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Iron Deficiency Anemia

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Title: Iron Deficiency Anemia


1
Iron Deficiency Anemia
Heather Escoto, MD Pediatric Hematology/Oncology
Childrens Center for Cancer and Blood Diseases
at St. Vincent
2
Disclosures
  • Nothing to disclose

3
Objectives
  • Review of the following
  • The definitions and classifications of anemia and
    factors affecting hemoglobin levels
  • The function, mechanisms of absorption,
    transport, and storage of iron
  • The incidence, risk factors, and etiology of iron
    deficiency
  • Physical exam findings, laboratory values,
    staging, and differential diagnosis of iron
    deficiency and iron deficiency anemia
  • AAP Screening recommendations, prevention, and
    treatment of iron deficiency
  • 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
  • Age Hgb (g/dL)
  • 26-30 week 13.4 (11)
  • 28 week 14.5
  • 32 week 15.0
  • Term (cord) 16.5 (13.5)
  • 1-3 day 18.5 (14.5)
  • 2 week 16.6 (13.4)
  • 1 month 13.9 (10.7)
  • 2 month 11.2 (9.4)
  • 6 month 12.6 (11.1)
  • 6 mo-2 year 12.0 (10.5)
  • 2 year-6 year 12.5 (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)
  • 12-18 year (male) 14.5 (13)
  • 12-18 year (female) 14.0 (12)

10
Age and Hemoglobin levels

11
Hemoglobin differences between African-American
and Caucasian children
Mean Hgb g/dL
Males
Females
12
Sexual Maturity and Hematocrit
Daniel et al. Hematocrit maturity relationship
in adolescence. Pediatrics 197352388394.
13
Sexual Maturity and Hematocrit
Daniel et al. Hematocrit maturity relationship
in adolescence. Pediatrics 197352388394.
14
Heredity and Hemoglobin
15
Basic Laboratory Evaluation of Anemia
  • Complete blood count
  • Red blood cell indices- MCV, MCHC, RDW
  • Reticulocyte count
  • Peripheral smear-red cell morphology
  • 5. Other labs as clinically indicated- iron
    studies, electrophoresis, hemolytic workup, Coombs

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 6.4 - 3 X 2,080,000 /100ARC 62,400
  • Hgb 11.2 - 3 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
  • Microcytic Normocytic
  • -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

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 worlds young children
  • Decline in prevalence in industrialized
    countries- but still common
  • In US, most common in lower income infants and
    toddlers 12-36 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

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

Fe3
Ferritin Fe 2
apoferritin
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) gtgt non-heme iron sources
  • -(30-50 vs. lt10)
  • -Ferrous sulfate gtgt 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 Fe3 to Fe2 by
    ferrireductase
  • Fe2 transported across mucosal surface of
    enterocyte by DMT1, stored as ferritin
  • Ferritin releases Fe2 which is transported
    across basolateral surface of enterocyte with
    help of ferroportin
  • Fe2 converted back to Fe3 by Hephaestin
  • Fe3 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
  • Fe3 bound to transferrin attaches to
    transferrin receptor on erythroblast
  • Transferrin and Fe3 separate, Fe3 combines with
    heme to make hemoglobin
  • Extra Fe stored as ferritin
  • Apotransferrin exported out of erythoblast

39
Iron uptake by the erythroblast
Fe3
Binding of iron-transferrin to its receptor
Release of
apotransferrin
TfR
Incorporation into iron-protein
Release of iron to storage

to storage
Ferritin
Hemosiderin
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

42
Incidence of ID and IDA in US adolescents
  • Adolescent females
  • Iron deficiency- 9-11
  • Iron deficiency anemia- 2-5
  • Adolescent males
  • Iron deficiency lt 1

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 lt12 months -3.8
  • Bottle fed gt24 months- 12.4

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
2007120568 Pizzaro et al. Iron status with
different infant feeding regimens relevance to
screening and prevention of iron deficiency. J
Pediatr. 1991 May118(5)687-92
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
  • Milk mg Fe/Liter
  • Breast milk 0.5-1
  • Whole cow 0.5-1
  • Skim 0.5-1
  • Formula (low iron) 2- 4
  • Formula (high iron) 10-12
  • Foods mg/serving
  • Infant cereal 6
  • Baby foods 0.3-1.2
  • more bioavailable

49
Iron content of Common Toddler foods/drinks
  • Foods daily value/serving
  • Fruit snacks 0 mg
  • Chicken nuggets 8
  • Macaroni and cheese 10
  • Chips 5
  • Graham crackers 17
  • 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
  • -cows 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
(No Transcript)
56
PICA
57
PICA
58
PICA and iron deficiency
  • Compulsive ingestion of usually a single
    non-nutritive substance
  • Behavior cured with therapeutic iron therapy
  • Typical ingested substances
  • Rocks Carpet
  • Dirt Hair
  • Paint chips Clothing
  • Cardboard Insects
  • Clay Ice 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
61
3 stages of Iron Deficiency
gt11
gt11
gt11
lt11
62
Diagnosis of Iron Deficiency Laboratory Workup
  • Laboratory Value
  • Ferritin lt12 µg/dL
  • Serum iron lt40 µg/dL
  • Serum transferrin (TIBC) gt400 µg/dL
  • Transferrin saturation ratio (Fe/TIBC) lt10
  • Hemoglobin lt11 g/dL
  • MCV lt70 fl
  • RDW gt16
  • Reticulocyte count lt1

63
Diagnosis of Iron Deficiency Laboratory Workup
  • Other supporting labs
  • -Platelet count elevated
  • -Serum transferrin receptor gt35
  • -Reticulocyte hemoglobin content lt26
  • -Hemoglobin A2 reduced
  • -Free erythrocyte protoporphyrin gt100
  • Hepcidin reduced
  • C reactive protein
  • first laboratory test abnormal

64
Diagnosis peripheral smear
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
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

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 18-24 months of age?

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

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 18-24 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 lt4 gm/dl)
    AND oral iron

74
Types of Oral iron
  • Ferrous sulfate Carbonyl iron
  • - 20 elemental iron -100 elemental iron
  • - well absorbed -15 mg tab
  • - 325 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

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
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