Causes of Falsely Low Ferritin Levels
Critical Understanding: Ferritin is Rarely Falsely Low
Ferritin is an acute-phase reactant that typically becomes falsely elevated rather than falsely low, as it rises during inflammation, infection, liver disease, and tissue damage independent of actual iron stores 1, 2, 3. The clinical challenge is almost always interpreting falsely high ferritin levels, not falsely low ones.
True Causes of Inappropriately Low or Misleading Ferritin
Pre-Analytical Factors
Recent iron supplementation cessation: Ferritin can drop rapidly after stopping iron supplements, potentially underestimating true iron stores if measured too soon after discontinuation 2.
Timing of blood draw: While ferritin itself doesn't have significant diurnal variation like serum iron, testing should ideally be performed in the morning with fasting conditions to ensure accurate concurrent transferrin saturation measurement 2.
Recent dietary iron intake: Although this primarily affects serum iron and transferrin saturation rather than ferritin directly, patients should avoid iron-containing supplements and high-iron foods for at least 24 hours before testing to prevent confounding interpretation of the complete iron panel 2.
Clinical Conditions That May Mask Iron Deficiency
Concurrent inflammation with true iron deficiency: This is the most clinically relevant scenario where ferritin may be "falsely normal" rather than appropriately low. A patient with true iron deficiency who also has inflammation may have ferritin levels in the 30-100 ng/mL range that appear normal but are actually inappropriately low given the inflammatory state 1. The NCCN guidelines note that "chronic inflammation may elevate serum ferritin in patients with cancer" even when iron deficiency is present 1.
Functional iron deficiency in chronic kidney disease: In CKD patients on erythropoiesis-stimulating agents, ferritin may remain in the 100-700 ng/mL range while transferrin saturation drops below 20%, indicating iron is sequestered and unavailable despite seemingly adequate ferritin levels 1, 2, 4, 5. This represents a relative rather than absolute falsely low ferritin.
Laboratory and Assay Considerations
Assay variability: The reference interval for serum ferritin depends on the specific laboratory and assay method used 1. Different immunoassays may yield slightly different results, though this rarely causes clinically significant misclassification.
Hemolysis: Severe hemolysis can theoretically interfere with ferritin assays, though this is uncommon and usually flagged by the laboratory 1.
Conditions That Do NOT Cause Falsely Low Ferritin
Medications
Statins (HMG-CoA reductase inhibitors): There is no evidence in the provided guidelines or research that statins cause falsely low ferritin levels. Statins do not interfere with iron metabolism or ferritin measurement.
Anticonvulsants: While certain anticonvulsants like phenytoin can cause macrocytic anemia through folate metabolism interference 1, they do not cause falsely low ferritin levels. If ferritin is low in a patient taking anticonvulsants, it represents true iron deficiency requiring investigation.
Liver Disease
Chronic liver disease: Liver disease typically causes elevated ferritin due to hepatocellular injury and release of ferritin from damaged hepatocytes 1, 2, 6, 3. Ferritin is synthesized and stored in hepatocytes, so liver damage releases ferritin into serum, raising levels rather than lowering them.
Alcoholic liver disease: Chronic alcohol consumption increases iron absorption and causes hepatocellular injury, leading to elevated ferritin levels 1, 2.
Chronic Kidney Disease
- CKD does not cause falsely low ferritin: In CKD, ferritin levels are typically normal or elevated due to chronic inflammation 1, 4, 5. The NKF-K/DOQI guidelines specifically note that ferritin is an acute-phase reactant that can be elevated in CKD patients even when functional iron deficiency exists 1.
Diagnostic Approach When Ferritin Seems Inappropriately Low
Step 1: Confirm True Iron Deficiency
Measure transferrin saturation simultaneously with ferritin 1, 2, 4. Absolute iron deficiency is defined as ferritin <100 ng/mL (or <30 ng/mL in some guidelines) with transferrin saturation <20% 1.
Check complete blood count with MCV to assess for microcytic anemia 1.
Step 2: Assess for Concurrent Inflammation
Measure inflammatory markers (CRP, ESR) to determine if inflammation is masking the severity of iron deficiency 1, 2, 4.
If CRP is elevated with ferritin 30-100 ng/mL, the patient likely has both iron deficiency and inflammation, and the ferritin is inappropriately low for the degree of inflammation 2.
Step 3: Consider Advanced Testing if Diagnosis Unclear
Soluble transferrin receptor (sTfR): Elevated in true iron deficiency but not affected by inflammation, making it useful when ferritin interpretation is confounded 1, 6, 5.
sTfR/log ferritin ratio: A ratio >1.5 indicates iron-deficient erythropoiesis even when ferritin appears normal due to inflammation 1, 5.
Reticulocyte hemoglobin content (CHr or RET-He): Provides direct assessment of iron availability to erythropoiesis 2.
Critical Clinical Pitfalls
Never assume medications like statins or anticonvulsants cause falsely low ferritin—if ferritin is low, investigate for true iron deficiency and blood loss 1.
Do not dismiss low-normal ferritin (20-100 ng/mL) in patients with inflammation—this may represent masked iron deficiency requiring further evaluation with transferrin saturation and inflammatory markers 1, 2.
Avoid checking ferritin within 4 weeks of IV iron administration, as circulating iron can interfere with assays and lead to spurious results 2.
In CKD patients, ferritin <100 ng/mL with transferrin saturation <20% indicates absolute iron deficiency requiring treatment, regardless of inflammatory markers 1, 4, 5.