How should I evaluate and manage a patient with low serum iron, low transferrin saturation, and elevated red cell distribution width?

Evaluation and Management of Low Serum Iron, Low Transferrin Saturation, and Elevated RDW

Immediate Diagnostic Interpretation

This laboratory pattern indicates iron-deficient erythropoiesis requiring urgent evaluation for the underlying cause and prompt iron repletion. The combination of low serum iron, low TSAT, and elevated RDW strongly suggests either absolute iron deficiency or functional iron deficiency in the setting of chronic inflammation 1, 2.

Step 1: Determine Iron Deficiency Type Based on Ferritin and Inflammatory Status

Without Active Inflammation

• Absolute iron deficiency is confirmed when ferritin <30 ng/mL with TSAT <20% 1, 2
• This pattern mandates investigation for chronic blood loss, particularly gastrointestinal bleeding in men and postmenopausal women 1
• Gastrointestinal evaluation including endoscopy is mandatory to exclude malignancy 2

With Chronic Inflammatory Conditions

• Functional iron deficiency is diagnosed when ferritin 100-300 ng/mL with TSAT <20% 1, 2
• In inflammatory states (CKD, heart failure, IBD, cancer), ferritin up to 100 ng/mL may still indicate true iron deficiency despite appearing "normal" 1, 2
• TSAT <20% is the critical diagnostic threshold in inflammatory conditions because it is less affected by inflammation than ferritin 1, 2

Step 2: Complete Initial Laboratory Workup

Essential Tests

• Complete blood count with hemoglobin, MCV, and RDW to assess severity 1
• Serum ferritin as surrogate marker for iron stores 1
• Transferrin saturation (serum iron/TIBC × 100) to assess iron available for erythropoiesis 1, 2
• Inflammatory markers (CRP, ESR) to identify chronic inflammatory states 1, 2

Additional Evaluation

• Reticulocyte count to assess bone marrow response; low reticulocytes suggest inadequate iron for erythropoiesis 1
• Vitamin B12 and folate to exclude combined deficiencies 1
• Renal function (creatinine, GFR) because CKD is a common cause of functional iron deficiency 1, 2, 3
• Thyroid function tests in patients with heart failure or unexplained anemia 1

Clinical Significance of RDW

• Elevated RDW (>15%) has 94% sensitivity for iron deficiency and reflects the severity of iron depletion 4, 5, 6
• RDW shows inverse correlation with hemoglobin level and transferrin saturation in iron deficiency 4
• RDW >17.1 strongly suggests iron deficiency anemia rather than thalassemia trait 4

Step 3: Identify Underlying Chronic Conditions

High-Risk Populations Requiring Evaluation

• Chronic kidney disease: Anemia prevalence increases dramatically when GFR <30 mL/min/1.73m² 2, 3
• Chronic heart failure: High prevalence of iron deficiency defined by ferritin <100 μg/L or TSAT <20% 1, 2
• Inflammatory bowel disease: Ferritin up to 100 μg/L may still indicate deficiency 1, 2
• Active malignancy: Requires hematology consultation 1, 2

Step 4: Treatment Algorithm Based on Iron Deficiency Type

Absolute Iron Deficiency (Ferritin <30-100 ng/mL, TSAT <20%)

Oral Iron Trial

• Oral ferrous sulfate 325 mg three times daily for patients without chronic inflammatory conditions 7
• Expect hemoglobin increase of 1-2 g/dL within 4-8 weeks if compliant and absorbing 2
• Lack of response to oral iron mandates trial of IV iron to distinguish malabsorption from functional deficiency 2

Intravenous Iron Indications

• CKD patients (all stages) because oral iron is poorly absorbed 1, 3
• Heart failure NYHA class II-III with ferritin <100 ng/mL or 100-300 ng/mL with TSAT <20% 1, 2
• Active IBD where hepcidin blocks intestinal iron absorption 1, 2
• Intolerance or failure of oral iron therapy 2, 7

Functional Iron Deficiency (Ferritin 100-300 ng/mL, TSAT <20%)

Pathophysiology

• Hepcidin activation traps iron in storage sites making it unavailable for hemoglobin synthesis despite adequate stores 1, 2
• This explains the paradox of low TSAT with elevated ferritin 2

Treatment Approach

• IV iron is mandatory because it bypasses hepcidin-mediated blockade of intestinal absorption 2
• Iron sucrose dosing: 100-200 mg IV over 2-5 minutes, repeated 5 times within 14 days; or 500 mg infusions on Day 1 and Day 14 7
• Target TSAT ≥20% after repletion to ensure adequate iron availability for erythropoiesis 1, 2, 7

Special Considerations for CKD Patients

• Absolute iron deficiency in CKD: TSAT ≤20% with ferritin ≤100 μg/L (predialysis/peritoneal dialysis) or ≤200 μg/L (hemodialysis) 2, 3
• Functional iron deficiency in CKD: TSAT ≤20% with elevated ferritin levels 3
• IV iron is preferred route for all dialysis-dependent CKD patients 1, 3

Step 5: Monitoring Response to Treatment

Timing of Follow-up Testing

• Do not measure iron parameters within 4 weeks of IV iron infusion because circulating iron interferes with assays 2
• Optimal reassessment window is 4-8 weeks after last IV iron dose 2, 7
• Reticulocytosis occurs at 3-5 days after IV iron administration, indicating bone marrow response 2

Expected Response

• Hemoglobin should increase 1-2 g/dL within 4-8 weeks of adequate iron therapy 2
• Target ferritin ≥30-45 ng/mL with TSAT ≥20% in patients without chronic inflammation 2
• Target ferritin ≥100 ng/mL with TSAT ≥20% in patients with chronic inflammatory conditions 2

If No Response to IV Iron

• Consider erythropoiesis-stimulating agents (ESAs) with continued iron supplementation, particularly in CKD or heart failure 1, 2
• ESAs require ongoing iron supplementation throughout therapy to optimize dose-response 2
• Coordinate with nephrology and cardiology for management decisions 2

Critical Pitfalls to Avoid

Diagnostic Errors

• Relying solely on ferritin without TSAT leads to missed functional iron deficiency in inflammatory states 1, 2
• Failing to account for inflammatory status when interpreting ferritin can cause misdiagnosis 1, 2
• Not recognizing that ferritin 100-300 ng/mL with TSAT <20% represents true iron deficiency requiring IV iron 1, 2

Treatment Errors

• Using oral iron in functional iron deficiency is ineffective because hepcidin blocks intestinal absorption 2
• Measuring iron parameters too soon after IV iron produces falsely elevated results 2
• Failing to investigate for GI bleeding in men and postmenopausal women with absolute iron deficiency 1, 2