IRON CHELATION THERAPY IN CHILDREN: CRACKING CODE OF THEORY

Iron overload results from:

1. Ongoing transfusion therapy
2. Increased gut absorption of iron
3. Chronic hemolysis.

Extra Iron can be

1. Bound to transferrine & Ferritine
2. NTBI (unstable) (Non chelatable) Fe+3------ >Fe+2 (chelatable) ----->Produces Free Radical ----->Damage to body tissues (Liver,Heart)

1ml RBC=1.16mg of iron

This Extra iron should be removed to prevent organ damage.

OBJECTIVES OF CHELATION THERAPY ARE:

1. To bind free extracellular iron
2. To remove excess intracellular iron
3. To attain a negative iron balance (i.e., iron excretion > iron input).

COMPLICATIONS OF IRON OVERLOAD:

1. Hepatic fibrosis
2. Cardiac complications
3. Endocrinalàdelayed puberty, DM, damage to thyroid &parathyroid

WHAT ARE AVAILABLE CHELATORS ?

1. Desferrioxamine (DFO)
2. Deferiprone (1,2 dimethyl-30hydroxypyrid-4-one)(L1)
3. Exjade (ICL 670) /Desferasirox


A. DESFERRIOXAMINE

Trihydroxamic acid
Produced by Streptomyces pilosus
Relatively specific for Ferric iron

MOA

1. Slow process: DFO + iron----> Ferrioxime----> excreted
2. Rapid process: Mopping the free radiclas

WHEN TO START DFO

1. General rule to be started when patient has received 10-20 transfusion or
2. Ferritin level >1000mcg/lit
3. Usually above 3yrs of age

DOSE

1. 1 g of DFO binds to 85 mg of iron
2. Absorbed little by gut
3. 20-40mg/kg 10% solution as 8-12 hrs slow subcutaneous infusion
4. 5-6days/week

SITE OF INFUSION

1. Abdominal wall, skin over deltoid, lateral aspect of thigh

TYPE OF INFUSION/ METHOD

1. CONTINUOUS 24 HOURS IV INFUSION

Life saving technique in patient with massive iron overloading and associated cardiac complication

Indications:

1. Severe iron overloading with serum ferritin level persistently > 2500µg/lit or liver biopsy iron concentration >15µg/g/dry weight of liver

2. Cardiac complications
3. Female patient planning for pregnancy with high serum ferritin

2. IV 8-12 HOURS INFUSION

3. IV ADMINISTRATION OF DFO DURING BLOOD TRANSFUSION

4. IM ADMINISTRATION

Therapeutic index calculated by:

PORTER INDEX = Mean daily dose of DFO mg/kg /S.Ferritin μg/L
Toxic effects can be avoided if  kept less than .025

EVALUATION OF EFFECTIVENESS OF DFO THERAPY

1. Liver iron concentration (LIC): Good reference standard for measuring iron overload

Methods

1. Invasive : Liver biopsy
2. Non-invasive : MRI T2 

SQUID: superconducting quantum interface devise
LIC >15mg/gm associated with high risk of cardiac complications
LIC of less than 7 mg/gm of dry weight of liver weight is not associated with complications

COMPLICATIONS OF DFO

1. Local skin reactions : itching, pain ,swelling, soreness, lump
2. Severe sensitivity : severe allergy is rare, symptoms are: dizziness, tingling, tachypnea,tachycardia
3. Chronic systemic side effects:

a. Ototoxicity
b. Ocular toxicity

c. Increased susceptibility of infections:  yersinia,PCP,mucormycosis,klebsiella
d. Cartilagenous dysplasia in children less than 3 years

ROLE OF VITAMIN C USE ALONG WITH CHELATORS

1. Reducing agent
2. Convert ferric to ferrous iron ,hence make it available for chelation
3. RDA: for
< 10 years=50mg/day
>10yrs=100mg/day

B. DEFERIPRONE (L1):

Oral iron chelator
Is a bidentate ligand (having 2 binding sites)
chelator molecules are required for to form neutral complex with single iron atom

Physical properties:

Low molecular weight
Water soluble
Highly stable at PH 1-12
Resistant to gastric digestive enzymes

MOA: 

Binds with ferric iron with high affinity & rapidly absorbed by stomach
Peak concentration with in 1 hr
Compared with DFO, it is very slowly removed from blood
90%-excreted in urine in 5-6 hrs

Advantages:

1. It readily enter both parenchymal and reticuloendothelial cell

2. Also chelates iron from transferrin –account for 20%
3. Chelates iron from intact RBCs

SHUTTLE HYPOTHESIS:

1. L1 is small molecule can enter cell more easily than DFO hence
2. L1 makes iron available for DFO out side the cells this is shuttle hypothesis
3. Combined DFO & L1 has additive effect

Adverse effects:

1. Neutropenia and Agranulocytosis
2. Arthropathy
3. GI side effects: Nausea, vomiting , diarrhea
4. Zinc deficiency
5. Liver toxicity: increased liver enzyme

Monitoring Therapy:

1. CBC Q1W
2. Serum ferritin Q3 monthly
3. Liver enzymes
4. Serum Zn level Q 3-6 M

C. EXJADE (ICL 670): (Deferosirox)

New highly efficient , specific for Iron, powerful intracellular iron chelator
Convenient once daily use
Two molecules combined to form complex with ferric iron
Iron excretion predominantly fecal through bile
It chelates iron from both reticuloendothelial cell and parenchymal cells
It prevent myocardial iron uptake
It remove iron from myocardium , exchange with DFO
It is more potent chelator than DFO (5times) and L1 (10times)
It is highly specific for iron and does not promote excretion of Zinc and cupper
It reduce liver iron concentration as good as DFO

DOSE: 80mg/kg/day

Adverse effects: 

Generally well tolerated
GI side effects are more common (nausea,abdominal pain ,constipation)
It also has ‘shuttle effect’ along with DFO 

1. Desferrithiocin
2. Hydroxybenzyl -ethylediamine- diacetic acid
3. Pyridoxal isonicotinyl hydrazone
4. GT56-252