In a patient with total iron‑binding capacity 409 µg/dL (normal), unsaturated iron‑binding capacity 355 µg/dL (normal), serum iron 54 µg/dL (low‑normal) and transferrin saturation 13 % (low), what is the most likely diagnosis and what should be the next step in evaluation and management?

Iron Deficiency with Low Transferrin Saturation

This patient has iron deficiency, confirmed by a transferrin saturation of 13% (well below the diagnostic threshold of 16%), and the next step is to measure serum ferritin to quantify iron stores and guide treatment decisions. 1

Diagnostic Interpretation

Your patient's iron panel demonstrates a classic pattern of iron deficiency:

• Transferrin saturation of 13% is diagnostic of iron deficiency, falling below the 16% threshold recommended by the CDC for adults without inflammation 1
• The low TSAT indicates iron-deficient erythropoiesis, meaning the bone marrow lacks sufficient available iron to produce hemoglobin, regardless of what the ferritin ultimately shows 2
• Normal TIBC (409 µg/dL) does not exclude iron deficiency—in fact, TIBC typically rises when iron stores are depleted as the body attempts to maximize iron-binding capacity 1
• The elevated UIBC (355 µg/dL, representing 87% of total binding capacity) confirms that transferrin has a high proportion of vacant iron-binding sites, consistent with iron deficiency 1

Critical Diagnostic Pitfall to Avoid

Do not dismiss iron deficiency based on "normal" serum iron (54 µg/dL) or normal TIBC. Serum iron exhibits marked day-to-day variability and is influenced by recent meals, diurnal changes, and inflammation—making it an unreliable diagnostic marker. Ferritin and transferrin saturation are far more accurate for diagnosis. 1

Next Step: Measure Serum Ferritin

The immediate next laboratory test is serum ferritin to quantify iron stores and determine the severity of deficiency:

• Ferritin <30 µg/L in patients without inflammation definitively confirms absolute iron deficiency 1
• Ferritin <15 µg/L in women of childbearing age has 100% specificity for depleted iron stores 1
• If inflammation is present (check CRP), ferritin up to 100 µg/L may still indicate true iron deficiency because ferritin is an acute-phase reactant that rises with inflammation 1, 2

Mandatory Workup to Identify the Underlying Cause

Iron deficiency rarely occurs without an identifiable source of loss or inadequate intake, so investigation of the underlying cause is mandatory 1:

In All Patients:

• Complete blood count to assess hemoglobin, hematocrit, and MCV (microcytosis suggests chronic deficiency) 1
• C-reactive protein to assess for inflammation, which affects ferritin interpretation 1

Source of Blood Loss (Most Common):

• Gastrointestinal evaluation is mandatory in men and postmenopausal women to exclude malignancy—stool guaiac testing followed by colonoscopy if positive 1
• In premenopausal women, assess menstrual blood loss (heavy or prolonged menses) 1
• Consider NSAID use, which causes occult GI bleeding 1

Malabsorption:

• Screen for celiac disease (tissue transglutaminase antibodies) and inflammatory bowel disease if GI symptoms are present 1

Dietary Insufficiency:

• Assess for restrictive diets (vegetarian/vegan), eating disorders, or food insecurity 1

Other Causes:

• Frequent blood donation or high-impact athletic activity causing hemolysis 1
• Chronic kidney disease (check creatinine and eGFR)—anemia prevalence increases dramatically when GFR <30 mL/min/1.73m² 2

Treatment Algorithm Based on Ferritin Results

If Ferritin <30 µg/L (Absolute Iron Deficiency):

• Oral iron therapy: Ferrous sulfate 200 mg three times daily 3
• Target: Ferritin ≥30–45 µg/L and TSAT ≥20% in patients without chronic inflammation 2
• Expected response: Hemoglobin should rise 1–2 g/dL within 4–8 weeks 2
• If no response after 4–8 weeks, consider IV iron due to malabsorption, continued bleeding, or intolerance 1

If Ferritin 30–100 µg/L with Elevated CRP (Mixed Picture):

• This suggests coexistent iron deficiency and anemia of chronic disease 3
• IV iron is preferred because it bypasses hepcidin-mediated blockade of intestinal absorption that occurs in inflammatory states 2
• Target ferritin ≥100 µg/L and TSAT ≥20% in patients with chronic inflammation 2

If Ferritin >100 µg/L (Functional Iron Deficiency):

• Despite adequate iron stores, the low TSAT indicates iron is sequestered and unavailable for erythropoiesis due to inflammation 2
• Investigate underlying chronic inflammatory conditions: CKD, heart failure, IBD, malignancy 2
• IV iron bypasses hepcidin blockade and is the treatment of choice 2

Monitoring Response to Treatment

• Recheck CBC and iron parameters 4–8 weeks after starting oral iron (or 4–8 weeks after the last IV iron dose) 2
• Do not measure iron parameters within 4 weeks of IV iron because circulating iron interferes with assays 2
• If hemoglobin does not rise 1–2 g/dL after 4–8 weeks, consider malabsorption, continued bleeding, or switch to IV iron 1, 4

Key Clinical Pearls

• TSAT <16% has 93% specificity for true iron deficiency in women of childbearing age, making it more reliable than ferritin alone in many clinical contexts 2
• Normal ferritin does not exclude iron deficiency in inflammatory states—always interpret ferritin alongside TSAT and CRP 1
• Gastrointestinal malignancy is found in 9% of patients >65 years with iron deficiency anemia, making endoscopic evaluation critical in this age group 4