Iron Deficiency Anemia - bhs.be · Iron Deficiency Anemia BHS Training Seminar Red Blood Cells disorders November 9th 2013 Axelle Gilles

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!