Clinical characteristics: HFE hemochromatosis is characterized by inappropriately high absorption of iron by the small intestinal mucosa. The phenotypic spectrum of HFE hemochromatosis includes:
Persons with clinical HFE hemochromatosis, in whom manifestations of end-organ damage secondary to iron overload are present;
Individuals with biochemical HFE hemochromatosis, in whom transferrin-iron saturation is increased and the only evidence of iron overload is increased serum ferritin concentration; and
Non-expressing p.Cys282Tyr homozygotes, in whom neither clinical manifestations of HFE hemochromatosis nor iron overload are present.
Clinical HFE hemochromatosis is characterized by excessive storage of iron in the liver, skin, pancreas, heart, joints, and anterior pituitary gland. In untreated individuals, early symptoms include: abdominal pain, weakness, lethargy, weight loss, arthralgias, diabetes mellitus; and increased risk of cirrhosis when the serum ferritin is higher than 1,000 ng/mL. Other findings may include progressive increase in skin pigmentation, congestive heart failure, and/or arrhythmias, arthritis, and hypogonadism. Clinical HFE hemochromatosis is more common in men than women.
Diagnosis/testing: The diagnosis of HFE hemochromatosis in a proband is established by identification of biallelic HFE pathogenic variants on molecular genetic testing.
Management: Treatment of manifestations:
Clinical HFE hemochromatosis: induction treatment by phlebotomy to achieve serum ferritin concentration ≤50 ng/mL.
Biochemical HFE hemochromatosis: start phlebotomy when serum ferritin concentration is >300 ng/mL.
Non-expressing p.Cys282Tyr homozygotes: phlebotomy is not indicated, because these individuals do not have iron overload.
Prevention of secondary complications: Vaccination against hepatitis A and B.
Clinical HFE hemochromatosis: Once the serum ferritin concentration is ≤50 ng/mL, monitor serum ferritin concentration every three to four months. Maintain serum ferritin <300 ng/mL (men) and <200 ng/mL (women) thereafter; perform standard screening for primary liver cancer in individuals who have cirrhosis.
Biochemical HFE hemochromatosis and non-expressing p.Cys282Tyr homozygotes: Begin annual measurement of serum ferritin concentration when serum ferritin concentration exceeds 300 ng/mL (men) and 200 ng/mL (women).
Agents/circumstances to avoid: Medicinal iron, mineral supplements, excess vitamin C, and uncooked seafood; alcohol consumption in those with hepatic involvement; and daily ingestion of more than 500 mg of supplemental ascorbic acid / vitamin C.
Evaluation of relatives at risk: Offer molecular genetic testing to the adult sibs of a proband homozygous for p.Cys282Tyr to allow early diagnosis and surveillance.
Genetic counseling: HFE hemochromatosis is inherited in an autosomal recessive manner.
Risk to sibs: When both parents of a person with hemochromatosis are heterozygous for an HFE p.Cys282Tyr variant, the risk to sibs of inheriting two HFE p.Cys282Tyr variants is 25%. Because the HFE p.Cys282Tyr heterozygote prevalence in persons of European origin is high (11%, or 1/9), some parents of HFE p.Cys282Tyr homozygotes have two abnormal HFE alleles. If one parent is heterozygous and the other parent homozygous for two abnormal HFE alleles, the risk to each sib of inheriting two HFE pathogenic alleles is 50%.
Risk to offspring: Offspring of an individual with HFE hemochromatosis inherit one HFE p.Cys282Tyr variant from the parent with HFE hemochromatosis. Because the chance that the other parent is a heterozygote for HFE p.Cys282Tyr is 1/9, the risk that the offspring will inherit two HFE p.Cys282Tyr variants is approximately 5%.
Prenatal testing: Although prenatal testing for a pregnancy at increased risk is possible once the HFE pathogenic variants have been identified in an affected family member, prenatal testing is not usually performed because HFE hemochromatosis is an adult-onset, treatable disorder with low clinical penetrance.
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