Iron Deficiency Anemia

Iron deficiency anemia is the most common type of anemia worldwide. This form of anemia is caused by insufficient iron due to a decreased supply, an increased loss, or an increased demand. Iron deficiency anemia is seen across all ages, sexes, and socioeconomic strata, however, children, women of childbearing age, and patients from lower socioeconomic strata are at higher risk. Symptoms include pallor, particularly of the mucous membranes, easy fatigability, and headaches. Iron studies are the key to diagnosis. Treatment is based on the underlying cause of iron deficiency and consists of supplementation.

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Overview

Definition

Anemia is defined as a hemoglobin level that is 2 standard deviations below the mean for age, sex, and ethnicity. Because iron is a fundamental building block of hemoglobin, a deficiency in this mineral can result in decreased hemoglobin production and anemia.

Epidemiology

  • Most common cause of anemia worldwide (50% of all anemias)
  • More prevalent in developing countries
  • 5%–10% of menstruating women are affected.
  • Infants (6–24 months) consuming cow’s milk have a greater incidence of iron deficiency because consumption of cow’s milk leads to increased GI losses of iron.
  • More common in families with low income/lower socioeconomic status

Etiology

  • Decreased absorption
    • Restricted diets 
      • Vegan/vegetarian diets low in iron
      • Diets rich in dairy (e.g., an infant on cow’s milk)
    • Malabsorption: 
      • Insufficient production of gastric acid which normally facilitates iron absorption (e.g., patients on proton pump inhibitor (PPI))
      • Celiac disease
      • Inflammatory bowel disease
      • After gastrectomy/small bowel resection
  • Increased loss
    • Hemorrhage (e.g., trauma, menorrhagia, cancer, peptic ulcer disease)
    • Hemolysis
    • GI parasites 
    • Chronic lower GI bleed 
    • Urinary/pulmonary hemosiderosis
  • Increased demand
    • During pregnancy, increased demand due to maternal blood volume expansion/fetal needs
    • Treatment with erythropoietin in the setting of CKD
  • Functional deficiency
    • Seen in chronic disease
    • Iron from breakdown of old hemoglobin is not released into circulation by macrophages.
    • Due to chronic inflammation and production of hepcidin

Pathophysiology

  • Iron metabolism is a closely regulated balance of absorption, use, and excretion. 
  • Normal iron needs: 0.5–1 mg/day 
    • Menstruating women: 1–2 mg/day 
    • Pregnant women: 3–5 mg/day
  • Heme synthesis: 
    • Involves combination of ferrous iron (Fe²⁺) with protoporphyrin
    • Decreased bioavailable iron results in deficiency of heme synthesis and oxygen-carrying capacity.
    • Low levels of Fe²⁺ triggers erythropoiesis and up-regulation of transferrin receptors on RBCs to enhance the delivery of iron to tissues.
  • Stages of iron depletion:
    • Normal iron homeostasis
    • Iron deficiency without anemia:
      • Iron stores are depleted, but sufficient iron is obtained from breakdown of old hemoglobin to make new.
      • No anemia is evident, but individual is vulnerable to it.
    • Iron deficiency with anemia
  • When Fe²⁺ supply decreases, the following processes are affected as well:
    • Ferritin, the storage form of excess iron in the body, decreases.
    • Transferrin, a protein that binds iron in the blood, increases.

Clinical Presentation

Signs and symptoms

  • Pallor
  • Fatigue
  • Shortness of breath
  • Light-headedness
  • Syncope
  • Koilonychia (spoon-shaped, brittle nails)
  • Brittle hair
  • Pica syndrome (craving for nonfood items: dirt, ice, paint, etc.)
  • Restless leg syndrome
  • Mood disturbances: irritable, shorter attention span

Plummer-Vinson syndrome

  • Dysphagia: to solids only, due to esophageal webs
  • Glossitis: beefy-red tongue
  • Cheilosis
  • Iron deficiency anemia

Diagnosis

The diagnosis of anemia is clinical, but to qualify it further as iron deficiency anemia, lab testing is necessary.

  • CBC:
    • Hypochromic microcytic anemia
    • ↓ Hb
    • ↓ MCV ( < 70)
    • ↓ MCH (< 25)
    • ↑↑ Red cell distribution width
    • Thrombocytosis: ↑ platelets
  • Iron studies: 
    • ↓ Iron
    • ↓↓ Ferritin
    • ↑↑ Total iron-binding capacity
    • ↑ Transferrin
    • ↓↓ Transferrin saturation
  • Peripheral blood smear
    • Microcytosis and hypochromic RBC
    • Anisocytosis
    • Target cells
    • Pencil cells
  • Bone marrow aspiration
    • Gold standard (but rarely done)
    • Prussian blue stain: decreased iron in erythroblasts 
  • Find underlying cause: GI workup in men or postmenopausal women
  • 1 of the following findings is necessary for diagnosis:
    • Serum ferritin < 30 ng/mL
    • Transferrin saturation < 19%
    • Anemia resolves with iron supplementation.
    • Bone marrow aspirate without stainable iron
Peripheral blood smear shows hypochromic microcytic cells

Peripheral blood smear shows hypochromic microcytic cells:
Pencil cells and target cells (bull’s-eyes) are also present in this film.

Image: “Peripheral Smear Shows Hypochromic microcytic cells” by Ed Uthman. License: CC BY 2.0

Management

Treat underlying cause

  • Decrease cow’s milk intake in infant. 
  • Suspend interfering medications.
  • Treat inflammatory bowel disease.

Supplementation

  • Oral
    • Ferrous sulfate/ferrous gluconate/ferrous fumarate
    • Duration: 3–6 months
    • Enhance absorption with acidic juice (lowers pH)
  • IM/IV: indicated in those who can’t tolerate oral intake or who have malabsorption
  • Blood transfusion: for severely anemic patient with baseline tachycardia

Response verification

Reticulocytes should increase in 1 week.

Differential Diagnosis

  • Anemia of chronic disease: anemia resulting from chronic illness that presents with entrapment of iron in macrophages or in ferritin. Most commonly seen in chronic renal failure due to lack of epoetin production. TIBC is low and hepcidin levels are increased in these cases.
  • Sideroblastic anemia: form of anemia in which iron levels are normal, but iron cannot be incorporated into the heme molecule. Causes of sideroblastic anemia include lead poisoning, vitamin B6 deficiency, and isoniazid. 
  • Thalassemia: hereditary hemoglobinopathy that presents with clinical picture similar to that of iron deficiency anemia. However, iron studies are normal in thalassemia and thus iron supplementation can be detrimental.

References

  1. Kassebaum NJ, Jasrasaria R, Naghavi M, Wet al. (2014). A systematic analysis of global anemia burden from 1990 to 2010. https://pubmed.ncbi.nlm.nih.gov/24297872/ 
  2. Centers for Disease Control and Prevention (CDC). (2002). Iron deficiency—United States, 1999–2000. MMWR Morb Mortal Wkly Rep. https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5140a1.htm
  3. Cook JD, Skikne BS. (1989). Iron deficiency: definition and diagnosis. J Intern Med. https://pubmed.ncbi.nlm.nih.gov/2681511/ 
  4. Annibale B, Capurso G, Chistolini A, D’Ambra G, DiGiulio E, Monarca B, DelleFave G. (2001). Gastrointestinal causes of refractory iron deficiency anemia in patients without gastrointestinal symptoms. Am J Med. https://pubmed.ncbi.nlm.nih.gov/11690568/ 
  5. Lopez A, Cacoub P, Macdougall IC, Peyrin-Biroulet L. (2016). Iron deficiency anaemia. Lancet. https://pubmed.ncbi.nlm.nih.gov/26314490/

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