What is the gold standard test for diagnosing iron deficiency in adults, particularly those with a history of stroke or at risk for stroke?

Gold Standard Test for Iron Deficiency

Bone marrow aspiration showing absent stainable iron remains the gold standard for diagnosing iron deficiency, though serum ferritin is the most practical and specific non-invasive test in clinical practice. 1

Bone Marrow Examination: The Definitive Standard

• The lack of stainable iron (hemosiderin) in bone marrow biopsy is the gold standard for absolute iron deficiency diagnosis, particularly when results from other tests are unclear or equivocal 1
• Bone marrow aspiration is the most sensitive test for diagnosing iron deficiency in hospitalized patients, correctly identifying iron deficiency when serum tests may be misleading 2
• This invasive procedure is rarely performed in routine clinical practice and is reserved for complex cases where diagnosis remains uncertain despite comprehensive serum testing 1

Serum Ferritin: The Practical Gold Standard

In the absence of inflammation, serum ferritin is the most powerful and specific non-invasive test for iron deficiency. 1

Diagnostic Thresholds

• Ferritin <15 μg/L is highly specific (specificity 0.99) for iron deficiency and indicates absent iron stores 1
• Ferritin <30 μg/L generally indicates low body iron stores in most clinical contexts 1
• A ferritin cut-off of 45 μg/L provides optimal balance between sensitivity and specificity (specificity 0.92) and should be considered for investigation, especially with concurrent inflammation 1
• Ferritin >150 μg/L makes absolute iron deficiency highly unlikely, even with inflammation present 1

Critical Limitation: Inflammation

• Ferritin is an acute phase reactant and can be falsely elevated in inflammatory conditions, malignancy, or hepatic disease, masking true iron deficiency 1
• In inflammatory states, higher ferritin thresholds (>100 μg/L) are required to exclude iron deficiency 1
• Most common iron status indices including serum iron, hemoglobin, MCV, transferrin, transferrin saturation, TIBC, and hepcidin are all influenced by inflammation 1

Complementary Diagnostic Tests

When Inflammation Complicates Diagnosis

• Soluble transferrin receptor (sTfR) is not influenced by inflammation and reflects tissue iron demands, making it particularly useful when ferritin interpretation is unclear 1, 3
• The sTfR/log ferritin ratio may provide superior discrimination compared to either test alone, especially in chronic disease states 1
• Hepcidin measurement may prove most precise for diagnosing deficiency in inflammatory conditions, though not yet widely available 1

Additional Markers

• Transferrin saturation <20% supports iron deficiency diagnosis, particularly when ferritin is in the 100-300 μg/L range 1
• Reticulocyte hemoglobin content reflects iron available in bone marrow for erythropoiesis and can be helpful 1
• Zinc protoporphyrin/heme ratio increases in iron deficiency and may be useful for screening, especially in children 1

Algorithmic Approach for Clinical Practice

For patients without inflammation:

• Start with serum ferritin 1
• Ferritin <15 μg/L confirms iron deficiency (no further testing needed)
• Ferritin 15-45 μg/L warrants clinical correlation and possible GI investigation
• Ferritin >150 μg/L excludes iron deficiency

For patients with inflammation (elevated CRP):

• Measure both ferritin and transferrin saturation simultaneously 1
• Consider sTfR or sTfR/ferritin ratio if available 1
• Ferritin <100 μg/L with low transferrin saturation (<20%) indicates iron deficiency 1
• If diagnosis remains uncertain and clinically important, bone marrow examination provides definitive answer 1

Special Considerations for Stroke Patients

• Iron deficiency prevalence is remarkably high (45-48%) in acute stroke patients and increases to 77% one year post-stroke 4, 5
• Iron deficiency in stroke patients is independently associated with lower functional capacity and poor rehabilitation outcomes 4
• Regular iron status assessment should be performed in stroke patients, as iron deficiency relates to reduced muscle strength and impaired recovery 4, 5

Common Pitfalls to Avoid

• Never rely on ferritin alone in patients with known or suspected inflammatory conditions, malignancy, or liver disease 1
• Do not assume normal ferritin (12-100 μg/L) excludes iron deficiency in inflammatory states 1
• Hemoglobin and MCV may be normal in early iron deficiency (non-anemic iron deficiency) 1
• Combined deficiencies (e.g., folate and iron) may mask typical microcytosis 1