In a patient with suspected Adult‑Onset Still’s disease and low serum iron, is the anemia due to anemia of chronic disease or iron‑deficiency, and how should it be evaluated and treated?

Anemia in Adult-Onset Still's Disease: Distinguishing Iron Deficiency from Anemia of Chronic Disease

In a patient with suspected Adult-Onset Still's disease and low serum iron, the anemia is most likely anemia of chronic disease (ACD), but coexistent true iron deficiency can occur even with markedly elevated ferritin levels and requires specific diagnostic testing to identify.

Understanding the Diagnostic Challenge

Adult-Onset Still's disease presents a unique diagnostic dilemma because ferritin levels are characteristically extremely elevated (often >1,000 μg/L), yet true iron deficiency can coexist despite these massive elevations. 1 In one documented case, a patient had a ferritin of 26,387 μg/L while simultaneously having iron deficiency anemia—the diagnosis only became apparent when the Still's disease remitted and ferritin dropped to 6.5 μg/L. 1

The key pathophysiologic insight is that in active Still's disease, the hyperferritinemia consists predominantly of iron-free apoferritin rather than iron-loaded ferritin. 2 Studies show that ferritin iron saturation in Still's disease patients averages only 9.1% compared to 17.8% in healthy controls. 2

Diagnostic Algorithm

Initial Laboratory Assessment

Measure these specific parameters:

• Ferritin level: In inflammatory conditions like Still's disease, ferritin up to 100 μg/L may still indicate iron deficiency 3, but this threshold is inadequate for Still's disease where ferritin can be >10,000 μg/L
• Transferrin saturation: A value <20% suggests iron deficiency even with elevated ferritin 3
• Soluble transferrin receptor (sTfR): This is the most reliable marker for identifying true iron deficiency in the setting of inflammation 3, 2
• Mean cell volume (MCV) and mean cell hemoglobin (MCH): Microcytosis and hypochromia suggest iron deficiency, though these lose sensitivity in chronic disease 3

Interpretation Framework

If ferritin is elevated (as expected in Still's disease):

• Transferrin saturation <20% AND elevated sTfR = True iron deficiency coexisting with ACD 3, 2
• Transferrin saturation <20% with normal sTfR = Pure anemia of chronic disease 4, 5
• Ferritin 30-100 μg/L with transferrin saturation <20% = Mixed picture of iron deficiency and ACD 3

The sTfR/log₁₀ ferritin ratio provides superior discrimination compared to either test alone, particularly in chronic inflammatory disease. 3

Critical Pitfall to Avoid

Do not assume that markedly elevated ferritin excludes iron deficiency in Still's disease. 1 The British Society of Gastroenterology guidelines state that ferritin >150 μg/L is unlikely to occur with absolute iron deficiency in most inflammatory conditions 3, but Still's disease is a notable exception where ferritin can be elevated thousands-fold while true iron depletion exists. 1, 2

Treatment Approach

If True Iron Deficiency is Confirmed (elevated sTfR, low transferrin saturation):

Initiate iron replacement:

• Oral iron: Ferrous sulfate 325 mg (65 mg elemental iron) once daily on an empty stomach 6
• Take with vitamin C 250 mg to enhance absorption 6
• Continue for 3 months after hemoglobin normalization to replenish stores 6

However, consider intravenous iron preferentially because:

• Oral iron absorption is impaired by the systemic inflammatory process in Still's disease 3
• Hepcidin elevation (driven by inflammation) blocks iron absorption and mobilization 3, 5
• Intravenous iron bypasses these absorption barriers 3

If Pure Anemia of Chronic Disease (normal sTfR, adequate iron stores):

Focus on treating the underlying Still's disease as successful treatment of the inflammatory condition improves ACD. 5 Iron supplementation will not correct pure ACD—only erythropoietin therapy or disease control will improve this anemia. 4

Monitoring Strategy

• Recheck CBC and iron studies after 4-6 weeks of treatment, expecting hemoglobin rise of 1-2 g/dL if iron deficiency was present 6
• Monitor hemoglobin and ferritin every 3 months for the first year 6
• Recognize that ferritin will remain elevated until Still's disease activity is controlled 1

Additional Diagnostic Considerations

Screen for celiac disease with tissue transglutaminase IgA antibody (with total IgA level), as it is found in 3-5% of iron deficiency anemia cases and can contribute to malabsorption. 6 This is particularly relevant if iron deficiency persists despite treatment or if gastrointestinal symptoms are present.