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Hereditary Hemochromatosis QC

This study will evaluate the effectiveness of a test called MCV to guide phlebotomy (blood draw) therapy in patients with hemochromatosis, an inherited disorder that causes the intestine to absorb too much iron. Excess damages body tissues, most seriously the liver, heart, pancreas, and joints. Because iron is transported in the hemoglobin of red blood cells, drawing blood can effectively reduce the body’s iron stores.

Hemochromatosis patients undergo weekly phlebotomy treatments (1 pint per session) to deplete iron stores. This generally requires 10 to 50 treatments, after which blood is drawn every 8 to 12 weeks to prevent iron build-up. A test that measures ferritin, a protein involved in iron storage, is commonly used to guide phlebotomy therapy in patients with hemochromatosis.

This study will compare the usefulness of the ferritin test with that of the MCV, which measures the size of red blood cells, in guiding phlebotomy therapy. Additionally, the study will 1) examine whether keeping iron levels low during maintenance therapy can help cure severe liver disease and improve arthritis in affected patients, and 2) design a system to make blood collected from donors hemochromatosis is available for transfusion to other patients.

Patients 15 years of age or 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 will complete a symptom questionnaire. Participants will have the following procedures:

  • Phlebotomy therapy every 1 to 2 weeks, depending on iron levels
  • Collection of blood samples for blood cell counts and iron studies at each phlebotomy session
  • Collection of blood samples (approximately 2 tablespoons) every 1 to 2 weeks after iron stores have been depleted.
  • Phlebotomy every 8 to 12 weeks after iron stores are depleted to prevent build-up the excess iron

With each donation of blood 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 that are given to all regular volunteer blood donors. These include screening for HIV and hepatitis and syphilis viruses.

Patients who meet height and weight requirements may be asked to consider donations of “double red blood cells” by apheresis. In this procedure, whole blood is collected through a needle that is placed into a vein in the arm, similar to a routine phlebotomy.

The blood then circulates through a machine that separates it into its components. Red blood 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. The NIH Liver Service will offer an evaluation to patients who have very high iron levels or an enlarged liver.

Those who are considered to be at increased risk for cirrhosis may be recommended to undergo a liver biopsy. If cirrhosis is found, the patient will be asked to consider repeating the biopsy after 3 to 5 years of continuous iron depletion to see if healing has improved. Arthritis patients will be offered an evaluation by the NIH Arthritis Service and, based on symptoms, may be recommended to have X-ray studies or a biopsy of the joint.

Detailed Description

Hereditary hemochromatosis (HH) occurs in 1 in 200 to 250 individuals of Northern European descent and is the most common inherited disease in this population. Although the molecular pathophysiology is not yet fully understood, a homozygous mutation in the HFE gene (Cys282Tyr) is seen in nearly 100% of clinically confirmed cases. The clinical manifestations of HH are due to an inadequate increase in iron absorption with excessive iron deposition in the liver, heart, endocrine organs, and joints.

Phlebotomy treatment, with removal of iron contained in hemoglobin from red blood 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 generally allow a moderate level of iron overload to persist during maintenance therapy.

Since 1987, the DTM has tested the use of red blood cell mean corpuscular volume (MCV), along with hemoglobin, as a prospective guide for phlebotomy therapy in a small cohort of HH patients. In contrast to other retrospectively derived guidelines, this simple and inexpensive physiological method was found to be an accurate indicator of iron-limited erythropoiesis, and could be easily applied to adjust the rhythm of phlebotomy and prevent excessive iron re-accumulation.

Although the majority of people with HH meet the eligibility criteria for allogeneic blood donation, until recently regulatory guidelines restricted the use of therapeutically drawn blood for transfusions. The new regulations now allow greater 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) evaluate the course of severe liver disease and rheumatological symptoms after sustained iron depletion; and (3) establish safety and efficacy and document operational problems inherent in a program to collect therapeutically drawn blood for use in allogeneic transfusions.

These objectives are combined with the establishment of the simplest and safest system for donor processing, phlebotomy management, and transfusion of blood drawn from HH subjects.

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