History
The characteristic history in the congenital (hereditary) form of methemoglobinemia is the presence of diffuse, persistent, slate-gray cyanosis, often present from birth without evidence of cardiopulmonary disease. Patients with hereditary methemoglobinemia are asymptomatic despite the presence of cyanosis. The failure of 100% oxygen to correct cyanosis is very suggestive of methemoglobinemia.
Acute methemoglobinemia can be life-threatening and usually is acquired as a consequence of exposure to toxins or drugs. Therefore, obtaining a detailed history of exposure to methemoglobinemia-inducing substances is important. Such history may not always be forthcoming, but it should always be sought actively since long-term or repeated exposure may occur. Consultation with a toxicologist may be necessary, especially with exposure to a new medication, because the list of medications known to cause methemoglobinemia changes constantly.
Symptoms are proportional to the fraction of methemoglobin. A normal methemoglobin fraction is about 1% (range, 0-3%). At methemoglobin levels of 3-20%, a slight discoloration (eg, pale, gray, blue) of the skin may be present.
Signs and symptoms at levels of 20-50% include the following:
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Headache
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Dyspnea
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Lightheadedness, even syncope
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Weakness
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Confusion
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Palpitations, chest pain
Methemoglobin levels of 50-70% can cause the following:
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Cardiovascular - Arrhythmias
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CNS - Delirium, seizures, coma
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Metabolic - Profound acidosis
At methemoglobin fractions exceeding 70%, death usually results.
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 must be considered in infants and children include ingestion of water from wells contaminated with excess nitrates and exposure to local anesthetics in teething gels. [21] These factors can sometimes be elicited in a thorough history.
Any known family history of methemoglobinemia or glucose-6-phosphate dehydrogenase (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 (eg, nausea, vomiting, or diarrhea) may suggest the possibility of ingestion of a toxic substance.
The clinical effects of methemoglobinemia are exacerbated in the presence of anemia.
Physical Examination
The physical examination of patients with suspected methemoglobinemia should include examination of the skin and mucous membranes. Vital signs should be documented, and mental status should be assessed. Careful attention should be paid to the cardiac, respiratory, and circulatory examinations to assess for evidence of an underlying disease (either congenital or acquired).
Physical findings may include the following:
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Discoloration of the skin, mucous membranes, and blood (the most striking physical finding)
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Cyanosis - This occurs with the presence of greater than 1.5 g/dL of methemoglobin (compared with 5 g/dL of deoxygenated hemoglobin)
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Pallor of the skin or conjunctiva suggests anemia (and possible hemolysis), which can mask cyanosis if significant.
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Seizures
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Coma
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Cardiac dysrhythmias (eg, bradyarrhythmia or ventricular dysrhythmia)
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Acidosis
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Signs associated with cardiac and/or neurologic ischemia
Skeletal abnormalities and mental retardation are associated with certain types of methemoglobin reductase enzyme deficiencies.
Patients with hereditary methemoglobinemia are commonly described as being more blue than sick. They 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.
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 latter half of infancy.
Chaurasia and colleagues reported corneal epitheliopathy in four patients with congenital methemoglobinemia. They observed dark-colored conjunctival vessels and recurrent corneal epitheliopathy in three girls and one boy from two affected families. The corneal lesions resolved within 2 to 3 weeks with supportive therapy and vitamin C supplements. [68]
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Note chocolate brown color of methemoglobinemia. In tubes 1 and 2, methemoglobin fraction is 70%; in tube 3, 20%; and in tube 4, normal.
