What is the diagnostic workup and treatment for a patient with suspected iron deficiency anemia?

Iron Deficiency Anemia: Diagnosis and Treatment

Diagnose iron deficiency anemia when hemoglobin is <13 g/dL in men or <12 g/dL in non-pregnant women AND ferritin is <45 ng/mL, then proceed with systematic evaluation for the underlying cause while initiating iron replacement therapy. 1

Diagnostic Criteria

Laboratory Confirmation

• Hemoglobin thresholds: <13 g/dL (men), <12 g/dL (non-pregnant women), <11 g/dL (pregnant women) 1
• Ferritin cut-off: <45 ng/mL provides optimal sensitivity and specificity for iron deficiency 1

Special Considerations for Inflammation

Ferritin is an acute phase reactant and must be interpreted in context of inflammatory conditions. 1

• Without inflammation: Ferritin <30 ng/mL confirms iron deficiency 1
• With inflammation present: Ferritin up to 100 ng/mL may still indicate iron deficiency 1
• Confirmatory testing when ferritin 45-100 ng/mL: Use transferrin saturation (<20% suggests iron deficiency), soluble transferrin receptor, or reticulocyte hemoglobin 1

Minimum Diagnostic Workup

All patients require: 1

• Complete blood count with red cell indices (MCV, RDW)
• Reticulocyte count
• Serum ferritin
• Transferrin saturation
• C-reactive protein (CRP)

Extended workup when diagnosis unclear: Vitamin B12, folate, haptoglobin, lactate dehydrogenase, differential white blood cell count 1

Identifying the Underlying Cause

Risk Stratification by Demographics

Men and postmenopausal women: Strong recommendation for bidirectional endoscopy (moderate quality evidence) 1

Premenopausal women: Conditional recommendation for bidirectional endoscopy (moderate quality evidence) 1

• Younger premenopausal women with plausible causes (heavy menstrual bleeding) may reasonably choose initial empiric iron supplementation without endoscopy 1
• This approach is acceptable for those who prioritize avoiding endoscopy risks over detecting rare malignancy 1

Pre-Endoscopy Evaluation

Perform non-invasive testing first: 1

• H. pylori testing: Non-invasive testing recommended (conditional recommendation, low quality evidence) 1
• Celiac disease: Serologic testing with tissue transglutaminase antibody (IgA) plus total IgA level 1

If positive: Treat the identified condition before proceeding to endoscopy 1

If negative: Proceed to bidirectional endoscopy in appropriate patients 1

Endoscopic Evaluation Strategy

Bidirectional endoscopy includes: Upper endoscopy and colonoscopy 1

Biopsy recommendations: 1

• Avoid routine biopsies for celiac disease and H. pylori
• Reserve celiac biopsies for positive serologies requiring confirmation or endoscopic abnormalities
• Reserve H. pylori biopsies for endoscopic abnormalities with negative non-invasive testing

When Endoscopy is Unrevealing

For patients on antiplatelet/anticoagulant therapy with negative bidirectional endoscopy: Consider video capsule endoscopy to evaluate small bowel 1

For uncomplicated patients with negative endoscopy: Trial of iron supplementation over routine capsule endoscopy (conditional recommendation, very low quality evidence) 1

Treatment Approach

Oral Iron Therapy (First-Line)

Standard dosing: Ferrous sulfate 325 mg daily (equivalent to 65 mg elemental iron) 2, 3

Alternative dosing for better tolerance: Every-other-day dosing improves absorption and reduces side effects 4

Target daily elemental iron: 100-200 mg (lower dose if side effects occur) 5

Duration: 3-6 months typically required to normalize hemoglobin and replenish iron stores (target ferritin >100 ng/mL) 1, 5

Response assessment: Evaluate in 2-4 weeks 4

Intravenous Iron Therapy

Indications for IV iron: 1, 3

• Oral iron intolerance or inadequate response
• Malabsorption conditions (celiac disease, post-bariatric surgery, atrophic gastritis)
• Active inflammatory bowel disease with compromised absorption 1
• Ongoing blood loss
• Heart failure (improves exercise capacity)
• Chronic kidney disease
• Second and third trimesters of pregnancy

Portal hypertensive gastropathy: Start with oral iron; use IV iron if ongoing bleeding without response to oral therapy 1

Disease-Specific Considerations

Inflammatory bowel disease: 1

• Determine if anemia is from inadequate intake/absorption versus blood loss
• Treat active inflammation to enhance iron absorption
• Use IV iron with active inflammation and compromised absorption

Celiac disease: 1

• Ensure adherence to gluten-free diet to improve absorption
• Oral iron based on severity and tolerance
• IV iron if stores do not improve

Gastric antral vascular ectasia: Consider endoscopic therapy (band ligation or argon plasma coagulation) if inadequate response to iron replacement 1

Common Pitfalls

Ferritin misinterpretation: The most critical error is using ferritin <30 ng/mL as the sole diagnostic threshold without considering inflammatory states, which can falsely elevate ferritin and mask true iron deficiency 1

Premature endoscopy cessation: Approximately 50% of patients have decreased adherence to oral iron due to adverse effects, leading to treatment failure that may be misattributed to ongoing blood loss 4

Inadequate treatment duration: Stopping iron therapy when hemoglobin normalizes without replenishing iron stores (ferritin >100 ng/mL) leads to rapid recurrence 1, 5