substitutes for histidine creating an iron-phenolate complex resistant to reduction 1
• Alpha-globin variants cause cyanosis evident at birth, while beta-globin variants manifest at 6-9 months when β chains replace fetal γ chains 1
• Generally asymptomatic except for cyanosis, though some variants (HbM Saskatoon, HbM Hyde Park) may cause hemolytic anemia with jaundice 1

Unstable Hemoglobins

• Variants like HbChile (β28 Leu→Met) cause chronic methemoglobinemia associated with hemolytic anemia 1
• Other unstable hemoglobins (Hb Cheverly, Hb Evans) develop MetHb only after stressor events, potentially reaching very high levels (>90%) with documented fatalities 1, 4

Special Populations at Increased Risk

Infants

• Lower erythrocyte CYB5R activity (50-60% of adult values) makes infants more susceptible to methemoglobinemia 1, 5
• Higher levels of HbF which oxidizes more readily to MetHb than adult hemoglobin 1, 5
• Exposure to teething gels containing benzocaine represents a common pediatric cause 1

Patients with G6PD Deficiency

• Elevated MetHb may occur after exposure to oxidant drugs, with hemolysis as the main clinical presentation 1, 7
• Heinz body formation observable on peripheral blood examination 1
• Critical consideration as methylene blue is contraindicated in G6PD deficiency and may worsen methemoglobinemia 5

Patients with Comorbidities

• Anemia, heart failure, COPD and any pathology impairing oxygen delivery worsen symptoms of methemoglobinemia even at lower MetHb levels 1
• Almost all patients (94%) with methemoglobinemia are anemic 3

Key Clinical Pitfall

The most critical error is administering methylene blue to patients with G6PD deficiency without prior testing, as this causes hemolytic anemia and paradoxically worsens methemoglobinemia 5. Always test for G6PD deficiency before treatment in patients without known history of methemoglobinemia 1, 5.