This study will evaluate the effectiveness of a test called MCV in guiding phlebotomy (blood
drawing) therapy in patients with hemochromatosis an inherited disorder that causes too much
iron to be absorbed by the intestine. The excess damages body tissues, most severely in the
liver, heart, pancreas and joints. Because iron is carried in the hemoglobin of red blood
cells, removing blood can effectively lower the body s iron stores.
Patients with hemochromatosis undergo weekly phlebotomy treatments (1 pint per session) to
deplete iron stores. This usually requires 10 to 50 treatments, after which blood is drawn
every 8 to 12 weeks to prevent a re-build up of iron. A test that measures ferritin a protein
involved in storing iron is commonly used to guide phlebotomy therapy in hemochromatosis
patients. This study will compare the usefulness of the ferritin test with that of MCV, which
measures red blood cell size, in guiding phlebotomy therapy. In addition, the study will 1)
examine whether keeping iron levels low during maintenance therapy can help heal severe liver
disease and improve arthritis in affected patients, and 2) design a system for making blood
collected from hemochromatosis donors available for transfusion into other patients.
Patients 15 years and older with diagnosed hemochromatosis or very high iron levels
suggesting possible hemochromatosis may be eligible for this study. Candidates will have a
history, physical evaluation, review of medical records and blood tests, and complete a
symptoms questionnaire. Participants will have the following procedures:
- Phlebotomy therapy every 1 to 2 weeks, depending on iron levels
- Blood sample collection for blood cell counts and iron studies at every phlebotomy
- Blood sample collection (about 2 tablespoons) every 1 to 2 weeks after iron stores have
- Phlebotomy every 8 to 12 weeks after iron stores are used up to prevent re-build up of
With each blood donation that will be made available for transfusion to other patients,
participants will answer the same health history screening questions and undergo the same
blood tests given to all regular volunteer blood donors. These include screening for the HIV
and hepatitis viruses and for syphilis.
Patients who meet height and weight requirements may be asked to consider "double red cell"
donations using apheresis. In this procedure, whole blood is collected through a needle
placed in an arm vein, similar to routine phlebotomy. The blood then circulates through a
machine that separates it into its components. The red cells are removed and the rest of the
blood is returned to the body, either through the same needle or through a second needle in
the other arm. Patients who have very high iron levels or an enlarged liver will be offered
evaluation by the NIH Liver Service. Those judged to be at increased risk for cirrhosis may
be advised to undergo a liver biopsy. If cirrhosis is found, the patient will be asked to
consider a repeat biopsy after 3 to 5 years of continuous iron depletion to see if scarring
has improved. Patients with arthritis will be offered evaluation by the NIH Arthritis Service
and, depending on symptoms, may be advised to have X-ray studies or a joint biopsy.
Hereditary hemochromatosis (HH) occurs in 1 in every 200-250 individuals of northern European
descent, and is the most common inherited disease in this population. Although the molecular
pathophysiology remains incompletely understood, a homozygous mutation in the HFE gene
(Cys282Tyr) is observed in nearly 100% of clinically confirmed cases. The clinical
manifestations of HH are due to inappropriately increased iron absorption with excessive iron
deposition in the liver, heart, endocrine organs, and joints.
Phlebotomy treatment, with removal of iron contained in the hemoglobin of red cells, is the
only effective therapy for HH. Phlebotomy therapy relieves many of the symptoms of
iron-mediated tissue damage and prevents progression to cirrhosis. However, published
laboratory guidelines for monitoring phlebotomy therapy are based on retrospective data, and
in general allow a moderate level of iron overload to persist during maintenance therapy.
Since 1987, the DTM has piloted the use of the red cell mean corpuscular volume (MCV), in
conjunction with the hemoglobin, as a prospective guide to phlebotomy therapy in a small
cohort of HH patients. In contrast to other retrospectively-derived guidelines, this simple,
inexpensive, physiologic method was found to be a precise indicator of iron-limited
erythropoiesis, and could be easily applied to adjust the pace of phlebotomy and prevent
excess iron reaccumulation.
Although the majority of persons with HH meet eligibility criteria for allogeneic blood
donation, until recently regulatory guidelines restricted the use of therapeutically
withdrawn blood for transfusion. New regulations now permit increased flexibility in the use
of such units for this purpose. The purposes of this protocol are: (1) to prospectively study
the genotypic and phenotypic response to phlebotomy therapy in HH patients using the
MCV/hemoglobin monitoring guide, and to validate the use of this guide in a large study
cohort; (2) to evaluate the course of severe hepatic disease and rheumatologic symptoms
following sustained iron depletion; and (3) to establish the safety and efficacy and document
the operational issues inherent in a program to collect therapeutically withdrawn blood for
use in allogeneic transfusion. These goals have as their combined target the establishment of
the simplest, safest system for donor processing, phlebotomy management, and transfusion of
blood drawn from HH subjects.
- INCLUSION CRITERIA:
Confirmed diagnosis of HH, defined by the following HFE genotypes: C282Y/C282 or
C282Y/H63D. Up to 50 percent of the total study population may have received prior
Elevated transferrin saturation and/or ferritin level, but diagnosis of HH not yet
confirmed by genotype or liver biopsy.
Elevated transferrin saturation and/or ferritin level without genotype findings listed
above, but with elevated hepatic iron index on liver biopsy.
Family member screening (unknown HH phenotype or genotype)
Age less than 15 years.
Patients requiring therapeutic phlebotomy for reasons other than iron overload
Patients with iron overload not due to HH (e.g. hepatitis C infection, porphyria cutanea
tarda, Wilson s disease, alpha-1-antitrypsin deficiency, alcohol abuse).
Other medical illness or condition which, in the opinion of the Investigators, may
contraindicate participation due to risk to patient or to Donor Center.