Methemoglobinemia is a disorder characterized by the presence of a higher than normal level of methemoglobin (metHb) in the blood. Methemoglobin is a form of hemoglobin that does not bind oxygen. When its concentration is elevated in red blood cells, anemia and tissue hypoxia can occur.
Due to a deficiency of the enzyme diaphorase I (NADH methemoglobin reductase), methemoglobin levels rise and the blood of met-Hb sufferers has reduced oxygen-carrying capacity. Instead of being red in colour, the arterial blood of met-Hb sufferers is brown. This results in skin of white sufferers gaining a bluish cast. Hereditary met-Hb is caused by a recessive gene. If only one parent has this gene, offspring will have normal-hued skin, but, if both parents carry the gene there is a chance the offspring will have blue-hued skin.
Another cause of congenital methemoglobinemia is seen in patients with abnormal hemoglobin variants such as hemoglobin M (HbM), or hemoglobin H (HbH), which are not amenable to reduction despite intact enzyme systems.
Methemoglobinemia can also arise in patients with pyruvate kinase deficiency due to impaired production of NADH - the essential cofactor for diaphorase I. Similarly, patients with Glucose-6-phosphate dehydrogenase (G6PD) deficiency may have impaired production of another co-factor, NADPH.
Methemoglobinemia (methaemoglobinaemia) can also be acquired. The protective enzyme systems normally present in red blood cells maintain methemoglobin levels at less than one percent of the total hemoglobin in healthy people. Exposure to exogenous oxidizing drugs and their metabolites (such as benzocaine, dapsone and nitrates) may accelerate the rate of formation of methemoglobin up to one-thousandfold, overwhelming the protective enzyme systems and acutely increasing methemoglobin levels. Other classical drug causes of methemoglobinaemia include antibiotics (trimethoprim, sulphonamides and dapsone), local anaesthetics (especially articaine and prilocaine), and others such as aniline dyes, metoclopramide, chlorates and bromates. Ingestion of compounds containing nitrates (such as the patina chemical bismuth nitrate) can also cause methemoglobinemia.
Infants under 6 months of age are particularly susceptible to methemoglobinemia caused by nitrates ingested in drinking water, dehydration usually caused by gastroenteritis with diarrhea, sepsis and topical anesthetics containing benzocaine or prilocaine. Nitrates that are used in agricultural fertilizers leaked into the ground and may contaminate well water. The current EPA standard of 10 ppm nitrate-nitrogen for drinking water is specifically designed to protect infants.
Severe methemoglobinemia (methemoglobin >50%) patients have dysrhythmias, seizures, coma and death. Healthy people may not have many symptoms with methemoglobin levels < 15%, however patients with co-morbidities such as anemia, cardiovascular disease, lung disease, sepsis, or presence of other abnormal hemoglobin species (e.g. carboxyhemoglobin, sulfehemoglobin or sickle hemoglobin) may experience moderate to severe symptoms at much lower levels (as low as 5-8%).
The 'blue men of Lurgan' were a pair of Lurgan men suffering from what was described as 'familial idiopathic methaemoglobinaemia' who were treated by Dr. James Deeny in 1942. Deeny, who would later become the Chief Medical Officer of the Republic of Ireland, prescribed a course of ascorbic acid and sodium bicarbonate. In case one, by the eighth day of treatment there was a marked change in appearance and by the twelfth day of treatment the patient's complexion was normal. In case two, the patient's complexion reached normality over a month-long duration of treatment.