How would you treat a patient with the C282Y mutation and a family history of hemochromatosis?

Susan F. Leitman, MD
Director, Medical Research Scholars Program, National Institutes of Health

This month, Susan F. Leitman, MD, discusses managing a patient with the C282Y mutation and a family history of hemochromatosis.

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A 19-year-old woman had iron studies performed by her primary-care physician. The results showed ferritin in the 250 ng/mL range, transferrin saturation of 38 percent, and normal liver function. Family history is remarkable for a maternal aunt with hemochromatosis, and genetic testing shows that she is homozygous for the C282Y mutation. She has never been pregnant. She has no menses because of her oral contraceptive method and eats no red meat. Her most recent labs showed normal liver function; however, her iron studies showed a serum iron of 208 mg/dL, total iron-binding capacity of 268 mcg/dL, transferrin saturation of 78 percent, and ferritin 301 ng/mL. Would you start phlebotomy? And what would you use to decide on frequency of therapy? One hematologist told me to use transferrin saturation below 50 percent as a goal in pre-menopausal women.


Genetic hemochromatosis with homozygosity for the HFE p.Cys282Tyr (C282Y) mutation is one of the most frequent autosomal recessive disorders in the Caucasian population. Iron loading due to dysregulated iron absorption starts in childhood and may be manifested by an elevated serum ferritin and transferrin saturation in the teens, as in this patient. However, clinically significant iron burden in target organs, such as the liver, does not generally occur until after age 30. Iron loading proceeds at a faster pace in men than women and can be affected by diet. It is remarkable that at age 19, despite a diet low in heme iron, this patient already has biochemical evidence of excess iron, with a ferritin of 301 ng/mL (upper limit of normal is 150 ng/mL in women).

The most common symptom interfering with quality of life in patients with hemochromatosis is arthritis, occurring in 10 to 30 percent of subjects. The arthritis can be aggressive and debilitating; since its severity is correlated with the ferritin value at diagnosis, it is assumed that early initiation of phlebotomy can prevent arthropathy. Elevated alanine aminotransferase occurs in 10 to 40 percent of individuals, but advanced liver disease is uncommon, occurring in less than 5 percent of patients. Phlebotomy prevents liver disease and mitigates the risk of hepatocellular cancer.

Most experts recommend treatment when the ferritin rises above 300 ng/mL. Since this patient already has a significant ferritin elevation despite her young age, female sex, and low heme-iron diet, she appears to load iron at a more rapid pace than the typical patient with hemochromatosis, and I would initiate phlebotomy now. I would remove one 500-mL unit of blood every three to four months until the ferritin falls below 150 ng/mL, and then target a maintenance ferritin between 150 and 200 ng/mL. I would do this to prevent hemochromatosis-associated arthropathy, as well as liver injury. There is no reason to aim for tighter control at this early stage, and it is reasonable to leave her with iron reserves for future pregnancy. The frequency of bleeds necessary to maintain this range will depend on her weight, diet, and other factors. I suspect that maintenance bleeds every six to 12 months would be sufficient. Her ferritin level should be reassessed prior to any scheduled bleeds.

The transferrin saturation is a highly sensitive test for detecting the presence of an HFE C282Y variant, but its use is limited to screening and diagnosis. After that, it has no utility in monitoring response to therapy. It is susceptible to diurnal and dietary variation and can be quite high even when the ferritin is below targeted levels.

On a practical level, to maximize effective use of resources and minimize costs and inconvenience, I would refer her to a blood center for treatment. The U.S. Food and Drug Administration maintains a listing of blood collection establishments that deliver hemochromatosis phlebotomy care without charge to the patient.1 If the patient meets blood donor criteria, the blood units removed are made available for transfusion. Patients are usually delighted to find that their blood is used to help others rather than discarded.

The patient should be counseled to avoid alcohol excess for the rest of her life. She should be vaccinated against hepatitis B (if not already done) and strongly counseled to avoid behaviors that might expose her to hepatitis C virus. In addition, all siblings should be advised to undergo HFE genotype testing.


  1. U.S. Food and Drug Administration. “List of Establishments Granted Approval for a Variance to 21CFR640.3(d) and 21CFR640.3(f).” Accessed on March 20, 2018, from

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I have a 40-year-old patient who presented with complaints of fever lasting three months. He had a few atypical cells in his peripheral smear and his bone marrow (BM) aspiration was morphologically suggestive of acute promyelocytic leukemia. PML-RAR alpha was not detected from peripheral blood. He was started on all-trans retinoic acid plus arsenic trioxide. He developed cytopenia after starting hydroxyurea. How should I manage this patient? I repeated a BM aspiration and sent the aspirate for PML-RAR alpha. Fluorescence in situ hybridization results are pending. Does low promyelocyte count in the BM sample influence the PML-RAR alpha transcript detection?

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