Iron Deficiency Anemia

Aka: Iron Deficiency Anemia, Iron Deficiency

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II. Epidemiology

  1. Most common cause of Microcytic Anemia (50% of cases)
  2. Most common micronutrient nutritional disorder worldwide
  3. Incidence (U.S.)
    1. Children 1-5 years: 2-5%
      1. Rare before age 6 months in term infants
      2. Rare until birth weight doubles in Preterm Infants
      3. Associated with delayed cognitive development and higher risk of infectious disease
    2. Men: 2-3%
    3. Women (pregnant in third trimester): 25%
      1. Associated with increased perinatal mortality and Preterm Labor
    4. Women (non-pregnant): 12% when menstruating
      1. Drops to 6-9% after Menopause
      2. Incidence is 19-22% if Black or Mexican-American
  4. References
    1. (2002) MMWR Morb Mortal Wkly Rep 51:897-9 [PubMed]

III. Causes

  1. Children
    1. See Pediatric Anemia Causes
  2. Premenopausal women
    1. Menorrhagia: 2 mg/day iron lost
    2. Dietary Iron absorption: 1.5 - 1.8 mg/day iron gained
    3. Each Pregnancy: 500 to 1000 mg iron lost
  3. Males and Postmenopausal women
    1. Colon Cancer until proven otherwise
    2. Gastrointestinal blood Loss
      1. Gastritis from NSAID use
      2. Peptic Ulcer Disease
    3. Partial gastrectomy
    4. Bariatric Surgery (Gastric Bypass)
    5. Diverticulosis
    6. Gastrointestinal Angiodysplasia
    7. Ulcerative Colitis
    8. Celiac Sprue
    9. Increased iron requirements
      1. Pregnancy (see above)
      2. Childhood
  4. Uncommon Causes
    1. Gastrointestinal Parasites (e.g. Hookworms)
    2. Gastrointestinal blood loss in long distance Running
    3. Hereditary Hemorrhagic Telangiectasia
    4. Pulmonary Hemosiderosis

IV. Risk Factors

  1. Menorrhagia
  2. Low socioeconomic status
  3. Chronic Kidney Disease
  4. Decreased iron absorption
    1. Proton Pump Inhibitor use
    2. Bariatric Surgery history (esp. Roux-en-Y Bypass)
  5. Increased iron utilization
    1. Pregnancy
    2. Lactation
    3. Children age <5 years
    4. Puberty
    5. Endurance athletes

V. History

  1. Nutritional history
    1. Infants
      1. Exclusively Breastfed infants (Iron Supplementation starting at age 4 months)
      2. Infant formula should contain iron
    2. Children
      1. Excessive cow's milk intake
    3. Teens and adults
      1. Eating Disorders
      2. Vegetarian or Vegan diet
  2. Blood loss history
    1. Change in stool color (Melena or bright red blood)
    2. History of excessive menstrual flow (Menorrhagia)
    3. Recent surgery
    4. Recent pregnancy or delivery
    5. Frequent blood donation or lab blood draw
    6. Bleeding Disorders
    7. Hemodialysis
    8. Hemolytic Anemia
  3. Gastrointestinal condition history or Family History
    1. Gastrointestinal Bleeding (e.g. Peptic Ulcer Disease)
    2. Celiac Sprue
    3. Inflammatory Bowel Disease
    4. Colon cancer Family History
    5. Bariatric Surgery
    6. Helicobacter Pylori infection
    7. Parasitic Infections
  4. Medications
    1. Agents affecting iron absorption
      1. Chronic Antacid use (esp. Proton Pump Inhibitors)
    2. Agents predisposing to GI Bleeding
      1. NSAIDs
      2. Aspirin
      3. Corticosteroids

VI. Symptoms

  1. See Pica
  2. Iron Deficiency may be symptomatic even without Anemia
  3. Symptoms of Iron Deficiency Anemia
    1. Pica
    2. Dizziness
    3. Dyspnea or Fatigue on exertion
    4. Restless Leg Syndrome
    5. Tinnitus
    6. Palpitations
    7. Irritability (infants)
    8. Attention Deficit Hyperactivity Disorder (children)

VII. Signs

  1. See Anemia Signs
  2. Alopecia
  3. Atrophic Glossitis
  4. Brittle Nails
  5. Angular Cheilitis
  6. Dry Skin
  7. Koilonychia
  8. Pallor (including mucosal pallor)
  9. Tachycardia

VIII. Associated Conditions

  1. Generalized Pruritus
  2. Restless Leg Syndrome
  3. Glossitis
  4. Angular Cheilitis
  5. Fatigue
  6. Developmental Delay in children

IX. Labs

  1. First-Line Studies
    1. Complete Blood Count with Hemoglobin, MCV and RDW
    2. Serum Ferritin
    3. Serum Iron, Total Iron Binding Capacity and Transferrin Saturation (optional if Serum Ferritin is low)
  2. Complete Blood Count (CBC)
    1. See Hematocrit Cutoffs for Anemia
    2. Hemoglobin
      1. See Hemoglobin Cutoffs for Anemia
      2. Anemia values (WHO)
        1. Men: Hemoglobin <13 g/dl (130 g/L)
        2. Non-pregnant women: Hemoglobin <12 g/dl (120 g/L)
        3. Pregnancy and children age <5 years: Hemoglobin <11 g/dl (110 g/L)
    3. Mean Corpuscular Volume (MCV)
      1. General
        1. See MCV Cutoffs for Microcytic Anemia
        2. MCV cutoff varies by age and per reference
        3. MCV usually <75 in Iron Deficiency Anemia
        4. MCV >95 fl virtually excludes Iron Deficiency (Test Sensitivity >97%)
      2. Normocytic Anemia (MCV 80 to 100 fl)
        1. Normocytic early in course of Anemia
        2. Normocytic erythrocytes are found in 40% of Iron Deficiency patients
      3. Microcytic Anemia (MCV <80 fl)
        1. Microcytosis follows Hemoglobin drop of 2 g/dl
    4. Red Cell Distribution Width (RDW)
      1. Precedes change in Mean Corpuscular Volume
    5. Mean Corpuscular Volume to Red Blood Cell Count ratio
      1. See Mentzer Index
      2. Ratio <13: Thalassemia
      3. Ratio >13: Iron Deficiency Anemia, Hemoglobinopathy
  3. Iron Studies (in order of sensitivity)
    1. Serum Ferritin <30-45 ng/ml (usually <15-20 ng/ml)
      1. Falls before other indices
      2. Most sensitive for Iron Deficiency Anemia
        1. Serum Ferritin <30ng/ml is 92% sensitive and 98% specific for Iron Deficiency in age >5 years
        2. Serum Ferritin <12 ng/ml suggests Iron Deficiency in age <5 years
      3. Falsely elevated as acute phase reactant
        1. Serum Ferritin <50 ng/ml cutoff is used in Iron Deficiency with inflammatory states
        2. Serum Ferritin >100 ng/ml excludes Iron Deficiency despite inflammatory state
    2. Total Iron Binding Capacity (TIBC) rises
    3. Serum Iron
      1. Falls after Serum Ferritin
      2. Falls after Total Iron Binding Capacity (TIBC)
    4. Transferrin Saturation decreased (<5-9%, with some guidelines using <20%)
      1. Serum Iron to Total Iron Binding Capacity
      2. Falls after Serum Ferritin
    5. Serum Transferrin receptor assay (new)
      1. Increased in Iron Deficiency Anemia
      2. Normal in Anemia of Chronic Disease
  4. Other diagnostic tests (indicated in unclear diagnosis)
    1. Soluble Transferrin Receptor
      1. Indirect measure of Erythropoiesis
      2. Increased in Iron Deficiency
      3. Not affected by inflammatory states
    2. Erythrocyte Protoporphyrin level
      1. Heme precursor
      2. Increased in Iron Deficiency
      3. Similar timing as with Transferrin Saturation
    3. Bone Marrow Biopsy
      1. Indicated when diagnosis is unclear despite above testing
  5. Reticulocyte Count or Reticulocyte Index
    1. Does not assess degree of Iron Deficiency Anemia
    2. Useful in categorization of Anemia type (distinguish from non-Iron Deficiency causes)
  6. Images
    1. HemeoncAnemiaIronDeficiency.jpg
    2. HemeoncAnemiaIronDeficiencyOnTreatment.jpg

X. Differential Diagnosis

  1. See Microcytic Anemia
  2. Thalassemia
  3. Sideroblastic Anemia (Pearson Syndrome)
  4. Anemia of Chronic Disease

XI. Management: General

  1. Review general Anemia management in specific cohorts
    1. Pediatric Anemia
    2. Anemia in Older Adults
    3. Anemia in HIV
    4. Anemia in Pregnancy
    5. Anemia in the Intensive Care Unit
    6. Anemia of Chronic Disease
  2. Identify a source of blood loss
    1. Manage known blood loss sources (e.g. Menorrhagia)
    2. High correlation to Colon Cancer in older patients (up to 9%)
      1. Exercise caution in adult men and postmenopausal women with Iron Deficiency Anemia
      2. Bidirectional endoscopy (EGD, Colonoscopy) is recommended
      3. Ioannou (2002) Am J Med 113:276-80 [PubMed]
    3. Consider non-malignant occult gastrointestinal losses
      1. Peptic Ulcer Disease (and consider Helicobacter Pylori testing)
      2. Inflammatory Bowel Disease
      3. Celiac Sprue

XII. Management: Iron Supplementation

  1. Daily Iron absorption and utilization is limited
    1. Bone Marrow response limited to 20 mg/day elemental iron
    2. Hepcidin is secreted by the liver in response to oral iron intake
      1. Hepcidin suppresses iron absorption for the next 24-48 hours after Iron Ingestion
      2. Hepcidin triggers ferroportin degradation in enterocytes and Macrophages
      3. Hepcidin is also increased in chronic disease (e.g. CHF, CKD, infection)
      4. Iron intake more than once daily is unlikely to significantly raise body iron stores
        1. Iron taken every other day may be just as effective as once daily iron intake
  2. Typical adult dosing
    1. See Ferrous Sulfate for administration precautions
      1. Iron absorption reduced up to 40% when taken with meals (also reduced with Calcium, tea, coffee)
      2. Further absorption is reduced with gastric acid hyposecretion (e.g. Proton Pump Inhibitor use)
    2. Ferrous Sulfate
      1. Standard dose: 325 mg orally daily (65 mg elemental iron daily)
        1. Twice daily dosing (130 mg elemental iron) was often recommended initially
        2. Continue Ferrous Sulfate 325 mg orally daily for at least 3 months
        3. Additional 1-3 months may be required to replenish iron stores
      2. Lower dose: 15-20 mg elemental iron
        1. Low dose (15-20 mg) is as effective as 65-130 mg/day with less adverse effects
        2. Lo (2023) Eur J Haematol 110(2):123-30 +PMID: 36336470 [PubMed]
  3. Anticipated response
    1. Hemoglobin increases 1 gram/dl every 2-3 weeks
    2. Iron stores normalize after Hemoglobin is corrected
      1. May require additional 4 months to normalize
    3. Example timeline
      1. Week 1: Reticulocytosis begins by day 4 of oral iron
      2. Week 2: Reticulocytosis (<10%)
      3. Week 3: Increased Hemoglobin increases 1-2 g/dl (10-20 g/L)
      4. Week 4: Recheck Hemoglobin And if <1 g/dl increase, consider IV iron
      5. Week 8: Recheck Hemoglobin And iron studies and consider extending Iron Supplementation for 1-2 months
  4. Evaluate failure to respond to Iron Supplementation
    1. Noncompliance
    2. Poor iron absorption due to concurrent medications
      1. Concurrent Antacid use
      2. Calcium containing foods within 1 hour
      3. Tea or coffee within 1 hour
    3. Continued excessive blood loss
    4. Consider Parenteral Iron if true malabsorption
    5. Consider iron refractory conditions
      1. Malabsorption
      2. Vitamin B12 Deficiency
      3. Zinc Deficiency
      4. Chronic Kidney Disease
      5. Hematopoietic disorders
      6. Hepcidin dysregulation

XIII. Resources: Patient Education

  1. Information from your Family Doctor: Iron Deficiency
    1. http://www.familydoctor.org/healthfacts/009/

XIV. References

  1. (1998) MMWR Morb Mortal Wkly Rep 47:1-29 [PubMed]
    1. http://www.cdc.gov/mmwr/pdf/rr/rr4703.pdf
  2. Latimer (2025) Am Fam Physician 112(5): 538-45 [PubMed]
  3. Short (2013) Am Fam Physician 87(2):98-104 [PubMed]
  4. Shine (1997) Am Fam Physician 55(7): 2455-62 [PubMed]

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