What are the steps to diagnose and treat iron deficiency, including interpretation of iron studies and management of deficiencies?

Iron Studies: Interpretation and Management of Iron Deficiency

Diagnostic Approach to Iron Deficiency

Serum ferritin is the single most powerful test for diagnosing iron deficiency, with a threshold of <45 ng/mL recommended for diagnosis in patients with anemia. 1

Key Laboratory Parameters

Ferritin thresholds for diagnosis:

• <45 ng/mL: Diagnostic cutoff for iron deficiency anemia (preferred over the older 15 ng/mL threshold) 1
• <30 ng/mL: Confirms absolute iron deficiency in most contexts 2
• <12 μg/dL: Definitively diagnostic of iron deficiency 1
• >100 μg/dL: Iron deficiency is almost certainly not present 1

Critical caveat: Ferritin is an acute phase reactant and can be falsely elevated in inflammation, malignancy, chronic kidney disease, or hepatic disease. 1 In these situations, iron deficiency may exist despite ferritin levels of 12-100 ng/mL. 1

Transferrin saturation (TSAT):

• <20%: Indicates iron deficiency 1, 2
• <30%: May support diagnosis when ferritin is equivocal 1
• Calculate as: (serum iron/total iron binding capacity) × 100 1

Additional markers (less reliable):

• Mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and MCH concentration are unreliable for iron deficiency assessment 1
• Serum iron alone should not be used due to large diurnal variations 1
• Red cell distribution width (RDW) may be elevated, particularly in combined deficiencies 1

Functional Test for Diagnosis

A hemoglobin rise ≥10 g/L within 2 weeks of iron therapy is highly suggestive of absolute iron deficiency, even if iron studies are equivocal. 1 This therapeutic trial can confirm the diagnosis when laboratory results are unclear. 1

Investigation for Underlying Causes

Initial Workup

All patients with confirmed iron deficiency anemia require investigation for the underlying cause, as GI malignancies commonly present this way. 1

Essential initial investigations:

• Detailed history focusing on: dietary intake, menstrual history, NSAID/aspirin use, family history of bleeding disorders or thalassemia 1
• Urinalysis or urine microscopy 1
• Celiac disease screening (serologic testing) 1
• Helicobacter pylori testing (non-invasive) 1

Endoscopic Evaluation

For men and postmenopausal women with iron deficiency anemia: bidirectional endoscopy (gastroscopy and colonoscopy) is strongly recommended as first-line investigation. 1

For premenopausal women: bidirectional endoscopy is conditionally recommended. 1 Younger premenopausal women who prioritize avoiding endoscopy risks and have plausible alternative explanations (heavy menstrual bleeding) may reasonably choose initial iron replacement with close monitoring. 1

During upper endoscopy:

• Small bowel biopsies should be obtained, as 2-3% of iron deficiency anemia patients have celiac disease 1
• Reserve routine gastric biopsies for atrophic gastritis only if there is endoscopic abnormality or high clinical suspicion 1
• Upper endoscopy reveals a cause in 30-50% of patients 1

Colonoscopy alternatives:

• CT colonography is reasonable for patients unsuitable for colonoscopy 1
• Dual pathology (lesions in both upper and lower GI tract) occurs in approximately 10% of cases 1

Further Investigation for Negative Endoscopy

If bidirectional endoscopy is negative and there is inadequate response to iron therapy or recurrent iron deficiency anemia, proceed with small bowel evaluation. 1

Capsule endoscopy is the preferred test for small bowel examination due to high sensitivity for mucosal lesions. 1 CT/MR enterography are complementary for inflammatory and neoplastic disease assessment. 1

Treatment of Iron Deficiency

Oral Iron Therapy (First-Line)

Oral iron is first-line therapy for most patients with iron deficiency. 2, 3

Dosing:

• Ferrous sulfate 325 mg daily or on alternate days 2
• Alternate-day dosing may improve tolerability with similar efficacy 2

Expected response:

• Hemoglobin should rise ≥10 g/L within 2 weeks 1
• Continue therapy until iron stores are restored (ferritin >100 ng/mL) 1
• Recheck iron studies after 60-90 days of oral supplementation 4

Common pitfall: Most patients normalize hemoglobin with iron replacement, but iron deficiency recurs in a minority on long-term follow-up, necessitating periodic monitoring. 1

Intravenous Iron Therapy

Intravenous iron is indicated when:

• Oral iron intolerance or malabsorption (celiac disease, post-bariatric surgery) 2
• Chronic inflammatory conditions: chronic kidney disease, heart failure, inflammatory bowel disease, cancer 2
• Ongoing blood loss 2
• Second and third trimesters of pregnancy 2
• Inadequate response to oral iron 1

Ferric carboxymaltose dosing (for heart failure patients):

• Calculate total iron need based on hemoglobin and body weight 1
• For Hb <10 g/dL: 500-2000 mg depending on weight 1
• For Hb 10-14 g/dL: 500-1500 mg depending on weight 1
• For Hb 14-15 g/dL: 500 mg 1
• Do not administer if Hb >15 g/dL 1

Administration:

• Single doses of 500-1000 mg iron 1
• Minimum infusion time: 6 minutes for 500 mg, 15 minutes for 1000 mg 1

Monitoring after IV iron:

• Avoid checking iron studies within 4 weeks of IV iron administration, as ferritin increases markedly and cannot be used as a marker during this period 1
• Recheck ferritin and TSAT at next scheduled visit (preferably after 3 months) 1
• Subsequently monitor 1-2 times per year or if symptoms persist or hemoglobin decreases 1

Safety considerations:

• Hypersensitivity reactions occur at frequency of 0.1-1.0% 1
• Ensure proper IV line placement to avoid skin staining from extravasation 1
• Most common side effects (1-10%): dizziness, headache, hypertension, hypophosphataemia, injection-site reactions, nausea 1

Special Populations

Heart failure patients (LVEF ≤45%):

• Define iron deficiency as: ferritin <100 μg/L OR ferritin 100-299 μg/L with TSAT <20% 1
• IV ferric carboxymaltose improves functional capacity, symptoms, quality of life, and may reduce hospitalizations 1

Cancer patients:

• Absolute iron deficiency: TSAT <20% and ferritin <30 ng/mL 1
• Functional iron deficiency: TSAT 20-50% or ferritin 30-800 ng/mL 1
• IV iron preferred, especially when using erythropoiesis-stimulating agents 1

Chronic kidney disease:

• Different thresholds may apply compared to general population 1

Treatment Failure

If no response to appropriate iron therapy:

• Investigate for ongoing blood loss (particularly occult GI bleeding) 1
• Consider combined deficiencies (folate, vitamin B12) 1
• Proceed with small bowel evaluation if not already performed 1
• Evaluate for other causes of anemia 1