What is the likely diagnosis for an adult patient with low serum iron and total iron-binding capacity (TIBC) and elevated ferritin levels?

Anemia of Chronic Disease (Functional Iron Deficiency)

The most likely diagnosis for an adult patient with low serum iron, low TIBC, and elevated ferritin is anemia of chronic disease (ACD), also called anemia of inflammation. This pattern reflects iron sequestration in storage sites due to hepcidin activation, making iron unavailable for erythropoiesis despite adequate or elevated total body iron stores 1, 2, 3.

Understanding the Laboratory Pattern

The combination of these three findings creates a distinctive signature:

• Low serum iron indicates insufficient circulating iron available for red blood cell production 4, 2
• Low TIBC (and low transferrin) reflects suppressed transferrin synthesis due to chronic inflammation, distinguishing ACD from iron deficiency anemia where TIBC is typically elevated 4, 2, 5
• Elevated ferritin demonstrates that iron stores are present but sequestered in reticuloendothelial macrophages and hepatocytes, unable to be mobilized for erythropoiesis 1, 2, 3

This pattern occurs because inflammatory cytokines, particularly IL-6, stimulate hepatic production of hepcidin, which blocks iron release from macrophages and enterocytes 3. The result is functional iron deficiency—iron exists in the body but cannot be accessed for hemoglobin synthesis 1, 6.

Calculate Transferrin Saturation

You must calculate TSAT to confirm the diagnosis and assess severity:

• TSAT = (serum iron / TIBC) × 100 1
• TSAT <20% confirms iron-deficient erythropoiesis regardless of ferritin levels 1
• In ACD, expect TSAT to be low-to-normal, typically 10-20% 4, 2

Differential Diagnosis: Distinguishing ACD from Other Conditions

Anemia of Chronic Disease vs. Iron Deficiency Anemia

The key distinguishing features are:

Parameter	Iron Deficiency	Anemia of Chronic Disease
Serum Iron	Low	Low
TIBC/Transferrin	High	Low-to-normal
Ferritin	Low (<30 ng/mL)	Normal-to-high (>100 ng/mL)
TSAT	<16%	10-20%

4, 2, 5, 7

Mixed Picture: Combined Iron Deficiency and ACD

A critical pitfall is missing concomitant true iron deficiency in patients with chronic disease:

• Ferritin 30-100 ng/mL with TSAT <20% suggests both absolute iron deficiency and inflammatory iron sequestration 1
• In inflammatory states, ferritin up to 100 ng/mL may still indicate depleted iron stores because ferritin is an acute-phase reactant 1, 8
• Soluble transferrin receptor (sTfR) is the definitive test when ferritin and TSAT are discordant—elevated sTfR confirms true iron deficiency even in the presence of inflammation 1, 7

Investigate the Underlying Chronic Condition

ACD never occurs in isolation—you must identify the underlying disease:

Common causes include:

• Chronic infections (HIV, tuberculosis, endocarditis) 2, 5, 3
• Autoimmune/inflammatory diseases (rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus) 6, 5, 3
• Malignancy (solid tumors, lymphoma, multiple myeloma) 2, 6, 5
• Chronic kidney disease (GFR <30 mL/min/1.73m²) 1
• Chronic heart failure (NYHA class II-III) 1

Check inflammatory markers:

• CRP and ESR should be elevated, confirming active inflammation 1
• If CRP/ESR are normal with this iron pattern, reconsider the diagnosis 1

Treatment Algorithm

Step 1: Treat the Underlying Disease

The primary intervention is addressing the root cause of inflammation 4, 5. ACD resolves when the underlying disorder is corrected 2.

Step 2: Determine if Iron Supplementation is Indicated

Iron supplementation in ACD is controversial and context-dependent:

• Oral iron alone is generally ineffective and potentially harmful in pure ACD because hepcidin blocks intestinal iron absorption 4, 5
• Iron can promote microbial growth and tumor cell proliferation, and inhibits T-cell-mediated immunity 5
• However, if sTfR is elevated or ferritin is 30-100 ng/mL, concomitant true iron deficiency exists and requires treatment 1, 7

Step 3: Consider IV Iron in Specific Conditions

IV iron bypasses hepcidin-mediated intestinal blockade and may be beneficial in:

• Chronic kidney disease with TSAT <20% and ferritin <100 ng/mL (predialysis) or <200 ng/mL (hemodialysis) 1
• Heart failure (NYHA class II-III) with ferritin <100 ng/mL or 100-300 ng/mL with TSAT <20%—improves functional status and quality of life 1
• Inflammatory bowel disease with active inflammation and TSAT <20% 1

Target TSAT ≥20% after iron repletion 1.

Step 4: Erythropoiesis-Stimulating Agents (ESAs)

ESAs can correct ACD when the underlying disease cannot be cured:

• Recombinant erythropoietin overcomes the blunted erythropoietin response and cytokine-mediated inhibition of erythroid progenitors 2, 5
• ESAs require adequate iron availability—maintain TSAT >20% and ferritin >100-200 ng/mL during ESA therapy 1
• If no response to IV iron occurs, consider ESAs with continued iron supplementation, particularly in CKD or heart failure 1

Step 5: Transfusion for Severe Symptomatic Anemia

Do not base transfusion decisions solely on hemoglobin thresholds 4:

• Asymptomatic patients without comorbidities: observation and periodic reevaluation 4
• Asymptomatic with comorbidities or high risk: consider transfusion 4
• Symptomatic patients: transfuse 4

Critical Pitfalls to Avoid

• Do not assume elevated ferritin excludes iron deficiency—in inflammatory states, ferritin up to 100 ng/mL may still indicate depleted stores 1, 8
• Do not give oral iron alone in pure ACD—it is ineffective due to hepcidin blockade and potentially harmful 4, 5
• Do not overlook the underlying disease—ACD is always secondary to another condition that requires treatment 2, 5
• Do not rely on ferritin alone—always calculate TSAT and consider sTfR when the picture is unclear 1, 7
• Do not miss concomitant true iron deficiency—check sTfR if ferritin is 30-100 ng/mL with low TSAT 1, 7

Monitoring Response

• Repeat CBC, iron parameters (ferritin, TSAT), and inflammatory markers (CRP, ESR) at 4-8 weeks after initiating treatment 1
• If IV iron was given, wait at least 4 weeks before rechecking iron parameters, as circulating iron interferes with assays 1
• Expected response to IV iron: reticulocytosis at 3-5 days, hemoglobin rise ≥10 g/L within 2 weeks 1
• Lack of response suggests either inflammatory block is too severe or the underlying disease requires more aggressive treatment 1