eMedicine Specialties > Hematology > Red Blood Cells and Disorders

Methemoglobinemia

Author: Mary Denshaw-Burke, MD, FACP, Assistant Clinical Professor, Institute for Medical Research, Program Director of Hematology/Oncology Fellowship, Education Coordinator for Oncology, Lankenau Hospital; Consulting Staff, Roxborough Memorial Hospital
Coauthor(s): Deric C Savior, MD, Fellow in Hematology/Oncology, Lankenau Hospital; John Schoffstall, MD, Associate Professor, Department of Emergency Medicine, Medical College of Pennsylvania
Contributor Information and Disclosures

Updated: Nov 10, 2008

Introduction

Background

Methemoglobinemia is diagnosed when the percentage of methemoglobin (metHb) exceeds 1% in the blood. Methemoglobin differs from normal hemoglobin in that the oxygen-carrying ferrous (+2) iron in the heme groups has been oxidized to ferric (+3) iron. Methemoglobin is characterized by the inability to bind oxygen, resulting in a functional anemia and failure to deliver oxygen to the body's tissues.^1,2,3,4

The classic presentation of methemoglobinemia is cyanosis in the presence of a normal alveolar partial pressure of oxygen (PaO₂), with brown- or chocolate-colored blood that does not become red on exposure to oxygen. Additional symptoms such as shortness of breath, anxiety, palpitations, and confusion occur as the level of metHb increases.^3,5,6

Methemoglobinemia is a misnomer, because metHb is only increased within the red blood cells and is not dissolved in the plasma. Methemoglobinemia can be hereditary or acquired. Acquired methemoglobinemia is usually secondary to medications or various exogenous exposures.

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

Related eMedicine topics:
Methemoglobinemia [in the Emergency Medicine section]
Methemoglobinemia [in the Pediatrics: General Medicine section]

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Pathophysiology

Methemoglobin occurs naturally in the body due to oxidative stresses, but it is usually only in small amounts (<1% of total hemoglobin). levels exceeding 1% are termed methemoglobinemia. This 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.⁷ 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.^3,5,7,8 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.^7,9

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. Dapsone¹⁰ and benzocaine¹¹ 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)
• Antimalarials – Primaquine, chloroquine
• Rasburicase
• Antineoplastic agents – Cyclophosphamide, ifosfamide, flutamide
• Analgesics/antipyretics – Acetaminophen, acetanilid, phenacetin, celecoxib
• Zopiclone
• Herbicides – Paraquat (dipyridylium)
• Methylene blue (high dose or in G6PD deficient patients¹³ )
• 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 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.

Clinical

History

The history is important for distinguishing methemoglobinemia between cyanosis that is due to cardiopulmonary abnormalities and that from other causes of discoloration of the skin and mucous membranes. Acute methemoglobinemia can be life threatening and usually is due to toxic exposure or drugs. Therefore, obtaining a history of exposure to substances that can induce methemoglobinemia is important. In contrast, patients with hereditary methemoglobinemia are often asymptomatic despite the presence of cyanosis. The failure of 100% oxygen to correct cyanosis is suggestive of methemoglobinemia.

• Symptoms are proportional to the level of methemoglobin.
  • Less than 10% methemoglobin – No symptoms
  • 10-20% methemoglobin – Skin discoloration only (most notably
    on mucus membranes)
  • 20-30% methemoglobin – Anxiety, headache, dyspnea on
    exertion
  • 30-50% methemoglobin – Fatigue, confusion, dizziness,
    tachypnea, palpitations
  • 50-70% methemoglobin – Coma, seizures, arrhythmias, acidosis
  • Greater than 70% methemoglobin – Death
• Infants and children can develop methemoglobinemia in association with metabolic acidosis that is caused by prolonged dehydration and diarrhea. Sources of accidental toxin exposure that need to be considered in infants and children include the ingestion of water from wells contaminated with excess nitrates and exposure to local anesthetics in teething gels.¹⁴ These factors can sometimes be elicited in a thorough history.
• Any known family history of methemoglobinemia or G6PD deficiency is important to clarify. Even patients who are heterozygous for methemoglobin reductase enzyme deficiencies are susceptible to low doses of oxidant drugs with resultant methemoglobinemia.
• The presence of gastrointestinal (GI) symptoms (nausea, vomiting, diarrhea) may suggest the possibility of ingestion of a toxic substance.
• The clinical effects of methemoglobinemia are exacerbated in the presence of anemia.

Physical

The physical examination of patients suspected of methemoglobinemia should include careful examination of the skin and mucous membranes for discoloration or cyanosis.

• Vital signs should be documented, along with an assessment of the patient's mental status.
• Careful attention should be paid to the cardiac, respiratory, and circulatory examinations to assess for evidence of an underlying disease (either congenital or acquired).
• Pallor of the skin or conjunctiva may suggest anemia (and possible hemolysis).
• Significant anemia may mask the cyanosis of methemoglobinemia.
• Skeletal abnormalities and mental retardation are associated with certain types of methemoglobin reductase enzyme deficiencies.

Causes

The pathophysiology of methemoglobinemia has been previously discussed (see Pathophysiology). In general, methemoglobinemia can be acquired or congenital. Acquired methemoglobinemia is usually due to the ingestion of drugs or toxic substances. Congenital causes of methemoglobinemia include methemoglobin reductase enzyme deficiencies or abnormal hemoglobins (Hb M) that are more prone to form methemoglobin.

• Organic and inorganic nitrites/nitrates are common causes of methemoglobinemia. Many of these substances can also be absorbed through the skin, and many prescription cardiac medications contain these compounds. Dietary intake may occur in infants or adults who ingest well water that has been contaminated with nitrites caused by water runoff from fertilized fields.¹⁴
• Chlorates are another group of oxidizing agents that can cause methemoglobinemia. These substances are found in matches, explosives, and fungicides.
• Topical and injected local anesthetics have also caused methemoglobinemia. Predisposing factors for the development of this toxicity include the presence of a mucosal injury with resultant increased absorption or a previously undiagnosed methemoglobin reductase enzyme deficiency. This toxicity can also be idiosyncratic.
• Dapsone is another medication that can cause methemoglobinemia. It is used to prevent and treat Pneumocystis carinii pneumonia (PCP) and to treat leprosy and other skin diseases. This drug should be used with great caution in patients with known G6PD deficiency, methemoglobin reductase deficiency, or hemoglobin M.
• Patients with low catalase activity (inherited or acquired) may be at risk for the development of methemoglobinemia secondary to the formation of hydrogen peroxide after being treated with rasburicase for tumor lysis syndrome. Some authors have suggested that catalase activity be measured before initiating therapy with rasburicase in this setting.
• Red blood cells in patients with liver cirrhosis undergo severe oxidative stress, especially in the setting of bleeding complications. The level of methemoglobin is significantly higher in the red blood cells of these patients as compared with nonbleeding patients.
• Idiopathic methemoglobinemia can occur in association with systemic acidosis. This typically occurs in infants younger than 6 months and is usually caused by dehydration and diarrhea. Idiopathic methemoglobinemia is exacerbated by the lower levels of methemoglobin reductase enzyme found in infants (50% of adult levels).

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