What is ferritin?

What is Ferritin?

Ferritin is an intracellular iron storage protein that sequesters up to 4,500 iron atoms within its protein shell, and serum ferritin concentration directly reflects total body iron stores, with approximately 1 μg/L of serum ferritin corresponding to 10 mg of stored iron. 1, 2

Structure and Function

• Ferritin consists of a protein shell made of 24 subunits of two types: H-subunits and L-subunits, which perform different functions in iron mineralization. 2

• The protein stores iron as a ferrihydrite mineral and releases iron atoms when cellular demand for bioavailable iron increases. 2

• Different combinations of H and L subunits create isoferritins, which are functionally distinct and vary by cell type, proliferation status, and disease presence. 2

Serum Ferritin as a Clinical Biomarker

• Serum ferritin is the mainstay for assessing total body (intracellular) iron stores, reflecting both reticuloendothelial system (RES) and parenchymal iron stores. 3

• Low ferritin levels (<15 μg/L) are highly specific (99% specificity) for iron deficiency, making it the earliest and most specific marker of depleted iron stores. 1, 4

• Serum ferritin is a secretory component of intracellular ferritin synthesis, and in normal individuals, its plasma concentration reflects the size of iron stores. 5

Critical Limitation: Acute Phase Reactant

• Ferritin behaves as an acute-phase protein, meaning infections, inflammation, or tissue damage can elevate its concentration independently of iron status, potentially masking depleted iron stores. 3, 1

• In inflammatory conditions, ferritin lacks sensitivity for detecting iron deficiency because increased serum hepcidin causes an iron shift from circulation and parenchymal cells to the RES, reflected by increased ferritin and decreased transferrin saturation. 3

• Research demonstrates that ferritin protein generated during inflammation contains much less iron than "normal" ferritin, which is why measuring ferritin alongside transferrin saturation improves diagnostic accuracy. 6

Normal Reference Ranges

• Normal serum ferritin values are approximately 135 μg/L for men, 43 μg/L for women, and 30 μg/L for children aged 6-24 months. 1

• Adult normal ranges typically span 24-336 ng/mL for men and 11-307 ng/mL for women. 4

Diagnostic Thresholds

For Iron Deficiency:

• Ferritin <15 μg/L has 99% specificity for absolute iron deficiency and confirms the diagnosis definitively. 1, 4

• Ferritin <30 μg/L generally indicates low body iron stores and warrants treatment consideration. 1, 4

• In inflammatory conditions (IBD, chronic kidney disease, heart failure), the threshold shifts upward to <100 μg/L. 1

For Iron Overload:

• Elevated ferritin (>150 μg/L) rarely occurs with absolute iron deficiency, even in the presence of inflammation. 1

• Significant iron overload is typically associated with ferritin >1000 μg/L. 4

• In hemochromatosis, hyperferritinemia may indicate iron overload in C282Y homozygotes when confounding factors like inflammation, metabolic conditions, alcohol consumption, and hepatocellular necrosis are excluded. 3

Essential Clinical Interpretation

• Ferritin must be interpreted alongside transferrin saturation (TSAT) to distinguish between absolute iron deficiency (low ferritin, low TSAT), functional iron deficiency (normal/high ferritin, low TSAT), and anemia of chronic disease (high ferritin, low TSAT). 3, 1

• The combined assessment of ferritin and TSAT provides insight into potential toxicity of elevated ferritin, as parenchymal iron loading (indicated by high TSAT) is more toxic than RES iron overload. 3

Beyond Iron Storage

• Ferritin exists not only in the cytosol but also in organelles such as nuclei and mitochondria, with slightly different properties. 2

• Most intracellular ferritin regulates iron bioavailability, but some is secreted and internalized by other cells, potentially contributing to myelopoiesis control and immunological responses. 2

• Emerging roles for extracellular ferritin include iron delivery, angiogenesis, inflammation, immunity, signaling, and cancer biology. 7

Common Clinical Pitfalls

• Relying on ferritin alone without measuring TSAT or considering inflammatory markers (CRP, ESR) can lead to misdiagnosis. 1, 4

• Ignoring that ferritin is an acute-phase reactant may result in missing true iron deficiency in patients with concurrent inflammation. 3, 1

• Ferritin does not quantitatively reflect circulating iron available for immediate erythropoiesis—that role belongs to serum iron and TSAT. 1