Methemoglobinemia 

Methemoglobinemia occurs when red blood cells (RBCs) contain greater than 1% methemoglobin. This occurs from either congenital changes in methemoglobin affecting synthesis and metabolism or from exposure to toxins that acutely affect redox reactions involving methemoglobin. It is important to realize that methemoglobin is a naturally occurring oxidized metabolite of hemoglobin and physiologic levels (< 1%) are normal. Problems arise when levels increase, as methemoglobin does not bind oxygen, thus leading to a functional anemia.^{[1, 2, 3, 4]}

Clinically, methemoglobinemia has a variable course. It is likely that many mild cases go undiagnosed because of its nonspecific findings. Symptoms are proportional to the methemoglobin concentration and include skin color changes (cyanosis with blue or grayish pigmentation) and blood color changes (brown or chocolate color) at methemoglobin levels up to 15%. As levels of methemoglobin rise above 15%, neurologic and cardiac symptoms arise due to hypoxia. levels above 70% are usually fatal.^[4]

Methemoglobin has an oxidized ferric iron (Fe +3) rather than the reduced ferrous form (Fe 2+) found in hemoglobin. This structural change is responsible for methemoglobin's inability to bind oxygen. In addition, ferric iron has slightly greater affinity for oxygen due to its chemical structure, thus shifting the oxygen dissociation curve of partially oxidized hemoglobin molecules to the left, resulting in decreased release of oxygen in tissues. The findings of anemia and cyanosis despite oxygen treatment result from both of these effects.^{[5, 4]}

For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Anemia.

Under normal conditions, methemoglobin levels remain below 1%; however, under conditions that cause oxidative stress, levels will rise. The low level of methemoglobin is maintained through a system of enzymatic functions that reduces methemoglobin to hemoglobin through successive electron transfers.

The major enzymatic system involved is adenine dinucleotide (NADH)–dependent methemoglobin reduction.^[6] This has also been called the diaphorase pathway. Cytochrome b5 reductase plays a major role in this process by transferring electrons from NADH to methemoglobin, which results in the reduction of methemoglobin to hemoglobin. This enzyme system is responsible for the removal of 95-99% of the methemoglobin that is produced under normal circumstances.

Another enzyme system, nicotinamide adenine dinucleotide phosphate (NADPH)–dependent methemoglobin reduction, usually plays only a minor role in the removal of methemoglobin. This enzyme system utilizes glutathione production and glucose-6-phosphate dehydrogenase (G6PD) to reduce methemoglobin to hemoglobin. This secondary enzymatic system assumes larger and more important role in methemoglobin regulation in patients with cytochrome b5 reductase deficiencies.

Methylene blue accelerates the NADPH-dependent methemoglobin reduction pathway.^{[3, 7, 6, 8]} In the absence of further accumulation of methemoglobin, these methemoglobin reduction pathways can clear methemoglobin at a rate of approximately 15% per hour.

At least 2 forms of congenital cytochrome b5 reductase deficiency states exist. Both are inherited in an autosomal recessive pattern. Type Ib5R deficiency is the more common form. In this clinical entity, cytochrome b5 reductase is absent only in red blood cells. Homozygotes appear cyanotic, but they are usually otherwise asymptomatic. Methemoglobin levels are typically in the range of 10-35%. Life expectancy is not adversely influenced, and pregnancies are not complicated. Heterozygotes may develop acute, symptomatic methemoglobinemia after exposure to certain drugs or toxins.

Type IIb5R cytochrome reductase deficiency is more uncommon and accounts for only 10-15% of cases of congenital cytochrome b5 reductase deficiency. In this condition, cytochrome b5 reductase is deficient in all cells (not just red blood cells). It is associated with multiple other medical problems, including mental retardation, microcephaly, and other neurologic complications. Life expectancy is severely compromised, and patients usually die at a very young age. The exact mechanism for the neurologic complications is not known.

Abnormal hemoglobins can also cause methemoglobinemia. These abnormal hemoglobins are called hemoglobin M (Hb M) because they are associated with methemoglobinemia. In most of them, a tyrosine replaces the histidine residue, which binds heme to globin. This replacement displaces the heme moiety and permits oxidation of the iron to the ferric state. Then, hemoglobin M is more resistant to reduction by the methemoglobin reduction enzymes previously described. The end result is a functionally impaired hemoglobin with a decreased affinity for oxygen.

The inheritance pattern for this hemoglobin M disorder is autosomal dominant. Patients appear cyanotic but are otherwise generally asymptomatic. The cyanosis in patients with hemoglobin M may appear somewhat brownish gray in color. Two varieties of hemoglobin M exist. The alpha chain variant causes cyanosis from birth, whereas the beta chain variant does not cause cyanosis until several months after birth, when the level of fetal hemoglobin decreases.^{[6, 9]}

Most cases of methemoglobinemia are due to excessive production of methemoglobin following exposure to oxidant drugs, chemicals, or toxins. This increased production of methemoglobin overwhelms the physiologic regulatory mechanisms previously discussed. These agents can cause an increase in methemoglobin levels either by ingestion or by absorption through the skin. Such agents fall into 2 general categories: nitrites or aromatic amines. Dapsone^[10] and benzocaine^[11] are common causes for methemoglobinemia.^[12]

Clinical evidence of cyanosis is dependent on the level of methemoglobin. Skin discoloration can occur in patients who are not anemic when as little as 1.5 g/dL, or approximately 10%, of hemoglobin is in the methemoglobin form. This compares with a level of as much as 5 g/dL of deoxyhemoglobin required to produce cyanosis. In methemoglobinemia, cyanosis is usually the first presenting symptom, in contrast to other causes of hypoxemia in which it is a later finding. In patients with severe anemia, a higher percentage of methemoglobin is required for cyanosis to occur. These patients may exhibit signs of hypoxemia with less cyanosis than in patients who do not have anemia.

Substances that can cause methemoglobinemia

• Inorganic agents

  • Nitrates – Fertilizers, contaminated well water, preservatives, industrial products
  • Chlorates
  • Copper sulfate – Fungicides
• Organic nitrites/nitrates

  • Amyl nitrite
  • Isobutyl nitrite
  • Sodium nitrite
  • Nitroglycerin
  • Nitroprusside
  • Nitric oxide
  • Nitrogen dioxide
  • Trinitrotoluene (TNT), combustion products
• Others
• Local anesthetics – Benzocaine, lidocaine, prilocaine, phenazopyridine (Pyridium)^{[13, 14]}
• Antimalarials – Primaquine, chloroquine^[15]
• Rasburicase^[16]
• Antineoplastic agents – Cyclophosphamide, ifosfamide, flutamide
• Analgesics/antipyretics – Acetaminophen, acetanilid, phenacetin, celecoxib
• Zopiclone^[17]
• Herbicides – Paraquat (dipyridylium)
• Methylene blue (high dose or in G6PD deficient patients^[18] )
• Indigo Carmine (Indigotindisulfonate)
• Resorcinol
• Antibiotics – Sulfonamides, nitrofurans, P-amino-salicylic acid, Dapsone
• Industrial/household agents – Aniline dyes, nitrobenzene, naphthalene (moth balls), aminophenol, nitroethane (nail polish remover)

Frequency

United States

Hereditary methemoglobinemia is a rare condition. The most common cause of congenital methemoglobinemia is cytochrome b5 reductase deficiency (type Ib5R). This enzymatic deficiency is endemic in certain Native American tribes (Navajo and Athabascan Alaskans).

Most cases of congenital methemoglobinemia are acquired and result from exposure to certain drugs or toxins. One of the more common causes of acquired methemoglobinemia is exposure to topical benzocaine during medical procedures. An estimated 0.115% of patients undergoing transesophageal echocardiography (TEE) develop methemoglobinemia.^{[11, 19, 20]} The incidence with other agents is not known.

Infants are more susceptible to the development of methemoglobinemia after toxin exposure, because they have a decreased ability to clear methemoglobin once it is formed. Premature infants are particularly susceptible.

A retrospective study from 2 large teaching hospitals in the United States identified 138 cases of acquired methemoglobinemia over a period of 28 months.^[12]

International

Methemoglobinemia occurs rarely throughout the world. Cytochrome b5 reductase deficiency (type Ib5R) is also endemic in the Yakutsk people of Siberia.

Mortality/Morbidity

Acquired toxic methemoglobinemia can be life threatening, but it is usually not fatal with proper treatment. This is particularly true when the exposure is intentional or the condition is not recognized. One fatality and 3 near-fatalities were reported in a study of 138 patients.^[12] Acquired toxic methemoglobinemia usually responds to treatment when it is recognized and properly treated.

The clinical course of hereditary forms of methemoglobinemia is generally benign. However, individuals with type IIb5 cytochrome reductase deficiency are an exception to this rule. These persons have a markedly shortened life expectancy primarily due to multiple neurologic complications.

Race

The congenital form of methemoglobinemia due to cytochrome b5 reductase deficiency (type Ib5R) is endemic in certain ethnic groups. These groups include the Navajo, Athabascan Alaskans, and the Yakutsk people in Siberia.

Sex

No difference exists in disease occurrence of acquired methemoglobinemia between males and females. The inheritance pattern of the congenital enzyme deficiency form of the disease is autosomal recessive. Hemoglobin M is inherited in an autosomal dominant pattern.

Age

Infants (especially premature infants) are more susceptible to the development of methemoglobinemia after drug or toxin exposure. This is because infants have significantly lower levels of cytochrome b5 reductase.