I. Physiology and pathophysiology

  1. Iron is essential component of hemoglobin, myoglobin, and cytochromes
  2. When iron intake is adequate, total body Fe (avg. about 3.8g in men and 2.3g in women) is distributed in:
    1. Functional Iron
      1. Hemoglobin (about 55%)
      2. Myoglobin and intracellular enzymes (about 15%)
    2. Iron stores
      1. As ferritin
        1. 70-80% of total body iron
        2. A soluble protein complex-mostly intracellular; some in serum
        3. Used as an index of Fe stores, decreasing with decreasing amount of stored Fe (note that ferritin is also an acute phase reactant and will be increased in acute illness, etc.)
      2. As hemosiderin
        1. 20-30% of total body iron
        2. An insoluble protein complex
      3. Both are located primarily in liver, bone marrow, spleen, and skeletal muscle
      4. Iron stores are depleted in times of negative Fe balance, before functional Fe is decreased
  1. Transport iron (attached to serum Transferrin--the Fe/TIBC ratio is the "percent saturation" used to diagnose and quantify iron deficiency--note that the %sat can be artificially increased in acute illness and malnutrition and decreased in oral contraceptive use and pregnancy)
  1. Fe absorption from the GI tract
    1. Regulated according to total body Fe needs--will be taken up more avidly in presence of increased Fe needs or low Fe stores
    2. Typically, about 10% of the 10-20mg/d of dietary iron is absorbed
    3. Heme Fe (meat, fish, poultry) is 2-3x more bioavailable than non-heme Fe (plant-based foods, Fe-fortified foods)
    4. Absorption of non-heme Fe is enhanced by vitamin C, tannins, calcium, and heme Fe
  1. Normal adults lose have net loss of Fe about 1mg/d for men; 1.3-1.5mg/d for women (form sweat, GI tract, skin sloughing, and menstrual flow in women)
  1. In children
    1. About 80% of a newborn's iron stores are accuulated during 3rd trimester so premature infants are at risk for iron deficiency
    2. Maternal anemia, IUGR, or diabetes mellitus can result in low fetal iron stores
    3. In full-term infants with normal iron stores, iron stores last long enough that Fe deficiency anemia is very rare before 3mos of age
    4. Human breast milk has very little iron
    5. Children < 2yo are at particularly increased risk for Fe deficiency b/c of increased needs due to rapid frowth and frequent inadequate dietary intake.

II. Clinical features

  1. In children
    1. Associated with developmental delay and behavioral disturbances which may be permanent
    2. Also may predispose to lead poisoning because it increases GIi tract's tendency to absorb heavy metals
  2. In pregnant women, associated with increased risk for preterm delivery and low birth weight

III. Risk factors for Fe deficiency

  1. Age < 5yo
  2. Children fed non-Fe-fortified formula for > 2mos
  3. Prematurity and/or low birth weight
    1. Risk increases with degree of prematurity (most iron is acquired by fetus in last trimester)
    2. Can develop iron deficiency earlier than full-term infants, i.e. within first 6mos of life
  1. Infants exclusively breast-fed
  2. Children introduced to cow's milk at < 12mos old or consumption of > 24oz of cow's milk daily
    1. Cow's milk has little iron and may be replacing foods with higher iron content
    2. Also, may cause occult GI bleeding, particularly in kids < 12mos old
  3. Women of childbearing age, particularly if menses are heavy
  4. Pregnancy
  5. Low-iron diet
  6. Limited access to food b/c of poverty or neglect
  7. Chronic illness
  8. Previous h/o Fe-deficiency anemia
  9. Consider Celiac sprue as a possible cause for poor iron absorption leading to iron deficiency

IV. Screening recommendations per CDC 1998--recommends all screening be done with Hb or HCT

  1. Screen infants who were preterm or low-birth weight and not fed Fe-fortified formulae before 6mos of age
  2. Screen all children at risk (see above) once between 9-12mos, 6mos later, then annually from 2-5yo
    1. AAP 2010 (See Pediatrics, November 2010) recommends univeral screening for anemia at 12mos with Hb measurement and assessment for Fe deficiency risk factors; consider additional screening for children  at risk 1-3yo; consider further evaluation if Hb < 11g/dL at 12mos)
  3. For children 5-12yo and adolescent boys, only screen if h/o Fe deficiency, "special health care needs," or low Fe intake
  4. Screen all nonpregnant women of childbearing age Q5-10y
    1. Screen annually if risk factors are present (extensive menstrual or other blood loss, low Fe intake, previous dx of Fe deficiency)
  5. Screen all pregnant women at intake
  6. Screen at-risk women 4-6wks postpartum
  7. CDC doesn't recommend screening adult men or postmenopausal women
  8. USPSTF recommends screening only high-risk infants and pregnant women
  9. Alternate screening measure: Reticulocyte Hemoglobin Content (CHr)
    1. In a prospective cohort study of 202 infants 9-12mo, CHr with a cutoff of 27.5pg had sensitivity/specificity of 83%/72%, compared with 26%/95% for hemoglobin with a cutoff of 11g/dL, for diagnosis of iron deficiency (defined as transferrin saturation < 10%).  The area under the receiver operating characteristics curve was greater for CHr than hemoglobin. (JAMA 294:924, 2005-abst)

V Diagnosis

  1. See Anemia section for reference values for Hb and HCT
  2. CDC recommends presumptive dx of Fe-deficiency in children, adolescent girls, and women of childbearing age if Hb or HCT are is low on 2 separate checks and pt is not ill
  3. Low serum Fe, low Fe/TIBC ("% saturation"), low serum ferritin, low MCV, high RDW

VI. Prevention

  1. In infants, per CDC 1998 (see also AAP guidelines in Pediatrics, November 2010)
    1. Encourage exclusive breastfeeding x 4-6mos and continued breastfeeding in addition to solids thereafter
    2. If using formula, encourage iron-fortified formulas with 12mg/dL Fe (no more Gi side f/x than non-iron-fortified formula except darker stools)
    3. When adding foods beyond breast milk or formula, encourage consumption of iron-rich foods (Fe-fortified infant cereal 2 servings/d will do it)
    4. After age 6mos, baby should receive > 1mg/kg/d of Fe; if don't get it from foods, encourage oral iron supplements
    5. After age 6mos, encourage foods rich in vit. C at least QD, to improve Fe absoprtion
    6. Discourage use of low-iron milks (cow's milk, soy milk, goat milk) until age 12mos
  2. Preferm/low-birth-weight infants
    1. Total intake should be 2mg/kg/d until 12mos of age
    2. Note-infants who receive multiple RBC transfusions may not need such supplementation
    3. If exclusively breast-fed, should refeice supplemental elemental Fe 2 mg/kg beginning from 1mo-1y of age (OK to d/c if weaned to iron-fortified formula or receiving sufficient iron-containing foods)
    4. If formula-fed, typically will be on high-calorie preterm infant formula (22kcal/ounce) with higher Fe content (14.6 mg/L; standard has 12mg/L) than standard formula than standard infant formulas-Usually continued until catch-up growth occurs or 1 year of age.
    5. Defer cow’s milk until 1 year of adjusted, not chronologic, age.
  3. After age 4mos, exclusively breastfed infants should receive supplemental iron 1mg/kg/d until getting that much from diet
  4. Preschool children
    1. Recommended intake from 1-3yo is 7mg/d
    2. Encourage limiting cow's, goat, or soy milk to 24oz/d for kids 1-5yo
  5. Educate all adolescent girls and women about Fe-rich foods
  6. Universal supplementation in pregnant women with Fe 30mg QD per CDC 1998
    1. Such supplementation decreases incidence of Fe-deficiency anemia, but trials looking at maternal and infant outcomes are "inconclusive" per CDC 1998
    2. Note that all prenatal multivitamins in PDR as of 1998 have at least 30mg of Fe

VII. Treatment

Ferrous sulfate: Elemental iron dose is 20% of the mass of the ferrous sulfate
Ferrous fumarate: Elemental iron dose is 33% of the mass of the ferrous fumarate

  1. In children < 5yo, oral Fe 3mg/kg/d between meals; Fe-rich diet
    1. Recheck Hb or HCT in 4 weeks; increase in Hb of 1mg/dl or HCT of 3% can be considered confirmatory of Fe deficiency
    2. If dx is confirmed as above, continue tx and recheck in 2mos; continue until HCT or Hb are normal (at least 2mos) and recheck 6mos afterward
    3. If dx is not confirmed as above, w/u further, e.g. with MCV, RDW, and serum ferritin
  1. Children 5-12yo, tx with Fe 60mg QD
  2. Adolescent boys, tx with Fe 120mg QD
  3. Adolescent girls and women (including pregnant women), tx with Fe 60-120mg QD
    1. Test for response as for children above
    2. Keep in mind Thalassemias and Sickle Cell Trait as common causes of mild anemia

(Source: MMWR 47 (RR-3):1, 1998)