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chapter 29
Metabolism of Iron and Heme
satisfactory; however, sometimes parenteral therapy is pre-
ferred, e.g., in proven malabsorption problems, gastroin-
testinal disease and excessive blood loss, and for patients
who cannot be relied on to take oral medication.
Iron-Storage Disorders
A type of iron storage disorder characterized by general
increase in tissue iron levels without damage to parenchy-
mal cells is known as
hemosiderosis.
Hemosiderin is
a storage form of iron in which ferric hydroxide is
present as micelles. It appears as insoluble granules that
contain denatured aggregated ferritin, nonferritin pro-
teins, lipids, heme, and other pigments. Hemosiderosis
results when iron is present in excessive quantities in
a diet that permits maximum iron absorption. For ex-
ample, the African Bantu eat a diet high in corn (low
in phosphate) cooked in iron pots, drink an indige-
nous beer brewed in iron pots, and suffer from
Bantu
siderosis.
Hemosiderosis can progress to
hemochro-
matosis
with hepatic cirrhosis and diabetes mellitus.
H2N — (C H 2)6— N — C — (C H 2)2—
1
II
HO
0
Excessive accumulation of iron (chronic iron overload)
can result from the following.
1. Defective erythropoiesis (dyserythropoiesis);
impaired hemoglobin synthesis leading to lack of
utilization and consequent accumulation of iron in
mitochondria, e.g., from inhibition of ALA synthase
activity by dietary vitamin B
6
deficiency; inhibition of
heme synthesis by lead; impairment of pyridoxine
metabolism in alcoholic patients; familial
sideroblastic anemias; and
Cooley’s anemia.
2. Repeated blood transfusions, e.g., in Cooley’s anemia
or sickle cell disease.
3. Hereditary hemochromatosis, an autosomal recessive
defect in which there is increased rate of absorption of
iron in the presence of normal or enlarged iron stores
and normal hematopoiesis (discussed later).
4. High dietary iron and substances that enhance its
absorption (e.g., Bantu siderosis).
5. Hereditary atransferrinemia.
In all of these disorders, the gastrointestinal tract can-
not limit absorption of iron to significant extent. Thus,
the “mucosal block” responsible for keeping out un-
needed iron on a daily basis is susceptible to disruption,
perhaps at more than one point. Iron overload leads to
progressive deterioration in pancreatic, hepatic, gonadal,
and cardiac function. Clinical manifestations include cir-
rhosis, diabetes mellitus, life-threatening arrhythmias, and
intractable heart failure. Removal of excess iron produces
clinical improvement, particularly of diabetes and conges-
tive heart failure.
In iron storage diseases accompanied by normal ery-
thropoiesis (e.g., hereditary hemochromatosis), removal
of excessive iron is accomplished by repeated bloodlet-
ting (phlebotomy). Therapeutic phlebotomy of a unit of
blood (which contains about 250 mg of iron) may be per-
formed up to three times per week. When the iron stores
become depleted, reaccumulation of iron is prevented by
four to six phlebotomies per year. In asymptomatic pa-
tients, periodic determination of serum ferritin provides a
measure of storage of iron.
In hemochromatosis secondary to refractory anemias
(e.g., Cooley’s anemia, sickle cell anemia), patients re-
quire repeated blood transfusions to survive childhood
and adulthood. Therapy consists of administration of iron-
chelating agents. Deferoxamine, an iron chelator isolated
from
Streptomyces pilosis,
has the structure:
:— N — (C H 2)5— N — C — (C H 2)2— C — N — (C H 2)5— N — C — C H 3
I
I
II
II
I
I
II
I
H
H O
0
O
H
HO
0
It contains six nitrogen atoms separated by fairly long,
flexible stretches of methylene groups. Since each iron
atom can bind six ligands, one molecule of deferoxamine
is probably capable of occupying all six coordination sites
and producing a
1 : 1
iron-deferoxamine complex.
For ferric iron, the
K
assoc of deferoxamine is about 1030,
while the A
'assoc for Ca2+ is about 102. Iron in hemopro-
teins is not affected by this agent, while the ferric iron of
ferritin and hemosiderin is chelated in preference to that
found in transferrin. Such selectivity makes the compound
useful in treatment of iron storage problems and acute iron
poisoning.
The deferoxamine-iron complex is excreted in urine.
(Iron is not normally excreted by this route.)
Deferoxamine given orally complexes with dietary iron,
making the drug and the iron unavailable for absorption.
The preferred route of administration is by intramuscular
injection. Irritation and pain at the site of administration
and the need for daily injections make the treatment un-
popular. In addition, even with coadministration of large
amounts of ascorbic acid, the iron loss produced is far be-
low that necessary to remove all of the iron accumulated
during chronic transfusion therapy.
Slow, continuous intravenous infusion or continuous
subcutaneous administration may be more effective in
