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

Here’s how readers responded to a You Make the Call question about managing a patient with the C282Y mutation and a family history of hemochromatosis.


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Start phlebotomy, initially once every two months, to keep transferrin saturation below 50 percent. Monitor iron parameters once every three months.

Javid Gaziev, MD, PhD
Mediterranean Institute of Hematology
Rome, Italy

I would consider bringing her ferritin below 50 ng/mL with weekly phlebotomy, then check ferritin every two to three months.

Nagesh H. Jayaram, MD
Southeastern Medical Oncology Center
Jacksonville, NC  (Nagesh)

I would follow this patient very closely, keeping transferrin saturation well below 50 percent. She may have one phlebotomy of 450 mL initially to be repeated every two months, then perhaps every three months if the ferritin and transferrin saturation don’t escalate. Would also check the hepcidin level. Also, consider checking endocrine function since she appears to be amenorrheic. Birth control should not necessarily cause amenorrhea. Did she have a glucose tolerance test?

Marion Sternbach, MD
McMaster University
Ontario, Canada

We have had similar findings with heterozygotes at our pediatric center and have sent those with elevated saturations to get liver imaging for iron levels. If they have evidence of liver iron overload, we start intermittent phlebotomy.

Depending on the levels and whether the patient is female and premenarchal, we sometimes wait until menarche to decide whether phlebotomy is necessary.

Tiffany F. Lin, MD
University of California, San Francisco

I recommend periodic phlebotomy to maintain transferrin saturation below 50 percent.

Donald H. Mahoney Jr., MD
Texas Children’s Hospital Cancer and Hematology Centers
Houston, TX

I would use quantitative phlebotomy to assess mobilizable iron stores, then decide on a course of action. Some patients with that level of ferritin and classical hemochromatosis can have significantly increased iron stores. With normal liver function, no hepatomegaly, and ferritin less than 1,000 ng/mL, there is no risk of occult cirrhosis.

Pradyumna D. Phatak, MBBS
Rochester Regional Health
Rochester, NY

I would do an MRI to measure liver and cardiac iron. If those are normal, no phlebotomy.

David S. Leibowitz, MD
Palo Alto Medical Foundation
Palo Alto, CA

Why not wait until the ferritin level increases? Any data to support venesection (phlebotomy) just based on rising transferrin saturation?

Glenn J. Shamdas, MD
Veterans Affairs Medical Center
Fargo, ND 

It’s unusual for a pre-menopausal woman to become iron overloaded if she is menstruating. I would change her to a birth control option that allows for monthly menses (i.e., ask her to take her placebo pills if she is skipping them) or offer a copper IUD, which provides pregnancy protection but with continued monthly periods. She might also consider using condoms. If we can get her to “self-phlebotomize” every month, she can avoid a program of therapeutic phlebotomy.

Rebecca Karp Leaf, MD
Massachusetts General Hospital
Boston, MA

Phlebotomize to keep ferritin in the normal range. Probably only needed a few times per year.

Colleen A. Edwards, MD
Icahn School of Medicine
New York, NY

No way this patient needs phlebotomy.

The majority of C282Y homozygotes do not develop iron overload sufficient to cause any problems. In fact, some estimates have found that less than 1 percent of patients who are homozygous for C282Y will ever develop any clinical manifestations from iron overload (Lancet. 2002;359:211-8).

There are good studies to indicate that a man who is found to be homozygous for HFE C282Y in adulthood and has a ferritin level less than 1,000 ng/mL will do fine without intervention (Blood. 2004;103:2914-9; Hepatology. 2010;52:925-33). For these patients, it is likely sufficient to check ferritin levels every five to 10 years and to intervene with phlebotomy only with a progressive rise in ferritin. Women need to be followed a little more closely when they stop menstruating. Individuals with ferritin levels greater than 1000 ng/mL need to undergo phlebotomy therapy to deplete iron stores.

Patients who are compound heterozygotes for C282Y and H63D have an even lower risk of developing clinically important iron overload. Some studies have suggested that clinical progression does not occur in this setting unless there are associated comorbid factors such as steatosis, diabetes, or excess alcohol consumption (Clinical Gastroenterology and Hepatology. 2006;4:1403-10).

David Baer, MD
Kaiser Permanente
Oakland, CA

Initiate phlebotomy to get the ferritin down into the 50 to 100 ng/mL range and, ideally, iron saturation below 50 percent.

Frederick S. Ey, MD
OHSU Knight Cancer Institute
Beaverton, OR 

No [phlebotomy], follow her ferritin levels annually. Most patients do not need phlebotomy, particularly pre-menopausal women.

Donald I. Feinstein, MD
USC University Hospital
Los Angeles, CA

I’d recommend changing her contraception method so she has monthly menses, and avoiding therapeutic phlebotomies because of the cost, inconvenience, etc. That should help her for about 30 years until menopause. Check ferritin levels every six months or so.

Jess F. Armor, MD
Mercy Oncology
Oklahoma City, OK

If the patient has hemochromatosis, I would start a phlebotomy program to keep ferritin levels below 200 ng/mL and transferrin saturation below 40 to 50 percent.

The patient could be studied also with T2* MRI for a better definition of the iron overload in the heart and liver.

Donatella Baronciani, MD
Cagliari, Italy

I would start the phlebotomy initially every four weeks to bring the transferrin saturation below 50 percent and ferritin levels below 100 ng/mL.

Ila Shah-Reddy, MD
Wayne State University
Detroit, MI

Venesection until ferritin levels are less than 50 percent.

Michalis D. Michael, MD, PhD
Nicosia, Cyprus

I would first consider a liver biopsy to check her hepatic iron index. I would strongly consider phlebotomy, as she is homozygous for the C282Y mutation and has a family history of clinical hemochromatosis. I would phlebotomize to a target ferritin level of less than 20 ng/mL and iron saturation less than 20 percent as long as she can tolerate the phlebotomy.

Purvi Shah, MD
Virginia Cancer Institute
Richmond, VA

Better to keep ferritin below 50 ng/mL by regular venesection.

Saifudeen, MBBS, MD
Sultan Qaboos Hospital
Salalah, Oman

This young woman is at risk of iron overload. At age 19, she should just be finishing iron repletion after her adolescent growth spurt, so borderline low iron stores would not be surprising. Instead, she has well above average iron stores, in a context of genetic predisposition for and a family history of hemochromatosis.

The combination of C282Y homozygosity and generous iron stores does not disqualify one from being a blood donor; each donation removes about 225 mg of iron (as does each therapeutic phlebotomy). That may well be sufficient to put her into mildly negative iron balance and thereby provide good prophylaxis against iron overload disease. So, a simple approach would be to recruit her as a routine blood donor and check some follow-up ferritin and transferrin saturation values to make sure her stores are declining rather than continuing to rise. (There are provisions whereby a hemochromatosis patient may donate at shorter-than-standard intervals; there are, however, some administrative hurdles and no clear criteria for when “at risk” becomes “hemochromatosis.”)

Most patients who present with end-organ damage from iron overload have higher ferritin levels than this patient. That might suggest that delay is okay. If we had only a single ferritin value and did not have the genetic findings, we could follow the ferritin and begin phlebotomy only after an upward trend had been documented, using 500 ng/mL as a trigger. Here, though, we have little doubt that she is destined for trouble, and I’d suggest starting an iron management program now rather than waiting.

If she is not a suitable blood donor, I would initiate a therapeutic phlebotomy program now, seeking to maintain a ferritin value in the low-normal range. At a ferritin value of around 300 ng/mL, I don’t think she needs an intensive initiation of therapy, so I would (admittedly arbitrarily) start with one 500 mL phlebotomy every six weeks – twice the usual blood donor draw (per month) for a young adult woman – and would adjust the interval according to her follow-up ferritin values.

I would also review any supplements or vitamins she might be taking to make sure that she is not actually taking in a lot more iron than her no-red-meat diet might suggest.

Dale E. Hammerschmidt, MD
University of Minnesota
Minneapolis, MN

I would rule out metabolic syndrome. I would do the genetic testing for HFE. Can she have thalassemia intermedia? Is her complete blood count normal? Would check liver iron by MRI. I would use transferrin saturation below 50 percent for phlebotomy.

Zahra Pakbaz, MD
Riverside University Health System
Moreno Valley, CA 

I would start weekly phlebotomy immediately with the objective of reducing transferrin saturation to less than 50 percent and iron deficiency is induced. She should be monitored with serum ferritin. Phlebotomy should be preceded by hemoglobin evaluation in each case. An iron chelating agent may be introduced in the absence of any significant improvement in the iron profile. Efforts should be made to prevent iron deposit in the heart.

Muheez A. Durosinmi, MD
Obafemi Awolowo University
Osun, Nigeria

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