Chapter 099. Disorders of Hemoglobin (Part 1)

Harrisons Internal Medicine Chapter 99. Disorders of HemoglobinDisorders of Hemoglobin: IntroductionHemoglobin is critical for normal oxygen delivery to tissues; it is also present in erythrocytes in such high concentrations that it can alter red cell shape, deformability, and viscosity. Hemoglobinopathies are disorders affecting the structure, function, or production of hemoglobin. These conditions are usually inherited and range in severity from asymptomatic laboratory abnormalities to death in utero. Different forms may present as hemolytic anemia, erythrocytosis, cyanosis, or vasoocclusive stigmata.Hemoglobin StructureDifferent hemoglobins are produced during embryonic, fetal, and adult life (Fig. 99-1). ...
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Chapter 099. Disorders of Hemoglobin (Part 1) Chapter 099. Disorders of Hemoglobin (Part 1) Harrisons Internal Medicine > Chapter 99. Disorders of Hemoglobin Disorders of Hemoglobin: Introduction Hemoglobin is critical for normal oxygen delivery to tissues; it is alsopresent in erythrocytes in such high concentrations that it can alter red cell shape,deformability, and viscosity. Hemoglobinopathies are disorders affecting thestructure, function, or production of hemoglobin. These conditions are usuallyinherited and range in severity from asymptomatic laboratory abnormalities todeath in utero. Different forms may present as hemolytic anemia, erythrocytosis,cyanosis, or vasoocclusive stigmata. Hemoglobin Structure Different hemoglobins are produced during embryonic, fetal, and adult life(Fig. 99-1). Each consists of a tetramer of globin polypeptide chains: a pair of α-like chains 141 amino acids long and a pair of β-like chains 146 amino acids long.The major adult hemoglobin, HbA, has the structure α2β2. HbF (α2β2) predominatesduring most of gestation, and HbA2 (α2δ2) is minor adult hemoglobin. Embryonichemoglobins need not be considered here. Figure 99-1 The globin genes. The α-like genes (α,s) are encoded on chromosome 16;the β-like genes (β,γ,δ,ε) are encoded on chromosome 11. The s and ε genesencode embryonic globins. Each globin chain enfolds a single heme moiety, consisting of aprotoporphyrin IX ring complexed with a single iron atom in the ferrous state(Fe2+). Each heme moiety can bind a single oxygen molecule; a molecule ofhemoglobin can transport up to four oxygen molecules. The amino acid sequences of the various globins are highly homologous toone another. Each has a highly helical secondary structure. Their globular tertiarystructures can cause the exterior surfaces to be rich in polar (hydrophilic) aminoacids that enhance solubility and the interior to be lined with nonpolar groups,forming a hydrophobic pocket into which heme is inserted. The tetramericquaternary structure of HbA contains two αβdimers. Numerous tight interactions(i.e., α1β1 contacts) hold the αand βchains together. The complete tetramer is heldtogether by interfaces (i.e., α1β2 contacts) between the α-like chain of one dimerand the non-α chain of the other dimer. The hemoglobin tetramer is highly soluble but individual globin chains areinsoluble. Unpaired globin precipitates, forming inclusions that damage the cell.Normal globin chain synthesis is balanced so that each newly synthesized α ornon-α globin chain will have an available partner with which to pair. Solubility and reversible oxygen binding are the key properties deranged inhemoglobinopathies. Both depend most on the hydrophilic surface amino acids,the hydrophobic amino acids lining the heme pocket, a key histidine in the F helix,and the amino acids forming the α1β1 and α1β2 contact points. Mutations in thesestrategic regions tend to be the ones that alter clinical behavior. Function of Hemoglobin To support oxygen transport, hemoglobin must bind O 2 efficiently at thepartial pressure of oxygen (PO2) of the alveolus, retain it, and release it to tissues atthe PO2 of tissue capillary beds. Oxygen acquisition and delivery over a relativelynarrow range of oxygen tensions depend on a property inherent in the tetramericarrangement of heme and globin subunits within the hemoglobin molecule calledcooperativity or heme-heme interaction. At low oxygen tensions, the hemoglobin tetramer is fully deoxygenated(Fig. 99-2). Oxygen binding begins slowly as O2 tension rises. However, as soonas some oxygen has been bound by the tetramer, an abrupt increase occurs in theslope of the curve. Thus, hemoglobin molecules that have bound some oxygendevelop a higher oxygen affinity, greatly accelerating their ability to combine withmore oxygen. This S-shaped oxygen equilibrium curve (Fig. 99-2), along whichsubstantial amounts of oxygen loading and unloading can occur over a narrowrange of oxygen tensions, is physiologically more useful than the high-affinityhyperbolic curve of individual monomers.