What are the diagnostic approaches and treatment options for unexplained iron deficiency anemia?

Diagnostic Approaches and Treatment Options for Unexplained Iron Deficiency Anemia

Gastrointestinal investigation is essential in all patients with confirmed unexplained iron deficiency anemia (IDA), as approximately one-third of men and postmenopausal women have underlying pathological abnormalities, most commonly in the GI tract. 1

Diagnostic Approach

Initial Laboratory Assessment

• Confirm iron deficiency with:
  • Serum ferritin: Most powerful diagnostic test for iron deficiency
    • <12 μg/dL is diagnostic of iron deficiency
    • May be falsely elevated (12-100 μg/dL) in patients with concurrent inflammation, malignancy, or hepatic disease 1
  • Transferrin saturation <30% can help confirm diagnosis 1
  • Complete blood count with red cell indices (MCV typically low) 2
  • Red cell distribution width (RDW) may be elevated 1

Gastrointestinal Evaluation

1. Upper GI Endoscopy:

   • First-line investigation in most cases
   • Reveals a cause in 30-50% of patients
   • Small bowel biopsies should be taken to rule out celiac disease (present in 2-3% of IDA cases) 1

2. Lower GI Examination:

   • Colonoscopy should follow upper GI endoscopy unless carcinoma or celiac disease is found
   • CT colonography is a reasonable alternative if colonoscopy is not suitable 1
   • Dual pathology (lesions in both upper and lower GI tract) occurs in 10-15% of cases 1

3. Small Bowel Investigation:

   • Capsule endoscopy is the preferred test for examining the small bowel after negative bidirectional endoscopy 1
   • Not routinely required unless IDA is transfusion-dependent, there is visible blood loss, or anemia persists after iron replacement 1
   • CT/MR enterography may be considered in those not suitable for capsule endoscopy 1

Common Causes of Unexplained IDA

Gastrointestinal Causes

1. Occult GI Blood Loss:

   • Colonic cancer/polyps
   • Angiodysplasia (most common finding on capsule endoscopy) 3
   • Gastric cancer
   • NSAID-induced ulcerations 1

2. Malabsorption:

   • Celiac disease (2-3% of IDA cases)
   • Atrophic gastritis
   • Post-gastrectomy
   • Inflammatory bowel disease 1, 4, 5

3. Other GI Causes:

   • Small bowel tumors (lymphoma, leiomyoma)
   • Meckel's diverticulum
   • Hookworm infestation 1

Non-GI Causes

• Inadequate dietary iron intake
• Pregnancy
• Chronic kidney disease
• Heart failure
• Chronic inflammatory conditions 5

Treatment Options

Iron Replacement Therapy

1. Oral Iron:

   • First-line therapy: One tablet daily of ferrous sulfate, fumarate, or gluconate
   • If not tolerated, reduce to one tablet every other day 1
   • Continue for 3 months after normalization of hemoglobin to replenish iron stores 1
   • Monitor hemoglobin response within first 4 weeks 1

2. Intravenous Iron (Ferric Carboxymaltose):

   • Indicated for patients with:
     • Intolerance to oral iron
     • Poor absorption (celiac disease, post-bariatric surgery)
     • Chronic inflammatory conditions
     • Ongoing blood loss 6, 5

3. Blood Transfusion:

   • Limited transfusion may be required for symptomatic IDA
   • Iron replacement therapy still necessary post-transfusion 1

Follow-up

• Monitor hemoglobin and red cell indices at regular intervals (every three months for one year, then after another year)
• Additional iron should be given if hemoglobin or MCV falls below normal
• Further investigation only necessary if hemoglobin and MCV cannot be maintained with iron therapy 1

Special Considerations

Elderly Patients

• Iron deficiency is common and often multifactorial
• Carefully consider risks and benefits of invasive investigations in those with major comorbidities 1

Persistent or Recurrent IDA

• Consider repeat endoscopic procedures if IDA recurs
• Capsule endoscopy has high diagnostic yield in cases with negative bidirectional endoscopy 1, 3
• Complete resolution of IDA can be achieved in over 95% of cases with appropriate diagnosis and treatment 3

Common Pitfalls to Avoid

• Accepting a positive dietary history as the sole cause of IDA without GI investigation
• Accepting findings such as esophagitis, erosions, or peptic ulcer as the cause of IDA without completing lower GI evaluation
• Misinterpreting ferritin levels in the presence of inflammation
• Inadequate duration of iron therapy
• Deferring iron replacement while awaiting investigations 1, 2