Clinical Information

Methemoglobin:

Methemoglobin forms when the hemoglobin (Hb) molecule iron is in the ferric (Fe3[+]) form instead of the functional ferrous (Fe2[+]) form. Methemoglobinemia can be hereditary or acquired and is present by definition when methemoglobin levels are greater than the normal range. Acquired methemoglobinemia results after toxic exposure to nitrates and nitrites/nitrates (fertilizer, nitric oxide), topical anesthetics (“caines"), dapsone, naphthalene (moth balls/toilet deodorant cakes), and industrial use of aromatic compounds (aniline dyes).

Congenital methemoglobinemias are rare. They are due either to:

-A deficiency of cytochrome b5 reductase (methemoglobin reductase) in erythrocytes, an autosomal recessive disorder resulting from genetic variants in either CYB5R3 or CYB5A.(1,2) Type IV is thought to be extraordinarily rare. Type III is no longer a category.

-One of several intrinsic structural disorders of Hb, called M-Hbs; all of which are inherited in an autosomal dominant manner.(3,4) Classically, M-Hbs result from histidine-to tyrosine substitutions at the proximal or distal histidine important in coordinating the oxygen molecule. These include alpha-, beta- and gamma-chain variants. Rarely, other substitutions outside the proximal and distal histidine location can cause Hb variants that increase methemoglobin or sulfhemoglobin levels. Most M-Hb variants are readily identified by high performance liquid chromatography (HPLC) or mass spectrometry methods with characteristic electrophoresis patterns; however, some require more specialized techniques. Most are associated with increased methemoglobin with or without an increase in sulfhemoglobin. Alpha chain M-Hb variants can be associated with increased sulfhemoglobin without an increase in methemoglobin.

Sulfhemoglobin:

Sulfhemoglobin cannot combine with oxygen. When acquired, sulfhemoglobinemia can be associated with cyanosis and often accompanies methemoglobinemia. Sulfhemoglobinemia has been associated with exposure to sumatriptan, sulfonamides, metoclopramide, paint or varnish vapors, dimethyl sulfoxide, acetanilide, phenacetin, trinitroluene, zinc ethylene bisdithiocarbamate (a fungicide), and flutamide. It is important to note that some Hb variants are known to interfere with this test (especially M-Hbs) and sulfhemoglobin absorbance can be increased due to the Hb variant. Hb evaluation that includes the HPLC method is recommended to exclude this possibility.

In contrast to methemoglobinemia, sulfhemoglobinemia persists until the erythrocytes containing it are destroyed. Therefore, blood level of sulfhemoglobin declines gradually over a period of weeks.