What is the significance of ferritin, transferrin (Tf), Total Iron Binding Capacity (TIBC), and serum iron in diagnosing iron-related conditions?

Understanding Iron Profile Parameters and Diagnostic Approach

The iron profile must be interpreted as a panel—not in isolation—with ferritin as the cornerstone for assessing iron stores and transferrin saturation (TSAT) for evaluating iron availability for erythropoiesis, but always in the context of inflammatory status. 1

Core Parameters and Their Significance

Serum Ferritin

• Reflects total body iron stores (both reticuloendothelial system and parenchymal iron stores) 1
• Most specific marker when low: Ferritin <15 μg/L indicates absolute iron deficiency in the absence of inflammation 1
• Critical limitation: Acts as an acute-phase reactant, becoming falsely elevated during inflammation, infection, or chronic disease 1
• Reference ranges: 20-250 μg/L in men, 20-200 μg/L in women 1

Transferrin Saturation (TSAT)

• Calculated as: (Serum Iron ÷ TIBC) × 100% 1
• Represents circulating iron available for erythropoiesis and other tissues 1
• More reliable than ferritin during inflammation as it is less affected by acute-phase reactions 1
• TSAT <16% indicates insufficient iron for erythropoiesis 1
• TSAT <20% has high sensitivity for diagnosing absolute or functional iron deficiency 1
• Normal range: 20-50% 1

Total Iron Binding Capacity (TIBC)

• Measures the capacity of transferrin to bind iron (250-370 mg/dL or 45-66 mmol/L) 1
• Increases in iron deficiency as the body produces more transferrin to capture available iron 1
• Decreases in inflammation and chronic disease 1
• TIBC measurement alone outperforms serum iron and saturation indices in predicting iron deficiency 2

Serum Iron

• Measures circulating iron (50-175 mg/dL) 1
• Least reliable single parameter: Exhibits significant diurnal variation and is affected by recent iron intake 1
• Decreases in both iron deficiency and inflammation 1

Diagnostic Algorithm by Clinical Scenario

Without Inflammation (Normal CRP/ESR)

Iron Deficiency Anemia:

• Ferritin <15-30 μg/L 1
• TSAT <16% 1
• Low serum iron 1
• Elevated TIBC 1
• Low MCV and MCH (late findings) 1

Normal Iron Status:

• Ferritin >30 μg/L 1
• TSAT 20-50% 1
• Normal TIBC 1

With Inflammation (Elevated CRP/ESR)

The diagnostic thresholds shift dramatically in inflammatory states because ferritin becomes unreliable 1

Absolute Iron Deficiency with Inflammation:

• Ferritin <100 μg/L (not <30 μg/L) 1
• TSAT <16% 1
• Elevated TIBC (if not suppressed by severe inflammation) 1

Anemia of Chronic Disease (ACD):

• Ferritin >100 μg/L 1
• TSAT <16% 1
• Low-normal or decreased TIBC 1
• Low serum iron 1

Mixed Picture (Iron Deficiency + ACD):

• Ferritin 30-100 μg/L 1
• TSAT <16% 1
• This is the most challenging scenario clinically and requires additional testing 1

Advanced Markers for Complex Cases

Soluble Transferrin Receptor (sTfR)

• Elevated in true iron deficiency, remains normal or low in pure ACD 1
• Particularly useful for distinguishing iron deficiency from ACD in inflammatory conditions 1
• Not affected by inflammation 1
• Limitation: Also elevated in hemolytic anemia and conditions with high erythroid proliferation 1

Reticulocyte Hemoglobin Content (CHr or RET-He)

• Reflects iron availability in bone marrow over the past few days 1
• More sensitive than traditional markers for detecting functional iron deficiency 1
• Advantage: Immediately available on certain automated analyzers 1
• Useful for monitoring response to iron therapy 1

Hepcidin

• May be the most precise marker in inflammatory conditions but not widely available 1
• Low in iron deficiency, elevated in inflammation 1

Critical Pitfalls to Avoid

1. Never interpret ferritin alone without assessing inflammatory status (check CRP or ESR) 1

2. Do not use serum iron as a standalone test—it has poor diagnostic performance compared to TIBC/transferrin 2

3. In CKD patients on dialysis, ferritin is particularly unreliable due to chronic inflammation; prioritize TSAT 1

4. Transferrin saturation >800 g/L is toxic and should be avoided 1

5. Do not check iron parameters within 4 weeks of IV iron administration—circulating iron interferes with assays 1

6. In malnourished patients, decreased TIBC may erroneously elevate TSAT, masking iron deficiency 3

7. Soluble transferrin receptor may not be elevated in iron-deficient infants <1 year of age 1

Practical Clinical Approach

Step 1: Obtain complete iron panel (ferritin, TSAT, serum iron, TIBC) plus inflammatory markers (CRP or ESR) 1

Step 2: Determine inflammatory status to select appropriate ferritin threshold 1

Step 3: Interpret ferritin and TSAT together—never in isolation 1

Step 4: If results are discordant or patient has inflammation with ferritin 30-100 μg/L, consider sTfR or reticulocyte hemoglobin content 1

Step 5: In refractory cases where diagnosis remains unclear, bone marrow biopsy showing absent stainable iron remains the gold standard 1