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 محاضرة اليوم 20.1.2009 للدكتورة رزيقة العبادي Iron overload

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تاريخ التسجيل : 15/09/2008

مُساهمةموضوع: محاضرة اليوم 20.1.2009 للدكتورة رزيقة العبادي Iron overload   الأربعاء يناير 21, 2009 3:35 am


سم الله الرحمن الرحيم
في تمام الساعة الثانية عشر من ظهر اليوم الثلاثاء وضمن نشاط المستشفى التعليمي وحسب توجيهات السيد مدير المستشفى ألقت الطبيبة الأختصاصصية في طب الأطفال د- رزيقة العبادي محاضرة قيمة في قاعة التعليم الطبي المستمر في بهو الأطباء حضرها مجموعة كبيرة من العاملين في الحقل الطبي من أطباء الأطفال وقسم الثلاسيميا وقسم المختبر ومجموعة من الصيادلة وطبيبات من قسم الأسنان ومجموعة من الأداريين والعاملين في المجال الصحي والأداري والقانوني ... وهذه بعض الصور لغرض التكبير أضغط على الصورة المطلوبة





]

مكان الصور لاحقا

وباسم أدارة المنتدى أتقدم بخالص الشكر والتقدير للدكتورة رزيقة العبادي لجهودها في أعداد وتقديم المحاضرة ولكل الأخوة الحضور متمنيا دوام الأستمرار بهذه النشاطات والفعاليات العلمية لتقويم المسيرة العلمية والطبية وتقديم الفائدة العلمية للجميع وفيما يلي بعض من جوانب محاضرتها



Iron overload in Thalassaemia
Dr.Razeqa Al-Abadi
M.B.Ch.B. DCH
Hereditary Anemia Center
Ibn Al-Bildi Hospital
Baghdad
Lines of Management in Thalassaemia:
Blood transfusion
Iron chelation
Splenectomy
Support therapy
Psychological support

Iron overload occurs when iron intake is increase over a sustained period of time, Frequent blood transfusion (thalassaemia major)
Increased intestinal iron absorption (more in thalassaemia intermedia).
Because there is no mechanism in humans to excrete the excess iron, this has to be removed by chelation therapy
.
Role of Hepcidine:
Hepcidin is a small peptide that inhibits iron absorption in the small bowel.
Hepcidin levels normally increase when iron stores are elevated.
Low hepcidin in thalassemia ?
Hepcidin levels were found to be inappropriately low in patients with thalassemia intermedia and thalassemia major.

Calculation of transfusional iron:
Simple method:
1 blood unit contains 200 mg of iron

whole blood 0.47 mg iron/mL (haematocrit 0.35)
‘pure’ red cells 1.08 mg iron/mL (haematocrit 1.0)

More precise method:
Iron transfused (mg) =
blood volume transfused x hematocrit x 1.08

The Rate of Iron Loading in thalassaemia:

100-200 ml of pure RBC / kg / year are transfused
116-232 mg of iron / kg / year or
0.32-0.64 mg/kg/day.


Increased gastro-intestinal absorption of iron:
1-2 mg/day Normal intestinal iron absorption,
In non-transfused thalassaemic patients, iron absorption increases several folds.
3-4 mg/day In poorly transfused patient (1-2 gm/ year).

Normal total adult body iron is approximately 34 g

Iron toxicity:

Iron is highly reactive because it can easily alternate between Iron III and Iron II .
This results in the gain and loss of electrons & generates harmful free radicals that can damage lipid membranes, organelles and DNA leading to cell death & fibrosis.

In health, iron is “kept safe” by binding to molecules such as transferrin, which becomes saturated in iron overload.

The NTBI is cleared only by chelation therapy but rapidly reappears once chelators are cleared from blood.
LPI assay can measure the NTBI as a guide for prognosis.

Complications of iron overload :
Causes
excessive blood consumption:
high transfusion or hypersplenism
poor compliance with chelation therapy
unavailability of necessary chelation therapy
inadequate treatment in early life à irreversible tissue damage
inappropriate prescription of chelation therapy

Mortality in the second decade of life, is usually from
cardiac complications.

Clinical sequelae of iron overload :

Pituitary → impaired growth
Heart → cardiomyopathy,
cardiac failure

Gonads hypogonadism, infertility
hypothyroidism, hypoparathyroidism
Liver → hepatic cirrhosis
Pancreas → diabetes mellitus
Monitoring Iron Overload :
s.ferritin every three months.
< 2500 ng/mL reduce the risk of cardiac complications,
1000 ng/mL or less is recommended.
Inflammation, ascorbate status & hepatitis may affect serum ferritin
LIC:
chemical determination on a liver biopsy sample.
< 7 mg/g dry weight à no high risk of cardiac or liver complications.
> 15 mg/g dry weight à high risk of cardiac death.
non-invasively by magnetic biosusceptometry (SQUID),
magnetic resonance imaging (MRI).

Heart function monitoring every 6 months using
Radioisotope studies: MUGA (Multiple Uptake Gated Acquisition)
CMR; cardiac magnetic resonance imaging ( T2* measurement).
Sever; T2*<6 ms, 8-20 ms indicate mild to moderate effect.

Growth & sexual development
Yearly GTT
Assessment for hypothyroidism & hypoparathyroidism.
Urinary iron estimation

When to start chelation therapy:
Thalasaemia major:
10-20 transfusions or
ferritin level > 1,000 ng/mL.
3 years of age,
careful monitoring of growth and bone development and reduced desferrioxamine dosage are advocated.
Thalassaemia intermedia:
the rate of iron loading is highly variable and the relationship between serum ferritin and body iron can be different from thalassaemia major.
Estimation of liver iron is advisable before starting treatment to see whether iron has exceeded safe levels.

Desferrioxamine therapy:dysferal

produced and purified from the microbe Streptomyces pilosus in 1960s & used in early 1970s. S.C use in 1980s

1 molecule of DFO binds 1 atom of iron ---- highly stable iron complex.
Big molecule; 1 gram of DFO could bind almost 93 mg of iron.

DFO has a short plasma half-life (0.3h),
eliminated rapidly in urine and bile.
Once an infusion of DFO stops, iron chelation will cease soon thereafter.

Because only a small proportion of body iron is available for chelation, the longer the duration of infusion, the more efficient the chelation process.

In iron overload, vitamin C (ascorbate) is oxidised rapidly, resulting in vitamin C deficiency. This decreases iron excretion with DFO.
disadvantages of Desferal : costly & has to be used parenterally.

Dose of desferrioxamine :

desferrioxamine dose is adjusted according to body iron load and age.
20 - 40 mg/kg/d for children,
up to 50 mg/kg/d for adults,
slow subcutaneous infusion of
a 10% desferrioxamine solution,
using an infusion pump for 8-12 hour
a minimum of 6 nights a week
Therapeutic index = mean daily dose (mg/kg) / s.ferritin (µg/l)
mean daily dose =
actual dose received on each occasion (mg/kg) x doses / wk
The aim is to keep the index < 0.025 at all times
In order not to waste a costly drug, the dose can be adjusted to the nearest whole bottle, alternating between the number of bottles used daily.

Maintain:
s. ferritin <2500 ng/mL (1000 ng/mL recommended)
Liver iron concentration (LIC) <7 mg/g dry weight

Intensify:
50, 60 or even 100mg/kg/day of desferal s.c. or i.v. infusion 24hr/day for 7days/week (rescue therapy).
If severe iron overload:
serum ferritin persistently >2500 ng/mL
LIC >15 mg/g dry weight.
In significant cardiac disease, dysrrhythmias or heart failure.
Prior to pregnancy or BMT.


continue

[/center]


عدل سابقا من قبل Admin في الخميس يناير 22, 2009 2:48 am عدل 8 مرات
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عدد الرسائل : 4044
العمل/الترفيه : طبيب أختصاصي طب الأطفال وحديثي الولادة
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تاريخ التسجيل : 15/09/2008

مُساهمةموضوع: رد: محاضرة اليوم 20.1.2009 للدكتورة رزيقة العبادي Iron overload   الأربعاء يناير 21, 2009 3:38 am



The Vitamin C / Ferritin / Iron Connection:
Since the 1960's that vitamin C has been known to be intimately involved in iron metabolism. When it was given to treat scurvy, serum iron levels increased.

It is essential for intestinal absorption of iron from foods.

Not long after Desferal was introduced, it was found that vitamin C could double the amount of iron removed during its administration.

There has been no cardiac dysfunction reported when vitamin C and Desferal are used appropriately.

Vitamin C is a very powerful antioxidant.

By converting the ferric iron to metabolically active ferrous iron in the cell, vitamin C increases the pool of iron available for chelation by Desferal.

Ascrobic acid decreases the migration of ferritin complexes to the lysosomes( converted to stable hemosiderin).
Thus directly increasing the amount of ferritin-sequestered iron in the cell and

indirectly increase the reactive iron, which can then move out of the ferritin molecule.

However, too much free iron can cause heart and other organs problems.

Vitamin C & the Heart :

The myocardium has a limited ability to make ferritin.
Therefore it has less ability to sequester any free iron released into the body to prevent it from depositing in and damaging the heart.

Since vitamin C increases the amount of ferrous iron circulating through the body,
the myocardium's lack of ferritin makes it extra vulnerable to iron damage.

This is the probable mechanism of vitamin C-induced cardiomyopathy.
Use of vitamin C:
Started several weeks after desferrioxamine infusion used for the first time.

-Not more than 2-3 mg/kg/day as supplements; at the time of the desferrioxamine infusion so that liberated iron is rapidly chelated.

-Only after acute heart dysfunction has settled-

- People who are heavily iron overloaded should not ingest citrus in large quantities.
5 portions of fruit and vegetables daily are recommended.

- It is better to have the piece of fruit or glass of fruit juice on its own, in between meals and not during or immediately after meal.

Complications of Desferrioxamine :

Very common: Local skin reactions: itching, erythema, induration
Uncommon: Growth retardation: (<3yrs age) and higher doses. Reversible when dose reduced to <40 mg/kg/ day,
no response to hormonal treatment.
Do not exceed 40 mg/kg until growth has ceased.
Skeletal changes: Rickets-like lesions, genu valgum, metaphyseal changes, particularly in the vertebrae & short trunk.
Radiographic features : vertebral demineralisation & flat vertebral bodies.
regularly check such changes, as they are irreversible.
Rarely: complications of excessive dosage:
Hearing problems: High frequency sensory neural loss, tinnitus, deafness, (young children with low iron burden), when the therapeutic index is exceeded (>0.025)].
Minor sensory neural deficit may be reversible, but significant hearing loss is usually permanent--- audiometry yearly.
Ophthalmic (>100mg/kg/day). night-blindness, impaired colour vision , visual fields and visual acuity.
retinitis pigmentosa, more in diabetics or with phenothiazine treatment.
temporarily stop and reintroduce at lower doses later.

Complications of Desferrioxamine

Very rare:
Infections: susceptibility toYersinia enterocolitica.
temporarily discontinue treatment, consider in any patient with febrile illness, abdominal pain, diarrhoea or joint pains.
Severe allergy to desferrioxamine: rarely; Desensitisation.
Renal impairment & interstitial pneumonitis (RDS)at very high doses of 10 mg/kg/h or more.
In patients without iron overload, desferrioxamine has induced reversible coma when used with a phenothiazine derivative.
Rapid i.v. injection during flushing of a line containing desferrioxamine, must be avoided.
Zinc deficiency.


oral chelators

Deferiprone (Ferriprox®, Kelfer®, L1)


Three molecules of deferiprone are required to bind one iron atom
75 mg/kg/day divided on 3 doses . For patients who are poorly compliant to desferrioxamine (<10yr age?)
250 & 500 mg cap.
Compliance is needed also. Large number of cap./day.
Vit.C not recommended.

Side effects
most common adverse events :
neutropenia or agranulocytosis. ANC 500-1500/microL (1.5-2%),
elevated hepatic enzymes (25%) ,
gastrointestinal discomfort (3-24%) &
arthropathy(4.5-15%).
The effect of hepatic iron deposition versus that of hepatitis C on hepatic fibrosis is controversial.
Very rarely: Thrombocytopenia, neurological, ophthalmic, auditory complications & zinc deficiency.

Agranulocytosis :

Frequency: 1.5–2% of thalassemia patients using DFP
Usually in the first year of treatment
Rapidly reversible after cessation of therapy
Treatment with granulocyte colony-stimulating factor may be considered.
Usually recurs upon rechallenge
Requires close surveillance (complete blood count every 7–10 days)

Effects on heart iron
deferiprone in higher doses may be superior in removing myocardial iron compared with deferoxamine

Deferasirox (Exjade®, ICL670):

dispersible tablet
2005 approved by FDA
Highly specific for iron
70% oral bioavailability,
Half-life of 8–16 hours supports once-daily dosing
Biliary excretion
(fecal elimination)


Deferasirox efficacy:
At baseline patients had evidence of clinically significant iron overload
Deferasirox removed iron from the body in proportion to the amount of drug administered
Deferasirox was efficacious at 20 and 30 mg/kg/day for maintaining or reducing LIC and serum ferritin
Similar effect as comparable doses of DFO

Deferasirox safety:

Deferasirox was generally well tolerated
Most common AEs were
mild-to-moderate gastrointestinal side effects and rash
Mild, non-progressive creatinine elevations were manageable with dose reduction
Occasional increases in liver transaminases
No agranulocytosis, growth failure, or bone abnormalities

Monitoring Exjade Therapy:


Serum ferritin monthly with dose adjustment based on 3-6 month evaluations.

Renal function tests before initiating deferasirox therapy & monthly during therapy.

Liver function tests monthly during therapy

Auditory and ophthalmic testing before the start of deferasirox therapy & annually during therapy

Thank you with my best wishes
Dr. Razika Alabadi

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مُساهمةموضوع: رد: محاضرة اليوم 20.1.2009 للدكتورة رزيقة العبادي Iron overload   الأربعاء يناير 21, 2009 3:45 am


شكري وتقديري الخالص للدكتورة رزيقة العبادي على المحاضرة الثرية بالمعلومات القيمة والحقيقة بعد أذنها أني حبيت أنشرها لتكون مرجع للجميع للرجوع اليه وقت الحاجة ... والحقيقة جهود مضنية ومتعبة فألف شكر نيابة عن الجميع لزميلتنا الدكتورة والمحاضرة استغرقت أكثر من ساعتين أجابت فيها عن كل الأسئلة منن قبل الحاضرين

_________________
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مُساهمةموضوع: رد: محاضرة اليوم 20.1.2009 للدكتورة رزيقة العبادي Iron overload   الأحد يناير 25, 2009 4:20 am


شكرنا وتقديرنا الخالص لك يا د عبد الهادي وتحياتنا للدكتوره رزيقه على هذه المحاضره القيمة
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مُساهمةموضوع: رد: محاضرة اليوم 20.1.2009 للدكتورة رزيقة العبادي Iron overload   الأحد يناير 25, 2009 6:47 pm


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محاضرة اليوم 20.1.2009 للدكتورة رزيقة العبادي Iron overload
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