What are the causes of methemoglobinemia?

Causes of Methemoglobinemia

Methemoglobinemia results from either acquired exposures to oxidizing substances (most common) or inherited genetic defects affecting hemoglobin reduction pathways. 1

Acquired Causes (Most Common)

Acquired methemoglobinemia is far more frequent than congenital forms and results from exposure to substances that oxidize hemoglobin directly or indirectly. 1

Medications

Dapsone is the most frequent cause of acquired methemoglobinemia in both pediatric (73.3%) and adult (65.3%) populations. 2 This is the single most important drug to recognize in clinical practice.

Other high-risk medications include: 1

• Local anesthetics: Benzocaine (particularly topical formulations), lidocaine, prilocaine, articaine
• Antimalarials: Chloroquine, primaquine
• Antibiotics: Sulfonamides, trimethoprim
• Urinary analgesics: Phenazopyridine (available over-the-counter, making it a common culprit) 3
• Other agents: Phenacetin, metoclopramide, rasburicase, cyclophosphamide, flutamide

Nitrate Compounds

Nitrate derivatives are critical causes to identify: 1

• Medical nitrates: Nitroglycerin, nitroprusside, amyl nitrite, inhaled nitric oxide (second most common cause after dapsone at 18.1% pediatric, 13.2% adult) 2
• Recreational nitrites: Amyl nitrite, isobutyl nitrite ("poppers") 2
• Sodium nitrite: Increasingly used in suicide attempts (recent epidemiologic trend showing rise in intentional ingestions with one fatality reported) 2

Environmental and Chemical Exposures

Industrial and environmental sources include: 1

• Aniline dyes
• Naphthalene
• Aminophenols
• Chlorates and bromates
• Herbicides and pesticides
• Contaminated well water or food: Excessive nitrates from fertilizers or inappropriate manure utilization (particularly dangerous for infants and pregnant women) 1

Clinical Conditions

Certain medical conditions can precipitate methemoglobinemia: 1

• Infections (particularly in susceptible individuals)
• Sepsis (documented as causing methemoglobinemia in multiple cases) 2

Inherited Causes

Type I: Cytochrome b5 Reductase Deficiency (Autosomal Recessive)

Biallelic mutations in the CYB5R3 gene cause NADH cytochrome b5 reductase deficiency, with over 80 different disease-causing variants reported. 1

• Type I deficiency: Enzyme deficiency restricted to red blood cells only, typically presenting with MetHb levels above 25%, causing cyanosis, headache, fatigue, and dyspnea 1
• Most patients present in infancy, but adult presentation can occur (case reported at age 37 years with new mutation) 4
• Patients often exhibit erythrocytosis as a compensatory mechanism 1
• Cyanosis may be the only clinical sign in many cases 1

Type II: Generalized Cytochrome b5 Reductase Deficiency (Autosomal Recessive)

Type II involves generalized enzyme deficiency affecting all cells, presenting in the first year of life with severe neurodevelopmental disorder and profound neurological deficits. 1

Hemoglobin M Disease (Autosomal Dominant)

Autosomal dominant variants in globin genes (HBA1, HBA2, HBB, HBG1, HBG2) cause structural hemoglobin abnormalities where tyrosine substitutes for histidine residues, creating an iron-phenolate complex resistant to reduction. 1

• At least 13 different HbM variants reported (including Hb M-Boston, M-Saskatoon, M-Iwate, M-Hyde Park) 1
• MetHb levels typically range 12.5%-25% 1
• Patients are cyanotic but usually otherwise asymptomatic 1
• Family history may reveal autosomal dominant inheritance pattern 1
• Historically recognized as "Kochikuro" (black mouth) in Japan since the 1800s 1

Associated Hemolytic Conditions

Elevated MetHb can occur secondarily in patients with unstable hemoglobins and G6PD deficiency, particularly after exposure to oxidant drugs. 1 In these cases, hemolysis is the primary manifestation with methemoglobinemia appearing as a secondary feature, and Heinz bodies may be observed on peripheral blood examination. 1

Clinical Pitfalls

A critical pitfall is assuming adult-onset methemoglobinemia is always acquired—congenital Type I cytochrome b5 reductase deficiency can present in adulthood without prior symptoms or known triggers. 4 Always consider genetic testing in cases without clear oxidant exposure, even in adults.

Infants are at substantially greater risk due to lower erythrocyte CYB5R activity, making them more susceptible to both acquired and congenital forms. 1