What is the appropriate assessment and management approach for a patient with suspected iron deficiency anemia, particularly in relation to ferritin levels and oral iron supplementation with ferrous sulfate (iron(II) sulfate)?

Assessing Ferritin in Iron Deficiency

Serum ferritin is the most powerful test for diagnosing iron deficiency, with a level <12-15 μg/L being diagnostic in the absence of inflammation, though ferritin <45 ng/mL (or <100 ng/mL with inflammation) should prompt iron replacement therapy. 1

Diagnostic Thresholds for Iron Deficiency

In Patients Without Inflammation

• Ferritin <45 ng/mL is diagnostic of iron deficiency 1, 2
• Ferritin 46-99 ng/mL plus transferrin saturation <20% also confirms iron deficiency 3
• The original British Society of Gastroenterology guideline established ferritin <12 μg/L as definitively diagnostic 1
• For healthy adults >15 years, a ferritin cut-off of 30 μg/L is appropriate for treatment decisions 4

In Patients With Inflammation or Chronic Disease

• Ferritin <100 ng/mL indicates iron deficiency even in inflammatory states 1, 3
• If ferritin >100 μg/L, iron deficiency is almost certainly not present 1
• Ferritin is an acute phase reactant and can be falsely elevated by malignancy, hepatic disease, chronic kidney disease, or inflammatory conditions 1
• Always check C-reactive protein to exclude acute phase reaction when interpreting ferritin 4

Complementary Iron Studies

When Ferritin is Equivocal

• Transferrin saturation <20% has high sensitivity for diagnosing absolute or functional iron deficiency 1, 2, 3
• Transferrin saturation <30% may help confirm diagnosis when ferritin is borderline 1
• In chronic kidney disease patients on erythropoiesis-stimulating agents, maintaining ferritin >200 ng/mL and transferrin saturation >20% optimizes anemia correction 1

Advanced Testing (When Available)

• Soluble transferrin receptor (sTfR) is more sensitive in inflammatory conditions where ferritin is unreliable 1
• Reticulocyte hemoglobin content (CHr) or reticulocyte hemoglobin equivalent (RET-He) provides direct assessment of functional iron availability 1
• Red cell distribution width (RDW) may be elevated, suggesting combined deficiency (e.g., with folate) 1

Clinical Context for Assessment

Anemia Confirmation

• Hemoglobin <13 g/dL in men or <12 g/dL in non-pregnant women defines anemia 1
• Microcytosis may be absent in combined deficiencies 1

Mandatory Gastrointestinal Evaluation

• Small bowel biopsies should be taken during upper endoscopy as 2-3% of patients with iron deficiency anemia have celiac disease 1
• Bidirectional endoscopy is strongly recommended for men and postmenopausal women (moderate quality evidence) 1
• For premenopausal women, bidirectional endoscopy is a conditional recommendation; empiric iron supplementation alone may be reasonable in younger women who prioritize avoiding endoscopy risks 1
• Non-invasive testing for H. pylori and celiac disease should be performed before endoscopy 1, 3

Treatment Initiation Based on Ferritin

Oral Iron Therapy

• Ferrous sulfate 325 mg daily or on alternate days is first-line therapy for most patients 2, 3
• Every-other-day dosing improves absorption and reduces adverse effects 3
• Preparations with 28-50 mg elemental iron content optimize compliance 4
• Evaluate response in 2-4 weeks; hemoglobin should increase by 1-2 g/dL within 4-8 weeks 1, 3

Intravenous Iron Indications

• Oral iron intolerance or malabsorption (celiac disease, post-bariatric surgery) 2, 3
• Chronic inflammatory conditions: chronic kidney disease, heart failure, inflammatory bowel disease, cancer 2, 3
• Second and third trimesters of pregnancy 2
• Ongoing blood loss 2
• Heart failure patients benefit from increased exercise capacity with IV iron 3

Post-Treatment Monitoring

Timing of Reassessment

• Do not check iron parameters within 4 weeks of total dose infusion, as circulating iron interferes with assays 1
• Recheck CBC and iron parameters (ferritin, transferrin saturation) 4-8 weeks after last infusion 1
• Target ferritin is 50 ng/mL in the absence of inflammation, regardless of sex 1
• For patients with recurrent losses, repeat basic blood tests every 6-12 months 4

Common Pitfalls

• Never provide long-term daily oral or IV iron supplementation when ferritin is normal or high—this is potentially harmful 4
• Approximately 50% of patients have decreased adherence to oral iron due to gastrointestinal adverse effects 3
• Patients who fail oral therapy or cannot tolerate it should receive intravenous iron 3
• In chronic kidney disease with elevated ferritin (500-1200 ng/mL) but low transferrin saturation (<25%), IV iron may still increase hemoglobin, though safety data are limited 1