Management implications of results of HFE genetic testing

Management implications of results of HFE genetic testing

Genotype	Risk for iron overload and its complications*	Testing/interventions
C282Y/C282Y -or- C282Y/H63D	Increased (1% in women to approximately 28% in men) for C282Y/C282Y. Lower in C282Y/H63D. Sex and age-related (generally after menopause in women or after age 40 in men). May be further increased by other inherited or acquired conditions.^¶	If not obtained previously, obtain iron studies (can defer until adulthood). Counsel first-degree relatives about the risk of inheriting the variant and the risk of possible iron overload, with shared decision-making regarding genetic testing and/or iron studies.
C282Y/wildtype -or- H63D/wildtype -or- H63D/H63D	Likely to be similar to the general population. May be increased by other inherited or acquired conditions.^¶	Iron studies are generally not required unless indicated for another reason.^¶ For C282Y heterozygotes, counsel first-degree relatives about the risk of inheriting the variant and possible iron overload, with shared decision-making regarding genetic testing and/or iron studies.
Negative for C282Y and H63D^Δ	Likely to be similar to the general population. May be increased by other inherited or acquired conditions.^¶	Iron studies are generally not required unless indicated for another reason.^¶ Counseling and testing of first-degree relatives generally not indicated unless previously obtained iron studies are abnormal.

This presentation is not meant to imply that genetic testing should precede iron studies testing. Genetic testing is typically performed when iron studies indicate that HH may be present. This information is only a guide and should not replace clinical judgment or shared decision-making with the tested individual or their at-risk relatives. Any individual with a positive family history of iron overload not due to an acquired condition should be tested; in these individuals, iron studies may be a better initial test than HFE genetic testing.

HFE: hereditary hemochromatosis gene; HH: hereditary hemochromatosis; CLIA: Clinical Laboratory Improvement Amendments.

* Complications of iron overload may include:

Liver damage, which can progress to cirrhosis
Cardiac toxicity, with heart failure and/or arrhythmias in severe cases
Diabetes
Other endocrinopathies including hypopituitarism, hypogonadism, and hypothyroidism
Arthropathy
Skin pigmentation (bronze skin)
Increased susceptibility to infection

¶ Conditions other than HFE-associated HH that can cause or exacerbate iron overload include:

Multiple transfusions (more than 10 to 20 units)
Thalassemia or other conditions with ineffective erythropoiesis
Rare genetic conditions such as juvenile hemochromatosis
Liver disease (alcohol or non-alcohol related)

Δ Refer to UpToDate for caveats regarding genetic test results, including the need to confirm testing in a CLIA-certified laboratory, and settings in which more extensive genetic testing may be indicated.

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Management implications of results of HFE genetic testing