Iron Overload and Chelation Therapy for Thalassemia

4th Pediatric Infectious Diseases Conference

ISSN 0973 - 0958

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Results

MODERN TRENDS IN MANAGEMENT OF THALASSEMIA

Related Topics

Thalassemia Epidemiology and Pathophysiology

b-thalassemia Clinical Manifestations,Diagnosis and Management

Transfusion Therapy in Thalassemia

Splenectomy,Bone Marrow Transplantation and Neocyte Transfusion

Pharmacological Methods To Increase Gamma Chain Production and Gene Manipulation

Dr.M.R.Lokeshwar
Consultant Pediatric Hematologist,
Imperial Mahal, 3rd floor, Dadar TT, Mumbai - 400014.

IRON OVERLOAD AND CHELATION
THERAPY :

Two factors contribute to iron overload in a thalassemic child:

Enhanced gastrointestinal absorption of iron.

Transfusional siderosis

Normal body iron content is 3-5 gm, whereas in a thalassemic child it could be around 0.75 gm/kg.
It results from increased GI absorption of iron and blood received during transfusion therapy.
In normal individual 1 mg of iron/day is absorbed from the gut, while in a thalassemic child it may be as high as 10mg/day.
Each cubic centimeter of packed cells contains 1-1.6 mg of iron. With an average annual transfusion requirement of 180 cc/kg of packed cells, the body accumulates 200 mg/kg of iron every year.
Transfusional iron overload leads to deposition of iron in the heart leading to cardiomyopathy and irregularity of heartbeats, in the pancreas, in the Islet of Langerhans leading to diabetes, in the liver and spleen leading to hepatosplenomegaly, hepatic fibrosis and cirrhosis of liver, in the pituitary glands leading to growth retardation, delayed puberty character, in the thyroid and parathyroid gland leading to those subclinical or clinical organ dysfunction, and in the skin leading to bronze or black discoloration of skin.
Increased susceptibility to bacterial infection especially Yersenia is seen with iron overload, because relatively high serum iron levels may favor bacterial growth, or because of blockage of the mononuclear phagocyte system by the excessive red cell destruction.
Iron accumulation in the myocardium can lead to death, either by involving the conducting tissues or by causing intractable cardiac failure due to cardiomyopathy.
Serum ferritin concentration reflects the iron overload and is usually above 1000 ug/L. S. Ferritin above 7500 ug/L are found to be lethal.
Despite extensive research for ideal chelating agent, desferrioxamine is currently the only chelating agent of real value for the management of thalassemia, being able to promote the excretion of iron.

DESFERRIOXAMINE (DFO) :

Desferrioxamine is a hydroxylamine compound produced by streptomyces pyloses.
A single gram of DFO is able to bind 85 mg of iron.
Desferal (Desferrioxamine) should be started before the age of 3-5 years.
Given on daily basis for a minimum of 5-6 times per week, it is given subcutaneously over 6-8 hours using an infusion pump. The daily dose of Desferal is about 30-70 mg/kg and should be tailored according to the need of the patient.
In general, the goal is to keep the serum ferritin level below 1000 ng/ml.

TOXICITY OF DESFERAL :

Toxicity is minimal, no tachyphylaxis has been observed.
When given parenterally there may be liberation of histamine leading to bradycardia, hypo/hypertension, rigors, headache, photophobia, feeling cold and hot etc.
When given subcutaneously- local pain, induration, irritability and redness may occur.
Visual abnormality may occur and includes decreased acuity of vision, peripheral field vision defects, defective dark adaptation, thinning of retinal vessels, retinal stippling and abnormal visual evoked responses and cataract, in 4-10% of patients.
High incidence of high frequency sensori-neural hearing loss has been reported in 4-38% of patient. As the auditory and visual toxicity are reversible, yearly slit lamp examination and audiometry are mandatory.
Delayed linear growth has also been reported in children under three years of age treated with Desferal and may be accompanied by mild skeletal abnormalities such as short trunk, sternal protrusion and genu valgum.

ROLE OF VITAMIN 'C' :

Ascorbic acid deficiency increases insoluble iron (hemosiderin). Vitamin C helps in conversion of hemosiderin into ferritin from which iron can be chelated.
High doses of Vitamin C can lead to increased free radical reaction and lipid peroxidation resulting in tissue damage and rapid cardiac decompensation and even death. Addition of vitamin C 100 mg daily prior to DFO therapy increases iron excretion. 60% of DFO chelated iron is excreted in urine and 40% in stool.

NEWER CHELATING AGENTS:

Over the last 20 years, more than 500 oral chelating compounds have been tried all over the world in search of an ideal chelating agent which can be effective, cheap, safe and can be given orally.
Among the various drugs under trial, few have completed animals studies, a few are being tried in human volunteers.

The only drug which has entered human trial is Dimethylhydroxy Pyridone (1,2 Diemethy1-3-Hydroxy Pyrid-4-one (L1), developed in Hider's laboratory-London (40), also called as Deferiprone and is available in India with the brandname of Kelfer.

Deferiprone (L1):

It mobilizes iron from transferrin, ferritin and hemosiderin. It is undergoing extensive trials in USA, UK, Canada, India and various other centres.
Doses administered are 50-100 mg/kg body weight.
Results show that it is 70-100% as effective as desferrioxamine.
There has been no evidence of ear or eye toxicity. Urinary excretion of Ca, Cu, Mn, Mg was not affected. Kidney and liver parameters did not show any alteration.
A few children had GI symptoms like nausea, vomiting, pain in abdomen and diarrhea.
20-30% children had arthropathy which was reversible after reducing the dose or on stopping L1. Physical findings included synovial thickening, synovial effusion, chondromalacia, mild flexion deformity of the knee, painful external rotation of the hip and vague generalized backache.
ANA, dsDNA, antihistone antibodies were positive in a few cases.
Drug-included lupus has been reported in few cases.
Absolute neutropenia and thrombocytopenia also have been reported in occasional cases.
Physical examination particularly of the joints and complete blood count including platelet count must be done regularly when child is on Deferiprone (L1) therapy.