eMedicine Specialties > Pediatrics: General Medicine > Hematology

Methemoglobinemia

Author: Michael J Verive, MD, Medical Director, Pediatric Intensive Care, Department of Pediatrics, St Mary's Hospital for Women and Children
Coauthor(s): Mudra Kumar, MD, MBBS, MRCP, Associate Professor, Department of Pediatrics, University of South Florida College of Medicine
Contributor Information and Disclosures

Updated: Oct 6, 2009

Introduction

Background

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.

Pathophysiology

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_{Hyde Park}, 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

Age

Hereditary forms appear early in life. Young infants, especially infants aged 3-4 months, are more susceptible to acquired methemoglobinemia.

Clinical

History

• Congenital methemoglobinemia: The characteristic history is diffuse persistent slate-gray cyanosis, often present from birth, without evidence of cardiopulmonary disease.
• Acquired methemoglobinemia
  • Presentation may be dramatic, with cyanosis, dyspnea, lethargy, headache, dizziness, deterioration of mental functioning, or stupor.
  • History of exposure to a known toxin or drug may not always be available but should be sought because long-term or repeated exposure may occur. 
  • Discussion with a toxicologist may be necessary, especially when methemoglobinemia occurs shortly after exposure to a new medication, because the list of medications known to cause methemoglobinemia constantly changes. A comprehensive review of all medications, herbs, and other nutritional supplements may disclose exposure to a toxin not previously known to cause hemoglobinemia.

Physical

• Congenital methemoglobinemia
  • These patients are described as being more blue than sick.
  • Patients appear cyanotic with a diffuse slate-gray appearance.
  • Cyanosis is easily observed on the nose, cheeks, fingers, toes, and in the mucous membranes, including the fundi, and may go unrecognized for a long time in patients with more heavily pigmented skin or in patients with moderate-to-severe anemia. Clubbing is absent.
  • Methemoglobin levels of 10-20% are tolerated with no clinical symptoms, whereas levels of 30-40% may be associated with headaches and dyspnea, especially upon exertion.
• Patients with hemoglobin M disease with the alpha chain variant can present at birth with cyanosis, whereas patients with the beta chain variants present in the later half of infancy.

Causes

• Acquired methemoglobinemia: Exposure to various drugs or toxins may result in acquired methemoglobinemia. These include the following:
  • Nitrites, particularly in well water (Prepackaged foods [including baby food] may contain significant levels of nitrites.)^5,6
  • Aniline dyes
  • Silver nitrate
  • Nitroprusside
  • Antimalarials
  • Zopiclone⁷
  • Local anesthetics (eg, Benzocaine, prilocaine, and lidocaine), particularly when applied to mucosa, such as during bronchoscopy, or after repeated cutaneous exposure to eutectic mixture of lidocaine-prilocaine (EMLA(R) cream) over a short period of time
  • Nitric and nitrous oxides
  • Dapsone, rasburicase, and phenazopyridine
  • Inadequately cooked vegetables (eg, spinach, beets, carrots) contaminated with bacteria (Infants and patients on gastric acid-reduction therapy are particularly prone to developing methemoglobinemia because gastric acid production may not be sufficient to maintain low levels of nitrate-reducing bacteria in the intestine.)
• Hereditary methemoglobinemia: This may be due to the deficiency of nicotinamide adenine dinucleotide (NADH) cytochrome b5 reductase or NADPH-flavin reductase or the presence of hemoglobin M.

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