What is the likely diagnosis and recommended treatment for a patient with serum iron 16 µg/dL, unsaturated iron‑binding capacity 352 µg/dL, and transferrin saturation 4%?

Severe Iron Deficiency Requiring Immediate Intravenous Iron Therapy

Your patient has profound absolute iron deficiency with depleted iron stores, confirmed by a transferrin saturation of 4% (diagnostic threshold <16%), serum iron of 16 µg/dL, and markedly elevated UIBC of 352 µg/dL—all indicating the body has exhausted its iron reserves and is desperately attempting to capture any available iron for red blood cell production. 1, 2

Diagnostic Interpretation

Your iron panel reveals:

• Transferrin saturation 4% is far below the diagnostic threshold of <16% for absolute iron deficiency in adults, confirming iron-deficient erythropoiesis 1, 2
• Serum iron 16 µg/dL is markedly low, though this value alone has poor diagnostic accuracy due to high day-to-day variability 1, 2
• UIBC 352 µg/dL is severely elevated, reflecting compensatory upregulation of transferrin production when iron stores are completely depleted—this is a more accurate marker of empty iron stores than serum iron or transferrin saturation alone, with diagnostic accuracy of 0.80-0.97 2, 3
• The combination of low serum iron + elevated UIBC + TSAT <16% definitively confirms absolute iron deficiency with depleted stores 1, 2

This pattern represents a compensatory mechanism to mobilize all traces of tissue iron to maintain erythropoiesis, occurring before serum iron falls in the evolution of iron deficiency 4.

Mandatory Diagnostic Work-Up

Immediate Laboratory Tests

• Complete blood count with hemoglobin, hematocrit, MCV, and reticulocyte count to assess anemia severity and red cell indices 1, 2
• Serum ferritin to quantify iron stores: <30 ng/mL confirms absolute deficiency without inflammation; <100 ng/mL confirms deficiency even with inflammation present 5, 1
• C-reactive protein to identify concurrent inflammation that may falsely elevate ferritin and alter treatment thresholds 1, 2
• Renal function tests (creatinine, eGFR) to evaluate for chronic kidney disease, which influences iron metabolism and treatment choice 2

Investigation of Underlying Cause

In men and postmenopausal women, gastrointestinal evaluation is mandatory to exclude malignancy as a source of chronic blood loss: 5, 1

• Upper endoscopy with small bowel biopsies to detect celiac disease (present in 2-3% of IDA patients) 5
• Colonoscopy to exclude colonic cancer, polyps, angiodysplasia, or inflammatory bowel disease 5
• Stool guaiac testing for occult GI bleeding 2

In premenopausal women: 2

• Assess menstrual blood loss patterns as the primary source
• Still consider GI evaluation if menstrual losses do not fully explain the severity

Additional considerations: 2

• Dietary history for restrictive diets or inadequate intake
• NSAID use (stop if possible)
• Malabsorption disorders (celiac disease, IBD, bacterial overgrowth)
• Frequent blood donation or high-impact athletic activity causing hemolysis

Treatment Algorithm

Step 1: Determine Iron Deficiency Type

Inflammation Status (CRP)	Ferritin Threshold	TSAT Threshold	Deficiency Type
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, 2

Step 2: Choose Iron Supplementation Route

Intravenous iron is strongly preferred over oral iron in your patient because: 1, 2, 6

• Transferrin saturation of 4% indicates such severe depletion that oral iron absorption will be inadequate to meet the body's needs, even at 200 mg elemental iron daily 1, 2
• Only a small fraction of oral iron is absorbed, and absorption declines further as stores begin to replenish 1, 2
• Daily oral dosing sustains elevated hepcidin for 24 hours, markedly reducing subsequent iron uptake 2

Specific indications for IV iron (any one of the following): 1, 2, 6

• Lack of hematologic response after 4-8 weeks of adequate oral iron therapy
• Gastrointestinal intolerance to oral iron (nausea, constipation, diarrhea)
• Chronic kidney disease with eGFR <30 mL/min/1.73 m²
• Heart failure (NYHA class II-III) with ferritin <100 ng/mL or ferritin 100-300 ng/mL plus TSAT <20%
• Active inflammatory bowel disease
• Documented malabsorption

IV iron formulations and dosing (for patients ≥50 kg): 6

• Ferric carboxymaltose (Injectafer): 750 mg IV × 2 doses separated by ≥7 days (total 1,500 mg per course), or single 1,000 mg dose
• Iron sucrose: up to 200 mg per infusion
• Low-molecular-weight iron dextran: high-dose infusion (requires test dose)

If oral iron must be used (when IV iron is unavailable): 1, 2

• Alternate-day dosing (every other day) markedly improves absorption by avoiding hepcidin blockade
• Administer on an empty stomach (≥1 hour before or ≥2 hours after meals)
• Reduce dose to 50-100 mg elemental iron per administration (higher doses do not increase absorption)
• Avoid proton-pump inhibitors or H₂-blockers, which impair iron absorption

Step 3: Treatment Targets

After iron repletion, aim for: 1, 2

• Transferrin saturation ≥20% to ensure adequate iron availability for erythropoiesis
• Ferritin ≥100 ng/mL to ensure sufficient iron stores (≥30 ng/mL if no inflammation)
• Hemoglobin increase of 1-2 g/dL within 4-8 weeks of treatment initiation

Step 4: Monitoring Response

• Do NOT repeat iron studies within 4 weeks of IV iron infusion because circulating iron interferes with assay accuracy and ferritin may be falsely elevated 1, 2
• Optimal timing for reassessment: 4-8 weeks after last IV iron dose, or 8-10 weeks after initiating oral iron 1, 2
• Reticulocytosis occurs at 3-5 days after IV iron, indicating bone marrow response 1

Step 5: If No Response to Iron Therapy

Consider erythropoiesis-stimulating agents (ESAs) with continued iron supplementation if: 1, 2

• Chronic kidney disease or heart failure is present
• No hematologic response despite achieving TSAT ≥20% and ferritin ≥100 ng/mL
• ESAs require iron supplementation throughout therapy to optimize dose-response
• Maintain TSAT >20% during ESA therapy

Common Diagnostic Pitfalls

• Normal serum iron does NOT exclude iron deficiency due to high day-to-day variability, diurnal fluctuations, and post-prandial changes—ferritin and TSAT are far more reliable 1, 2
• Relying solely on ferritin can miss iron deficiency in early/functional deficiency or when inflammation is present; both ferritin and TSAT must be interpreted together 1, 2
• Measuring iron parameters too early after IV iron (within 4 weeks) yields falsely elevated results 1, 2
• Oral iron is ineffective in functional iron deficiency with active inflammation because hepcidin blocks intestinal absorption; IV iron is required 1, 2
• Failing to investigate the underlying cause in men and postmenopausal women can miss gastrointestinal malignancy 5, 1

Special Considerations

• 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
• In women of childbearing age with TSAT <16%, the specificity for true iron deficiency is 93%, though sensitivity is only 20% 1
• Check serum phosphate levels in patients requiring repeat IV iron courses within 3 months, as hypophosphatemia can occur 6