Iron Deficiency Anemia

Heather Escoto, MDPediatric Hematology/Oncology

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

Disclosures

Nothing to disclose

ObjectivesReview 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

“Anemia 101”

Definition

Classification

.

Definitions of AnemiaPhysiologic 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

• Age• Sex• Race• Puberty• Altitude• Heredity

.

Hemoglobin levels in infants- the physiologic

nadirTerm 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

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-18th edition.

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)

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)

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-18th edition.

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.)

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: 377-380.

Males Females

Sexual Maturity and Hematocrit

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

Sexual Maturity and Hematocrit

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

Heredity and Hemoglobin

Siimes et al, J Pediatr 1994 Jan;124(1):100-2. Effect of Hereditary on Hemoglobin Concentration.

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

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Reticulocyte count and anemia

Reticulocyte

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

Increased heart rate

Increased stroke volume

Vasodilation

Decreased oxygen affinity (right shift in oxygen-hemoglobin dissociation curve)

Classification of AnemiaMechanism-

-Decreased production

-Hemolysis

-Blood loss

RBC size-

-Microcytic

-Macrocytic

-Normocytic

.

Classification of anemiaMechanism-

Decreased production

-Marrow infiltration-malignancy

-Marrow injury- infections, toxins

-Nutritional deficiency

-Ineffective erythropoesis (thalassemias)

-Erythropoietin deficiency

-Labs: Low reticulocyte count, variable MCV

Classification of anemiaBlood 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

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

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Iron Deficiency Anemia

.

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? -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• 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?

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.

Iron distribution in the body

Hemoglobin- 4 globin chains (2 alpha and 2 beta

globin chains)- 4 heme molecules with iron in the

center

Heme moleculeHemoglobin

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+

FerritinFe 2+

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• 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• 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 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 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

.

Iron absorption

Ferroportin and HepcidinHepcidin

-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

• 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 erythroblast

Katz JH. Iron and protein kinetics studied by means of doubly labeled human crystalline transferrin. J Clin Invest 1961;40:2143-2152.

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

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

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):973-976.•Hay et al. Iron status in a group of Norwegian Children aged 6-24 months. Acta Paediatr. 2004;93(5): 592-598.

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):973-976.

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; 159:1038-1042. .

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;568Pizzaro 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

• Growth spurts• Heavy menses• Chronic illness • H pylori infection• Endurance training• Vegetarian diets• Obesity• Poverty• Pregnancy

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 • 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 contentMilk 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

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%

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 foodsHeme 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•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

• Short gut• Celiac disease• Medications (GERD)• Chronic Giardiasis• IRIDA (Iron Refractory Iron

deficiency anemia)

• Dx: Iron absorption test

Diagnosis: History and Physical

History• blood loss?• dietary history• GI symptoms? • Heavy menses? • Irritability? • Weakness?• PICA?

Physical exam- • pallor, tachycardia, irritability

PICA

PICA

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

• Iron deficiency PICA• PICA lead ingestion• Iron deficiency increases lead

absorption from intestine • Lead toxicity does not

cause microcytic anemia

Diagnosis of Iron Deficiency:

Staging

3 stages of Iron Deficiency

FIG. 4.5. 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 >11 <11

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%

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 reducedC reactive protein

**first laboratory test abnormal

Diagnosis: peripheral smear

l

HypochromiaMicrocytosisThrombocytosis

Differential diagnosis of microcytic/hypochromic

anemiaIron deficiency

Thalassemia

Inflammation

Hemoglobin C or Hemoglobin E disease

Hereditary hyropoikilocytosis

Copper deficiency

Sideroblastic anemia

Congenital atransferrinemia

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 trait IDA

Hemoglobin (g/dL)

12.6 11.3 10.2

Red cell count (X10^6/µL

5.6 4.7 4.67

MCV (fl) 65.5-72.2 60.8 67

MCHC 23.2 20.3 21.8

HgB A2 Normal or decreased

Elevated Normal or decreased

Mentzer index (MCV/RBC

<13 >13

Differential Diagnosis of Microcytic Hypochromic

AnemiaAnemia 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; 116:4754-4761

*increased hepcidin blocksrelease of iron from macrophages

Differential Diagnosis of Low Serum Iron

-Iron deficiency

-Infection

-Inflammation

-Malignancy

-Postoperative

-Stress

.

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?

Pediatrics 2010; 126:1040-1060

Screening for Iron Deficiency Anemia in

AdolescentsAAP 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, 6th ed, Kleinman, RE (ED). American Academy of Pediatrics, Elk Grove Village, IL 2009. p. 419

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

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 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)

.

Oral iron therapy- side effects

-BAD TASTE!

-GI intolerance

-Dark stools

-Staining of teeth

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

-Non-compliance ***

-Incorrect administration***

-Incorrect diagnosis

-Incorrect dosing

-Ongoing blood loss

-Malabsorption

-IRIDA

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 therapyPreparations:• 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

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; 129-382. 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.

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; :CD008132. Ekiz et al. Hematol J 2005; 5:579. Benedict et al. J Chld Neurol 2004; 19;526.