What is the clinical significance of total iron, ferritin, and saturation levels in an iron panel for diagnosing and managing iron deficiency anemia or iron overload in patients?

Understanding the Iron Panel: Total Iron, Ferritin, and Transferrin Saturation

The iron panel consists of three key components that each reflect different aspects of iron metabolism: serum ferritin indicates total body iron stores, transferrin saturation (TSAT) reflects circulating iron availability for erythropoiesis, and serum iron measures the amount of iron bound to transferrin at a given moment. 1

Components of the Iron Panel

Serum Ferritin

• Ferritin is an iron-storage protein that directly reflects total body iron stores 1, 2
• Low ferritin (<45 ng/mL) indicates iron deficiency with 85% sensitivity and 92% specificity 1
• Critical caveat: Ferritin is an acute-phase reactant that becomes falsely elevated during inflammation, infection, chronic kidney disease, or malignancy, potentially masking true iron deficiency 1, 3
• In inflammatory states, ferritin levels may appear normal or elevated despite depleted iron stores 3
• For iron overload screening (hemochromatosis), elevated ferritin >200 μg/L (females) or >300 μg/L (males) combined with TSAT >45% suggests iron overload 1

Transferrin Saturation (TSAT)

• TSAT is calculated from serum iron divided by total iron binding capacity (TIBC) or transferrin, and reflects the percentage of transferrin binding sites occupied by iron 1, 2
• TSAT <20% indicates insufficient iron available for red blood cell production (functional iron deficiency) 1, 3
• TSAT >45% suggests iron overload and warrants evaluation for hemochromatosis 1
• TSAT is less affected by inflammation than ferritin, making it valuable when inflammatory conditions are present 3

Serum Iron

• Serum iron measures circulating iron bound to transferrin at the time of blood draw 2
• This value has significant diurnal variation and is the least reliable single marker 2
• Serum iron is primarily useful as part of the TSAT calculation rather than as a standalone value 1

Clinical Interpretation Algorithm

For Iron Deficiency Diagnosis

In patients without chronic disease:

• Ferritin <45 ng/mL confirms iron deficiency 1
• If hemoglobin is also low (<13 g/dL in men, <12 g/dL in non-pregnant women), this establishes iron deficiency anemia 1

In patients with chronic inflammatory conditions (chronic kidney disease, heart failure, malignancy, autoimmune disease):

• When ferritin is 30-300 ng/mL, measure TSAT to differentiate true iron deficiency from inflammatory elevation 3
• If TSAT <20% with elevated inflammatory markers, treat as iron deficiency despite intermediate ferritin 3
• Consider soluble transferrin receptor (sTfR) testing when ferritin is unreliable due to inflammation—sTfR has 86% sensitivity and 75% specificity for distinguishing true iron deficiency from anemia of chronic disease 3
• The sTfR/log ferritin ratio provides superior discrimination in chronic disease states 3

Functional iron deficiency (common in cancer, chronic kidney disease):

• Defined as ferritin <800 ng/mL AND TSAT <20% 1
• Indicates adequate iron stores but insufficient iron mobilization for erythropoiesis 1
• Responds to IV iron supplementation 1

For Iron Overload Evaluation

Screening thresholds:

• TSAT >45% AND ferritin >200 μg/L (females) or >300 μg/L (males) warrant genetic testing for hemochromatosis 1
• In hemochromatosis, both TSAT and ferritin are typically markedly elevated 1

Common Pitfalls to Avoid

• Never rely on ferritin alone in patients with known or suspected inflammation—always obtain a complete iron panel including TSAT 1, 3
• Do not use a ferritin threshold of <15 ng/mL for iron deficiency diagnosis, as this has only 59% sensitivity and will miss many cases 1
• In cancer patients, ferritin values can be falsely elevated by chronic inflammatory states; use TSAT <20% as the primary indicator of functional iron deficiency 1
• Serum iron alone should never be used to diagnose iron deficiency or overload due to high variability 2
• In premenopausal women with ferritin 30-100 ng/mL, consider menstrual blood loss and dietary intake before extensive workup 1

When to Order Additional Testing

• If ferritin is 30-300 ng/mL with chronic disease, add sTfR or trial IV iron (50-125 mg weekly for 8-10 doses) to assess response 3
• If bidirectional endoscopy is unrevealing in iron deficiency anemia, consider video capsule endoscopy for small bowel evaluation 1
• Target ferritin >100 ng/mL after iron repletion to confirm adequate restoration of iron stores 1