What is iron deficiency anemia, including its assessment, pharmacology, and pathophysiology?

Iron Deficiency Anemia: Assessment, Pharmacology, and Pathophysiology

Iron deficiency anemia (IDA) is a condition characterized by insufficient hemoglobin production due to inadequate iron stores, resulting in reduced oxygen-carrying capacity of blood and potentially serious negative effects on morbidity, mortality, and quality of life. 1

Pathophysiology

Iron deficiency progresses through several stages before anemia develops:

1. Depletion of iron stores - Iron stores in bone marrow, liver, and spleen are depleted
2. Iron-deficient erythropoiesis - Reduced iron supply for red blood cell production
3. Iron deficiency anemia - Hemoglobin synthesis is compromised, resulting in microcytic, hypochromic anemia

The primary causes of iron deficiency include:

• Blood loss - Most common cause in adults (gastrointestinal bleeding, menstruation)
• Inadequate dietary intake - Particularly in developing countries
• Malabsorption - Celiac disease, post-bariatric surgery, atrophic gastritis
• Increased requirements - Pregnancy, rapid growth periods
• Chronic inflammation - Reduces iron absorption and utilization

Approximately one-third of men and postmenopausal women with IDA have an underlying pathological abnormality, most commonly in the gastrointestinal tract, making investigation essential. 1

Assessment and Diagnosis

Laboratory Evaluation

A comprehensive laboratory evaluation for IDA should include:

• Complete blood count (CBC) with red cell indices

  • Hemoglobin (Hb) < 12.0 g/dL in women, < 13.0 g/dL in men 2
  • Reduced mean corpuscular volume (MCV) < 80 fL (microcytosis)
  • Reduced mean corpuscular hemoglobin (MCH) (hypochromia)
  • Elevated red cell distribution width (RDW) 2

• Iron studies

  • Serum ferritin < 30 μg/L (most specific test for iron deficiency) 1
  • Low transferrin saturation (TSAT) < 20% 2, 3
  • Low serum iron, elevated total iron-binding capacity (TIBC) 1

• Additional tests

  • Reticulocyte count (to assess bone marrow response) 2
  • C-reactive protein (to assess inflammation) 2

Diagnostic Challenges

• Inflammatory conditions - Ferritin is an acute phase protein and may appear normal or elevated despite iron deficiency. In inflammatory states, a higher ferritin cutoff (up to 100 μg/L) may be appropriate 1

• Functional iron deficiency - May occur despite normal ferritin levels, particularly in chronic kidney disease 1

• Response to therapy - A hemoglobin rise ≥10 g/L within 2 weeks of iron therapy strongly suggests iron deficiency, even with equivocal iron studies 1

Clinical Evaluation

Patients with IDA may present with:

• Fatigue, weakness, reduced exercise tolerance
• Irritability, difficulty concentrating, depression
• Restless legs syndrome (32-40% of cases)
• Pica (40-50% of cases)
• Dyspnea, lightheadedness
• Worsening heart failure in cardiac patients 3

Pharmacology and Treatment

Oral Iron Therapy

• First-line treatment for most patients with IDA 3
• Dosage: 3-6 mg/kg of elemental iron per day or 60-120 mg/day 2, 4
• Formulations: Ferrous salts (sulfate, gluconate, fumarate) provide better absorption than ferric forms
• Administration: Best absorbed on an empty stomach; may be taken with vitamin C to enhance absorption
• Duration: Continue for 3 months after normalization of hemoglobin to replenish iron stores 2
• Side effects: Gastrointestinal disturbances (nausea, constipation, diarrhea, abdominal pain)

Intravenous Iron Therapy

Indications for IV iron include:

• Oral iron intolerance or poor response
• Malabsorption (celiac disease, post-bariatric surgery)
• Chronic inflammatory conditions (IBD, CKD, heart failure)
• Ongoing blood loss
• Need for rapid correction of severe anemia 5, 3

Available formulations include iron sucrose, ferric carboxymaltose, iron dextran, and ferumoxytol, with varying doses and infusion rates.

Potential adverse effects include hypersensitivity reactions, hypophosphatemia, and iron overload.

Special Considerations

Pregnancy

• Higher iron requirements (30-60 mg/day)
• Iron deficiency affects up to 84% of women in the third trimester
• IV iron may be indicated in the second and third trimesters when oral iron is ineffective 3

Chronic Kidney Disease

• Functional iron deficiency common due to hepcidin dysregulation
• Higher ferritin cutoffs used for diagnosis (often >100 μg/L)
• Often requires IV iron and erythropoiesis-stimulating agents 1

Athletes

• Iron deficiency common in female athletes (prevalence 15-35%)
• May present as reduced performance and lethargy
• Regular screening recommended (twice yearly in female athletes) 1

Clinical Pitfalls to Avoid

1. Incomplete evaluation - Relying solely on hemoglobin/hematocrit without iron studies may miss iron deficiency without anemia 6

2. Failure to investigate underlying cause - Especially important in men and postmenopausal women where GI malignancy may be present 1

3. Inappropriate ferritin cutoffs - Using standard cutoffs in inflammatory conditions may miss iron deficiency

4. Premature discontinuation of therapy - Treatment should continue for 3 months after hemoglobin normalization to replenish stores 2

5. Overlooking functional iron deficiency - May require different diagnostic criteria and treatment approaches

6. Excessive supplementation in patients with thalassemia or other conditions predisposing to iron overload 2

By understanding the pathophysiology, proper assessment techniques, and appropriate treatment strategies for iron deficiency anemia, clinicians can effectively manage this common condition and improve patient outcomes.