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Iron Deficiency Anemia
BHS Training Seminar
Red Blood Cells disorders
November 9th 2013Axelle Gilles
IRON DEFICIENCY ANEMIAEpidemiology
• The most common cause of anemia in the world
• Iron deficiency : 2.2 billion people (WHO 1991)
- 11 % of women and 4 % of men in industrial world- Prevalence higher in developing world
• Iron deficiency anemia : 1.2 billion people- 1 to 2% adults- 47 % of non pregnant women - 60 % of pregnant women - 16.6% > 65 y old
Prevalence in industrialized countriesWHO 2001
Prevalence in developping countriesDe Maeyer 1989
Autre schema new england
NEJM 350;23:2383
Total body iron stores 2-4g
• Increased iron losses
• Decreased iron intake
- Inadequate diet - Impaired absorption
• Increased iron requirements
- Infancy (prematurity) - Pregnancy- Lactation
IRON DEFICIENCY ANEMIAEtiology
• The major cause of IDA in affluent countries (either overt or occult)
• Organic pathology
- Gastrointestinal
- Gynecologic (excessive menstrual flow)
- Urinary (hematuria or hemoglobinuria)
- Pulmonary (alveolar hemorrhage)
- Cutaneo-mucous (telangiectasia, RenduOsler)
• Disorders of hemostasis
• Runner’s anemia Buckman, M. Gastrointestinal bleeding in long-distance runners. Ann Intern Med 101:127, 1984
• Blood donation, blood tests, hemodialysis
• Self-induced bleeding
IDA:Etiology :increased losses Bleeding
Gynecologic losses:What is excessive menstrual flow?
• Soaking through one or more sanitary pads or tampons every hour for several consecutive hours
• Needing to use double sanitary protection to control your menstrual flow
• Needing to wake up to change sanitary protection during the night
• Bleeding for a week or longer
• Passing large blood clots with menstrual flow
• Restricting daily activities due to heavy menstrual flow
• Hemorrhoids
• Corticosteroids, NSAIDs
• Peptic ulcer
• Hiatal hernia
• Diverticulosis
• Neoplasm (in men and postmenopausal women IDA-> Odds ratio for GI malignancy in the 2 Y: 31 Am J Med 2002 ;113:276)
• Inflammatory bowel disease (ulcerative colitis)
• Hookworm (ankylostomiasis), schistosomiasis, ...
• Milk proteins induced colitis in infants
• Angiodysplasia
IDA: Etiology : Increased losses : GI bleeding
Iron metabolism: facts and figures
8
Salad
Cooked corn
Spinach
Cooked soybeans
Fried fish
Roasted chicken
Fried calf liver
90
100
90
90
100
90
85
0 1 2 3 4 5 6 7 8 9 10 11
Absorption(%)
4.4
1.8
1.4
7
6
18
15
Gram
Iron content in mg
7 Scrimshaw NS, 1991
No
n-h
aem
iro
nH
aem
iro
n
Daily intake in the usual western diet: 11 mg (women) à 13 mg (men)
only 10-15% iron resorbtion (biodisponibility)
-> 1-2 mg (0.25-0.5 ‰ of total body iron)
Polyphenols; phytates ;calcium ; soy proteins / ascorbic acid, pH…
IDA etiology: decreased iron intakeinadequate diet/nutritional deficiencies
IDA Etiology: decreased iron intakeDecreased absorption
• Should be considered in patients with otherwise unexplained ID and/or refractory to oral iron therapy
• achlorhydria
• gastric surgery
• duodenal disease
• H. Pylori infection
• atrophic gastritis
• celiac disease ( up to8,5 % of pt unresponsive to oral iron therapy)
• Pica: geophagia
« Gastropathic » IDA
• Decreased total body iron at birth
- prematurity (hidden ID)
- twins :Twin twin transfusion syndrome
- low birth weight (< 2.5 kg)- early clamping of cord- feto-maternal hemorrhage
• Growth : 1st year of life, particularly in premature infants
• Inadequate diet : cow’s milk before 12months, unsupplemented formula
• Blood losses : occult GI hemorrhage (milk protein induced colitis, Meckel’s diverticulum)
• No direct correlation between iron status of mother and baby
• Overt fetal iron deficiency only with severe maternal iron deficiency
IDA:Etiology : Increased requirements: Infancy
Iron Amount
• Lost to fetus 270 mg
• Lost in placenta and cord 90 mg
• In blood lost at delivery 150 mg
• Normal body iron loss 170 mg
• Added to expanded red cell mass 450 mg
Total 1130 mg
Recovered after delivery - 450 mg
Net loss 680 mg
Breast feeding: 0,3 mg a day• Increased risk of preterm delivery, with adjusted odds ratio (OR: Anemia : 1.3; IDA: 2.7)
• Increased risk of low birth weight for gestational age; fetal abnormalities ? ; fetal death)
IDA: Etiology: increased requirements: Pregnancy
• Increased risk of maternal death- Severe anemia : 11 % if Hb < 4 g/dl, 5 % if Hb < 6 g/dl- Moderate anemia : rate doubled if Hb < 9 g/dl
• Lower working capacity
• Lower performance during delivery ?
• Decreased immuno-competence ?
• No effect on lactation performance
• Larger placenta secondarily to chronic hypoxia
IDA and pregnancyEffects on the mother
IRIDA: Iron Refractory Iron Deficiency Anemia
• Refractory (or partially refractory) to IV iron
• Noncongruent iron parameters: microcytosis +
– High transferrin saturation and high serum ferritin
– Low transferrin saturation and high serum ferritin
• Ringed sideroblasts (any percentage)
• Familial cases
• High hepcidin (TMPRSS6 mutations)
Camaschella, Haematologica 93:1441, 2008
DMT1 Mutations
MCV 45–55 fL
Serum iron ++
Tf saturation ++
sTfR ++
BM sideroblasts -
FEP +
Liver iron +++
Neonatal appearance
+
Effect oral/IV Fe -/-
Serum or urinary hepcidin
-
Inheritance AR
Therapy Epo
• Severe microcytic anaemia with high
transferrin saturation
• Severe hypochromia with liver iron overload
and normal ferritin levels
• DMT1 is essential in erythropoiesis
• DMT1 is not essential for liver iron uptake
• DMT1 is not essential for duodenal iron
absorption
– Alternative pathways?
– Heme absorption?
• Increased iron absorption occurs in the
presence of iron overload because of low
hepcidin levels
• Partial response of anemia to erythropoietin
treatment
1. Iolascon A, et al. Blood. 2006;107:349-354. 2. Iolascon A, et al. J Pediatr. 2008;152:136-139.
Graphic courtesy of Dr. Achille Iolascon.
• Asthenia, muscular weakness
• Hair Loss and Nail anomalies : flattening, koilonychia
• Atrophy of lingual papillae,glossitis, angular stomatitis, dysphagia
• Gastritis, achlorhydria
• Pica : pagophagia
• Impairment of cell-mediated immunity and bacterial killing(no increased risk of infection)
• Increased absorption of toxic cations (lead, cadmium, aluminium…)
• Pregnancy : prematurity
• Infancy : impaired psychomotor development
• Childhood : altered scholastic performance, attention deficit
IRON DEFICIENCY ANEMIASymptoms and signs due to ID
• Asthenia, fatigue when exercising
• Pallor (nailbeds, mucous membranes, palmar creases, conjunctivae)
• Weakness, dizziness, syncope
• Palpitations, systolic murmur, forceful systolic murmur, forceful apical impulses, hyperactive heart sounds
• Exercise dyspnea
• Angina, claudication, severe GI or CNS symptom (localized ischemia)
• Edema
• Loss of appetite, indigestion
• Insomnia, headache, inability to concentrate, disorientation
IRON DEFICIENCY ANEMIASymptoms and signs due to anemia
IRON DEFICIENCY ANEMIAStages
Hillman & Finch,
Red cell manual
1985
IRON DEFICIENCYDiagnostic tools
• Serum ferritin:• <12 ng/ml 100% specific for iron deficiency
• Low sensitivity ( 10-15 ng/ml sens 59% spe 99%)
• Cut off limit 30 ng/ml ( sens 92% spe 98%)
• Inflammation? Cutoff 100ng/ml
• Transferrin saturation
• TfSat = SI/TIBC x 100
• Tfsat<15% ( sens 80% spe 65%)
• Isolated Serum iron ?
• Soluble transferrin receptor : sTfr
• Directly proportionnal to the erythropoietic rate
• Inversely proportionnal to tissue iron availability but not specific!!!
• STfr/Log 10 ferritin:
• <1 suggests ACD
• > 2 suggests IDA
• Erythropoiesis parameters
• LDH reticulocytes MCV r CHr
IRON DEFICIENCY Differential diagnosis
Low Tsat
Ferritin< 30 ng/ml
30-100 ng/mlOr
> 100 ng/ml
sTfR
Iron deficiency
High N
Functional ID(ACD)
HYPOCHr
ReticMCVrLDH
Increasederythropoiesis
High N Low
IRON DEFICIENCY Differential diagnosis
Low Tsat
Ferritin< 30 ng/ml
30-100 ng/mlOr
> 100 ng/ml
sTfR/log ferritin>2 <1
ACDACD with true ID
High N Low
Iron deficiency anemia
Weiss et al, NEJM 352:1011, 2005
IRON DEFICIENCY ANEMIAWork-up
No
InfancyPregnancy
GI Work-up
Young femaleMale
Post-menopausal
Gynecol. History?
Occult blood?Yes
Treatment
Yes No
NegativeRefractory Further WU
• Celiac disease :
- Endomysial antibodies - Gliadin antibodies
• Autoimmune atrophic gastritis
- Elevated gastrin - Parietal cell antibodies
• H. Pylori chronic gastritis
- H. Pylori antibodies- Urea breath test
IRON DEFICIENCY ANEMIAAdditional work-up
Otherwise
Unexplained
IDA
• Diagnosis and treatment of underlying cause
• Treatment of iron deficiency1.Correction of anemia2.Restoration of adequate iron stores3.Prevention of relapse (in some cases)
= 2 simultaneous therapeutic measures
IRON DEFICIENCY ANEMIATreatment
IRON DEFICIENCY ANEMIAStorage and Hb iron
Log (ferritin) - log (12) = gr ironor
Ferritin 1 µg/l = 120 µg/Kg storage iron
70 kg Storage iron (mg)
12 0
100 920
120 1000
300 1400
Ferritin (µg/l)
1 gr Hb = 3.4 mg iron
70 kg
Total Hb iron (mg)
14 2166
10 1547
6 928
1 155
Hb (gr/dl)
BV = 65 ml/kg, i.e. 4550 ml for 70 kg
x 45.5 x 3.4
• Prematurity, low birth weight (< 2.5 kg), twins : - from 0-2 months till 1 year of age - 2 mg/kg (max 15 mg/day)
• Term infants : - from 4 months till 1 year of age - 1 mg/kg (max 15mg/day)
• Encourage breast rather than formula feeding
• Use iron-fortified formula
• -> bioavailability of iron!
• Diversify diet (meat) as soon as possible
IRON DEFICIENCY ANEMIAIron prevention : infancy
• First half of pregnancy-Multiparity- Twin or multiple pregnancy- Low socio-economical status- Diet low in meat and ascorbic acid- Ferritin < 80-100 µg/L- Teenage mums
• - Chronic blood loss, menorrhagia, blood donation, aspirin
• Second half of pregnancy-All women
-> 60 mg elemental iron daily
IRON DEFICIENCY ANEMIAIron prevention : pregnancy
• How much?• 200 mg elemental iron per day
• What?• Ferrous salts -> Ferric salts not absorbed ( but well tolerated)
• Ferric iron-polysaccharide complex : better tolerated but efficacy not demonstrated in appropriate studies
• Ascorbic and succinic acid : enhance absorption if given in large amount (5-6 times iron dose).
• Ascorbate increases side effects
• Enteric-coated or sustained release preparations : better tolerated but iron less absorbed
IRON DEFICIENCY ANEMIAOral iron therapy
IRON DEFICIENCY ANEMIAOral iron therapy
• How long?
• Duration : 3-6 months(1) 1-3 months for correction of anemia(2) 2-3 additional months for restoration of iron stores
• Side effects • gastric intolerance, diarrhea, constipation, black stools
• Absorption decreased with:• inflammation, renal failure, cancer, poor transit
IRON DEFICIENCY ANEMIAOral iron therapy :
ferrous salts available in Belgium
Brand Name Concentration Elemental iron Remarks
Losferron gluconate 695 mg 80mg
Fero-gradumet sulfate 525mg 105 mg Enteric coated
Fero-grad 500 sulfate 525mg 105mg Ascorbic acid 500mgEnteric coated
Gestiferrol fumarate 200mg 65mg Folic acid 0,5mg
IRON DEFICIENCY ANEMIAOral iron therapy : response
Improved feeling of well being in the first few daysReticulocytosis maximal at 7-10 days
- Hb concentration rises slowlyUsually in the 1 to 2 Wk of treatment
-+ 2g/dl over the ensuing 3 Wk
- Deficit halved in one month
- Returned to normal in 6 to 8 Wk
• Explanations :- Incorrect diagnosis- Complicating illness- Non-compliance- Inadequate prescription (dose and form)- Iron losses in excess of intake (Rendu-Osler)- Iron malabsorption- IRIDA/DMT1 mutation?
• Alternatives :- Optimize oral iron treatment- Parenteral iron
IRON DEFICIENCY ANEMIAFailure of oral iron therapy
IRON DEFICIENCY ANEMIAParenteral iron therapy : indications
• Intolerance/failure of oral iron
• Non-compliance
• Blood losses too rapid (Rendu-Osler, autotransfusion, …)
• Large Hb deficit
• GI disorder aggravated by oral iron
• Poor iron absorption
• Erythropoiesis too intense (EPO therapy)
• Intramuscular : - iron-dextran (Fercayl : 100 mg)
• -> Never indicated!!! Slow and incomplete removal from IM sites; slightly superior to oral iron; lot of side effects
• Intravenous : - Fe+++ saccharate (Venofer : 100 mg)
• 200 to 300mg in 150 to 250 ml sterile saline over 1 hour (TEST DOSE)
• - Fe+++ carboxymaltose (Injectafer 100 mg/2ml,500mg/10ml)• 200mg bolus injection Up to 1000mg over 15 minutes
IRON DEFICIENCY ANEMIAParenteral iron therapy:medications
IRON DEFICIENCY ANEMIAParenteral iron therapy : toxicity
- pain and iron tattooing : IM- GI tract: dose related- anaphylaxis : mostly with iron dextran
urticariaupper airway angioedemaanaphylactoid reactionsanaphylactic shock (and death) : only
dextran
- increased risk of infection : no but exacerbates active infection- increased oxydative stress : maybe but very short duration
- increased anthracycline cardiac toxicity: if simultaneous
Transferrin (2Fe)
pH 11
pH 7.4
Iron saccharose
Venofer ®
Transferrin (2Fe)
pH 7.4
pH 7.4
Iron carboxymaltose
injectafer ®
IRON DEFICIENCY ANEMIAParenteral iron therapy : toxicity
• Precautions :
- iron-dextran : test dose !!
- iron-sucrose :limit total dose/infusion : 300 mg
- never in patients with sepsis
- not simultaneously with chemotherapy
- not if Tsat > 50%
• Hemoglobin-iron deficit : (normal Hb - patient’s Hb [gr/dL]) x BW (kg) x 2.4 where : normal Hb = 15 in men, 13 in women
2.4 = 0.0034 x 0.07 x 1000(Fe=0.34% of Hb, BV=7% of BW)
• Storage-iron deficit : 500 mg (5 to 10 mg/Kg body weight)
IRON DEFICIENCY ANEMIAParenteral iron therapy : dose
Exemple : 70 kg male with Hb = 8 gr/dL
(15 - 8) x 70 x 2.4 = 1176 mg + 500 mg = 1676 mg
What about iron deficient non anaemic patients?
• Supplementation may be beneficial on systemic symptoms
• Several studies with IV or oral supplementation
• The lower the ferritin the better the response
IRON DISORDERSCase 1
• 25-yr-old female
• Hodgkin, stage IV, ABVD
• Hb 9.5 g/dL, normocytic
• Serum ferritin 856 µg/L
• Tsat 14%1. EPO
2. Oral iron
3. IV iron
4. EPO + oral iron
5. EPO + IV iron
6. None
IRON DISORDERSCase 1
• 25-yr-old female
• Hodgkin, stage IV, ABVD
• Hb 9.5 g/dL, normocytic
• Serum ferritin 856 µg/L
• Tsat 14%1. EPO
2. Oral iron
3. IV iron
4. EPO + oral iron
5. EPO + IV iron
6. None
IRON DISORDERSCase 2
• 65-yr-old female
• Active rhumatoid arthritis, CRP 184 mg/L
• Hb 11.5 g/dL, microcytic
• Serum ferritin 42 µg/L
• Tsat 17%1. EPO
2. Oral iron
3. IV iron
4. EPO + oral iron
5. EPO + IV iron
6. None
IRON DISORDERSCase 2
• 65-yr-old female
• Active rhumatoid arthritis, CRP 184 mg/L
• Hb 11.5 g/dL, microcytic
• Serum ferritin 42 µg/L
• Tsat 17%1. EPO
2. Oral iron
3. IV iron
4. EPO + oral iron
5. EPO + IV iron
6. None
IRON DISORDERSCase 3
• 15-yr-old female
• Asthenia, dyspnea when running
• Hb 9.5 g/dL, microcytic
• Serum ferritin 12 µg/L
• Tsat 8% 1. EPO
2. Oral iron
3. IV iron
4. EPO + oral iron
5. EPO + IV iron
6. None
IRON DISORDERSCase 3
• 15-yr-old female
• Asthenia, dyspnea when running
• Hb 8.5 g/dL, microcytic
• Serum ferritin 12 µg/L
• Tsat 8% 1. EPO
2. Oral iron
3. IV iron
4. EPO + oral iron
5. EPO + IV iron
6. None
Thank you for your attention!
