You Make the Call
Each month in “You Make the Call,” we pick a challenging clinical question submitted through the Consult a Colleague program
and post the expert’s response, but we also want to know what you would do. Send in your response to next month’s clinical
dilemma and see how your answer matches up to the expert’s in the next print issue.
This month, Susan F. Leitman, MD, discusses managing a patient with the C282Y mutation and a family history of hemochromatosis.
Clinical Dilemma:
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.
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Expert Opinion
Susan F. Leitman, MD
Director, Medical Research Scholars
Program
National Institutes of Health
Bethesda, MD
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 fer-
ritin 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 bio-
chemical 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 aggres-
sive 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 signif-
icant 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 va