Chapter 099. Disorders of Hemoglobin (Part 1) pptx

Chapter 099. Disorders of
Hemoglobin
(Part 1)

Harrison's Internal Medicine > Chapter 99. Disorders of Hemoglobin
Disorders of Hemoglobin: Introduction
Hemoglobin 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 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 α
2β2
. HbF (α
2
β
2
) predominates
during most of gestation, and HbA
2
(α
2
δ
2
) is minor adult hemoglobin. Embryonic

hemoglobins need not be considered here.
Figure 99-1


The globin genes. The α-like genes (α,s) are e
ncoded on chromosome 16;
the β-
like genes (β,γ,δ,ε) are encoded on chromosome 11. The s and ε genes
encode embryonic globins.


Each globin chain enfolds a single heme moiety, consisting of a
protoporphyrin IX ring complexed with a single iron atom in the ferrous state
(Fe
2+
). Each heme moiety can bind a single oxygen molecule; a molecule of
hemoglobin can transport up to four oxygen molecules.
The amino acid sequences of the various globins are highly homologous to
one another. Each has a highly helical secondary structure. Their globular tertiary
structures can cause the exterior surfaces to be rich in polar (hydrophilic) amino
acids that enhance solubility and the interior to be lined with nonpolar groups,
forming a hydrophobic pocket into which heme is inserted. The tetrameric
quaternary structure of HbA contains two αβdimers. Numerous tight interactions
(i.e., α
1
β
1
contacts) hold the αand βchains together. The complete tetramer is held
together by interfaces (i.e., α
1

β
2
contacts) between the α-like chain of one dimer
and the non-α chain of the other dimer.
The hemoglobin tetramer is highly soluble but individual globin chains are
insoluble. Unpaired globin precipitates, forming inclusions that damage the cell.
Normal globin chain synthesis is balanced so that each newly synthesized α or
non-α globin chain will have an available partner with which to pair.
Solubility and reversible oxygen binding are the key properties deranged in
hemoglobinopathies. 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 α
1
β
1
and α
1
β
2
contact points. Mutations in these
strategic regions tend to be the ones that alter clinical behavior.

Function of Hemoglobin
To support oxygen transport, hemoglobin must bind O
2
efficiently at the
partial pressure of oxygen (P
O2
) of the alveolus, retain it, and release it to tissues at
the P

O2
of tissue capillary beds. Oxygen acquisition and delivery over a relatively
narrow range of oxygen tensions depend on a property inherent in the tetrameric
arrangement of heme and globin subunits within the hemoglobin molecule called
cooperativity or heme-heme interaction.
At low oxygen tensions, the hemoglobin tetramer is fully deoxygenated
(Fig. 99-2). Oxygen binding begins slowly as O
2
tension rises. However, as soon
as some oxygen has been bound by the tetramer, an abrupt increase occurs in the
slope of the curve. Thus, hemoglobin molecules that have bound some oxygen
develop a higher oxygen affinity, greatly accelerating their ability to combine with
more oxygen. This S-shaped oxygen equilibrium curve (Fig. 99-2), along which
substantial amounts of oxygen loading and unloading can occur over a narrow
range of oxygen tensions, is physiologically more useful than the high-affinity
hyperbolic curve of individual monomers.