What is the diagnosis and management for a patient with hypoferritinemia not being the case, but rather anemia of chronic disease, given lab results showing low transferrin, low total iron-binding capacity (TIBC), low serum iron, normal ferritin, and low hemoglobin (hgb)?

Anemia of Chronic Disease (ACD)

This laboratory pattern—low transferrin, low TIBC, low serum iron, normal ferritin, and low hemoglobin—is diagnostic of anemia of chronic disease (ACD), also called anemia of inflammation. 1

Understanding the Diagnosis

The key distinguishing feature here is the low TIBC combined with normal ferritin, which differentiates ACD from iron deficiency anemia where TIBC would be elevated. 2, 3

Pathophysiology

• Inflammatory cytokines (especially IL-6) increase hepcidin production, which blocks iron release from macrophages and hepatocytes, creating functional iron deficiency despite adequate iron stores. 4
• Iron is sequestered in the reticuloendothelial system rather than being available for erythropoiesis, resulting in low serum iron and low transferrin saturation despite normal or elevated ferritin. 2, 4
• Inflammatory cytokines also directly suppress erythropoietin production and inhibit bone marrow response, contributing to the anemia independent of iron availability. 2

Diagnostic Criteria

In the presence of inflammation, ACD is diagnosed when serum ferritin is >100 μg/L and transferrin saturation is <20%. 1

• If ferritin is between 30-100 μg/L with inflammation present, this suggests combined iron deficiency and ACD. 1
• Check inflammatory markers (CRP, ESR) to confirm the presence of an underlying inflammatory process. 1

Critical Diagnostic Algorithm

Step 1: Calculate Transferrin Saturation

• TSAT = (serum iron × 100) ÷ TIBC 1
• TSAT <20% confirms inadequate iron delivery to bone marrow for erythropoiesis. 1

Step 2: Assess Ferritin in Context of Inflammation

• Ferritin <30 μg/L without inflammation = absolute iron deficiency 1
• Ferritin 30-100 μg/L with inflammation = mixed iron deficiency and ACD 1
• Ferritin >100 μg/L with inflammation and TSAT <20% = pure ACD 1

Step 3: Identify the Underlying Cause

Search for chronic inflammatory conditions: 1

• Inflammatory bowel disease (IBD) - most common in gastroenterology practice
• Chronic kidney disease - check creatinine and eGFR
• Malignancy - especially hematologic or solid tumors
• Chronic infections - including HIV, hepatitis C, osteomyelitis
• Autoimmune diseases - rheumatoid arthritis, lupus, vasculitis
• Heart failure - chronic inflammatory state

Management Strategy

Primary Treatment: Address the Underlying Disease

The most effective treatment for ACD is controlling the underlying inflammatory condition. 1

• Treating active IBD, controlling infection, or managing autoimmune disease will improve anemia by reducing hepcidin levels and restoring iron availability. 1

Iron Supplementation Considerations

Iron supplementation in pure ACD (ferritin >100 μg/L) is generally ineffective because iron is sequestered and cannot be mobilized due to hepcidin-mediated blockade. 2, 4

However, if ferritin is 30-100 μg/L (suggesting mixed deficiency), iron supplementation is recommended: 1

• Oral iron: 30-60 mg elemental iron daily or alternate-day dosing 5
• Intravenous iron may be superior in IBD or CKD patients with active inflammation, as oral absorption is impaired 1

Erythropoiesis-Stimulating Agents (ESAs)

For CKD patients with ACD, ESAs can correct anemia when the underlying disease cannot be fully treated. 6, 7

ESA therapy should only be initiated when: 6, 7

• Hemoglobin <10 g/dL in CKD patients
• Iron stores are adequate: ferritin ≥100 μg/L and TSAT ≥20% 6, 7
• Target hemoglobin should NOT exceed 11 g/dL due to increased cardiovascular risks and mortality 6, 7

Before starting ESAs, ensure iron supplementation: 6, 7

• Administer supplemental iron when ferritin <100 μg/L or TSAT <20%
• Most CKD patients require ongoing iron supplementation during ESA therapy

Critical Pitfalls to Avoid

• Do NOT assume normal ferritin excludes iron deficiency in inflammatory states - ferritin is an acute-phase reactant that rises with inflammation, potentially masking depleted stores. 1, 5
• Do NOT give iron supplementation when ferritin >100 μg/L and TSAT >20% - this indicates adequate iron stores and risks iron overload. 1
• Do NOT target hemoglobin >11 g/dL with ESAs - this significantly increases risks of death, stroke, and cardiovascular events. 6, 7
• Do NOT overlook soluble transferrin receptor (sTfR) testing when ferritin and TSAT are discordant - elevated sTfR confirms true iron deficiency even in the presence of inflammation. 1, 8

Monitoring and Follow-Up

• Recheck CBC, iron panel, and inflammatory markers in 4-8 weeks after initiating treatment of the underlying condition. 1
• If hemoglobin does not increase by ≥1 g/dL after 4 weeks of appropriate therapy, reassess for other causes of anemia (B12/folate deficiency, hemolysis, bone marrow disease). 1
• Monitor ferritin and TSAT monthly if on ESA therapy to ensure adequate iron availability. 6, 7