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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.

HFE Genotypes

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?

HFE Genotype Frequencies

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

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.

illustration of HFE mutation subset
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.

Population Screening

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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