section 29.1
Iron Metabolism
683
establishing negative iron balance and eliminating stored
iron. A small, labile (chelatable) iron pool may be in slow
equilibrium with a much larger (storage) pool. When de-
feroxamine is administered, the labile pool is rapidly emp-
tied. Any deferoxamine that remains in the body or is ad-
ministered thereafter finds no iron to bind. Thus, most of a
single intramuscular dose is simply excreted unchanged.
If the chelator is given as a continuous infusion, the labile
pool is initially depleted and kept empty. As iron is re-
leased from storage sites, it is immediately chelated and
removed. Removal of up to 180 mg of iron per day has
been accomplished by this method, making it as effective
as phlebotomy. Massive intravenous injections of defer-
oxamine have also been reported to produce excretion of
large amounts of iron in iron-overloaded patients.
Hereditary Hemochromatosis
Hereditary hemochromatosis
is a common inherited au-
tosomal recessive disorder of excessive iron accumulation
in parenchymal cells of liver, heart, pancreas, endocrine
organs, skin, and joints. The term hemochromatosis is
used when organ damage has occurred in the presence of
impaired function. It occurs predominately in Caucasian
populations; about 1 in 200-400 Caucasians are at risk for
developing clinical symptoms. Individuals with hereditary
hemochromatosis absorb about 3-4 mg/d of iron as com-
pared with a normal rate of about 1-2 mg/d. This excess
iron, absorbed over several years, causes accumulation of
as much as
2 0 ^ - 0
g as compared to normal amounts of
about 4 g. In untreated patients, progressive iron accumu-
lation can cause organ damage resulting in hepatic dys-
function, diabetes, cardiomyopathy, hypogonadism with
infertility, arthritis, and skin hyperpigmentation. Death can
occur due to cirrhosis, diabetes, cardiomyopathy or hepa-
tocellular carcinoma.
Hereditary hemochromatosis is associated with a gene
on the short arm of chromosome
6
near the MHC
gene complex. This gene is known as
HFE
and codes
for HFE protein. The roles of HFE protein along with
/32-microglobulin in the regulation of intestinal iron ab-
sorption and iron sequestration in the form of ferritin
and hemosiderin have been discussed previously. Gene
knockout mice for either HFE protein or /32-microglobulin
develop an iron overload disorder similar to human
hemochromatosis, thus substantiating the roles of HFE
protein and /32-microglobulin in iron homeostasis.
Two missense mutations (C282Y and H63D) in the
HFE
gene have been identified in hereditary hemochromato-
sis. The substitution of a tyrosyl residue for a cysteinyl
residue at position 282 results in the loss of formation of a
disulfide linkage necessary for the proper association with
/32-microglobulin (Figure 29-1). In the absence of this
disulfide linkage, HFE protein fails to reach the normal
membrane location and is rapidly degraded. Thus, C282Y
is a loss of function (knockout) mutation. The H63D mu-
tation has no effect on the HFE protein’s association with
/3
2
-microglobulin. However, this mutation may compro-
mise the protein regulation of the interaction between
transferrin and its receptor.
Population studies among Caucasians have shown that
about 1 in 10 are heterozygous for the C282Y mutation.
Homozygosity of C282Y has been observed in 85-90%
of hereditary hemochromatosis patients, In about 4% of
the hereditary hemochromatosis patients, heterozygosity
of C282Y and H63D has been observed. There are still
unanswered questions concerning hereditary hemochro-
matosis. For example, some C282Y homozygotes exhibit
neither biochemical nor clinical evidence of iron accumu-
lation. On the contrary, some hemochromatosis patients
do not possess a C282Y mutation. Thus, other yet-to-be-
identified genetic and environmental factors must play a
role in the development of hemochromatosis.
Other forms of hemochromatosis include neonatal and
juvenile types in which biochemical defects have not yet
been identified. Patients with
aceruloplasminemia
result-
ing from mutations in the ceruloplasmin gene exhibit ac-
cumulation of iron in neural and glial cells in the brain,
in hepatocytes, and in pancreatic islet cells. Ceruloplas-
min, a copper-containing protein, has ferroxidase activity
and participates in the release of iron from cells. Aceru-
loplasminemia associated with iron overload is a different
disorder from that of
Wilson’s disease
(hepatolenticular
degeneration) in which biliary excretion of copper and
incorporation of copper into ceruloplasmin are defective
(Chapter 37).
Porphyria cutanea tarda,
a disorder of por-
phyrin biosynthesis (discussed later), usually is accom-
panied by iron accumulation. Thirty percent of patients
with porphyria cutanea tarda are either homozygous or
heterozygous for the C282Y mutation affecting the HFE
protein.
Treatment of hereditary hemochromatosis is therapeu-
tic phlebotomy (discussed earlier). This method is safe,
effective, and life saving, and ideally should begin before
symptoms develop. Serum ferritin levels are used as a sur-
rogate marker for estimating total-body iron stores. Mor-
phologic studies and quantitative determination of iron
in liver tissue obtained by biopsy have been used in the
assessment of early hereditary hemochromatosis and the
degree of liver injury.
Finally, hereditary hemochromatosis is a treatable dis-
ease. Biochemical screening for the identification of the
