Pediatric Methemoglobinemia 

Methemoglobinemia is a condition in which the iron within hemoglobin is oxidized from the ferrous (Fe²⁺) state to the ferric (Fe³⁺) state. Because iron needs to be in the ferrous state to allow hemoglobin-to-oxygen binding, methemoglobinemia results in variable degrees of deficiencies of oxygen transport. Clinically, this condition causes cyanosis, often posing a diagnostic dilemma.

Methemoglobinemia in children usually results from exposure to oxidizing substances (such as nitrates or nitrites; aniline dyes; or medications, including lidocaine, prilocaine, phenazopyridine hydrochloride [Pyridium], and others) or is the result of inborn errors of metabolism (especially glucose-6-phosphate dehydrogenase [G6PD] deficiency and cytochrome b5 oxidase deficiency) or severe acidosis, which impairs the function of cytochrome b5 oxidase. This is particularly evident in young infants with diarrhea,^[1] in whom excessive stool bicarbonate loss leads to metabolic acidosis, which exacerbates the relatively immature cytochrome b5 oxidase system.

Hemoglobin molecules are tetrameric and contain iron within a porphyrin heme structure. The iron moiety in hemoglobin is normally in the ferrous state (Fe²⁺) in both oxyhemoglobin and deoxyhemoglobin and is capable of reversibly binding with oxygen only in this (ferrous) state. The oxidation of iron to the ferric state (Fe³⁺) results in the formation of methemoglobin, which alters absorption and causes a brownish discoloration of the blood.

In healthy children, the ferric iron in methemoglobin is readily reduced to the ferrous state, primarily through the function of cytochrome b5 oxidase (also referred to as methemoglobin reductase), which is present in erythrocytes and other cells. Patients who are deficient in cytochrome b5 reductase are particularly prone to methemoglobinemia, especially when exposed to oxidizing medications and other chemicals, including nitrates, nitrites, prilocaine and lidocaine, nitric oxide, and aniline dyes. Because methemoglobin is incapable of reversibly binding and transporting oxygen or carrying carbon dioxide, if it is present in significant amounts, methemoglobinemia can result in impaired oxygen delivery to (and carbon dioxide removal from) all tissue beds.

Cyanosis is commonly caused by either an excess of deoxygenated hemoglobin (usually in amounts >5 g/dL) or significant amounts of abnormal hemoglobins such as methemoglobin (>1.5 g/dL) or sulfhemoglobin (>0.5 g/dL), resulting in a grayish-bluish coloration of the skin and mucous membranes. Because the absolute amount of deoxygenated or abnormal hemoglobin (rather than its percentage) is required for cyanosis to be clinically evident, patients with moderate-to-severe anemia may not appear cyanotic, even with elevated percentages of deoxygenated or abnormal hemoglobins.

In healthy individuals, ongoing RBC exposure to various oxidizing agents produces small amounts of methemoglobin; however, the concentration of methemoglobin (as a fraction of total hemoglobin) is maintained below 1% by a reduction enzyme system (mainly cytochrome b5 along with nicotinamide adenine dinucleotide [NADH] reductase), with additional protection provided by other systems, including glutathione reductase and G6PD. Methemoglobinemia occurs if the rate of oxidation is significantly increased and overwhelms the protective and reductive capacities of the cells, if the structure of hemoglobin is altered and is resistant to reduction, or if the rate of reduction of methemoglobin is decreased. Methemoglobinemia may be acquired or congenital.

Acquired methemoglobinemia

Acquired methemoglobinemia is more common than congenital forms. Exposure to oxidant drugs and toxins in amounts that exceed the enzymatic reduction capacity of RBCs precipitates symptoms of methemoglobinemia.^[2]

Acquired methemoglobinemia is more frequent in premature infants and infants younger than 4 months. The following factors may have a role in the higher incidence in this age group:

• Fetal hemoglobin may more easily (auto) oxidize than adult hemoglobin.
• The level of NADH reductase is low at birth and increases with age; it reaches reference range limits by age 4 months.
• Higher gastric pH in infants may facilitate bacterial proliferation, resulting in increased conversion of dietary nitrates to nitrites.
• An association between methemoglobinemia and acute gastroenteritis in infants has been noted in several studies and may be due to acidosis from stool bicarbonate loss impairing the already immature function of the methemoglobin reductase system in these young patients.

Congenital (ie, hereditary) methemoglobinemia

Hereditary methemoglobinemias may be divided into 2 categories: methemoglobinemia due to an altered form of hemoglobin (hemoglobin M) and enzyme deficiency (NADH reductase deficiency) that decreases the rate of reduction of iron in the hemoglobin molecule.^[3] Four types of hereditary methemoglobinemias are secondary to deficiency of NADH cytochrome b5 reductase. All types are autosomal recessive disorders. Heterozygotes have 50% enzyme activity and no cyanosis. Homozygotes that have elevated methemoglobin levels above 1.5% have clinical cyanosis.

• Type I: This is the most common variant, and the enzyme deficiency is limited to the erythrocytes causing cyanosis.
• Type II: Widespread deficiency of the enzyme occurs in various tissues, including erythrocytes, liver, fibroblasts, and brain. It is associated with severe CNS symptoms, including encephalopathy, microcephaly, hypertonia, athetosis, opisthotonus, strabismus, mental retardation, and growth retardation. Cyanosis is evident at an early age.
• Type III: Although the hemopoietic system (platelets, RBCs, white cells including lymphocytes and granulocytes) is involved, the only clinical consequence is cyanosis.
• Type IV: Similar to type I, this type has isolated involvement of the erythrocytes but results in chronic cyanosis.

Deficiency of nicotinamide adenine dinucleotide phosphate (NADPH)–flavin reductase can also cause methemoglobinemia.

An amino acid substitution in or near the heme pocket affects the heme-globin bond, and the hemoglobin molecule becomes more stable in the oxidized form, resisting reduction. Several variants of hemoglobin M have been described, including hemoglobin Ms, hemoglobin M_Iwate, hemoglobin M_Boston, hemoglobin M_HydePark, and hemoglobin M_Saskatoon. These are usually autosomal dominant in nature. Alpha chain substitutions cause cyanosis at birth, whereas those in the beta chain become clinically apparent in infants aged 4-6 months.

Frequency

United States

Theexact incidence is unknown.

International

The exact incidence is unknown.

Mortality/Morbidity

Patients with congenital methemoglobinemia are generally asymptomatic other than cyanosis. Life expectancy is normal, unless the methemoglobin level is above 25-40%. Acquired methemoglobinemia is usually mild but may be severe and rarely fatal, depending on the cause. Mild-to-moderate transient methemoglobinemia may be present but may escape clinical detection; a high index of suspicion must be maintained.^[4]

Race

Congenital methemoglobinemia is more prevalent among populations with endemic cytochrome b5 reductase deficiency, including Alaskan and Native American Indian populations.

As G-6-PD deficiency is a risk factor for acquired methemoglobinemia, so populations endemic for G-6-PD deficiency, including populations of Mediterranean and African descent, are at higher risk for acquired methemoglobinemia.

Sex

There is no association between sex and congenital methemoglobinemia. However, because G-6-PD deficiency is X-linked, there is a higher risk of acquired methemoglobinemia in males with G-6-PD deficiency when they are subjected to oxidative stress.

Age

Hereditary forms appear early in life. Young infants, especially infants aged 3-4 months, are more susceptible to acquired methemoglobinemia, as the ability to reduce methemoglobinemia is not well developed at birth, but reaches reference range limits by age 4 months. Free iron deposition in the brains of sudden fetal and infant death victims has been identified as a possible catabolic product of maternal methemoglobinemia and may be a marker of maternal nicotine exposure.^[5]