“Iron overload is a predictable complication in chronic transfusion therapy, but it may also occur in patients with limited or no history of transfusions”
Zanella et al, 1993, 2001
Chronic iron overload, also known as hemosiderosis, is a condition in which the body absorbs too much iron. It is a common complication of pyruvate kinase deficiency for both transfusion and non-transfusion dependent patients with pkd. The body needs iron, but too much iron is very dangerous to the organs. With the exception of menstruation, humans have few natural mechanism to rid their bodies of extra iron. Without treatment, any excess iron will find its way into the body tissues such as the liver, heart, pituitary and pancreas, causing damage and eventual failure of these organs. The most common site of iron overload in pyruvate kinase deficiency is in the liver. The following is a list of some health problems that can be associated with iron overload:
- Liver disease
- Heart failure / Cardiac arrhythmias
- Osteoporosis / osteopenia
- Irregular periods
- Thyroid problems
How is iron measured?
It is critical that patients with pk deficiency have their iron closely monitored. There are two important measurements doctors use to evaluate iron levels in these patients. – Liver Iron Concentration (LIC) and Serum Ferritin (SF).
Liver Iron Concentration (LIC)
This measurement is taken with liver biopsy, R2 (Ferriscan®) or T2* magnetic resonance imaging (MRI), or SQUID imaging. Historically, liver iron was measured through liver biopsy. Now most patients have their liver iron measured by imaging. Imaging allows an assessment of the entire liver. In addition, some of the imaging modalities, such as MRI, also measure iron in the heart and pancreas. Evaluation of iron status should be considered after 10-20 red cell transfusions, ferritin >500 ng/ml, or, for those who are infrequently transfused, when a patient can tolerate a non-sedated MRI.
Serum Ferritin (SF)
This is a simple blood test that measures how much iron is in the blood. Although ferritin levels are a convenient way of monitoring iron overload, it can be a misleading indicator of total body iron content. Many doctors advise keeping ferritin levels below 1,000 ng/ml, while others advise that levels be kept even lower (500 ng/ml), particularly in adults. Ferritin tends to underestimate iron overload, so measurement by imaging should be considered when ferritin >500 ng/ml.
Treatment for iron overload in patients with PKD
Physicians monitor iron levels closely in order to adequately remove excess iron from the patient while at the same time preventing any potential drug toxicity. It should be noted that young children are more prone to iron chelator toxicity. The lower the LIC and SF the greater the chance of drug toxicity due to over-chelation.
The two treatment options for removing extra iron from the body are phlebotomy (blood removal) and medication (chelation).
Therapeutic phlebotomy is the same procedure that is used when a person donates blood. This treatment is prescribed by a doctor whose non-transfusion dependent patient has too much iron stored in his/her body and has a hemoglobin level high enough to tolerate the loss of blood. A typical phlebotomy removes about 500 cc’s of blood, but with pk deficiency patients who are anemic, carefully administered “mini” phlebotomies may be a treatment option. Close monitoring by the patient’s physician is needed to assess whether the patient is tolerating the phlebotomies. The frequency of phlebotomies varies with severity of iron overload. Often they are performed weekly to once per month.
Medications called iron chelators are the only option for iron removal in transfusion dependent patients and a commonly used method of removing iron in non-transfusion dependent patients with pyruvate kinase deficiency. Compliance with medications is of utmost importance for adequate iron unloading. At this time there are three iron chelating medications available to patients. For some patients, they may be used in combination.
- Deferroxamine (Desferal)
- Deferasirox (Exjade or Jadenu)
- Deferiprone (L1)
Important note: Though these chelating medications have been found to be safe and effective in patients with thalassemia, because of the rarity of pk deficiency, there have been no comprehensive studies completed on large groups of patients with pkd using these chelators.
“Some nights I really, really want to skip wearing my Desferal pump, but then I picture the iron sitting in my organs…destroying them. That keeps me on track”
Female, PKD Patient
Though Deferoxamine (Desferal, DFO) can be given intravenously, it is most often administered subcutaneously (with a short needle under the skin) using a portable infusion pump. Typically the pump is worn 8-15 hours, 5-7 days per week. Dosage and frequency is individualized and based on the degree of iron overload and the weight of the patient. DFO has been on the market and studied in patients longer than any other iron chelator available.
Click here for information on dosage, toxicity, and side effects of Desferal.
Deferasirox (Exjade, Asunra, Desirox) is a daily oral chelator (tablet) that is mixed with water, orange juice, or apple juice. Although it is recommended that it be taken on an empty stomach about 30 minutes before or after eating, recent data indicate that taking Exjade with food is effective for patients who have difficulty taking it on an empty stomach. The most dangerous potential side effect of this medication is kidney damage. It is important that creatinine levels be monitored monthly. Gastrointestinal side effects (nausea, vomiting, diarrhea, abdominal pain) are the most common and usually subside over time. If these symptoms persist a doctor may reduce the dose or stop the drug and start it up again by gradually increasing the dose up to the desired level. Many patients have also responded with fewer side effects by splitting the prescribed dose into two – taking one half in the morning and one half in the evening.
Since the beginning of 2017 Exjade is made as a film-coated tablet which makes taking it much easier. It is recommended taken on an empty stomach or after a light breakfast. Because it has a coating the tablet disolves slower and therefore gives less side affects for most people. When people still have the side affects they can split the dosage into two or three times a day.
Click here for more information on dosage, toxicity, and side effects of Exjade.
Jadenu is the newest iron chelator available. It is Deferasirox, but in a film coated tablet form that does not get dissolved. It is taken with water or another liquid once daily. In Europe the same medicine is given out under the name Exjade since the beginning of 2017.
Click here for more information on dosage, toxicity, and side effects on Jadenu.
Deferiprone (Ferriprox , L1, Kelfer) is an iron chelator that is administered to transfusion dependent patients, which is often picked as second or third choice when their current chelator is not effective or has intolerable side effects. It is a tablet that is taken orally 3 times per day. This drug can cause a very low white blood cell count (neutropenia). Severe neutropenia is called agranulocytosis, which can lead to significant illness or death. Therefore, any patient taking this drug needs to have his/her white blood cell counts checked once per week.
Click here for more information on dosage, toxicity, and side effects of Ferriprox.
Barton, James C., et al. Handbook of Iron Overload Disorders. 1st ed. Cambridge: Cambridge University Press, 2010.
Vichinsky E, et al. Standards of Care Guidelines for Thalassemia. UCSF Benioff Children’s Hospital Oakland. 2000, revised 2009.
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