Hemoglobin (Hb) is the oxygen-carrying
protein within red blood cells (RBCs). It is composed of four globular
protein subunits, called globins, and four oxygen-binding
heme groups, which are attached to each globin. The two main types
of globins are the α-globins and the β-globins, which
are made in essentially equivalent amount in precursors of RBCs.
Normal adult Hb (Hb A) has two α-globins and two β-globins
(α2 β2). Genes
on chromosomes 16 and 11 encode the α- and β-globins,
respectively. There are also distinct embryonic, fetal, and minor
adult analogs of the α- and β-globins,
all of which are encoded by separate genes. Most important among
these are the γ- and δ-globins,
which are the fetal and minor adult analogs of α-
and β-globin, respectively. See Chapter 429 for a discussion of the developmental changes in Hb production.
Disorders of Hb can be classified as qualitative or quantitative
disorders. Qualitative abnormalities of Hb arise from mutations
that change the amino acid sequence of the globin, thereby producing
structural and functional changes in the Hb. There are four ways
in which Hb can be qualitatively abnormal: (1) decreased solubility, (2)
instability, (3) altered oxygen affinity, and (4) altered oxidation
state of the heme-coordinated iron. Qualitative Hb disorders are
often referred to as hemoglobinopathies, even though the term can
technically apply to both qualitative and quantitative disorders.
Quantitative Hb disorders result from the decreased and imbalanced production
of generally structurally normal globins. For example, if β-globin
production is diminished by a mutation, there will be a relative
excess of α-globins. Such imbalanced production
of α- and β-globins damages RBCs
and their precursors in the bone marrow. These quantitative Hb disorders are
called thalassemias. Both qualitative and quantitative disorders
of Hb can be subdivided by the particular globin that is affected;
for example, there can be α-thalassemias and β-hemoglobinopathies.
We begin this chapter with a review of several of the common qualitative
Hb disorders and end with a discussion of the thalassemias.
Sickle cell disease (SCD) is the name for a group of related
disorders caused by sickle Hb (Hb S).1 Hb S is
a qualitatively abnormal Hb caused by a point mutation of the β-globin gene. The
sixth codon of the normal β-globin gene, GAG,
codes for glutamic acid. In Hb S, the adenine nucleotide is replaced by
thymidine, producing GTG,
which is a codon for valine. This mutation replaces a hydrophilic glutamic
acid with a hydrophobic valine, permitting abnormal hydrophobic
interactions between adjacent deoxyhemoglobin molecules. This change
decreases the solubility of Hb S in the deoxygenated state. Thus,
as sickle red blood cells (RBCs) traverse the circulation, cycling
through oxygenated and deoxygenated states, Hb S repeatedly forms
rigid polymers that damage the RBC membrane, causing a hemolytic
anemia and, ultimately, the manifestations of SCD.
Sickle cell trait, the heterozygous or carrier state for the ...