section 29.1
Iron Metabolism
A diagrammatic representation of the transmembrane HFE protein. The extracellular portion of the HFE protein consists
of three
domains. The
}2-microglobulin is noncovalently associated with the
« 3
domain of HFE protein, stabilizing
its structure. The extracellular missense mutations H63D and C282Y are identified in patients with hereditary
hemochromatosis. HFE protein is involved in sensing circulating iron concentration and participates in the regulation of
gene expression of products involved in iron absorption, transport, or storage. [Reproduced with permission from: A
novel MHC class 1-like is mutated in patients with hereditary hemochromatosis. J. N.Feder, A. Gnirke, W. Thomas et al.
Nature G enetics
13, 399 (1996).]
of divalent metal ions, including Mn2+, Cu2+, Zn2+, Cd2+,
and Pb2+.
At normal levels of iron intake, absorption requires up-
take from the intestinal lumen by the mucosa and transfer
from the mucosa to the portal blood. Both events are in-
versely affected by the state of body iron stores. In iron
deficiency states, nonferrous metals such as cobalt and
manganese, which have an ionic radius similar to that of
iron and form octahedral complexes with six-coordinate
covalent bonds, also are absorbed at an increased rate.
Oral administration of a large dose of iron reduces (or
temporarily inhibits) the absorption of a second dose of
iron by the absorptive enterocytes even in the presence
of systemic iron deficiency. The mechanism of mucosal
block, which resists acquiring additional iron by the en-
terocytes with high amounts of intracellular iron, is not
yet understood. It probably involves set points established
in the enterocytes for iron recently consumed in the diet
(dietary regulator).
Iron absorption also is affected by erythropoiesis.
When erythropoiesis is accelerated by bleeding, hemol-
ysis, or hypoxia, iron absorption is increased. Conversely,
diminished erythropoiesis due to starvation, blood trans-
fusion, or return to sea level from a high altitude de-
creases iron absorption. How the size of body iron
stores and the rate of erythropoiesis transmit informa-
tion to the duodenum is not known. Feedback control
seems to be weak or absent, since in iron-deficient
subjects enhanced iron absorption continues long after
hemoglobin is restored to normal levels. Furthermore,
in chronic hemolytic anemia, iron absorption is in-
creased, persists for prolonged periods, and leads to iron
The need for dietary iron is ultimately determined by
the rate of iron loss from the body and the amount required
for maintenance and growth. Iron is tightly conserved once
it is absorbed. Its excretion is minimal and unregulated,
and facilitated by normal exfoliation from the surfaces of
the body (dermal, intestinal, pulmonary, urinary), loss of
blood by gastrointestinal bleeding, and loss in bile and
sweat. Insignificant amounts are lost in urine, since iron
in plasma is complexed with proteins that are too large to
pass through the kidney glomerular membrane. Iron in fe-
ces is primarily unabsorbed dietary iron. Obligatory iron
previous page 709 Bhagavan Medical Biochemistry 2001 read online next page 711 Bhagavan Medical Biochemistry 2001 read online Home Toggle text on/off