Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

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Chapter | 9 Iron Metabolism and Its Disorders
FIGURE 9-1 Iron cycle. Iron (Fe) is highly conserved in the body. Iron
in plasma is bound to transferrin, a transport protein that is synthesized
in the liver. Iron is transported to all tissues, but most iron is utilized to
synthesize hemoglobin in developing erythroid cells. Aged blood erythrocytes
are phagocytized by macrophages, and hemoglobin is degraded.
Released iron is either returned to plasma or stored in macrophages as
ferritin and hemosiderin. Nearly all of the iron in plasma under normal
conditions comes from the release of iron by macrophages that have
phagocytized and degraded erythrocytes (large arrow). Only about 3% of
the iron in plasma results from gastrointestinal (GI) enterocyte absorption
in normal individuals (small arrow).
FIGURE 9-2 Overview of iron metabolism. Ferric iron (Fe 3 ) ions present
in the diet are reduced to ferrous iron (Fe 2 ) ions and absorbed by
duodenal enterocytes. Once inside enterocytes, Fe 2 may be oxidized and
stored as ferritin or exported to plasma where it is oxidized and bound to
transferrin (Tf) for transport to the tissues. Iron stored as ferritin is returned
to the small intestine lumen when enterocytes are sloughed at the tip of the
villus. Iron is incorporated into many proteins in all tissues, but most iron
is utilized to synthesize hemoglobin in developing erythroid cells, where
Fe 3 must be reduced to Fe 2 during heme synthesis. Aged blood erythrocytes
are phagocytized by macrophages. Hemoglobin is degraded and iron
is either returned to plasma or stored in macrophages as ferritin and hemosiderin.
Modification of Kaneko, 1964 , with permission.
Iron absorption from the small intestine compensates for
the small amount of iron lost each day, largely from skin
exfoliation and cell desquamation in urine, bile, sweat, and
feces ( Beutler, 2006b ; Underwood, 1977 ).
II. IRON DISTRIBUTION
The relative distribution in the body is shown in Figure 9-2 .
Normally about 60% to 70% of total body iron is present
in hemoglobin. About 20% to 30% is stored as ferritin and
hemosiderin (primarily within macrophages and hepatocytes),
3% to 7% is present in myoglobin (with the higher
values occurring in myoglobin-rich species such as dogs,
horses, and cattle), 1% is present in enzymes, and less than
0.1% is bound to transferrin in plasma ( Ponka et al ., 1998 ).
A. Hemoglobin
Hemoglobin accounts for more than 90% of the protein
within erythrocytes ( Quigley et al ., 2004 ). It contains 0.34%
iron by weight; consequently, each milliliter of packed
erythrocytes contains 1.1mg of iron. Hemoglobin plays vital
roles in oxygen transport, carbon dioxide transport, and buffering
of hydrogen ions (see Chapter 7 for details). It is a tetrameric
protein consisting of four polypeptide globin chains,
each of which contains a heme prosthetic group. Heme is a
planar molecule composed of the tetrapyrrole protoporphyrin
IX, containing a central iron ion. A hemoglobin tetramer
is capable of binding four molecules of oxygen when fully
saturated. To bind oxygen, iron ions within heme molecules
must be in the Fe 2 state. Methemoglobin is formed when
iron is oxidized to the Fe 3 state. Fortunately, the oxidation
of Fe 2 ions to Fe 3 ions is minimized by the location of
heme groups within hydrophobic pockets of globin chains,
and methemoglobin that forms can be reduced enzymatically
within erythrocytes.
B. Storage Iron
Ferritin is a ubiquitous iron storage protein that is detected
in almost all animal and plant tissues, as well as in bacteria
and fungi. The binding of iron in ferritin minimizes
its potential to catalyze the formation of damaging free
radicals ( Arosio and Levi, 2002 ). Each mammalian ferritin
molecule is composed of a protein shell of 24 apoferritin
H or L monomeric subunits surrounding a central
cavity that can accommodate as many as 4000 iron atoms
in a ferric hydroxide core. The inner surface of the protein
shell has catalytic sites (associated with H subunits) that
promote the oxidation of Fe 2 ions to Fe 3 ions ( Arosio
and Levi, 2002 ). The L subunit lacks ferroxidase activity,
but it is more efficient than the H subunit in the enucleation
and mineralization of iron in the ferritin core ( Levi
et al ., 1994 ). Subunit composition varies between cell types,
with the H subunit predominating in erythrocytes and muscle,
and the L subunit predominating in liver, spleen, and