Methemoglobinemia is a condition in which the oxygen-carrying capacity of circulating hemoglobin is diminished, causing a functional anemia. This occurs when the iron molecule of the hemoglobin complex remains in an oxidized state and can't reversibly bind oxygen. There are two types of methemoglobinemia: congenital and acquired.

The congenital type is due to a deficiency of the enzyme NADH-cytochrome b5 reductase, which impairs the ability of hemoglobin to bind oxygen, leading to poor oxygenation of body tissues. Cyanosis and hypoxia result. Congenital methemoglobinemia is further subcategorized into erythrocyte type (type 1) and generalized type (type 2). In type 1 disease, the enzyme is deficient only in erythrocytes, which accounts for up to 80% of the congenital methemoglobinemias. Cyanosis and mild polycythemia are the only symptoms. In type 2 disease, the membrane-bound form of the enzyme is deficient, causing deficiency in all tissues, manifesting with severe developmental abnormalities, severe intellectual disability, neurologic impairment, and premature death, usually in the first year of life.

Acquired methemoglobinemia is the more common type and is usually caused by ingestion of or exposure to oxidizing agents that oxidize hemoglobin directly to methemoglobin, or to the free radical O2-, which in turn oxidizes hemoglobin to methemoglobin. Some drugs / toxins that cause methemoglobinemia include (but are not limited to) benzocaine, prilocaine, dapsone, nitric oxide, phenytoin, rifampin, silver nitrate, sulfasalazine, aniline, and aniline dyes, among others. Classic examples include patients exposed to benzocaine in the endoscopy suite and infants exposed to nitrite from well water. Severe methemoglobinemia secondary to intentional ingestion of toxic sodium nitrite levels can result in death. Of note, nitric oxide is produced at higher levels in patients with sepsis and therefore causes elevated levels of methemoglobin.

In addition to cyanosis and hypoxia, other signs and symptoms of methemoglobinemia include neurological changes (hyperkinetic movements, seizures, or quadriparesis), microcephaly, mental deficiency, poor feeding, and failure to thrive. It can be life threatening or lead to greatly reduced functionality and shortened life expectancy.