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Iron Deficiency Anemia Heather Escoto, MD Pediatric Hematology/Oncology Children’s Center for Cancer and Blood Diseases at St. Vincent.

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Presentation on theme: "Iron Deficiency Anemia Heather Escoto, MD Pediatric Hematology/Oncology Children’s Center for Cancer and Blood Diseases at St. Vincent."— Presentation transcript:

1 Iron Deficiency Anemia Heather Escoto, MD Pediatric Hematology/Oncology Children’s Center for Cancer and Blood Diseases at St. Vincent

2 Disclosures Nothing to disclose

3 Objectives Review of the following: 1.The definitions and classifications of anemia and factors affecting hemoglobin levels 2.The function, mechanisms of absorption, transport, and storage of iron 3.The incidence, risk factors, and etiology of iron deficiency 4.Physical exam findings, laboratory values, staging, and differential diagnosis of iron deficiency and iron deficiency anemia 5.AAP Screening recommendations, prevention, and treatment of iron deficiency 6.Effects of iron deficiency and iron deficiency anemia

4 “Anemia 101 ” Definition Classification.

5 Definitions of Anemia Physiologic definition: -Hemoglobin too low to meet oxygenation demands Laboratory definition: -Hemoglobin at least 2 standard deviations below mean value based on age, gender, and race **Laboratory definition of anemia does not always agree with physiologic definition of anemia!

6 Factors that affect hemoglobin levels Age Sex Race Puberty Altitude Heredity.

7 Hemoglobin levels in infants- the physiologic nadir Term infant -nadir- 12 weeks of age -hemoglobin 9.5 gm/dL at nadir Premature infant - nadir- 6-8 weeks of age -hemoglobin 7.0 gm/dL at nadir -nadir earlier and lower!!!.

8 Age specific Hemoglobin levels Data from Table 14.1, the Harriet Lane Handbook: A manual for pediatric house officers/ the Harriet Lane Service, Children’s Medical and Surgical Center of the Johns Hopkins Hospital; editors, Jason Custer, Rachel Rau-18 th edition. Age Hgb (g/dL) week 13.4 (11) 28 week week15.0 Term (cord)16.5 (13.5) 1-3 day18.5 (14.5) 2 week16.6 (13.4) 1 month13.9 (10.7) 2 month11.2 (9.4) 6 month12.6 (11.1) 6 mo-2 year12.0 (10.5) 2 year-6 year12.5 (11.5)

9 Age specific Hemoglobin levels (cont.) Age Hgb (g/dL) 2 year- 6 year 12.5 (11.5) 6 year-12 year 13.5 (11.5) year (male) 14.5 (13) year (female) 14.0 (12) Data from Table 14.1, the Harriet Lane Handbook: A manual for pediatric house officers/ the Harriet Lane Service, Children’s Medical and Surgical Center of the Johns Hopkins Hospital; editors, Jason Custer, Rachel Rau-18 th edition.

10 Age and Hemoglobin levels Hemoglobin and mean conpuscular volume (MCV) percentile curves for girls and boys. (Redrawn from Dallman PR, Siimes MA: Percentile curves for hemoglobin and red cell volume in infancy and childhood. J Pediatr 1979; 94:28.)

11 Hemoglobin differences between African-American and Caucasian children Data from: Dallman et al. Hemoglobin concentration in white, black and Oriental children: is there a need for separate criteria in screening for anemia? Am. J. Clin. Nutr.:1978; 31: MalesFemales Mean Hgb g/dL

12 Sexual Maturity and Hematocrit Daniel et al. Hematocrit: maturity relationship in adolescence. Pediatrics 1973;52:388–394.

13 Sexual Maturity and Hematocrit Daniel et al. Hematocrit: maturity relationship in adolescence. Pediatrics 1973;52:388–394.

14 Heredity and Hemoglobin Siimes et al, J Pediatr 1994 Jan;124(1): Effect of Hereditary on Hemoglobin Concentration.

15 Basic Laboratory Evaluation of Anemia 1.Complete blood count 2.Red blood cell indices- MCV, MCHC, RDW 3.Reticulocyte count 4.Peripheral smear-red cell morphology 5. Other labs as clinically indicated- iron studies, electrophoresis, hemolytic workup, Coombs Quote or statistic could go here. Either the same one throughout, or change from page to page.

16 Reticulocyte count and anemia Reticulocyte

17 Reticulocyte count- absolute and percentage Reticulocyte count (percentage)- - % of absolute concentration of RBCs containing precipitated RNA (reticulin) -non-invasive measure of new red cell production by bone marrow -dependent on RBC count -overestimated with severe anemia Absolute reticulocyte count % Reticulocytes X RBC count/100 Hgb % X 2,080,000 /100=ARC 62,400 Hgb % X 3,470,000 /100= ARC 104,100.

18 Physiologic response to anemia Increased heart rate Increased stroke volume Vasodilation Decreased oxygen affinity (right shift in oxygen-hemoglobin dissociation curve)

19 Classification of Anemia Mechanism- -Decreased production -Hemolysis -Blood loss RBC size- -Microcytic -Macrocytic -Normocytic.

20 Classification of anemia Mechanism - Decreased production -Marrow infiltration-malignancy -Marrow injury- infections, toxins -Nutritional deficiency -Ineffective erythropoesis (thalassemias) -Erythropoietin deficiency -Labs: Low reticulocyte count, variable MCV

21 Classification of anemia Blood loss- -Reticulocyte count usually elevated- bone marrow trying to compensate -MCV usually normal to slightly elevated Hemolysis- -Acquired -autoimmune process, vessel injury, -Inherited RBC defect -Reticulocyte count usually elevated -MCV normal to slightly elevated

22 Classification of anemia- morphology MicrocyticNormocytic - Iron deficiency-Chronic disease -Thalassemia-Malignancy -Chronic disease-Renal failure -Copper deficiency-Blood loss Macrocytic -Hemolytic disorders - Folate deficiency-Hemoglobinopathies -Vitamin B12 deficiency -Inherited bone marrow failure -Hypothyroidism -Drug induced -Active hemolysis Quote or statistic could go here. Either the same one throughout, or change from page to page.

23 Iron Deficiency Anemia.

24 Why is iron deficiency important? Remains most common nutrient deficiency in developing countries Over 1 billion people affected, nearly half of the world’s young children Decline in prevalence in industrialized countries- but still common In US, most common in lower income infants and toddlers months of age and teenage girls Over 700,000 toddlers affected in the US, 1/3 with anemia, over 7.8 million adolescent females/women Long term effects on neurodevelopment, behavior, neurotransmitter myelination, energy metabolism Increased susceptibility to lead toxicity

25 Why is Iron important? -Essential component of hemoglobin and myoglobin -Component of certain proteins important for respiration and energy metabolism -Component of enzymes involved in the synthesis of collagen and some neurotransmitters -Essential for normal immune function

26 Iron: too much is bad Generates free radicals Causes oxidative damage to cells Protective mechanisms Intracellular and intravascular iron bound to carrier proteins- transferrin, ferritin, hemoglobin, etc. Iron absorption tightly regulated Iron overload- most commonly from chronic transfusions: 1ml PRBCs has 1 mg iron.

27 Iron: How much do we need? Preterm infants: 2-4 mg/kg/day Full term infants: 1 mg/kg day Children 1-3 years old: 7 mg/day Children 4-8 years old: 10 mg/day Children 9-13 years old: 8 mg/day Males 14-18: 11 mg/day Females 14-18: 15 mg/day Food and Nutrition Board of the Institute of Medicine. Iron in: Dietary reference intakes for Vitamin A, Vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. National Academy Press, Washington DC, 2000; p. 339.

28 Iron distribution in the body

29 Hemoglobin -4 globin chains (2 alpha and 2 beta globin chains) -4 heme molecules with iron in the center Heme molecule Hemoglobin

30 Ferritin Intracellular protein that stores and releases iron in a controlled fashion Aggregates of ferritin form hemosiderin Ferritin is also an acute phase reactant- acts to protect iron from being used by an infective agent apoferritin Fe3+ Ferritin Fe 2+

31 Iron containing enzymes - Important in oxidative metabolism and DNA synthesis Heme proteins: -Cytochromes -Catalase -Peroxidase -Cytochrome oxidase Flavoproteins: -Cytochrome C reductase -Succinic dehydrogenase -NADH oxidase -Xanthine oxidase.

32 Iron Balance Intake= 10 mg/day Absorption= 1 mg/day- variable Loss- 1 mg/day- mainly by sloughing of enterocytes (and menstruation in females) Iron stored in macrophages and hepatocytes

33 Iron absorption 10% of dietary iron is absorbed Absorption depends on: -dietary iron content - bioavailability (heme vs. non- heme) - mucosal cell receptor number Main absorption occurs in duodenum.

34 Iron absorption -Heme (meat) >> non-heme iron sources -(30%-50% vs. <10%) -Ferrous sulfate >> ferric sulfate -Enhanced by red meat, ascorbic acid, breast milk -Diminished by vegetable fiber, cow milk, egg yolk, tea, phytates, phosphates (soda)

35 Iron absorption Iron is converted from Fe 3+ to Fe 2+ by ferrireductase Fe 2+ transported across mucosal surface of enterocyte by DMT1, stored as ferritin Ferritin releases Fe 2+ which is transported across basolateral surface of enterocyte with help of ferroportin ***** Fe 2+ converted back to Fe 3+ by Hephaestin Fe 3+ binds to transferrin in plasma

36 . Iron absorption

37 Ferroportin and Hepcidin Hepcidin -Blocks ferroportin -Prevents absorption of iron from enterocytes -Prevents iron exportation from macrophages -Increased in inflammation -Leads to reduced serum iron, microcytic anemia, and incomplete response to iron therapy Ferroportin -Transporter protein in enterocytes and macrophages -Blocked by hepcidin

38 Iron uptake by the erythroblast Fe 3+ bound to transferrin attaches to transferrin receptor on erythroblast Transferrin and Fe 3+ separate, Fe 3+ combines with heme to make hemoglobin Extra Fe stored as ferritin Apotransferrin exported out of erythoblast

39 Iron uptake by the erythroblast Katz JH. Iron and protein kinetics studied by means of doubly labeled human crystalline transferrin. J Clin Invest 1961;40: Release of apotransferrin Binding of iron- transferrin to its receptor Fe3+ Hemosiderin Ferritin Release of iron to storage to storage Incorporation into iron-protein TfR

40 Iron deficiency- definitions Iron deficiency (ID)- deficient in iron, no anemia Iron deficiency anemia (IDA)- deficient in iron leading to anemia Anemia- 2 SD below defined “normal” mean based on age and gender

41 Incidence of ID and IDA in US Infants -no national statistics on incidence of ID and IDA in infants before 1 year of age -Norwegian cohort showed 4% incidence at 6 months increasing to 12% incidence at 12 months Toddlers (1-3 years) Iron deficiency- 9%-15% Iron deficiency anemia- 3-5% Children Iron deficiency- 4% incidence Looker AC, et al. Prevalence of iron deficiency in the United States. JAMA. 1997;277(12): Hay et al. Iron status in a group of Norwegian Children aged 6-24 months. Acta Paediatr. 2004;93(5):

42 Incidence of ID and IDA in US adolescents Adolescent females Iron deficiency- 9-11% Iron deficiency anemia- 2-5% Adolescent males Iron deficiency < 1% Looker AC, et al. Prevalence of iron deficiency in the United States. JAMA. 1997;277(12):

43 Prevalence of iron deficiency in US children 1-3 years old Hispanic- 12% English speaking- 7% African American- 6% Non-English speaking- 14% Caucasian- 6% Overweight-20%Daycare- 5% Normal weight-7%No daycare- 10% Bottle fed <12 months -3.8% Bottle fed >24 months- 12.4% Brotanek et al. Iron Deficiency in Early Childhood in the United States: Risk Factors and Racial/Ethnic Disparities. Pediatrics 2007;120;568. Arch Pediatr Adolesc Med 2005; 159:

44 Risk factors for Iron Deficiency in Infants and Children -Prematurity or low birthweight -Exclusively breastfeeding beyond 4-5 months without iron supplementation -Cows milk before 1 year -Excessive milk intake -Obesity -Poverty/Low socioeconomic status -Malnutrition -Chronic illness or special health needs Brotanek et al. Iron Deficiency in Early Childhood in the United States: Risk Factors and Racial/Ethnic Disparities. Pediatrics 2007;120;568 Pizzaro et al. Iron status with different infant feeding regimens: relevance to screening and prevention of iron deficiency. J Pediatr May;118(5): J Pediatr.

45 Risk Factors for iron deficiency in Adolescents Growth spurts Heavy menses Chronic illness H pylori infection Endurance training Vegetarian diets Obesity Poverty Pregnancy

46 Etiology of Iron Deficiency Low birth stores Dietary- not enough intake to meet requirements Blood loss- majority of iron stored in RBCS Poor absorption

47 Newborn Iron Stores Endowed with 75 mg/kg of iron at birth Dependent on hemoglobin concentration at birth (majority of iron in circulating RBCs) Minimally dependent on maternal iron status Depleted by 3 months in low birth weight infants without supplementation Depleted by age 5-6 months in term infants Delayed cord clamping (by 2 minutes) leads to higher ferritin and iron stores at 6 months of age

48 Dietary iron content Milkmg Fe/Liter Breast milk0.5-1 ** Whole cow0.5-1 Skim0.5-1 Formula (low iron)2- 4 Formula (high iron)10-12 Foodsmg/serving Infant cereal6 Baby foods **more bioavailable

49 Iron content of Common Toddler foods/drinks Foods% daily value/serving Fruit snacks 0 mg Chicken nuggets 8% Macaroni and cheese10% Chips 5% Graham crackers17% Cheerios 25% Goldfish 2% Drinks% daily value Apple juice 5% Pediasure 15% Soda 0%

50 Cows milk and iron deficiency Poor source of iron Poor absorption (5-10%) Reduces consumption of other foods, especially with overconsumption Can cause microscopic GI bleeding.

51 Iron rich foods Heme iron (better bioavailability) Meat (beef and turkey best) Shellfish Non-heme iron (less bioavailability) Breakfast cereal (iron fortified) Pasta (iron fortified) Beans and lentils Baked potato with skin Foods that increase iron absorption Fruits, vegetables, meat, fish, poultry, white wine.

52 Causes of Iron deficiency: Blood Loss GI blood loss: -cow’s milk, IBD, esophageal varices, ulcers, anatomic lesions, parasitic infections Menorrhagia Epistaxis Other rare causes: pulmonary, renal, intravascular

53 Iron Deficiency: Malabsorption Short gut Celiac disease Medications (GERD) Chronic Giardiasis IRIDA (Iron Refractory Iron deficiency anemia) Dx: Iron absorption test

54 Diagnosis: History and Physical History blood loss? dietary history GI symptoms? Heavy menses? Irritability? Weakness? PICA? Physical exam- pallor, tachycardia, irritability

55

56 PICA

57

58 PICA and iron deficiency Compulsive ingestion of usually a single non-nutritive substance Behavior cured with therapeutic iron therapy Typical ingested substances RocksCarpet DirtHair Paint chipsClothing CardboardInsects ClayIce chips

59 Lead and iron deficiency Iron deficiency PICA PICA lead ingestion Iron deficiency increases lead absorption from intestine Lead toxicity does not cause microcytic anemia

60 Diagnosis of Iron Deficiency: Staging Depletion of iron stores Iron deficient erythropoiesis Iron deficiency anemia

61 3 stages of Iron Deficiency FIG Measurements of Iron Status in Relationship to Body Iron Stores (mg). J.D. Cook and C.A. Finch, "Assessing Iron Status of a Population," A J. Clin Nutr, 32: 2115 (1979) Graph in Methods for the Evaluation of the Impact of Food and Nutrition Programmes (UNU, 1984, 287 pages). >11 <11

62 Diagnosis of Iron Deficiency: Laboratory Workup Laboratory Value Ferritin <12 µg/dL Serum iron <40 µg/dL Serum transferrin (TIBC) >400 µg/dL Transferrin saturation ratio (Fe/TIBC) <10% Hemoglobin <11 g/dL MCV <70 fl RDW >16% Reticulocyte count <1%

63 Diagnosis of Iron Deficiency: Laboratory Workup Other supporting labs: -Platelet count elevated -Serum transferrin receptor >35 -Reticulocyte hemoglobin content **<26 -Hemoglobin A2 reduced -Free erythrocyte protoporphyrin >100 Hepcidinreduced C reactive protein **first laboratory test abnormal

64 Diagnosis: peripheral smear l Hypochromia Microcytosis Thrombocytosis

65 Differential diagnosis of microcytic/hypochromic anemia Iron deficiency Thalassemia Inflammation Hemoglobin C or Hemoglobin E disease Hereditary hyropoikilocytosis Copper deficiency Sideroblastic anemia Congenital atransferrinemia

66 Laboratory parameters in thalassemia trait and iron deficiency Nathan and Oski’s Hematology of Infancy and Children, 7 th ed. p.1054 table 20.7 Parameter α thal trait Β thal traitIDA Hemoglobin (g/dL) Red cell count (X10^6/µL MCV (fl) MCHC HgB A2Normal or decreased ElevatedNormal or decreased Mentzer index (MCV/RBC <13>13

67 Differential Diagnosis of Microcytic Hypochromic Anemia Anemia of inflammation Iron restricted erythropoesis: -Secondary to inflammation, chronic kidney disease, aging, chemotherapy, IRIDA -Due to sequestration of iron in macrophages -Increased hepcidin -Low serum iron -Low transferrin saturation -Normal or increased iron stores Goodenough et al, Blood 2010; 116:

68 *increased hepcidin blocks release of iron from macrophages

69 Differential Diagnosis of Low Serum Iron -Iron deficiency -Infection -Inflammation -Malignancy -Postoperative -Stress.

70 Screening for iron deficiency AAP recommendations: Determination of hemoglobin concentration -Term infants - 12 months of age -Preterm infants - 9 months of age Assessment of risk factors for ID/IDA: -Inadequate iron intake, poor nutrition, feeding problems, poor growth Additional screening at months of age? Pediatrics 2010; 126:

71 Screening for Iron Deficiency Anemia in Adolescents AAP recommendations: -Menstruating girls be screened annually by measuring hemoglobin concentration -Adolescent boys- screened once during peak growth period -Consider risk factors for anemia and screen appropriate patients at any time Committee on Nutrition, American Academy of Pediatrics. Screening for Iron Deficiency, in: Pediatric Nutrition Handbook, 6 th ed, Kleinman, RE (ED). American Academy of Pediatrics, Elk Grove Village, IL p. 419

72 Prevention of Iron Deficiency Anemia in Infants and Toddlers Breastfeeding for the first 6 months of life Iron fortified formula Iron fortified infant cereal beginning at 6 months of age Iron supplementation for preterm infants Iron supplementation for breastfeeding infants at 4 months of age Avoid cows milk before 1 year of age Limit cows milk intake to oz/day after 12 months of age

73 Iron Deficiency- Treatment Oral iron therapy Mild iron deficiency- 3 mg/kg/d elemental iron in daily dose Moderate to severe- 6 mg/kg/d elemental iron divided twice daily Severe- consider PRBC transfusion (Hgb <4 gm/dl) AND oral iron.

74 Types of Oral iron Ferrous sulfateCarbonyl iron - 20 % elemental iron-100% elemental iron - well absorbed**-15 mg tab mg tab- 65 mg elemental-15 mg/1.25 ml -75mg/0.8 ml – 15 mg elemental-less absorption -15mg/ml- 15mg elemental Ferrous gluconate Iron polysaccharide - 12% elemental iron -100% elemental iron -300 mg tab- 36 mg elemental -100mg/5 ml, 150 mg tab -well absorbed Ferrous fumarate -33% elemental iron -200 mg tab- 66 mg elemental -chewable tab 33 mg -extended release tabs- poorer absorption -Iron sprinkles (developing countries).

75 Oral iron therapy- side effects -BAD TASTE! -GI intolerance -Dark stools -Staining of teeth

76 Response to Oral Iron therapy Monitoring: 1-2 weeks- (for moderate to severe anemia) -increase in reticulocyte count - increase in hemoglobin (1-2 gm/dl) 4-6 weeks- -correction of hemoglobin Continue iron therapy for at least 3-4 months, possibly longer

77 Causes for poor response to oral iron - Non-compliance *** -Incorrect administration*** -Incorrect diagnosis -Incorrect dosing -Ongoing blood loss -Malabsorption -IRIDA

78 Indications for IV iron therapy Iron deficiency not responding to oral iron therapy -Poor compliance -Adverse effects -Malabsorption* -Ongoing hemorrhage* Anemia of chronic disease (iron restricted erythropoiesis) -Renal failure, inflammatory disorders.

79 IV iron therapy Preparations: Iron dextran (HMW and LMW) Ferric gluconate Iron sucrose Side effects: Anaphylaxis (2-3% with iron dextran) Chills, back pain, body aches.

80 Neurodevelopmental effects of ID and IDA Psychomotor development and cognitive function - MULTIPLE studies -conflicting studies for ID -moderate to severe IDA- long term decreased cognitive function-may not recover with correction of iron status Learning: NHANES III- lower math scores with iron deficiency, no effect seen with reading, verbal, and performance scores Attention, concentration and cognitive function: Meta-analysis of randomized trials in older children and adults showed some improvement in attention, concentration, and cognitive function with improvement in ID Lozoff, et al. J Pediatr 1996; Halterman et al. Pediatrics 2001; 107:1381. Lozoff et al. Arch Pediatr Adolesc Med 2006; 160:1108. Falkinham et al. Nutr J 2010; 9:4.

81 Other Effects of ID and IDA Changes in transmission through auditory and visual systems in young infants Mild to moderate defects in leukocyte and lymphocyte function Increased risk of cerebral vein thrombosis Breath holding spells Decreased exercise capacity PICA ? Febrile seizures Impaired myelination Neurotransmitter metabolism.Algarin et al. BMJ 1996;313:343. Hartfield et al. Clin Pediatr (Phil) 2009; 48:420. Zehetner et al. Cochrane Database Syst Rev 2010; :CD Ekiz et al. Hematol J 2005; 5:579. Benedict et al. J Chld Neurol 2004; 19;526.


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