Oxidation of the heme iron in hemoglobin from Fe2+ to Fe3+ produces methemoglobin, which cannot bind O2. This oxidation may be acquired and caused by the action of certain drugs, such as nitrates, or endogenous products such as reactive oxygen species (see p. 148). The oxidation may also result from congenital defects, for example, a deficiency of NADH-cytochrome b5 reductase (also called NADH-methemoglobin reductase), the enzyme responsible for the conversion of methemoglobin (Fe3+) to hemoglobin (Fe2+), leads to the accumulation of methemoglobin (Fig. 3.22). [Note: The RBC of newborns have approximately half the capacity of those of adults to reduce methemoglobin.] Additionally, rare mutations in the α-or β-globin chain can cause the production of HbM, an abnormal hemoglobin that is resistant to the reductase. The methemoglobinemias are characterized by “chocolate cyanosis” (a blue coloration of the skin and mucous membranes and brown-colored blood) as a result of the dark-colored methemoglobin. Symptoms are related to the degree of tissue hypoxia and include anxiety, headache, and dyspnea. In rare cases, coma and death can occur. Treatment is with methylene blue, which is oxidized as Fe3+ is reduced.
E. Thalassemias
The thalassemias are hereditary hemolytic diseases in which an imbalance occurs in the synthesis of globin chains. As a group, they are the most common single-gene disorders in humans. Normally, synthesis of the αand β-globin chains is coordinated, so that each α-globin chain has a βglobin chain partner. This leads to the formation of α2β2 (HbA). In the thalassemias, the synthesis of either the α-or the β-globin chain is defective, and hemoglobin concentration is reduced. A thalassemia can be caused by a variety of mutations, including entire gene deletions, or substitutions or deletions of one of many nucleotides in the DNA. [Note: Each thalassemia can be classified as either a disorder in which no globin chains are produced (α0-or β0-thalassemia), or one in which some chains are synthesized but at a reduced level (α+-or β+-thalassemia).] 1.