What is the relationship between iron and ferritin in the body?

Relationship Between Iron and Ferritin

Ferritin is the primary intracellular iron storage protein that reflects total body iron stores, with low ferritin being highly specific for iron deficiency and elevated ferritin indicating increased iron stores or inflammation. 1

Ferritin as an Iron Storage Protein

Ferritin functions as a hollow protein shell composed of 24 subunits (heavy chain FTH and light chain FTL) that stores iron within cells, preventing iron toxicity while maintaining iron availability for cellular processes. 2

• Ferritin reflects both reticuloendothelial system (RES) and parenchymal iron stores throughout the body 1
• The protein sequesters excess intracellular iron in a safe, bioavailable form 2
• Intracellular iron regulation involves iron-regulatory proteins (IRP) that control ferritin synthesis: under iron-replete conditions, ferritin translation is stimulated to store excess iron, while under iron-deficient conditions, ferritin synthesis is inhibited 1

Ferritin as a Biomarker of Iron Status

Serum ferritin serves as the mainstay for assessing total body iron stores, with low levels being highly specific for iron deficiency. 1

In Iron Deficiency

• Low ferritin levels (<15-30 μg/L) are highly specific for absolute iron deficiency 1, 3
• A ferritin <15 μg/L has 75% sensitivity and 98% specificity for iron deficiency 3
• The American Association for the Study of Liver Diseases notes that ferritin remains the best indicator of iron stores in the absence of inflammation 4

In Iron Overload

• Elevated ferritin correlates with increased body iron stores 5
• In hemochromatosis, serum ferritin is the best predictor of body iron burden among available tests, though the correlation is imperfect even in C282Y homozygotes 5
• Long-term ferritin elevations >2500 μg/L predict cardiac mortality in iron overload conditions, though risk increases even at levels >1000 μg/L 1

Critical Limitations: Ferritin as an Acute Phase Reactant

A major pitfall is that ferritin behaves as an acute phase reactant, becoming elevated during inflammation or infection independent of iron stores, which significantly reduces its sensitivity for detecting iron deficiency in inflammatory conditions. 1

• During inflammation, increased hepcidin causes iron sequestration in the RES, resulting in elevated ferritin despite functional iron deficiency 1
• Ferritin can be elevated in chronic inflammatory conditions (hepatitis, chronic liver disease, malignancy) without true iron overload 1, 6
• In dialysis patients, ferritin values between 200-2000 ng/mL may be increased due to inflammation rather than iron status 6
• Ferritin levels may also be decreased by vitamin C deficiency, independent of iron stores 1

Interpreting Ferritin in Clinical Practice

The combined assessment of ferritin with transferrin saturation (TSAT) is essential for accurate diagnosis of both absolute and functional iron deficiency. 1

• Low ferritin with low TSAT indicates absolute iron deficiency 1
• Normal or elevated ferritin with low TSAT suggests functional iron deficiency (inflammation-induced iron sequestration) 1
• High ferritin with high TSAT indicates true iron overload with risk of parenchymal iron deposition 1
• Single cross-sectional ferritin measurements may be misleading; trends over time provide more reliable information about iron status 1

Regulatory Relationship: Hepcidin-Mediated Iron Homeostasis

Hepcidin, the master regulator of systemic iron homeostasis, controls iron release from storage sites, and ferritin levels reflect the balance between iron storage and hepcidin-regulated iron mobilization. 1

• Hepcidin blocks ferroportin-mediated iron export from macrophages and enterocytes, causing iron accumulation in storage sites and increased ferritin 1
• In iron deficiency, hepcidin levels drop to mobilize stored iron, resulting in decreased ferritin 1
• In inflammation, elevated hepcidin causes iron shift from circulation to RES, reflected by increased ferritin and decreased TSAT 1