THERAPIES TO DECREASE IRON

Iron Reduction

Iron is removed therapeutically from the body in two ways, by blood donation (phlebotomy) or chelation therapy (pharmacological removal). The therapeutic approach used, the amount of iron removed, follow-up testing of iron levels, dietary and behavioral changes made will all differ according to the patient’s iron levels, general health, age and ability to tolerate the chosen approach.

Phlebotomy/Blood Donation 

Phlebotomy definition:
A phlebotomy is blood removal; when used as a treatment, it is called therapeutic phlebotomy (TP). The procedure is identical to blood donation, except that TP requires a doctor’s prescription. Physicians prescribe therapeutic phlebotomies for patients who have too much iron stored in their bodies and whose hemoglobin levels are sufficient to tolerate blood removal.Each blood donation, or phlebotomy treatment, removes about 500cc of blood and reduces the amount of iron in the body by about 250 milligrams.

Phlebotomy Phases of Therapy: induction, transition, and maintenance
Induction is when therapy is initiated. Transition is the phase in which iron reduction is taking place to return iron levels to a normal healthy range. Once iron levels reach satisfactory and healthy levels, a patient enters the maintenance phase.

Induction:
Key to successful iron reduction without generating symptoms or accelerating disease depends on several important factors. The single most important factor is how the doctor writes the order for phlebotomy. Besides this critical first step other important factors are patient compliance with scheduled phlebotomies, diet and behavior modifications and continued education. With few exceptions Iron Disorders Institute Advisory Board recommends a pre-treatment hemoglobin of 12.5g/dL. Exceptions will include some females or patients with liver or blood diseases. For most hemochromatosis patients, an order might be written as follows: “Phlebotomize 500 cc once a week** if Hgb=or >12.5g/dL” (38% hematocrit)

**period of time should reflect frequency desired.

Transition:
During this phase iron levels may be erratic or fall predictably. The frequency of phlebotomies may change from twice weekly, to weekly or monthly. Generally when a patient’s serum ferritin is less than 500ng/mL, the frequency of phlebotomy can be slowed to once a month. Each person is different and responds to treatment in a unique way. Much depends on age, the extent of iron saturation, serum ferritin levels, hemoglobin response, one’s physical condition including symptoms, and the speed with which an individual unloads iron. Also, compliance with therapy schedules and care with diet will impact this phase tremendously.

The goal of the transition period is the safely usher the patient from therapeutic phase into the maintenance phase. During this period, if iron levels are allowed to fall steadily, over time and not too rapidly, the body can reach healthy iron levels and possibly without competition from the genes that are programmed to load iron.

Maintenance: Maintenance patients are those who have reached healthy iron ranges and who can remain within those healthy ranges by donating blood periodically. A healthy range for ferritin is 25-150ng/mL. But patients in therapy for iron reduction should achieve a serum ferritin below 50ng/mL on at least one occasion. Thereafter, the ferritin can be maintained within the range of 25-75ng/mL.

The patient may donate blood routinely as defined by attending physician for optimum quality of health or may have periodic therapeutic phlebotomy by doctor’s order. Frequency of donation or therapeutic phlebotomy will depend upon patient’s Personal Health Profile as observed by patient and attending physician: age, weight, response to treatment, symptoms, rate of iron unloading and general physical condition. At anytime during treatment you experience symptoms of heart irregularities or severe abdominal pain or symptoms of anemia, alert your physician immediately.

Symptoms of anemia can often be mistaken by a patient as symptoms of iron overload. Symptoms of anemia or iron overload can include: fatigue, heart arrhythmia, headache, sensitivity to cold, shortness of breath, dizziness and restless legs syndrome. Lab tests are needed to distinguish between the two.

If excess iron has had enough time to damage critical organs, one may never restore these damaged organs to full function. Medications may be required to address these symptoms or disease that has developed.

During the maintenance phase, and so long as a patient remains symptom-free, the doctor will re-test iron levels about every 3 months. The initial three-month exam upon reaching healthy iron levels will provide a baseline or the first set of numbers after a series of phlebotomies whereby a person’s pattern of un-loading can be established. These numbers are very important to the management of iron balance.

The amount of time required to reach the maintenance phase of treatment will vary. Thereafter, how often that person must have a phlebotomy to keep iron levels in a normal range will depend on compliance. Many hemochromatosis patients abandon therapy once they achieve normal iron levels. This sets them up for irreversible organ damage and the need for repeat series of therapeutic phlebotomies.

For the hemochromatosis patient maintaining iron balance is a life-long effort—timely blood donation is their “drug”.

Serum Ferritin and Phlebotomy Frequency:
In most cases the serum ferritin will drop by about 30ng/mL with each full unit of blood removed.  This helps the physician to form an estimate of when the serum ferritin is will be below 1,000ng/mL.

For patients whose initial serum ferritin (SF) is greater than 1,000 ng/mL, phlebotomies can be as frequent as twice a week. The SF should be evaluated every 4-6 weeks until it is lowered below 750 ng/mL. SF above 750 but below 1,000 is still a very high and may require continued weekly phlebotomies. However, issues such as  inflammation and alcohol consumption should be taken into consideration when maintaining weekly or adjusting the frequency of blood removal.  A patient may need to continue on aggressive removal (at least once a week) if iron levels are dropping at a fairly steady pace. When serum ferritin falls dramatically, highly suspect are inflammation or other factors that influence serum ferritin levels.  

Ferritin drops by about 30-50ng/mL with each full unit of blood removed. Ferritin levels can be distorted. Individuals who have liver damage such as cirrhosis will unload iron faster than those without liver damage. Other factors that may skew ferritin include presence of inflammation or infection and alcohol or nicotine consumption (gums, patches, chews). Checking ferritin periodically can protect against undue iron deficiency anemia caused by overbleeding.

Patients undergoing de-ironing are at risk for overbleeding that can take place in the latter part of de-ironing. Bleeding a patient until the hemoglobin is below normal and the patient has mild iron deficiency anemia is no longer the best practice. There is no known benefit to the forced-sustained anemia, a practice that was established nearly three decades ago. Iron Disorders Institute Advisory Board recommends against phlebotomy (with few exceptions) for patients whose hemoglobin is lower than 12.5g/dL.

Prior to treatment, a patient will have a serum ferritin greater than 200ng/mL (females) or 300ng/mL (males) with an accompanying transferrin-iron saturation percentage greater than 45%. When ferritin is above 1000ng/mL phlebotomy treatments will be aggressive usually as frequent as twice weekly while tolerable and until ferritin drops below 1000ng/mL. Once serum ferritin is below 500ng/mL, the frequency of treatment may slow down from twice weekly to once a week or even to every other week depending upon the patient’s condition, behavior (eating habits) and ability to unload iron.

During de-ironing: blood contains water and other nutrients. Adequate fluid intake guards against dehydration. Patients are encouraged to take a once-a-day multi-vitamin without iron to support the loss of nutrients. Look for vitamins with minerals (except iron) and B complex. Otherwise, serum ferritin can be checked periodically such as every 3-6 months to determine the patient’s unloading pattern.

Most blood donation centers allow one donation every eight weeks. If you are a candidate for maintenance, then a periodic blood donation will suffice. If you are found to need treatment, needing more than one extraction in eight weeks, the attending physician will provide you with the necessary order for additional phlebotomies. Your gastroenterologist or hematologist may refer you back to your family physician for the maintenance phase of your therapy. Afterwards, you may resume a normal, happy healthy life with only a small adjustment to your schedule: a life-saving, blood donation every 8 to 10 weeks.

My Iron Levels
Body iron levels are determined by measuring serum ferritin, fasting serum iron and total iron binding capacity (TIBC). A patient’s transferrin saturation percentage (TS%), an important measure of the body’s capability to bind, transport and maintain safe levels of iron. TS% is calculated by dividing serum iron by TIBC multiplied by 100%. TS% is normally about 35-40%.
Serum ferritin is a measure of stored or contained iron. SF varies by age and gender. INSERT Ferritin chart

With the exception of infants and newborns, iron overload is suspect when both serum ferritin and TS% are elevated. There are other conditions of high body iron where only the serum ferritin is elevated. These individuals can benefit from periodic blood donation as elevated serum ferritin is a possible early warning that disease is forming.  

Hemoglobin indicates the amount of functional iron, that is, the iron that is carrying oxygen to tissues so that organs can function.

What is the role of hemoglobin in phlebotomy?

Hemoglobin value will determine if a person can tolerate phlebotomy to reduce iron levels. If the hemoglobin value is too low, but iron overload is present, iron chelation therapy is used to reduce excessively high iron levels.

For most hemochromatosis patients the hemoglobin levels will rebound and remain in a normal healthy range following phlebotomies or blood donation.  Patients with significant iron overload can tolerate frequent treatments because their hemoglobin will rebound very quickly. As the body manufactures new blood to replace that removed, the new liquid acts like a sponge; it draws the iron out of the body tissue (stored in ferritin) to synthesize hemoglobin in the new blood. Once iron becomes part of hemoglobin it can be safely removed with the next treatment.

Hemoglobin levels prior to blood donation should be 12.5g/dL with few exceptions.

Why do I need a phlebotomy?
Phlebotomy reduces excessive and life-threatening levels of body iron. Some patients diagnosed with hemochromatosis have already built up 5 or 10 grams (or more) of excess iron in their bodies. These patients will require aggressive treatment and sometimes will be phlebotomized (or give blood) as often as once or twice a week. For individuals whose iron levels are only modestly elevated, blood can be simply donated every eight weeks without a prescription.

If serum ferritin is less than 1,000ng/mL at the time of diagnosis, the chances of liver cancer is less than 1%. But if diagnosis occurs after serum ferritin has risen above the 1,000 mark, the risk of liver cancer jumps 20-200 fold depending on the individual.

Pretreatment Lab work:
Before the phlebotomy may be done, hemoglobin or hematocrit must be checked. Usually centers have labs on site where the results are forwarded to the attending nurse or phlebotomist. With few exceptions, if the hemoglobin is too low (below 12.5g/dL) the phlebotomy should be postponed to avoid the risk of over-bleeding and unnecessary iron deficiency. Otherwise a person can become iron avid and set themselves up for increased symptoms and struggles to achieve iron balance.

Keep good records:

You may request a copy of lab work from the office manager in charge of records in the doctor’s office. Obtaining lab results is highly recommended so that a journal may be compiled. Journals will become a valuable tool if you have to move to another town or seek treatment from another doctor. Knowing about your disorder and understanding the diagnostic process helps to speed recovery and avoid future health setbacks. Iron Disorders Institute provides a free copy of its Personal Health Profile in the Resource Center of the website. These forms are designed to help patients track important information that can be shared with the healthcare provider.

Where are phlebotomy treatments performed?
Phlebotomies might be performed at a blood donation center, as an outpatient in a hospital or even in a doctor’s office. Your doctor will probably advise places that provide the treatment. Consider convenience of location, cost to do the phlebotomy, and how responsive the center is to your situation.

In 1999 the FDA declared hemochromatosis blood to be safe for transfusion (to give to others) so long as the hemochromatosis patient qualifies to donate blood as volunteer donors. As a result, many private blood centers and one American Red Cross center offer hemochromatosis donor programs.

The Therapeutic Phlebotomy (TP) Procedure Described: The process varies slightly depending on the treatment site; following is a general step by step of what takes place.

After the preliminary tests for hemoglobin and hematocrit are finished, a phlebotomist prepares you for the procedure. The phlebotomist can sometimes be a nurse or doctor, but regardless, this individual is trained to perform needle sticks.

If your hemoglobin-hematocrit are sufficient and in accordance with the doctor’s order, you will be prepared for blood removal. Usually you will stretch out on a comfortable recliner chair. The attendant takes your blood pressure, temperature and heart rate (pulse). These numbers will be recorded on your medical chart for future reference.

An elastic band is tied around the upper part of the arm. This helps the vein to stand up. You may have to squeeze a soft rubber ball or make a fist several times to help the vein remain accessible. The nurse then swabs an iodine-based antiseptic on the vein and all around the area near the vein. This is to disinfect the area where the needle is to be inserted and to make certain no bacteria gets into your system during treatment.

A special needle is then inserted into the vein. You might feel a little pinch, but it lasts only a second. A piece of tape is placed over the needle to keep it stable; you just sit back and relax. The needle used is large enough for blood to flow quickly without clotting. Some patients have a fear of needles or vein access difficulties. There are ways to address these issues but they are not routine and require assistance from the healthcare provider and in some cases involve a surgeon. See Phlebotomy Problems and Issues

While the blood flows, some like to bring a headset with earphones or a good book to read during treatment. While relaxing, the blood flows from the needle, into a tube, and then into the blood bag. The blood bag sits onto a scale that measures the weight of the blood. When 500cc (about one-half pint) of blood is removed the donation or phlebotomy is complete. Some blood centers can offer Double Red Cell Apheresis (DRCA) treatment to hemochromatosis patients. DRCA removes more red blood cells but the amount is less than double.

About 250 mgs of iron are removed with each unit of blood removed. The procedure will take as few as ten minutes or as many as thirty; again, it depends on how hydrated you are, your vein access and the thickness of your blood.

After the Treatment:
After the phlebotomy, the nurse will remove the needle from your arm. You may need to keep the area bandaged or you may need to apply mild pressure if bleeding continues. You should rest for about 20 minutes following therapy. This is a precaution to insure you do not get weak or dizzy. You may be given a snack while you are resting and it is suggested you eat something after your therapy.

Your blood will be discarded unless you are enrolled in one the blood centers with an FDA variance to use hemochromatosis blood for transfusion. You can find a list of these centers on our website in the Resource Center.

Between phlebotomies:

To prepare yourself, be sure that you are getting adequate fluids. A daily multi-vitamin without iron is recommended because with treatment iron is removed but so are other nutrients. Nothing replaces a diet with variety but a daily multi can offer benefit during the phlebotomy phase. Be careful about water consumption. Gulping great amounts of water prior to therapy is not wise; you may actually cause yourself to become water intoxicated, a serious condition that can result in death. Hydrate yourself slowly over days; do not wait until the last moment.

Diet tips:

Eat more fiber, refrain from slow-cooking in an iron skillet, and limit Vitamin C to 200 milligrams per dose. Fiber impedes iron absorption while vitamin C enhances iron absorption. Drinking tea with meals is helpful as the tannin in tea also impedes iron absorption. Iron absorption is not known to be affected by caffeine. Nicotine will increase iron levels; nicotine gums and tobacco products should be avoided. Smoking should be discontinued; tobacco is rich in iron and inhalation of this smoke directly or second-hand is harmful to your lungs. Hydration can be accomplished by increasing consumption of fresh fruits and vegetables. There is no need for concern about the vitamin C or A content of fresh fruits or vegetables, although the less sugary choices are best. Fresh, whole fruits and vegetables provide antioxidant protection against harmful iron triggered free radical activity. It is this action that is believed to do the most damage to vital organs. You can read more about free radical activity and antioxidants in the Resource Center.

Exercise:

Regular, intense exercise or taking aspirin daily will cause some blood loss and thus iron loss. However, you should consult your doctor before incorporating any of these practices into your daily routine. Intense exercise (or marching) can result in a condition called “March Hemoglobinuria”, which causes the premature breakdown and destruction of red blood cells that results in anemia. Excessive aerobic exercise can create an environment for increased oxidative stress (free radical activity). Low impact exercise such as walking appears to offer the best benefit with the fewest injuries or side effects. Try to walk 10,000 steps a day if you can. Pedometers can record the number of steps that you take. You might be surprised to learn that most Americans take an average of only 2,500 steps a day!

WARNING: Aspirin can be dangerous for youths with fever and it can interact with some drugs. Your pharmacist may be able to provide you with drug interaction advice; if not, contact your doctor.

Problems and Issues:

Fear of needles is a powerful deterrent to iron reduction. It is a common complaint expressed by men and women alike. There are not too many alternatives for such a patient, but there are some steps that can help. Taking a light sedative (prescribed by the doctor) can relax a person sufficiently to insert the needle. Having a support person present to distract a nervous patient can be helpful. Listening to music through a headset can also be distracting. Double Red Cell Apheresis (DRCA) is a good choice for many of these patients. One stick allows nearly double the iron extraction saving the person from the anguish or anxiety of twice a week punctures.

Numbing agents such as Emla Cream can help in some cases. These creams temporarily numb the skin allowing the needle to be inserted. Check with your doctor about a prescription but first see if the blood center has any objections to the use of such a product.

Vein access is another issue. When patients require multiple and numerous blood extractions sometimes a chest port is an option to consider. Otherwise, veins in the legs can be used to remove blood.

Since scar tissue can build up significantly over time, a person whose arms are scarred might consider wearing a medical ID bracelet. This can distinguish them from individuals who may be chronic drug abusers.

Chelation Therapy

Definition: Iron chelation therapy is the removal of excess iron from the body with special drugs.  Chelate is from the Greek word “claw”.

Patients who have anemia (low hemoglobin) and iron overload at the same time cannot tolerate phlebotomy (blood donation). These patients need iron chelation therapy to remove the iron.

Anemia with iron overload is prominent in several conditions such as sickle cell disease, thalassemia major, myelodysplasic syndromes (MDS), enzyme disorders, iron transport or storage disorders, and some forms of cancers.  Patients with these conditions require repeated blood transfusions to survive.

Each unit of blood used in transfusion contains about 250 milligrams of iron. The body cannot excrete iron, except in tiny amounts-about one milligram per day, which is sloughed off in skin or perspiration. Therefore the excess iron is trapped in the tissues of vital organs, such as the anterior pituitary, heart, liver, pancreas and joints. When the iron reaches toxic levels, damage can result in diseases such as diabetes, cirrhosis, osteoarthritis, heart attack, and hormone imbalances. Hypothyroidism, hypogonadism, infertility, impotence and sterility can result from these hormone imbalances. The patient can experience symptoms of chronic fatigue, mood swings, loss of sex drive, confusion, and memory loss. If not addressed, excess iron can result in complete organ failure and death.

It is important to remove the unnecessary iron before damage can occur. Iron reduction is accomplished with chelation therapy, which is the removal of iron pharmacologically with an iron-chelating agent such as desferrioxamine, brand name Desferal or deferasirox, brand name Exjade. Both of these products are manufactured by Norvartis Pharmaceuticals and are currently the only two iron chelator drugs approved for use in the US. These drugs are specifically formulated to bind with iron so that the iron can be excreted in urine.

Other types of chelation
The type of chelation therapy used to de-iron patients should not be confused with EDTA (ethylenediaminetetra-acetic acid), a method used by some alternative medicine practitioners. EDTA is a broad-spectrum chelator, meaning that it binds with and removes a wide number of minerals, including iron, but it is not specific to iron.

Deferrioxamine, brand name Desferal is not absorbed in the intestinal tract; therefore, this drug must be administered intravenously at an infusion center. Or the drug can be given subcutaneously, using a portable battery-operated infusion pump. Generally, the pump is worn at night, where slow infusion of the iron chelating agent is administered over a period of about eight hours, for the duration of four to six nightly infusions per week. Patients are given a step-by-step demonstration of how to sterilize the skin, insert the needle and operate the pump. 

Before Desferal is administered by either method, a test dose is given to be certain that there are no immediate reactions to the drug. Desferal is administered slowly at first, beginning with 1.0 gram, three to four times per week with monitoring of iron excretion in a cumulative 24-hour urine sample. If effective, the dose can then be adjusted upwards, one gram at a time, up to four times per week, until the patient reaches a tolerable level. The dose should not to exceed 50 milligrams/kg weight, or about 3 grams per day. Periodic examination of the patient is necessary until positive response to treatment is confirmed. Patients might be given an additional two grams of Desferal intravenously for each unit of blood transfused. Desferal is injected separately from blood transfusions.

Desferal has been approved for use in the USA since the late 1970’s. Deferiprone also called L1, brand name Ferriprox is different from Desferal in that Ferriprox can be taken orally. In August of 1999, Apotex Inc., the Canadian Pharmaceutical Manufacturer of Ferriprox was granted approval in Europe by the European Agency for the Evaluation of Medicinal Products to use the oral chelator for treatment of iron overload in patients with thalassemia when desferrioxamine therapy is contraindicated or in those who develop serious toxicity with desferrioxamine therapy. Ferriprox is not approved for use in the USA.

The primary role of iron-chelation therapy is to prevent premature death from heart attack due to myocardial iron overload. Statistically 50% of patients with thalassemia major die of heart attack before the age of 35, primarily due to iron-related heart failure.

Side effects of IV iron chelation:

The urine can become orange colored, which is a harmless side effect. Immediate symptoms of adverse reaction to IV iron chelation therapy might include: visual disturbances, blurred vision, rash or hives, itching, vomiting, diarrhea, stomach or leg cramps, fever, rapid heart beat, hypotension (low blood pressure), dizziness, anaphylactic shock, and pain or swelling at site of intravenous entry. Long term problems might include kidney or liver damage, loss of hearing or cataracts.

Patients should report such symptoms immediately to their physician who can adjust dosage. Further, physicians might examine patient’s visual status with slit-lamp fundoscopy (examination of the eye) and hearing status with audiometry or hearing test. Liver enzymes (ALT, AST, GGT and ALP), a kidney function test such as BUN, serum ferritin and transferrin iron saturation percentage might also be measured by the attending physician.

Limitations of Desferal

Nursing mothers will need to talk with their physicians about iron chelation drugs.  It is not known how much of the drug gets into breast milk; thus, a mother who is receiving Desferal treatment might consider low iron soy formula substitutes.

When to begin iron chelation therapy

Initiating chelation therapy depends upon several factors: the patient’s overall health, hematologic values, especially hemoglobin, hematocrit and the tissue iron levels. Tissue iron is determined by measuring serum ferritin, and fasting serum iron and TIBC (total iron-binding capacity). Transferrin-iron saturation percentage (TS%) can be calculate with these last two tests (serum iron divided by TIBC multiplies by 100%). The results from these tests can be used to monitor iron build up and to address the excess iron as soon as possible. Some physicians will begin iron chelation therapy when serum ferritin is between 1,000-1,500ng/mL. Serum ferritin that is above 2,500 ng/mL before beginning iron chelation therapy might result in organ damage.