Chapter 18: Methemoglobinemia and Other Dyshemoglobinemias

DEFINITION

• Increased methemoglobin from a baseline of less than 1% occurs due to oxidation of ferro to ferric iron of hemoglobin from environmental agents or due to underlying germline mutations causing diminished reduction of methemoglobin to hemoglobin. Cyanosis is almost always seen.

• Dyshemoglobinemia is a term used for modified hemoglobins (eg, methemoglobin, carboxyhemoglobin, nitrosohemoglobin, and sulfhemoglobin) that are associated with normal amino acid sequence of hemoglobin tetramers; however in M hemoglobins the globins are mutated changing amino acid in hemoglobin tetramers. They can result in varying degree of clinical manifestations.

METHEMOGLOBINEMIA

Toxic Methemoglobinemia

• Drugs or chemicals may cause methemoglobinemia either by oxidizing hemoglobin directly or by enhancing its oxidization by molecular oxygen.

• Table 18–1 lists common agents that cause methemoglobinemia.

• Infants are more susceptible to acquired toxic methemoglobinemia after prototypical ingestion of well water containing nitrites because of low levels of an enzyme that converts methemoglobin to hemoglobin (cytochrome b₅ reductase) in the newborn period. A syndrome of diarrhea, acidosis, and methemoglobinuria of yet unexplained etiology can be seen in infancy.

• Severe acute methemoglobinemia impairs oxygen delivery, and levels exceeding 30% can be fatal.

• Chronic methemoglobinemia is usually asymptomatic, but at levels greater than 20%, mild erythrocytosis is often present.

• Treatment with intravenous methylene blue (given at 1 to 2 mg/kg over 5 minutes) is rapidly effective. Excessive amounts of methylene blue, or its use in patients with glucose-6-phosphate dehydrogenase deficiency, can cause acute hemolysis.

Cytochrome b₅ Reductase Deficiency

• Cytochrome b₅ reductase (also known as reduced nicotinamide [NADH] diaphorase) catalyzes the reduction of cytochrome b₅, which, in turn, reduces methemoglobin to hemoglobin.

• Heterozygosity for cytochrome b₅ reductase deficiency are usually not clinically significant but may predispose to toxic methemoglobinemia.

• Homozygosity of cytochrome b₅ reductase deficiency leads to methemoglobinemia and if restricted to erythrocytes, cyanosis is the only phenotype (type I cytochrome b₅ reductase deficiency). This is seen sporadically in all racial groups but is reported to be endemic in native Siberian ethnic groups of Yakutsk region, Navajo Indians, and Athabascan natives of Alaska.

• In some subjects, cytochrome b₅ reductase mutations are seen in all cells (not restricted to erythrocytes), and a less common hereditary syndrome of cyanosis with mental retardation and other developmental defects may occur (type II cytochrome b₅ reductase deficiency).

• Methemoglobin levels vary between 8% and 40%, and the cytochrome b₅ reductase level is less than 20% of normal.

• Treatment with ascorbic acid (200 to 600 mg/d orally, divided into four ...