What is the best approach for testing and treating iron deficiency?

Testing for Iron Deficiency

Serum ferritin is the single most powerful test for diagnosing iron deficiency, with a cutoff of <45 mg/dL recommended for individuals with anemia, though this threshold must be adjusted upward to <100 mg/dL in patients with concurrent inflammation, malignancy, or hepatic disease. 1

Primary Diagnostic Approach

Initial Laboratory Testing

• Serum ferritin is the first-line diagnostic test and most reliable single marker for iron deficiency 1, 2

  • A ferritin <12 μg/dL is diagnostic of iron deficiency in otherwise healthy individuals 1, 3
  • The American Gastroenterological Association recommends a cutoff of 45 mg/dL for optimal sensitivity and specificity in anemic patients 1
  • In patients with inflammatory conditions (IBD, malignancy, liver disease, chronic kidney disease), ferritin may be falsely elevated; use a threshold of <100 mg/dL in these populations 1, 3

• Complete blood count with red cell indices provides supportive evidence 3

  • Microcytosis (low MCV) is characteristic but not specific—can occur in thalassemia and hemoglobinopathies 1
  • Mean cell hemoglobin (MCH) may be more reliable than MCV as it's less affected by storage conditions 1
  • Elevated red cell distribution width (RDW >14%) with microcytosis strongly suggests iron deficiency 3

Confirmatory Testing When Ferritin is Equivocal

When ferritin results are borderline or potentially falsely elevated due to inflammation:

• Transferrin saturation <20-30% supports the diagnosis of iron deficiency 1, 3, 2
• Soluble transferrin receptor or reticulocyte hemoglobin equivalent can help distinguish true iron deficiency from anemia of chronic disease 1
• Therapeutic trial of oral iron for 2-3 weeks: a hemoglobin rise ≥10 g/L within 2 weeks is highly suggestive of absolute iron deficiency, even with equivocal iron studies 1, 3

Critical Pitfall to Avoid

Do not rely solely on hemoglobin and hematocrit for diagnosis—these are late indicators that only become abnormal after iron stores are depleted and iron-deficient erythropoiesis has progressed to anemia. 1, 3 Many patients have symptomatic iron deficiency (fatigue, restless legs, pica, exercise intolerance) before anemia develops. 2

Identifying the Underlying Cause

After confirming iron deficiency, a systematic evaluation for the source is mandatory:

Essential History Elements

• Dietary iron intake assessment—but never accept dietary insufficiency as the sole explanation without completing full evaluation 1, 3
• Menstrual blood loss in premenopausal women 1
• Medication review: NSAIDs, aspirin, anticoagulants—discontinue when possible 1, 3
• Family history of hemoglobinopathies (thalassemia), bleeding disorders, or hereditary hemorrhagic telangiectasia 1, 3
• Symptoms of gastrointestinal disease, though these rarely correlate with findings 1, 3

Gastrointestinal Evaluation

All adult men and postmenopausal women with confirmed iron deficiency anemia require gastrointestinal investigation unless there is documented significant non-GI blood loss: 1, 3

• Screen all patients for celiac disease with small bowel biopsies during upper endoscopy—2-3% of IDA patients have celiac disease, often without GI symptoms 1, 3
• Upper GI endoscopy should be performed first in most cases, revealing a cause in 30-50% of patients 1, 3
• Colonoscopy (preferred over CT colonography or barium enema) should follow unless upper endoscopy reveals carcinoma or celiac disease as the definitive cause 1, 3
• Dual pathology (lesions in both upper and lower GI tract) occurs in 10-15% of patients, so complete both evaluations even if one reveals a lesion 3
• Do not accept minor upper GI findings (erosions, small peptic ulcers) as the sole cause without completing lower GI evaluation 3
• Further small bowel visualization (capsule endoscopy, deep enteroscopy) is only necessary if symptoms suggest small bowel disease or if hemoglobin cannot be maintained with iron therapy 3
• Fecal occult blood testing has no role in the investigation of established iron deficiency anemia 3

Special Population Considerations

• Premenopausal women: Screen all for celiac disease, but use clinical judgment for other GI investigations based on risk factors (family history of GI malignancy, persistent symptoms, failure to respond to iron therapy) 3
• Patients with inflammatory bowel disease: Determine if IDA is from inadequate intake/absorption versus GI bleeding; treat active inflammation to enhance absorption 1
• Helicobacter pylori: Test and eradicate if present in patients with recurrent IDA and normal endoscopy 3

Hemoglobinopathy Screening

• Hemoglobin electrophoresis should be performed when microcytosis is present in patients of appropriate ethnic background (Mediterranean, African, Southeast Asian descent) to prevent unnecessary GI investigation for thalassemia trait 3

Treatment Principles

Oral Iron Therapy

• First-line treatment for most patients: ferrous sulfate 325 mg daily or on alternate days 2
• Expected response: Hemoglobin rise ≥20 g/L (2 g/dL) within 4 weeks indicates adequate response 3
• Continue therapy to replenish iron stores, not just correct anemia 1, 3

Intravenous Iron Indications

Use IV iron when: 1, 2

• Oral iron intolerance or side effects
• Malabsorption (celiac disease, post-bariatric surgery, atrophic gastritis)
• Inflammatory bowel disease with active inflammation 1
• Chronic kidney disease or heart failure 2
• Ongoing blood loss that cannot be controlled
• Second and third trimesters of pregnancy 2
• Portal hypertensive gastropathy with ongoing bleeding unresponsive to oral iron 1

Specific Disease-Directed Therapy

• Celiac disease: Ensure gluten-free diet adherence to improve absorption; use IV iron if oral supplementation fails 1
• Portal hypertensive gastropathy: Consider nonselective β-blockers to treat portal hypertension 1
• Gastric antral vascular ectasia: Endoscopic band ligation or argon plasma coagulation if inadequate response to iron replacement 1
• Small bowel angioectasias: Deep enteroscopy with distal attachment for detection and treatment using thermal ablation or hemostatic clips 1