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Hereditary Hemochromatosis: Early Detection of a Common Yet Elusive Disease

Hereditary Hemochromatosis: Early Detection of a Common Yet Elusive Disease

Although widely regarded as a rare
disorder, hereditary hemochromatosis
is the most common genetic disease in
Caucasians. In certain populations of
northern European descent, 1 of every
200 persons is homozygous for the
causative mutation.1

Hereditary hemochromatosis is
also the most common cause of primary
iron overload. Persons with this
disease are predisposed to absorb excess
iron from the GI tract; the excess
iron deposits in the parenchyma of organs
and produces such clinical manifestations
as diabetes, cirrhosis, and
heart failure. (In secondary iron overload,
excess iron results from cirrhosis,
sideroblastic anemias that cause ineffective
erythropoiesis, multiple transfusions,
or other exogenous sources.)

The diagnosis is frequently overlooked

  • Affected patients may have no obvious
  • The clinical manifestations are protean;
    they include osteoarthritis (OA)
    and diabetes.
  • Hereditary hemochromatosis is often
    not considered in the differential
    diagnosis because of its perceived

Early diagnosis is crucial--before
irreversible tissue damage occurs.
Here, I highlight the symptoms, laboratory
results, and biopsy findings that
suggest hereditary hemochromatosis,
even in its early stages. I also outline a
treatment approach and explore the
pros and cons of screening.

In North America, it has been estimated
that a physician will see a patient
with hereditary hemochromatosis
approximately every 3 weeks.2 This
estimate may be conservative.

In population studies, the prevalence
of hereditary hemochromatosis
is surprisingly high. Of 16,031 asymptomatic
patients from 22 ambulatory
practices in Rochester, NY, who were
screened with iron studies, 25 had
biopsy-proven hereditary hemochromatosis.
Another 22 patients met clinical
criteria for the disease but declined
biopsy.3 The prevalence was 4.5 per
1000 patients, which is consistent with
the known frequency of the hereditary
hemochromatosis mutation. Routine
screening of the general population for
hereditary hemochromatosis is controversial

How does the prevalence of
hereditary hemochromatosis compare
with that of a relatively common entity
such as iron deficiency anemia? In a
West German study, 3027 outpatients
and 3012 employees of industrial companies
were screened for both conditions.
4 All participants were asymptomatic.
Among the outpatients, 1.6%
of the men had hemochromatosis, and
only 1.5% had iron deficiency anemia.
In the employee group, 1% of the men
had hemochromatosis, and only 0.3%
had iron deficiency anemia. Among
the women, iron deficiency was more
common than iron overload; however,
1.9% of the female outpatients and
1.1% of the female employees had

These 2 studies included only
asymptomatic patients. Population
studies in patients with disorders that
might be related to iron overload reveal
an even greater prevalence of
hereditary hemochromatosis. For example,
the prevalence may be as high
as 5% in patients with peripheral arthritis,
6% in those with chronic liver disease
or cirrhosis, and 15% in those
with hepatocellular carcinoma.5

When persons with 2 or more disorders
that may be related to iron excess
are screened, the prevalence of
hereditary hemochromatosis skyrockets.
Persons with both liver disease
and diabetes are 43 times more likely
to have hereditary hemochromatosis
than are those with neither disease.
Patients who have diabetes and liver
neoplasia are 83 times more likely to
have hereditary hemochromatosis.6

During the past decade, the candidate
gene for hemochromatosis was
identified. The gene is found on chromosome
6 and encodes a major histocompatability
complex class I-like
protein that, like a typical HLA molecule,
spans cell membranes. Because
of this similarity, the gene was initially
named HLA-H, but was later renamed
HFE.7 Although the HFE protein is
found in many human cells, it is most
abundant in the duodenum--which
suggests a prominent role in the absorption
of iron. The mechanism by
which HFE regulates iron absorption
is not fully understood. Studies with
monoclonal antibodies have also confirmed
the presence of the protein in
crypt cells, where it is associated with
the transferrin receptor.8

Major mutation. Two missense
mutations of the HFE gene play an important
role in hereditary hemochromatosis.
The major HFE mutation,
C282Y, results in a cysteine to tyrosine
change at amino acid 282. Depending
on the population studied, between
69% and 100% of patients with hemochromatosis
exhibit this major
mutation on both chromosomes in a
pair--that is, are homozygotes.7,9-11
This is a significant percentage; of Caucasian
patients who have cystic fibrosis,
for example, only 70% exhibit the
most common mutation associated
with that disease (CFTR, or delta 508
mutation). It is estimated that 1 in 385
Americans is homozygous for the
major mutation associated with hereditary
hemochromatosis (C282Y).12

Minor mutation. Another significant
mutation, the "minor mutation,"
or H63D, also has a role in some patients.
Between 4% and 7% of patients
with hereditary hemochromatosis are
compound heterozygotes (persons
who exhibit both C282Y and H63D
mutations).7,11,13 Nearly 1 in 50 Americans
may be a compound heterozygote.
12 "Simple" heterozygotes (patients
who have either the C282Y or
H63D mutation but not both) may account
for 3% to 4% of cases of hereditary
hemochromatosis; these patients
may have other HFE mutations as
well.13,14 However, iron overload rarely
develops in simple heterozygotes unless
they have another concurrent
liver disease.

Although the HFE gene plays an
important role in hemochromatosis,
this role is still not clearly understood
or well-defined. Up to 7% of patients
with hereditary hemochromatosis exhibit
neither the major nor the minor
HFE mutation.9,13,15 Moreover, some
patients who are homozygous for the
major mutation or who are compound
heterozygotes have no clinical or biochemical
evidence of iron overload.
Thus, environmental or other genetic
influences also appear to have a role in
the disease.1


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