Methemoglobinemia pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Pathophysiology
Congenital methemoglobinemia
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 (thus making them "blue people"). 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), orhemoglobin 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.
Acquired/Toxic methemoglobinemia
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 andnitrates) 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 methaemoglobinaemia include antibiotics (trimethoprim, sulphonamides and dapsone), local anaesthetics (especially lignocaine and prilocaine), and others such as aniline dyes, metoclopramide, chlorates and bromates.
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.