A patient with serum iron 47 µg/dL, total iron‑binding capacity 302 µg/dL, transferrin saturation 16% and chronic fatigue—what is the likely diagnosis and how should it be evaluated and managed?

Iron Deficiency with Chronic Fatigue

This patient has iron deficiency confirmed by transferrin saturation of 16%, which meets the diagnostic threshold, and requires immediate evaluation for the underlying cause followed by iron repletion therapy. 1, 2

Diagnostic Interpretation

Your patient's iron panel definitively establishes iron deficiency:

• Transferrin saturation 16% is at the diagnostic cutoff for iron deficiency in adults without inflammation 1, 2
• Low serum iron (47 µg/dL) combined with elevated TIBC (302 µg/dL) indicates the body is attempting to capture more iron but cannot access adequate stores 3
• The elevated TIBC reflects increased transferrin production to compensate for depleted iron availability 3

Critical next step: You must obtain a serum ferritin level immediately to distinguish between absolute iron deficiency versus functional iron deficiency (anemia of chronic disease). 1, 2

Interpretation Framework Based on Ferritin

If ferritin < 30 ng/mL (without inflammation):

• Confirms absolute iron deficiency with depleted iron stores 1, 2
• This is the most straightforward scenario requiring investigation of iron loss

If ferritin 30-100 ng/mL:

• Suggests combination of true iron deficiency and anemia of chronic disease 1
• Check inflammatory markers (CRP, ESR) to assess for underlying chronic inflammation 1

If ferritin > 100 ng/mL with TSAT < 20%:

• Indicates functional iron deficiency where iron stores are sequestered by inflammation and unavailable for erythropoiesis 2
• Hepcidin activation traps iron in storage sites making it unavailable for red blood cell production 2

Mandatory Workup to Identify Underlying Cause

The presence of iron deficiency mandates a search for the source, as it rarely occurs without identifiable loss or inadequate intake. 3

Essential Investigations

Complete blood count with:

• Hemoglobin and hematocrit to quantify anemia severity 3
• MCV to assess if microcytic anemia is present 3
• Reticulocyte count to evaluate bone marrow response 2

Inflammatory markers:

• C-reactive protein and ESR to detect chronic inflammation 1, 3
• These determine which ferritin threshold to apply for diagnosis 1

Gastrointestinal evaluation (mandatory in adults):

• Fecal occult blood testing as GI bleeding is a common cause 3
• In men and postmenopausal women, gastrointestinal evaluation including endoscopy is mandatory to exclude malignancy 2
• Consider celiac disease screening and inflammatory bowel disease evaluation 3

Renal function:

• Serum creatinine and estimated GFR to assess for chronic kidney disease 3
• CKD with GFR < 30 mL/min/1.73m² dramatically increases anemia prevalence 2
• Urinalysis to detect proteinuria or hematuria 3

Additional considerations in specific populations:

• Menstrual history in premenopausal women (heavy menstrual bleeding is a common cause) 3
• Dietary assessment for restrictive diets or malabsorption 3
• Medication review for NSAIDs, which cause occult GI blood loss 3

Treatment Algorithm

Step 1: Determine Iron Deficiency Type

Without chronic inflammation (normal CRP):

• Target ferritin ≥ 30-45 ng/mL and TSAT ≥ 20% 2
• Oral iron is first-line unless contraindicated 2

With chronic inflammation (elevated CRP, or conditions like CKD, IBD, heart failure):

• Target ferritin ≥ 100 ng/mL and TSAT ≥ 20% 2
• Intravenous iron is preferred because it bypasses hepcidin-mediated blockade of intestinal absorption 2

Step 2: Choose Iron Formulation

Oral iron indications:

• Absolute iron deficiency without inflammation 2
• Patient tolerates oral therapy 2
• No malabsorption or active IBD 2

Intravenous iron indications:

• Functional iron deficiency (ferritin 100-300 ng/mL with TSAT < 20%) 2
• Chronic kidney disease with GFR < 30 mL/min/1.73m² 2
• Inflammatory bowel disease with active inflammation 2
• Heart failure (NYHA class II-III) 2
• Intolerance or lack of response to oral iron after 4-8 weeks 2

Preferred IV formulations: ferric carboxymaltose, iron sucrose, or low-molecular-weight iron dextran 2

Step 3: Monitor Response

Timing of follow-up labs:

• Recheck CBC and iron parameters (ferritin, TSAT) 4-8 weeks after completing iron therapy 2
• Do NOT check iron studies within 4 weeks of IV iron infusion as circulating iron interferes with assays 2

Expected response:

• Hemoglobin should increase by 1-2 g/dL within 4-8 weeks 2
• Reticulocytosis occurs at 3-5 days after IV iron administration 2

If no response occurs:

• Consider erythropoiesis-stimulating agents (ESAs) with continued iron supplementation, particularly if CKD or heart failure is present 2
• ESAs require ongoing iron supplementation to optimize response 2

Common Pitfalls to Avoid

Do not dismiss iron deficiency based on "normal" serum iron alone – serum iron has high day-to-day variability and is affected by meals, diurnal changes, and inflammation. 3 Transferrin saturation and ferritin are far more reliable. 3, 4

Do not assume normal ferritin excludes iron deficiency – in inflammatory states, ferritin can be falsely elevated up to 100 ng/mL while true iron deficiency persists. 1, 2, 3

Do not use oral iron in functional iron deficiency – hepcidin blocks intestinal absorption in inflammatory conditions, making IV iron necessary. 2

Do not check iron parameters too soon after IV infusion – wait 4-8 weeks to avoid falsely elevated results. 2

Do not overlook malignancy screening – in men and postmenopausal women, GI evaluation is mandatory to exclude cancer as the source of chronic blood loss. 2