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

Microcytic

Chronic Disease