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Hematology

Iron Deficiency

Overview of Iron Deficiency Anemia (IDA)

  • Definition: A microcytic, hypochromic anemia characterized by decreased red blood cell production due to insufficient iron stores
  • Etiology:
    • Inadequate iron intake
    • Increased iron loss (bleeding)
    • Impaired iron absorption
    • Increased iron requirements (e.g., pregnancy)
  • Epidemiology: The most common cause of anemia worldwide, particularly affecting women of childbearing age, infants, and children
  • Pathophysiology:
    • Iron is essential for hemoglobin synthesis
    • Insufficient iron leads to decreased hemoglobin production, resulting in smaller and paler red blood cells

Iron Metabolism

  • Dietary Iron:
    • Sources: Heme iron (from animal products) and non-heme iron (from plant-based foods)
    • Absorption: Heme iron is absorbed more efficiently than non-heme iron
  • Iron Absorption:
    • Occurs primarily in the duodenum and proximal jejunum
    • Non-heme iron is converted from ferric (Fe3+) to ferrous (Fe2+) form by duodenal cytochrome B reductase (DcytB)
    • Ferrous iron (Fe2+) is transported into enterocytes by divalent metal transporter 1 (DMT1)
    • Heme iron is transported into enterocytes by heme carrier protein 1 (HCP1)
  • Iron Storage:
    • Within enterocytes, iron can be stored as ferritin or transported into the bloodstream by ferroportin
    • Ferritin: The primary storage form of iron in cells (liver, spleen, bone marrow)
    • Hemosiderin: An insoluble storage form of iron that accumulates when iron stores are excessive
  • Iron Transport:
    • Ferroportin transports iron from enterocytes into the bloodstream
    • In the bloodstream, iron is oxidized back to the ferric form (Fe3+) by hephaestin or ceruloplasmin
    • Ferric iron (Fe3+) binds to transferrin, the iron transport protein
  • Iron Delivery:
    • Transferrin transports iron to various tissues, including the bone marrow for hemoglobin synthesis
    • Transferrin binds to transferrin receptors on cell surfaces, and iron is internalized via receptor-mediated endocytosis
  • Iron Recycling:
    • Senescent red blood cells are phagocytized by macrophages in the spleen and liver
    • Hemoglobin is broken down, and iron is released
    • Iron is either stored as ferritin or transported back to the bone marrow by transferrin for new RBC production
  • Regulation of Iron Metabolism:
    • Hepcidin: A hormone produced by the liver that regulates iron homeostasis
      • Increased hepcidin levels: Inhibit iron release from enterocytes and macrophages by binding to ferroportin, leading to its internalization and degradation. This decreases iron availability in the circulation
      • Decreased hepcidin levels: Promote iron release from enterocytes and macrophages, increasing iron availability in the circulation
    • Hepcidin production is regulated by:
      • Iron levels
      • Inflammation
      • Erythropoietic activity

Causes of Iron Deficiency Anemia

  • Inadequate Iron Intake:
    • Dietary deficiency (especially in infants, children, and vegetarians)
    • Malnutrition
  • Increased Iron Loss (Bleeding):
    • Chronic blood loss (e.g., menorrhagia, gastrointestinal bleeding)
    • Acute blood loss (e.g., trauma, surgery)
    • Frequent blood donations
  • Impaired Iron Absorption:
    • Gastrectomy or bariatric surgery
    • Celiac disease
    • Inflammatory bowel disease
    • Use of certain medications (e.g., proton pump inhibitors, antacids)
  • Increased Iron Requirements:
    • Pregnancy
    • Infancy and childhood (periods of rapid growth)
    • Erythropoietin-stimulating agent (ESA) therapy

Clinical Manifestations of Iron Deficiency Anemia

  • General Anemia Symptoms:
    • Fatigue
    • Weakness
    • Pallor (pale skin)
    • Shortness of breath
    • Dizziness
    • Headache
    • Tachycardia
  • Specific IDA Symptoms:
    • Pica (unusual cravings for non-food substances such as ice, dirt, or clay)
    • Koilonychia (spoon-shaped nails)
    • Angular cheilitis (inflammation and cracking at the corners of the mouth)
    • Glossitis (inflammation of the tongue)
    • Plummer-Vinson syndrome (rare): Dysphagia (difficulty swallowing), iron deficiency anemia, and esophageal webs

Laboratory Findings in Iron Deficiency Anemia

  • Complete Blood Count (CBC):
    • Hemoglobin (HGB): Decreased
    • Hematocrit (HCT): Decreased
    • Red Blood Cell Count (RBC): Decreased or normal
    • Mean Corpuscular Volume (MCV): Decreased (microcytic)
    • Mean Corpuscular Hemoglobin (MCH): Decreased (hypochromic)
    • Mean Corpuscular Hemoglobin Concentration (MCHC): Decreased (hypochromic)
    • Red Cell Distribution Width (RDW): Increased (anisocytosis - variation in RBC size)
    • Platelet Count: May be normal or slightly elevated
  • Peripheral Blood Smear:
    • Microcytes (small RBCs)
    • Hypochromia (pale RBCs)
    • Anisocytosis (variation in RBC size)
    • Poikilocytosis (variation in RBC shape)
      • Pencil cells (elongated, thin RBCs)
      • Target cells
  • Reticulocyte Count:
    • Low or normal (inappropriately low for the degree of anemia)
  • Iron Studies:
    • Serum Iron: Decreased
    • Total Iron-Binding Capacity (TIBC): Increased
    • Transferrin Saturation: Decreased
    • Ferritin: Decreased (most specific indicator of iron deficiency)
  • Other Tests:
    • Stool occult blood test: To detect gastrointestinal bleeding
    • Endoscopy and colonoscopy: To investigate gastrointestinal bleeding

Differential Diagnosis

  • Thalassemia: Microcytic anemia with normal or elevated iron studies
  • Anemia of Chronic Disease: Often normocytic or microcytic, with low serum iron, normal or low TIBC, and normal or high ferritin
  • Sideroblastic Anemia: Microcytic anemia with elevated serum iron and ferritin and ringed sideroblasts in the bone marrow

Treatment of Iron Deficiency Anemia

  • Identify and Treat Underlying Cause:
    • Address any sources of bleeding (e.g., treat ulcers, manage menorrhagia)
    • Treat underlying conditions affecting iron absorption (e.g., celiac disease)
  • Iron Supplementation:
    • Oral Iron:
      • Ferrous sulfate, ferrous gluconate, or ferrous fumarate
      • Take on an empty stomach (if tolerated) to maximize absorption
      • Vitamin C can enhance iron absorption
      • Avoid taking with calcium, antacids, or tea, which can inhibit absorption
      • Common side effects: Nausea, constipation, abdominal discomfort, and dark stools
    • Parenteral Iron (Intravenous or Intramuscular):
      • Used in patients who cannot tolerate oral iron, have severe malabsorption, or require rapid iron repletion
      • Iron dextran, iron sucrose, ferric gluconate, or ferumoxytol
      • Potential side effects: Allergic reactions, anaphylaxis (rare), and injection site reactions
  • Dietary Modifications:
    • Increase intake of iron-rich foods (e.g., red meat, poultry, fish, legumes, dark leafy greens)
    • Consume foods rich in vitamin C to enhance iron absorption
  • Monitoring Response to Treatment:
    • Reticulocyte count: Should increase within 1-2 weeks of starting iron supplementation
    • Hemoglobin: Should increase by at least 1 g/dL every 2-3 weeks
    • Continue iron supplementation for several months to replenish iron stores (as indicated by normalization of ferritin levels)

Key Terms

  • Iron Deficiency Anemia (IDA): Microcytic, hypochromic anemia due to insufficient iron stores
  • Ferritin: Primary storage form of iron in cells
  • Transferrin: Iron transport protein in the blood
  • TIBC (Total Iron-Binding Capacity): Measures the blood’s capacity to bind iron
  • Hepcidin: Hormone that regulates iron homeostasis
  • Microcytic: Small red blood cells (MCV < 80 fL)
  • Hypochromic: Decreased hemoglobin content (pale color)
  • Pica: Unusual cravings for non-food substances
  • Koilonychia: Spoon-shaped nails