Serum Ferritin

Ferritin is a 24-subunit intracellular protein that stores iron. A small amount circulates in serum, in proportion to body stores, and is measured by immunoassay. A low value is the most specific single test for iron deficiency. A high value is non-specific because ferritin is also an acute phase protein.

In an adult, 1 microg/L of ferritin corresponds to roughly 8 to 10 mg of stored iron. Isolated hyperferritinaemia is common, and in most patients it reflects inflammation, alcohol, fatty liver or metabolic syndrome, not iron overload.

Indications. Microcytic anaemia, suspected iron deficiency without anaemia, heart failure and chronic kidney disease, suspected iron overload, monitoring of iron therapy and chelation, unexplained very high inflammatory markers with fever.

Specimen. Serum or heparinised plasma. Fasting is not needed. Biotin supplements interfere with some immunoassays and should be stopped for at least 24 hours when possible.

Reference range. Men 30 to 400 microg/L. Pre-menopausal women 15 to 150 microg/L, rising after the menopause towards male values.

Iron deficiency.

• Under 15 microg/L: absent iron stores, with near complete specificity.
• Under 30 microg/L: iron deficiency in the absence of inflammation, with high sensitivity and specificity.
• 30 to 100 microg/L with raised C-reactive protein: iron deficiency remains possible, and TSAT, TIBC or soluble transferrin receptor is needed.
• Heart failure: ferritin under 100 microg/L, or 100 to 299 microg/L with TSAT under 20%.
• Chronic kidney disease: thresholds are higher, and ferritin up to 500 microg/L can coexist with functional iron deficiency. Use local renal thresholds.
• Children under 5 years: under 12 microg/L. Older children and adolescents: under 15 microg/L.
• Pregnancy: under 30 microg/L in the first trimester.

Iron overload.

• Over 200 microg/L in women or over 300 microg/L in men is raised.
• In HFE C282Y homozygotes, ferritin over 1000 microg/L carries a high risk of cirrhosis, particularly with raised transaminases or a platelet count under 200 x10⁹/L.
• Raised ferritin with a normal TSAT points away from haemochromatosis, towards metabolic or inflammatory causes.

Raised, with normal or high TSAT (true iron overload). Hereditary haemochromatosis, repeated transfusion, ineffective erythropoiesis (thalassaemia, myelodysplasia, sideroblastic anaemia), parenteral iron, chronic liver disease.

Raised, with normal or low TSAT (non-overload). Inflammation and infection, alcohol, non-alcoholic fatty liver disease and metabolic syndrome, malignancy, hepatocellular injury, chronic kidney disease, hyperthyroidism, Gaucher disease, rarely hyperferritinaemia cataract syndrome and ferroportin disease.

Very high values (over 10 000 microg/L). Haemophagocytic lymphohistiocytosis, adult onset Still disease (where the glycosylated fraction is typically under 20%), catastrophic antiphospholipid syndrome, severe hepatic necrosis, haematological malignancy, overwhelming sepsis, massive transfusional overload. In children, a value of this size is highly specific for haemophagocytic lymphohistiocytosis.

Lowered. Iron deficiency from blood loss, poor intake or malabsorption. Hypothyroidism and vitamin C deficiency can lower ferritin without iron deficiency.

Critical findings needing immediate action.

• Ferritin over 10 000 microg/L with fever, cytopenias, hepatosplenomegaly or rising triglycerides needs urgent assessment for haemophagocytic lymphohistiocytosis.
• Ferritin over 1000 microg/L with raised transaminases needs liver assessment for iron related fibrosis.

Interferences and pitfalls.

• Ferritin is an acute phase protein, so a normal or raised value does not exclude iron deficiency in inflammation, liver disease or malignancy.
• At extremely high concentrations, some assays show a hook effect and report falsely low values. Dilution is needed.
• Between assay differences of 30% or more limit comparison between laboratories.
• Intravenous iron raises ferritin for 4 weeks or longer. Do not interpret ferritin as a measure of stores in this period.
• Biotin interferes with some immunoassays.
• Recent transfusion and alcohol intake raise results.

Special groups.

• Pregnancy: ferritin falls physiologically, so use the lower first trimester threshold for deficiency.
• Neonates: values are high at birth and fall over the first months, and age specific ranges apply.
• Older adults: inflammation is common, so a ferritin up to 100 microg/L may still represent deficiency.
• Chronic kidney disease and heart failure: condition specific thresholds apply.

Follow up tests. Transferrin saturation, TIBC, C-reactive protein, full blood count, blood film, HFE genotyping, liver function tests, abdominal ultrasound, magnetic resonance imaging of liver iron, liver biopsy with iron quantification, coeliac serology, soluble transferrin receptor, bone marrow examination, soluble CD25 and triglycerides when haemophagocytic lymphohistiocytosis is suspected.