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 due to environmental agents or due to underlying germline mutations causing diminished reduction of methemoglobin to hemoglobin. Cyanosis is seen when total methemoglobin exceeds 15 g/L; thus, at 10% of methemoglobin, those with hemoglobin concentrations above 150 g/L would have cyanosis, whereas those with hemoglobin below 150 g/L would not.

• 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 degrees 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 (cytochrome b₅ reductase) that converts methemoglobin to hemoglobin in the newborn period. A syndrome of diarrhea, acidosis, and methemoglobinemia 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 1–2 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.

• Methylene blue, given to patients taking serotonergic psychiatric medications for indications other than for treatment of methemoglobinemia, can cause toxicity referred to as serotonin syndrome (see https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-serious-cns-reactions-possible-when-methylene-blue-given-patients).

• Prior to methylene blue administration, ascertain that patients with acute methemoglobinemia do not take serotonergic psychiatric medications.

• Serotonin syndrome has not yet been reported in subjects receiving methylene blue for treatment of methemoglobinemia.

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 is usually not clinically significant but may predispose to toxic methemoglobinemia.

• Homozygosity or compound heterozygosity for 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, Athabascan natives of Alaska, and Puerto ...