section 29.1

Iron Metabolism

677

FIGURE 29-1

A diagrammatic representation of the transmembrane HFE protein. The extracellular portion of the HFE protein consists

of three

a

domains. The

f

}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

overload.

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