A patient has serum iron 17 µg/dL (low), transferrin saturation 5 % (low), total iron‑binding capacity 375 µg/dL (normal‑high), and transferrin 268 mg/dL (normal). What is the most likely diagnosis and how should it be evaluated and managed?

Absolute Iron Deficiency: Diagnosis and Management

This patient has absolute iron deficiency confirmed by transferrin saturation of 5% (well below the diagnostic threshold of <16–20%) and low serum iron, requiring immediate iron repletion therapy. 1

Diagnostic Interpretation

Your patient's iron panel definitively establishes absolute iron deficiency:

• Transferrin saturation of 5% is markedly below the diagnostic threshold of <16% for adults without inflammation and <20% in inflammatory states, confirming iron-deficient erythropoiesis 1
• Serum iron of 17 µg/dL is low, indicating insufficient circulating iron for hemoglobin synthesis 1
• TIBC of 375 µg/dL (normal-high) reflects the body's compensatory attempt to maximize iron-binding capacity when stores are depleted 1, 2
• Transferrin of 268 mg/dL (normal) is consistent with the elevated TIBC, as TIBC directly correlates with transferrin concentration 1

This constellation—low iron, elevated TIBC, and severely low transferrin saturation—is the classic laboratory signature of absolute iron deficiency. 1, 2

Critical Next Step: Measure Ferritin

You must obtain a serum ferritin level immediately to quantify iron stores and guide treatment intensity. 1

• Ferritin <30 ng/mL (without inflammation) confirms absolute iron deficiency and mandates treatment 1
• Ferritin <100 ng/mL (with inflammation) still indicates true iron deficiency despite the seemingly "normal" value, because ferritin is an acute-phase reactant 1
• Measure C-reactive protein simultaneously to identify inflammation that may falsely elevate ferritin 1, 2

Common pitfall: Normal serum iron does not exclude iron deficiency due to high day-to-day variability and diurnal fluctuations; ferritin and transferrin saturation are far more reliable. 1, 2

Mandatory Evaluation for Underlying Cause

Iron deficiency rarely occurs without an identifiable source of loss or inadequate intake. 2

In Men and Postmenopausal Women

• Gastrointestinal evaluation is mandatory to exclude malignancy as a source of chronic blood loss 1, 2
• Perform upper and lower endoscopy to identify occult bleeding sources 2
• Screen for celiac disease (prevalence 3–5% among patients with iron-deficiency anemia) 2

In Premenopausal Women

• Assess for heavy menstrual bleeding (soaking through a pad/tampon every 1–2 hours or periods >7 days) 2
• If menstrual losses do not explain the severity, proceed with gastrointestinal evaluation 1

Additional Investigations

• Complete blood count to assess hemoglobin, MCV, and reticulocyte count 1, 2
• Renal function (creatinine, eGFR) to evaluate for chronic kidney disease, which alters iron metabolism 1, 2
• Urinalysis to detect hematuria or proteinuria as sources of chronic iron loss 2
• Dietary assessment for low heme-iron intake (vegetarian/vegan diets) 2
• Review medications: NSAIDs, anticoagulants, proton-pump inhibitors (which impair iron absorption) 2

Treatment Algorithm

Step 1: Determine Iron Deficiency Type

Inflammation Status (CRP)	Ferritin Threshold	TSAT Threshold	Diagnosis
Normal	<30 ng/mL	<16%	Absolute iron deficiency
Elevated	<100 ng/mL	<20%	Absolute iron deficiency
Elevated	100–300 ng/mL	<20%	Functional iron deficiency

1

Step 2: Choose Iron Supplementation Route

First-Line: Oral Iron (if no contraindications)

• Ferrous sulfate 325 mg (65 mg elemental iron) or equivalent, given on alternate days (not daily) to maximize absorption by avoiding hepcidin-mediated blockade 1, 2
• Administer on an empty stomach (≥1 hour before or ≥2 hours after meals) 2
• Expected response: hemoglobin increase of 1–2 g/dL within 4–8 weeks 1, 2

Common pitfall: Daily dosing sustains elevated hepcidin for 24 hours, markedly reducing subsequent iron uptake; alternate-day dosing improves fractional absorption. 2

Switch to Intravenous Iron If:

• Gastrointestinal intolerance to oral iron (nausea, constipation, diarrhea) 1, 2
• No hematologic response after 4–8 weeks of adequate oral therapy 1, 2
• Chronic kidney disease with eGFR <30 mL/min/1.73 m² 1, 2
• Documented malabsorption (celiac disease, inflammatory bowel disease, post-bariatric surgery) 2
• Ongoing blood loss exceeding oral replacement capacity 2
• Chronic inflammatory conditions (heart failure, CKD, IBD, cancer) where hepcidin blocks intestinal absorption 1, 2

Intravenous Iron Formulations

Formulation	Maximum Single Dose	Special Considerations
Ferric carboxymaltose	1,000 mg	Rapid administration; low hypersensitivity risk; FDA-approved [3]
Ferric derisomaltose	1,000 mg or 20 mg/kg (max 1,500 mg)	FDA-approved for total-dose infusion; reduces CV mortality in heart failure [2]
Iron sucrose	200 mg	No test dose required [2]
Low-molecular-weight iron dextran	High-dose infusion	Requires test dose due to anaphylaxis risk [2]

1, 2, 3

Clinical trial data: In patients intolerant to or failing oral iron, ferric carboxymaltose increased hemoglobin by 1.6 g/dL (Cohort 1) and 2.9 g/dL (Cohort 2) by Day 35, significantly outperforming oral iron and standard IV iron. 3

Step 3: Treatment Targets After Repletion

• Ferritin ≥30–45 ng/mL (without inflammation) or ≥100 ng/mL (with inflammation) 1
• Transferrin saturation ≥20% to ensure adequate iron availability for erythropoiesis 1, 2
• Hemoglobin ≥12 g/dL (adult females) or ≥13 g/dL (adult males) 2

Step 4: Monitoring Schedule

• Do not measure iron parameters within 4 weeks of IV iron infusion because circulating iron falsely elevates results 1, 2
• Optimal re-assessment window: 4–8 weeks after the last IV iron dose or 8–10 weeks after initiating oral iron 1, 2
• Repeat CBC and iron panel (ferritin, TSAT) at this interval 1

Special Considerations

If Ferritin Is Elevated (>100 ng/mL) Despite Low TSAT

This indicates functional iron deficiency in the setting of chronic inflammation, where hepcidin traps iron in storage sites making it unavailable for red-cell production. 1

• Intravenous iron is required because it bypasses hepcidin-mediated intestinal blockade 1
• Oral iron is ineffective in this scenario 1, 2
• Consider erythropoiesis-stimulating agents (ESAs) if no response to IV iron occurs, particularly in CKD or heart failure 1

If No Response to Oral Iron After 4–8 Weeks

Among early non-responders to oral iron, only 21% achieve hematologic improvement with an additional 4 weeks of oral therapy, whereas 65% respond when switched to IV iron. 2

Diagnostic pitfall: Continuing oral iron indefinitely without reassessment exposes patients to unnecessary gastrointestinal side effects and delays definitive treatment. 2

Key Diagnostic Pitfalls to Avoid

• Do not rely on "normal" serum iron to exclude deficiency; it has poor diagnostic accuracy due to high variability, diurnal changes, and post-prandial effects 1, 2
• Do not use ferritin alone in inflammatory states; it can be falsely elevated up to 100–300 ng/mL while true iron deficiency persists 1
• Do not measure iron studies too early after IV iron (within 4 weeks); wait 4–8 weeks to avoid misleadingly elevated values 1, 2
• Do not continue oral iron in functional iron deficiency (inflammation + ferritin 100–300 ng/mL + TSAT <20%); switch to IV iron 1, 2
• Do not delay investigation of underlying causes (GI evaluation in men/postmenopausal women) when iron deficiency is identified 1, 2