Page 46 - Color Atlas Of Pathophysiology (S Silbernagl Et Al, Thieme 2000)

Anemias Due to Disorders of Hemoglobin Synthesis
Erythrocytes (RBCs) serve to transport O 2 and way that results in sickle-shaped erythrocytes
CO 2 and also as a buffer. Hemoglobin (Hb) is es- (→ A). These sickle cells cannot be further de-
sential for all three functions. It is composed of formed and get stuck inside the capillaries,
four subunits (2α, 2β in HbA; see below), each causing occlusion of smaller blood vessels. Ag-
of which is formed from three components: gregation of HbS takes a few minutes so that
2+
protoporphyrin, iron (Fe ) and globin (α or β). it is especially those capillaries through which
When Fe 2+ is built into protoporphyrin, heme the blood flows slowly which are affected
is formed. If there is a deficiency or defect in (spleen; vasa recta of the renal medulla;
one of the components, Hb synthesis is im- → p.106). If blood flow is slowed in general
paired. In this case the RBCs are usually small (shock) or if hypoxia occurs (at high altitude,
(MCV↓) and their Hb content decreased during a flight, anesthesia), the abnormalities
(MCH↓) (microcytic hypochromic anemia). can spread to other organs (e.g., to the heart).
Disorders of protoporphyrin synthesis are Occlusion of the blood vessels further slows
due to inherited enzyme defects (→ p. 254), as down blood supply in the affected regions and
for example, in hereditary sideroblastic anemia, the Po 2 is further reduced, so that a vicious cir-
in which the formation of δ-aminolevulinic cle results (crisis). Sickle cell anemia occurs
acid (δ-ALA) from glycine and succinyl-CoA is nearly exclusively in blacks who themselves,
reduced, and thus also heme synthesis or whose forbears, come from regions of Cen-
Blood (→ A1). Heme inhibits δ-ALA synthase in a tral Africa with a high prevalence of malaria.
“Survival” of the defective gene in 40% of the
negative feedback loop. If heme concentration
3 is now reduced, inhibition of the enzyme is re- population in Central Africa, despite the fact
versed and, despite the defect, sufficient that until recently the disease was fatal in
amounts of heme are formed. Defects in sub- homozygous children, can be explained by the
sequent enzymes lead to an increase in the fact that heterozygous gene carriers are pro-
concentration of intermediary products. While tected against the dangerous forms of malaria
the rate of heme production is thus increased, (selective advantage).
these metabolites cause other disorders, In β-thalassemia the production of β-chains
namely porphyrias (→ p. 254). is restricted, thus leading to a deficiency of
Disorders of globin synthesis. Normally Hb HbA. It can be only partly compensated by an
is made up of 2 α chains of 141 amino acids increased production of HbA 2 and HbF. The in-
each and 2 β chains of 146 amino acids corporation of Fe 2+ is diminished so that it re-
(HbA 1 = HbAα 2 β 2 ). Only 2–3% of Hb contains mains in the erythrocytes (sideroachresia) and
so-called δ-chains (HbA 2 = Hbα 2 δ 2 ) instead of may accumulate excessively in the body (sec-
the β-chains. Before birth a form of Hb is ondary hemochromatosis; → p. 252). Although
formed that has a higher O 2 affinity (adapta- the RBCs’ osmotic resistance (→ p. 40) is actu-
tion to a lower Po 2 in the placenta). This fetal ally increased, their mechanical vulnerability
Hb (HbF) contains so-called γ-chains (Hbα 2 γ 2 ) is increased (rapid breakdown in the spleen,
instead of the β-chains. early hemolysis). While the heterozygous
The properties of Hb (solubility, O 2 affinity, form (T. minor) causes few symptoms, the
oxidizability, etc.) are dependent upon the par- homozygous form (T. major) may be fatal even
ticular amino acid sequence. However, most of before puberty. The rare α-thalassemia usually
the over 300 genetically-determined Hb var- causes death of the fetus, because without α-
iants which have been indentified so far do chains no HbF can be formed either. Hbγ 4 , pro-
not signficantly impair function. On the other duced in the fetus, and Hbβ 4 , occurring postna-
hand, even a single “false” amino acid (valine tally, are apparently inadequate substitutes for
instead of glutamate in position 6 in the β- the normal Hb forms.
chain = HbS; → A2) can lead to extensive func-
tional disorders, as seen in sickle cell anemia,
36 which is caused by a homozygous gene defect.
In the deoxygenated form, HbS aggregates in a
Silbernagl/Lang, Color Atlas of Pathophysiology © 2000 Thieme
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