Congenital Methemoglobinemias and Cyanosis
Cyanosis is a bluishcoloration of the skin caused by the
presence of more than 5 g of deoxyhemoglobin or methe-
moglobin per deciliter of blood in the subcutaneous cap-
illary beds. It occurs in severe cardiopulmonary disease
from poor oxygenation of normal hemoglobin or methe-
moglobin production. An extremely rare cause of cyanosis
is the presence of a hemoglobin variant with very low oxy-
gen affinity (e.g., Hb Kansas, Hb Beth Israel).
Two groups of genetic defects can cause methe-
1. Defects in oxidoreductase in erythrocytes
(methemoglobin reductase, glutathione reductase,
-phosphate dehydrogenase; Chapter 15).
Patients who have these defects usually are not
cyanotic unless subjected to oxidative stress (e.g.,
treatment with primaquine or sulfonamide).
2. Defects in which substitution of an amino acid in the
region of the heme pocket increases the stability of
Fe3+ in the heme group and produces
methemoglobin. Although heme oxidation occurs in
several unstable hemoglobins, cyanosis is principally
a manifestation of the Hbs M (Table 28-5). Since a
single mutation can affect only one type of subunit
(a or
), half of each tetramer is normal. Most of
these hemoglobins undergo reduced T-to-R
transitions but with more difficulty. In addition, since
only heterozygotes, for the Hbs M have been
identified, half the tetramers are normal, and the
carriers have no functional impairment. Cyanosis is
visible because only 1.5-2 g of methemoglobin are
needed to produce the same degree of discoloration as
5 g of deoxyhemoglobin. Diagnosis of patients with
Hbs M is important because of the seriousness of the
alternative causes of cyanosis.
Hemoglobin S and Sickling Disorders
The most common, severe, and best studied hemoglobin
mutation is HbS, which causes sickle cell anemia (or dis-
ease) in homozygous individuals and sickle cell trait in het-
erozygous individuals. The characteristic change in shape
of erythrocytes from biconcave disk to curved and sickle-
like occurs at low oxygen pressures. Carriers of sickle
cell trait are asymptomatic, since their red cells do not
sickle unless the Po
drops below about 25 mm Hg; this
happens only under unusual circumstances, such as unas-
sisted breathing at high altitudes, some severe forms of
pneumonia, and occasionally during anesthesia.
The symptoms of sickle cell anemia are due to seques-
tration and destruction of the abnormal, sickled erythro-
cytes in the spleen and to the inability of many sickled
cells to pass through capillaries. The normal life span of
days for red blood cells is decreased to
Painful vaso-occlusive crises can occur anywhere in the
body and are the major complication in sickle cell ane-
mia. These crises are caused by blockage of capillaries
in the affected tissue by the deformed red cells, which
causes hemostasis, anoxia, further sickling, and eventu-
ally infarction. Increased adhesion of sickled erythrocytes
to capillary endothelial cells may also contribute to cap-
illary obstruction. Crises occur only when the circulation
slows or hypoxia is present because the normal circula-
tory rate does not keep cells deoxygenated for the ap-
proximately 15 seconds required for sickling to begin.
In contrast to the splenomegaly usually seen in chronic
hemolytic anemias, a small, fibrous spleen is usually seen
in adults with sickle cell anemia. This autosplenectomy
is due to repeated infarction of the spleen. The clinical
complications of sickle cell disease are highly variable.
The severe forms of the disease occur in homozygous SS
disease and S//T-thalassemia and a milder disease occurs
in double heterozygous SC disease and S//I -thalassemia.
Patients who have a concurrent a-thalassemia trait or high
HbF levels have a mild course of the SS disease. The lat-
ter observation has been utilized in the pharmacological
approaches that raise HbF levels (discussed later).
Some of the clinical consequences in SS disease include
megaloblastic erythropoiesis, aplastic crisis, stroke, bone
pain crisis, proneness to infection particularly by
mococcus, Salmonella,
due to hypos-
plenism and acute chest syndrome. Prophylactic use of
penicillin and antipneumococcal and
cines has aided in the management of life-threatening in-
fectious complications of SS disease. Neonatal screening
has been used in the identification of infants with sickle cell
disease so that risk of infection can be modulated by ap-
propriate immunizations and penicillin prophylaxis. The
acute chest syndrome characterized by chest pain is due to
clogged pulmonary capillaries; in a small number of stud-
ies, patients have been treated with inhaled nitric oxide,
which dilates blood vessels with clinical improvement.
Sickle cell trait is present in about
% of black
Americans and to a much greater extent (as high as 45%)
in some black African populations. The homozygous con-
dition causes considerable morbidity and about 60,000-
80,000 deaths per year among African children. HbS also
occurs in some parts of India, the Arabian region, and
occasionally in the Mediterranean area. The HbS muta-
tion that occurs in eastern Saudi Arabia and India, known
as the Asian haplotype, has different flanking DNA se-
quences surrounding the /1-globin locus. Thus, the Asian
haplotype may represent an independent occurrence of
the HbS mutation that is distinct from its African coun-
terpart. The deleterious gene likely has persisted in these
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