section 29.1
Iron Metabolism
681
indirectly from the maximum (or total) iron binding ca-
pacity (TIBC) of plasma (reference range for adults,
25(M-00 /ig/dL). It can also be measured directly by
immunological
methods (reference range for adults,
220-400 mg/dL).
Hypertransferrinemia
(or increased
TIBC) can occur with diminished body iron stores as in
iron deficiency anemia or during pregnancy (because of
enhanced mobilization of storage iron to supply mater-
nal and fetal demands). Hypertransferrinemia of iron defi-
ciency is corrected by oral iron supplementation, whereas
that due to pregnancy is not. Exogenous administra-
tion of estrogens (e.g., oral contraceptives) also causes
hypertransferrinemia.
Hypotransferrinemiacan
result from protein malnutri-
tion and accompanies hypoalbuminemia. Since transfer-
rin has a much shorter half-life
( 8
days) than albumin
(19 days), measurement of the transferrin level may be
a more sensitive indicator of protein malnutrition than al-
bumin measurement (see also chapter 17). Hypotransfer-
rinemia also results from excessive renal loss of plasma
proteins (e.g., in nephrotic syndrome).
Disorders of Iron Metabolism
Iron Deficiency Anemia
Iron deficiency anemia
is the most prevalent nutritional
disorder. Its cause may comprise many overlapping fac-
tors: dietary iron deficiency; absence of substances that
favor iron absorption (ascorbate, amino acids, succinate);
presence of compounds that limit iron absorption (phy-
tates, oxalates, excess phosphates, tannates); lack of iron
absorption due to gastrointestinal disorders (malabsorp-
tion syndrome, gastrectomy); loss of iron due to menstru-
ation, pregnancy, parturition, lactation, chronic bleeding
from the gastrointestinal tract peptic ulceration, hemor-
rhoids, cancer, colonic ulceration, or hookworm infesta-
tion or the genitourinary tract (uterine fibroids); enhanced
demand for growth or new blood formation; deficiency
of iron transport from mother to fetus; abnormalities in
iron storage; deficiencies in release of iron from the retic-
uloendothelial system (infection, cancer); inhibition of
incorporation of iron into hemoglobin (lead toxicity); and
rare genetic conditions (transferrin deficiency, impaired
cellular uptake of iron by erythroid precursors).
In the initial phase of depletion of the iron content of the
body, the iron stores maintain normal levels of hemoglobin
and of other iron proteins. With exhaustion of stor-
age iron, hypochromic and microcytic anemia becomes
manifest.
The clinical characteristics of iron deficiency anemia are
nonspecific and include pallor, rapid exhaustion, muscular
weakness, anorexia, lassitude, difficulty in concentrating,
headache, palpitations, dyspnea on exertion, angina on
effort, peculiar craving for unnatural foods (pica), ankle
edema, and abnormalities involving all proliferating tis-
sues, especially mucous membranes and the nails. The
onset is insidious and may progress slowly over many
months or years.
Physiological adjustments take place during the grad-
ual progression of the disorder, so that even a severe
hemoglobin deficiency may produce few symptoms. Iron
deficiency may affect the proper development of the cen-
tral nervous system. Early childhood iron deficiency ane-
mia may lead to cognitive abnormalities.
Individuals who have
congenital atransferrinemia
lack
apotransferrin and suffer from severe hypochromic anemia
in the presence of excess iron stores in many body sites,
susceptibility to infection (transferrin inhibits bacterial,
viral, and fungal growth, probably by binding the iron re-
quired for growth of these organisms), and retardation of
growth. This condition does not respond to administration
of iron. Intravenous administration of transferrin normal-
izes the iron kinetics. A rare congenital defect in uptake of
iron by red cell precursors has been reported that leads to
severe hypochromic anemia with normal plasma iron and
transferrin levels.
Microcytic anemia occurs frequently in thalassemia
syndromes (Chapter 28), but these patients do not require
iron supplementation unless they have concurrent iron de-
ficiency as assessed by measurement of serum iron levels
and TIBC. Serum iron concentration exhibits a morning
peak and an evening nadir; this pattern is reversed in night-
shift workers. The circadian variation is primarily due to
differences in rate of release of iron by the reticuloen-
dothelial system. Transferrin levels do not show circadian
fluctuation. Iron deficiency anemia can also be assessed
from the plasma ferritin concentration (which when de-
creased reflects depleted iron stores), red cell protopor-
phyrin concentration (increased because of lack of con-
version to heme), and the number of sideroblasts in the
bone marrow (which parallels iron stores). Sideroblasts
are erythrocyte precursors (normoblasts) containing free
ferritin-iron granules in the cytoplasm that stain blue with
the Prussian blue reagent. There is a close correlation be-
tween plasma iron levels, TIBC, and the proportion of
sideroblasts in bone marrow. In hemolytic anemias, perni-
cious anemia, and hemochromatosis, the serum iron level
increases and sideroblast number reaches 70% (normal
range, 30-50% of total cells). In iron deficiency, the sider-
oblasts are decreased in number or absent.
Before treatment is initiated, the cause of the nega-
tive iron balance must be established. Treatment should
correct the underlying cause of anemia and improve the
iron balance. In general, oral therapy with ferrous salts is
