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

Transcription

1 Iron Deficiency Anemia BHS Training Seminar Red Blood Cells disorders November 9th 2013 Axelle Gilles

2 IRON DEFICIENCY ANEMIA Epidemiology Prevalence in industrialized countries WHO 2001 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 % > 65 y old Prevalence in developping countries De Maeyer 1989

3 Total body iron stores 2-4g Autre schema new england NEJM 350;23:2383

4 Increased iron losses Decreased iron intake - Inadequate diet - Impaired absorption Increased iron requirements - Infancy (prematurity) - Pregnancy - Lactation IRON DEFICIENCY ANEMIA Etiology

5 IDA:Etiology :increased losses Bleeding 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

6 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

7 IDA: Etiology : Increased losses : GI bleeding 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

8 Haem iron Non-haem iron IDA etiology: decreased iron intake inadequate diet/nutritional deficiencies 7 Scrimshaw NS, 1991 Iron metabolism: facts and figures Gram Absorption (%) Salad Cooked corn Spinach Cooked soybeans 90 7 Fried fish Roasted chicken Fried calf liver Iron content in mg Daily intake in the usual western diet: 11 mg (women) à 13 mg (men) only 10-15% iron resorbtion (biodisponibility) -> 1-2 mg ( of total body iron) Polyphenols; phytates ;calcium ; soy proteins / ascorbic acid, ph 8

9 IDA Etiology: decreased iron intake Decreased 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 «Gastropathic» IDA celiac disease ( up to8,5 % of pt unresponsive to oral iron therapy) Pica: geophagia

10 IDA:Etiology : Increased requirements: Infancy 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

11 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 mg Net loss IDA: Etiology: increased requirements: Pregnancy Breast feeding: 0,3 mg a day 680 mg 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)

12 IDA and pregnancy Effects on the mother 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

13 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

14 DMT1 Mutations MCV fl Serum iron ++ Tf saturation ++ stfr ++ BM sideroblasts - FEP + Liver iron +++ Neonatal appearance Effect oral/iv Fe -/- Serum or urinary hepcidin Inheritance Therapy + - AR 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: Iolascon A, et al. J Pediatr. 2008;152: Graphic courtesy of Dr. Achille Iolascon.

15 IRON DEFICIENCY ANEMIA Symptoms and signs due to ID 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

16 IRON DEFICIENCY ANEMIA Symptoms and signs due to anemia 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

17 IRON DEFICIENCY ANEMIA Stages Hillman & Finch, Red cell manual 1985

18 IRON DEFICIENCY Diagnostic tools Serum ferritin: <12 ng/ml 100% specific for iron deficiency Low sensitivity ( 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

19 IRON DEFICIENCY Differential diagnosis Low Tsat < 30 ng/ml Iron deficiency Ferritin ng/ml Or > 100 ng/ml High stfr N Retic High MCVr N Low LDH Increased erythropoiesis Functional ID (ACD) HYPO CHr

20 IRON DEFICIENCY Differential diagnosis Low Tsat < 30 ng/ml Ferritin ng/ml Or > 100 ng/ml Iron deficiency anemia >2 stfr/log ferritin <1 Weiss et al, NEJM 352:1011, 2005 ACD with true ID High N Low ACD

21 IRON DEFICIENCY ANEMIA Work-up Infancy Pregnancy Young female Male Post-menopausal Treatment Yes No Gynecol. History? Occult blood? No Yes GI Work-up Refractory Further WU Negative

22 IRON DEFICIENCY ANEMIA Additional work-up Celiac disease : - Endomysial antibodies - Gliadin antibodies Autoimmune atrophic gastritis - Elevated gastrin - Parietal cell antibodies Otherwise Unexplained IDA H. Pylori chronic gastritis - H. Pylori antibodies - Urea breath test

23 IRON DEFICIENCY ANEMIA Treatment Diagnosis and treatment of underlying cause Treatment of iron deficiency 1.Correction of anemia 2.Restoration of adequate iron stores 3.Prevention of relapse (in some cases) = 2 simultaneous therapeutic measures

24 IRON DEFICIENCY ANEMIA Storage and Hb iron Log (ferritin) - log (12) = gr iron or Ferritin 1 µg/l = 120 µg/kg storage iron 1 gr Hb = 3.4 mg iron BV = 65 ml/kg, i.e ml for 70 kg Ferritin (µg/l) 70 kg Storage iron (mg) Hb (gr/dl) 70 kg Total Hb iron (mg) x 45.5 x

25 IRON DEFICIENCY ANEMIA Iron prevention : infancy 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

26 IRON DEFICIENCY ANEMIA Iron prevention : pregnancy First half of pregnancy -Multiparity - Twin or multiple pregnancy - Low socio-economical status - Diet low in meat and ascorbic acid - Ferritin < µg/l - Teenage mums - Chronic blood loss, menorrhagia, blood donation, aspirin Second half of pregnancy -All women -> 60 mg elemental iron daily

27 IRON DEFICIENCY ANEMIA Oral iron therapy 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

28 IRON DEFICIENCY ANEMIA Oral 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

29 IRON DEFICIENCY ANEMIA Oral 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 500mg Enteric coated Gestiferrol fumarate 200mg 65mg Folic acid 0,5mg

30 IRON DEFICIENCY ANEMIA Oral iron therapy : response Improved feeling of well being in the first few days Reticulocytosis maximal at 7-10 days - Hb concentration rises slowly Usually 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

31 IRON DEFICIENCY ANEMIA Failure of oral iron therapy 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

32 IRON DEFICIENCY ANEMIA Parenteral 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)

33 IRON DEFICIENCY ANEMIA Parenteral iron therapy:medications 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

34 IRON DEFICIENCY ANEMIA Parenteral iron therapy : toxicity - pain and iron tattooing : IM - GI tract: dose related - anaphylaxis : mostly with iron dextran urticaria upper airway angioedema anaphylactoid reactions anaphylactic shock (and death) : only dextran ph 7.4 ph 11 Iron saccharose Venofer Transferrin (2Fe) - increased risk of infection : no but exacerbates active infection - increased oxydative stress : maybe but very short duration - increased anthracycline cardiac toxicity : if simultaneous ph 7.4 Iron carboxymaltose injectafer ph 7.4 Transferrin (2Fe)

35 IRON DEFICIENCY ANEMIA Parenteral 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%

36 IRON DEFICIENCY ANEMIA Parenteral iron therapy : dose 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 = 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) Exemple : 70 kg male with Hb = 8 gr/dl (15-8) x 70 x 2.4 = 1176 mg mg = 1676 mg

37 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

38 IRON DISORDERS Case 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

39 IRON DISORDERS Case 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

40 IRON DISORDERS Case 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

41 IRON DISORDERS Case 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

42 IRON DISORDERS Case 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

43 IRON DISORDERS Case 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

44 Thank you for your attention!