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Iron Deficiency Anemia. Heather Escoto, MD Pediatric Hematology/Oncology Children’ s Center for Cancer and Blood Diseases at St. Vincent . Disclosures. Nothing to disclose. Objectives. Review of the following:

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slide1

Iron Deficiency Anemia

Heather Escoto, MD

Pediatric Hematology/Oncology

Children’s Center for Cancer and Blood Diseases at St. Vincent

disclosures
Disclosures
  • Nothing to disclose
objectives
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
anemia 101
“Anemia 101”
  • Definition
  • Classification
definitions of anemia
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!
factors that affect hemoglobin levels
Factors that affect hemoglobin levels
  • Age
  • Sex
  • Race
  • Puberty
  • Altitude
  • Heredity
hemoglobin levels in infants the physiologic nadir
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!!!
age specific hemoglobin levels
Age specific Hemoglobin levels
  • AgeHgb (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)
age specific hemoglobin levels cont
Age specific Hemoglobin levels (cont.)
  • AgeHgb (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)
hemoglobin differences between african american and caucasian children
Hemoglobin differences between African-American and Caucasian children

Mean Hgb g/dL

Males

Females

sexual maturity and hematocrit
Sexual Maturity and Hematocrit

Daniel et al. Hematocrit: maturity relationship in adolescence.

Pediatrics 1973;52:388–394.

sexual maturity and hematocrit13
Sexual Maturity and Hematocrit

Daniel et al. Hematocrit: maturity relationship in adolescence.

Pediatrics 1973;52:388–394.

basic laboratory evaluation of anemia
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
reticulocyte count absolute and percentage
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 /100=ARC 62,400
  • Hgb 11.2 - 3% X 3,470,000 /100= ARC 104,100
physiologic response to anemia
Physiologic response to anemia
  • Increased heart rate
  • Increased stroke volume
  • Vasodilation
  • Decreased oxygen affinity (right shift in oxygen-hemoglobin dissociation curve)
classification of anemia
Classification of Anemia
  • Mechanism-
  • -Decreased production
  • -Hemolysis
  • -Blood loss
  • RBC size-
  • -Microcytic
  • -Macrocytic
  • -Normocytic
classification of anemia20
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
classification of anemia21
Classificationof 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
classification of anemia morphology
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
why is iron deficiency important
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 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

why is iron important
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
iron too much is bad
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
iron how much do we need
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
hemoglobin
Hemoglobin
  • 4 globin chains (2 alpha and 2 beta globin chains)
  • 4 heme molecules with iron in the center

Heme molecule

Hemoglobin

ferritin
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

iron containing enzymes
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
iron balance
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
iron absorption
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
iron absorption34
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)
iron absorption35
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
ferroportin and hepcidin
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
iron uptake by the erythroblast
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
iron uptake by the erythroblast39

Fe3+

Iron uptake by the erythroblast

Binding of iron-transferrin to its receptor

Release of apotransferrin

TfR

Incorporation into iron-protein

Release of iron to storage

to storage

Ferritin

Hemosiderin

iron deficiency definitions
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

incidence of id and ida in us
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
incidence of id and ida in us adolescents
Incidence of ID and IDA in US adolescents
  • Adolescent females
  • Iron deficiency- 9-11%
  • Iron deficiency anemia- 2-5%
  • Adolescent males
  • Iron deficiency < 1%
prevalence of iron deficiency in us children 1 3 years old
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%
risk factors for iron deficiency in infants and children
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. 1991 May;118(5):687-92

risk factors for iron deficiency in adolescents
Risk Factors for iron deficiency in Adolescents
  • Growth spurts
  • Heavy menses
  • Chronic illness
  • H pylori infection
  • Endurance training
  • Vegetarian diets
  • Obesity
  • Poverty
  • Pregnancy
etiology of iron deficiency
Etiology of Iron Deficiency
  • Low birth stores
  • Dietary- not enough intake to meet requirements
  • Blood loss- majority of iron stored in RBCS
  • Poor absorption
newborn iron stores
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
dietary iron content
Dietary iron content
  • Milkmg 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
  • Foodsmg/serving
  • Infant cereal 6
  • Baby foods 0.3-1.2
  • **more bioavailable
iron content of common toddler foods drinks
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%
cow s milk and iron deficiency
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
iron rich foods
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
causes of iron deficiency blood loss
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
iron deficiency malabsorption
Iron Deficiency: Malabsorption
  • Short gut
  • Celiac disease
  • Medications (GERD)
  • Chronic Giardiasis
  • IRIDA (Iron Refractory Iron deficiency anemia)
  • Dx: Iron absorption test
diagnosis history and physical
Diagnosis: History and Physical
  • History
  • blood loss?
  • dietary history
  • GI symptoms?
  • Heavy menses?
  • Irritability?
  • Weakness?
  • PICA?
  • Physical exam-
  • pallor, tachycardia, irritability
pica and iron deficiency
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
lead and iron deficiency
Lead and iron deficiency
  • Iron deficiency PICA
  • PICA lead ingestion
  • Iron deficiency increases lead absorption from intestine
  • Lead toxicity does not cause microcytic anemia
diagnosis of iron deficiency laboratory workup
Diagnosis of Iron Deficiency: Laboratory Workup
  • LaboratoryValue
  • 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%
diagnosis of iron deficiency laboratory workup63
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
  • Hepcidin reduced
  • C reactive protein
  • **first laboratory test abnormal
diagnosis peripheral smear
Diagnosis: peripheral smear

Hypochromia

Microcytosis

Thrombocytosis

differential diagnosis of microcytic hypochromic anemia
Differential diagnosis of microcytic/hypochromic anemia
  • Iron deficiency
  • Thalassemia
  • Inflammation
  • Hemoglobin C or Hemoglobin E disease
  • Hereditary hyropoikilocytosis
  • Copper deficiency
  • Sideroblastic anemia
  • Congenital atransferrinemia
differential diagnosis of microcytic hypochromic anemia67
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
slide68

*increased hepcidin blocks

release of iron from macrophages

differential diagnosis of low serum iron
Differential Diagnosis of Low Serum Iron
  • -Iron deficiency
  • -Infection
  • -Inflammation
  • -Malignancy
  • -Postoperative
  • -Stress
screening for iron deficiency
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?
screening for iron deficiency anemia in adolescents
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
prevention of iron deficiency anemia in infants and toddlers
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
iron deficiency treatment
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
types of oral iron
Types of Oral iron
  • Ferrous sulfateCarbonyl 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 gluconateIron 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)
oral iron therapy side effects
Oral iron therapy- side effects
  • -BAD TASTE!
  • -GI intolerance
  • -Dark stools
  • -Staining of teeth
response to oral iron therapy
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
causes for poor response to oral iron
Causes for poor response to oral iron
  • -Non-compliance ***
  • -Incorrect administration***
  • -Incorrect diagnosis
  • -Incorrect dosing
  • -Ongoing blood loss
  • -Malabsorption
  • -IRIDA
indications for iv iron therapy
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
iv iron therapy
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
neurodevelopmental effects of id and ida
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
other effects of id and ida
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