Iron - Toxicology of Metals - page 573

et al ., 1996; Fleming et al ., 2004; Pietrangelo, 2004). In
this population, HH occurs in 1 in 300 people, with
a remarkable carrier frequency of 1 in 10 individuals.
The primary defect in HH is the inability to down-
regulate intestinal Fe absorption when iron stores are
high. The gene responsible for HH, which is localized
on chromosome 6, has been cloned (Feder et al ., 1996).
The gene, termed HFE, encodes a predicted protein of
343 amino acids, including several cysteines that seem
to be required for maintaining proper structure of the
protein. Two missense mutations have been reported
in the gene, both causing amino acid substitutions
(C282Y and H63D), but to date only the C282Y muta-
tion has been found to clearly correlate with HH in
most affected patients. HFE is highly homologous
to genes in the major histocompatibility complex
(MHC) class I family. The HFE gene, like other MCH
class I genes, encodes a heterodimeric protein that is
complexed to

women. Typically, phlebotomy is performed at a rate
of 1 unit of blood per week until the patient has mild
hypoferritinemia. Thereafter, it is continued as needed
to keep the serum ferritin <50

g/L. On average, men
require phlebotomy three or four times per year, and
women require it one or two times per year.
Table 2 shows that genetic iron overload can have
causes other than the mutation of the HFE gene.
Although non-HFE iron-overloading conditions are
rare, analyses of the pathological effects caused by spe-
cifi c gene mutations offer important insights into the
functions of the products of these genes.

µ

6.3 Mechanisms of Tissue Damage
in Iron Overload
Damage to cells and organs arising from chronic
iron overload is remarkable in its ability to affect a
wide range of tissues (both replicative and nonreplica-
tive) and often causes a slow and insidious onset of
organ dysfunction. Foremost among the organs and
cell types affected by iron overload are the liver, heart,
and pancreatic beta cells. Hepatic disease (e.g., cirrho-
sis and hepatoma) causes a large number of premature
deaths among patients with primary hemochroma-
tosis (Niederau, 1985), whereas heart failure is most
frequent in patients with secondary hemochromato-
sis (Aldouri et al ., 1990; Gabutti and Borgna-Pitnatti,
1994). Both groups share a substantially increased risk
for development of diabetes compared with the nor-
mal population (Gabutti and Borga-Pitnatti, 1994).
In the etiology of this organ damage, it may be impor-
tant that the liver and heart have a high steady-state
production of superoxide [O 2 − ] and hydrogen peroxide
[H 2 O 2 ] (Chance et al ., 1979), largely derived from mito-
chondrial activity (Harman, 1983). The pancreatic beta

β 2 -microglobulin, and such coupling is
essential for cell surface expression of the functional
molecule. The cysteine-to-tyrosine mutation is very
close to the expected site of β 2 -microglobulin asso-

ciation and, hence, the association of HFE with

β 2 -
microglobulin is disrupted in HH. Although the exact
function of HFE gene product is unclear, it is known
that there is a physical interaction of the transferrin
receptor and HFE (Lebron et al ., 1998). However, the
relevance of this phenomenon to the pathogenesis of
HH is not clear.
Unlike many other genetic disorders, HH is treat-
able. If the disease is diagnosed early enough and the
patients are subjected to regular phlebotomies, their
life expectancy is normal. Ideally, therapy should begin
before symptoms develop, when the serum ferritin
levels exceed 200 µ g/L in nonpregnant, premenopau-

sal women or 300 µ g/L in men and postmenopausal

TABLE 2 Genetic Iron Overload

Disease Inheritance Mutated Gene Population Main Clinical Reference

Frequency Features

Hereditary AR* HFE 1:250 Liver disease Feder et al ., 1996;

hemochromatosis Pietrangelo, 2004

(HH type 1)
HH type 2 AR a) Hemojuvelin Rare Heart disease Papanikolaou, 2004

(Juvenile H) AR b) Hepcidin Rare Heart disease Roetto et al ., 2003

HH type 3 AR TfR2 Rare Liver disease Camaschella et al .,

2000

HH type 4 AD Ferroportin 1 Rare Liver disease Pietrangello, 2004

( ↑ Fe in

macrophages)

Atransferrinemia AR Transferrin Rare Liver disease Ponka, 2002

African Fe AR Unknown Common Liver disease Gordeuk, 2002

overload

* AR, autosomal recessive; AD, autosomal dominant