Iron overloading, as measured by a random (non-fasting) elevated transferrin saturation
(TS) value, is estimated to occur in 1 to 6 people per
100 in the United States.
- A lower percentage of people who initially have a random elevated TS
also have a persistently elevated TS: estimates range from 35% to 50%.
- An even lower percentage of people who have persistently elevated TS
measures also have an elevated serum ferritin (SF) value.
- Thus, the proportion of people who will develop clinical signs and
symptoms of hemochromatosis is even lower than the proportion of
people with elevated SF values.
The wide range of prevalence estimates in the medical literature reflect
laboratory cutoff values used to define elevated transferrin saturation and
serum ferritin values (i.e., cutoff or abnormal levels), as well as
differences in the study populations.
Hemochromatosis occurs as a result of significant iron overload; in the
United States this usually occurs as a result of HFE gene mutations and is
therefore called hereditary hemochromatosis. This course focuses on adult
onset HFE hereditary hemochromatosis.
The HFE gene mutation was discovered in 1996 (Feder JN). Two mutations on the
HFE gene, C282Y and H63D, account for the majority of
hereditary hemochromatosis cases in the United States (Steinberg KK, 2001).
- Hereditary hemochromatosis is inherited in an autosomal recessive
pattern.
- The C282Y/C282Y homozygous genotype accounts for the majority of cases
(Hanson EH, 2001).
- Other mutations have been described but their clinical significance is
unknown.
- HFE gene mutations account for the majority of cases, but only a small
proportion of individuals who inherit these mutations develop clinical
disease.
What are the possible
HFE gene mutations that a patient may have?
The population prevalence of the HFE mutations depends on race and
ethnicity but is most prevalent among persons of European origin and
descent.
- HFE gene mutations are found in a small but significant proportion of the
general population.
- Published estimates of HFE genotype frequencies vary depending on how
studies were performed and on the racial/ethnic distribution of the
populations tested.
What are the frequencies of
HFE genotypes in the general population and
among hemochromatosis patients?
Penetrance is the proportion of individuals with specific
genotypes who develop clinical disease.
Most prevalence estimates are based on the homozygous major mutation
(C282Y/C282Y). Because clinical signs and symptoms used to define hereditary
hemochromatosis differ among studies, penetrance estimates vary.
Early studies that used both self-reported symptoms and clinical signs to
define hemochromatosis, reported clinical penetrance estimates ranging from
40 to 70% (Bradley LA, 1996).
More recent studies that used clinical signs or objective laboratory
measures to define hemochromatosis, reported clinical penetrance estimates
ranging from <1 to 50% (Asberg A, 2001; Beutler E, 2002; Bulaj ZJ, 2000;
Olynyk JK, 1999).
Inconsistencies regarding penetrance estimates persist in the scientific
literature. Further studies are warranted to more fully understand the role
of genetic and environmental factors that may affect penetrance.
| Of people with HFE mutations, only a subset will
develop elevated TS. Of those with an elevated TS, only a subset
will develop an elevated SF. Of those with an elevated SF, only a subset
will develop hemochromatosis symptoms. Of those with symptoms, only a
subset will develop clinical signs consistent with hemochromatosis. |
 |
Most clinicians reserve the hemochromatosis diagnosis for patients whose
signs and symptoms are clearly referable to documented iron overload.
Iron status testing is more clinically relevant than genetic testing for
identifying those who have hemochromatosis.
Some experts advocate population screening for HFE mutations. In fact, it
has been suggested that hereditary hemochromatosis serve as a model for
formulating policy decisions about genetic diseases, in particular for
decisions about the usefulness of genetic screening.
- Of utmost concern is the uncertainty about what proportion of people with
HFE gene mutations will develop hemochromatosis.
- Current research suggests that penetrance may be low making population
screening inefficient.
Therefore, CDC does not currently recommend population screening for
HFE
mutations. However, genetic testing for HFE mutations can be useful to determine a
specific cause for iron overload. In addition, in families with known
hereditary hemochromatosis, genetic testing can determine which family
members do not have HFE gene mutations.
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