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Anemia, Iron Deficiency
Deborah R. Erlich, MD, MMedEd
image BASICS
DESCRIPTION
  • Low serum iron associated with low hemoglobin (Hgb) or microcytic, hypochromic red blood cells (RBCs)
  • Onset acute (rapid blood loss) or chronic (slow blood loss, deficient iron intake or absorption)
  • Both low Hgb per RBC and fewer RBC in total lead to blood oxygen deficiency, which can have serious systemic consequences.
  • System(s) affected: hematologic, lymphatic, immunologic, cardiac, gastrointestinal
Geriatric Considerations
Iron deficiency anemia is associated with increased hospitalization and mortality in older adults (1).
Pediatric Considerations
Infants who drink cow's milk or juice, live in poverty, are from developing countries or are of black or Native American descent are at high risk of iron deficiency anemia and should get iron supplements (2)[B].
Pregnancy Considerations
Iron supplements are recommended during pregnancy to improve maternal hematologic indexes, though significant clinical outcomes have not yet been proven (3)[A] other than neonatal birth weight (2)[B].
EPIDEMIOLOGY
  • Iron deficiency is the most common nutritional deficiency in the world (4,5) and iron deficiency anemia (IDA) is the most common cause of anemia (50%) (4,6).
  • Predominant age: all ages but especially toddlers and menstruating and pregnant women
  • Predominant sex: female
  • Predominant race: Mexican-American and black females (4)
  • Common in both developing and developed countries
Incidence
  • Adults: men 2%, women 15-20% annually
  • Infants and toddlers: 3-5% annually
  • Pregnant patients: maybe as high as 20% (2)
Prevalence
2 billion people worldwide (5)
  • Infants and children age <12 years: 4-7%
  • Men: 2-5%
  • Menstruating women: 30% (5)
ETIOLOGY AND PATHOPHYSIOLOGY
Depletion of iron stores leads to decrease in both reticulocyte count and production of Hgb. Causes:
  • Blood loss (menses, GI bleeding, trauma)
  • Poor iron intake
  • Poor iron absorption (e.g., atrophic gastritis, postgastrectomy, celiac disease)
  • Increased demand for iron (e.g., infancy, adolescence, pregnancy, breastfeeding)
RISK FACTORS
  • Premenopausal woman
  • Frequent blood donor
  • Pregnancy/lactation, young maternal age
  • Strict vegan diet
  • Use of NSAIDs
  • Hospitalized with frequent blood draws
  • Living in or visiting countries with endemic hookworm infection
GENERAL PREVENTION
  • Screen asymptomatic pregnant women and high risk children at 1 year of age (6).
  • Supplementation in asymptomatic children aged 6 to 12 months if at risk for IDA (e.g., malnutrition, abuse, cow's milk <12 months) (2,3)
  • Iron- and vitamin C-rich diet for menstruating women
  • Iron 30 mg/day for asymptomatic pregnant women (3)
COMMONLY ASSOCIATED CONDITIONS
  • GI tract malignancy, peptic ulcer disease (PUD), Helicobacter pylori infection, irritable bowel disease
  • Hookworm or other parasitic infestations
  • Hypermetrorrhagia
  • Pregnancy
  • Obesity treated with gastric bypass surgery
  • Malnutrition
  • Medications such as NSAIDs or antacids
image DIAGNOSIS
PHYSICAL EXAM
  • Pallor (skin, conjunctivae, sublingual)
  • Tachycardia, tachypnea
  • Cool extremities
  • Brittle nails/hair
  • Signs of heart failure
DIFFERENTIAL DIAGNOSIS
  • GI bleeding (e.g., gastritis, PUD, carcinoma, varices, celiac disease)
  • Chronic intravascular hemolysis (e.g., paroxysmal nocturnal hemoglobinuria, malfunctioning prosthetic valve)
  • Defective iron usage (e.g., thalassemia trait, sideroblastosis, G6PD deficiency)
  • Defective iron reutilization (e.g., infection, inflammation, cancer, hypothyroid, chronic diseases)
  • Hypoproliferation (e.g., decreased erythropoietin from hypothyroidism, renal failure)
  • Other anemias such as anemia of chronic disease, thalassemia, lead poisoning
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • Screen asymptomatic pregnant women and high risk children at 1 year of age (6).
  • Test with signs and symptoms of anemia, and fully evaluate if iron deficiency is confirmed (2,5).
  • Hgb (to define anemia):
    • <13 g in men and < 12 g in women (WHO standards) (7)
    • Patients with comorbidities (e.g., chronic hypoxemia, smokers, high altitudes) may be anemic at higher Hgb levels.
  • Mean corpuscular volume (MCV): <80 fL
    • MCV may be low normal in mild anemia, or hidden by large cells (reticulocytes, macrocytes).
  • Ferritin is most sensitive and specific for diagnosing iron deficiency as cause of anemia (5):
    • <15 µg/L diagnoses IDA (<45 µg/L likely) (2)
    • > 100 µg/L rules out iron deficiency
  • Iron studies:
    • Decreased: ferritin, serum iron, transferrin saturation
    • Increased: total iron-binding capacity (TIBC), transferrin
  • Red cell distribution width (RDW) increases with a mixed population of cells (e.g., mixed IDA and B12 deficiency).
  • CBC with differential, peripheral smear, reticulocyte count, and index
    • Peripheral smear usually shows hypochromia and microcytosis, but may be normal, and reticulocyte production index is low (2).
  • Consider testing for G6PD deficiency
  • Evaluate for thalassemia
    • Very low MCV <80, elevated Hgb A2 or Hgb F, family history, and especially high or high normal RBC count
    • Microcytosis with ovalocytosis and unresponsive to iron suggests the thalassemia trait.
  • IgA antiendomysial antibodies (IgA anti-EmA) and/or IgA antitissue transglutaminase (IgA- anti-TTG) for Celiac
  • TSH for hypothyroidism
  • An empiric trial of iron at 3 mg/kg/day may help diagnose decreased iron stores in children; reticulocytes become elevated in 7 to 10 days or Hgb increases > 1 g/dL weekly, indicating iron deficiency.
  • Drugs that may alter lab results:
    • Iron supplements or multivitamin-mineral preparations that contain iron
  • Disorders that may alter lab results:
    • Elevated ferritin: acute or chronic liver disease, Hodgkin disease, acute leukemia, solid tumors, fever, acute inflammation, renal dialysis
    • Elevated Hgb: smoking, chronic hypoxemia, high altitude
Diagnostic Procedures/Other
  • Stool guaiac
  • Stool for ova and parasites if at risk
  • Colonoscopy and endoscopy to evaluate for bleeding sites, and especially colorectal and gastric carcinoma for:
    • Premenopausal women with negative GYN workup and/or lack of response to iron
    • Men and postmenopausal women (6)[C]
  • Bone marrow aspiration rarely performed
image TREATMENT
GENERAL MEASURES
  • Search for underlying cause and correct
  • Avoid transfusions, except in rare cases.
MEDICATION
  • Elemental iron 60 to 200 mg/day for adults (5,8)[C]
  • Elemental iron 60 to 120 mg/day for pregnant women for treatment (8), 30 mg for prevention (3)[C]
  • P.49

  • Elemental iron 15 mg/day for patients > age 80
  • Elemental iron 3 to 6 mg/kg/day for children
  • Ferrous sulfate 325 mg TID or ferrous gluconate 300 mg 1 to 3 tablets BID-TID, or ferrous fumarate 324 mg 1 tablet BID on an empty stomach 1 hour before meals (6)[C]
  • Constipation will occur in ˜1/4 of patients. Consider a stool softener along with iron.
    • Medications that reduce gastric acid secretion such as proton pump inhibitors and H2 antagonists reduce iron absorption (6).
    • Special oral iron formulations (including enteric-coated iron) and compounds are expensive and reduce symptoms only to the degree that they reduce the delivery of iron.
  • Liquid iron preparations (used for children) can also be used in adults when tablets are not absorbed or low tolerance requires a dose reduction.
    • Continued bleeding and untreated hypothyroidism are causes for “failure to respond” to iron.
    • Formula to determine elemental iron needed (7): Elemental iron (mg) = Dose (mL) = 0.0442 (Desired Hb - Observed Hb) × LBW + (0.26 × LBW)
      • Desired Hb = target Hgb in g/dL
      • Observed Hb = current Hgb in g/dL
      • LBW = lean body weight in kg
      • For males: LBW = 50 kg + 2.3 kg for each inch of height over 5 feet
      • For females: LBW = 45.5 kg + 2.3 kg for each inch of height over 5 feet
      • Normal Hgb (males and females)
        • >15 kg (33 lbs) … 14.8 g/dL
        • <15 kg (33 lbs) … 12.0 g/dL
  • Consider parenteral iron for patients with an Hgb level <6 g/dL, malabsorption, chronic kidney disease, or failure to respond to higher oral doses with concomitant vitamin C (5).
  • Issues for parenteral iron formulations:
    • Give test dose for iron dextran prior to first dose to avoid anaphylaxis; ferric gluconate or iron sucrose may be safer alternatives. Dimercaprol increases risk of nephrotoxicity.
    • Dosing is product dependent; refer to individual product for suggested dosing
  • Blood transfusion for severe acute blood loss or severely symptomatic patients (e.g., demand ischemia due to anemia). Hgb threshold varies by risk factors and clinical scenario (5,9)[C].
  • Relative contraindications (oral iron):
    • Tetracycline
    • Allopurinol
    • Antacids
    • Penicillamine
    • Fluoroquinolones
    • Vitamin E
  • Precautions
    • Iron may cause dark stools and constipation.
    • Iron overdose is highly toxic; absorption is limited to 1 to 2 mg daily (5); keep tablets and liquids out of reach of small children.
ISSUES FOR REFERRAL
  • Men and postmenopausal women with IDA (test for colon cancer)
  • Pregnant women with Hgb level <9 g/dL
  • Men or nonpregnant women with an Hgb level <6 g/dL
  • Failure to respond to a 4- to 6-week trial of oral iron therapy
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
  • Monitor patients every 3 to 12 months after Hgb normalizes (6)[C].
  • Hgb increases 1 g/dL every 3 to 4 weeks.
  • Iron stores may take up to 4 weeks to correct after Hgb normalizes.
DIET
  • Iron-rich foods include red meat, poultry, and fish (all heme iron sources, best absorbed), and ironfortified breads/cereals, lentils, beans, dark green vegetables, and raisins (all nonheme iron sources, less well absorbed) (10)
  • Foods and beverages containing ascorbic acid (vitamin C) enhance iron absorption when taken simultaneously (7).
  • Avoid milk or dairy products within 2 hours of iron tablet ingestion.
  • Limit milk to 16 oz/day (adults).
  • Limit tea, coffee, and caffeinated beverages.
  • Increase fluid and dietary fiber to decrease likelihood of constipation.
  • Limit foods with high levels of chemicals (phytates and polyphenols).
PATIENT EDUCATION
  • http://familydoctor.org/familydoctor/en/diseases-conditions/anemia.html
  • http://patient.info/pdf/4392.pdf
PROGNOSIS
  • IDA can be resolved with iron therapy if the underlying cause is discovered and appropriately treated.
  • Treat coexisting subclinical hypothyroidism and IDA together. Failure to treat hypothyroidism results in poor response to iron therapy.
REFERENCES
1. Culleton BF, Manns BJ, Zhang J, et al. Impact of anemia on hospitalization and mortality in older adults. Blood. 2006;107(10):3841-3846.
2. Killip S, Bennett JM, Chambers MD. Iron deficiency anemia. Am Fam Physician. 2007;75(5):671-678.
3. McDonagh M, Cantor A, Bougatsos C, et al. Routine Iron Supplementation and Screening for Iron Deficiency Anemia in Pregnant Women: A Systematic Review to Update the U.S. Preventive Services Task Force Recommendation. Evidence Syntheses, No. 123. Rockville, MD: Agency for Healthcare Research and Quality (US); 2015.
4. Centers for Disease Control and Prevention. Iron deficiency—United States, 1999-2000. MMWR Morb Mortal Wkly Rep. 2002;51(40):897-899.
5. Camaschella C. Iron-deficiency anemia. N Engl J Med. 2015;372(19):1832-1843.
6. Short MW, Domagalski JE. Iron deficiency anemia: evaluation and management. Am Fam Physician. 2013;87(2):98-104.
7. Johnson-Wimbley TD, Graham DY. Diagnosis and management of iron deficiency anemia in the 21st century. Therap Adv Gastroenterol. 2011;4(3):177-184.
8. Recommendations to prevent and control iron deficiency in the United States. Centers for Disease Control and Prevention. MMWR Recomm Rep. 1998;47(RR-3):1-29.
9. Murphy MF, Wallington TB, Kelsey P, et al. Guidelines for the clinical use of red cell transfusions. Br J Haematol. 2001;113(1):24-31.
10. National Institutes of Health Office of Dietary Supplements. Dietary Supplement Fact Sheet: Iron
Additional Reading
  • Chertow GM, Mason PD, Vaage-Nilsen O, et al. On the relative safety of parenteral iron formulations. Nephrol Dial Transplant. 2004;19(6):1571-1575.
  • de Benoist B, McLean E, Egli I, et al, eds. Worldwide Prevalence of Anaemia 1993-2005. WHO Global Database on Anaemia. Geneva, Switzerland: World Health Organization; 2008. http://whqlibdoc.who.int/publications/2008/9789241596657_eng.pdf
  • Dubois RW, Goodnough LT, Ershler WB, et al. Identification, diagnosis, and management of anemia in adult ambulatory patients treated by primary care physicians: evidence-based and consensus recommendations. Curr Med Res Opin. 2006;22(2):385-395.
  • Mabry-Hernandez IR. Screening for iron deficiency anemia—including iron supplementation for children and pregnant women. Am Fam Physician. 2009;79(10):897-898.
  • Murray-Kolb LE, Beard JL. Iron deficiency and child and maternal health. Am J Clin Nutr. 2009;89(3):946S-950S.
  • Tefferi A, Hanson CA, Inwards DJ. How to interpret and pursue an abnormal complete blood cell count in adults. Mayo Clin Proc. 2005;80(7):923-936.
  • World Health Organization. Guideline: Intermittent Iron and Folic Acid Supplementation in Menstruating Women. Geneva, Switzerland: World Health Organization; 2011.
See Also
Algorithm: Anemia
Codes
ICD10
  • D50.9 Iron deficiency anemia, unspecified
  • D62 Acute posthemorrhagic anemia
  • D50.0 Iron deficiency anemia secondary to blood loss (chronic)
Clinical Pearls
  • IDA due to poor dietary iron intake is the most common anemia.
  • Blood loss and reduced iron stores due to malabsorption or poor utilization are major risk factors for IDA.
  • Premenopausal women and children are at the greatest risk for IDA.
  • Cow's milk should not be given to any child age <12 months.
  • Oral iron supplementation is the standard treatment for IDA.