What is the initial approach to diagnosing and treating anemia related to chronic disease?

Anemia of Chronic Disease: Initial Diagnostic and Treatment Approach

The initial approach to anemia of chronic disease requires a systematic two-step classification using MCV and reticulocyte count, followed by iron studies adjusted for inflammation, with treatment focused primarily on optimizing the underlying disease rather than iron supplementation alone. 1

Initial Diagnostic Workup

When anemia is suspected (hemoglobin <13 g/dL in men, <12 g/dL in women), obtain the following minimum laboratory panel 2, 1:

• Complete blood count with MCV, MCH, and red cell distribution width (RDW) 2, 1
• Reticulocyte count to assess bone marrow response 2, 1
• Serum ferritin and transferrin saturation to evaluate iron status 2, 1
• C-reactive protein (CRP) to quantify inflammation 2, 1

Critical diagnostic pitfall: Inflammation elevates ferritin as an acute phase reactant, masking true iron deficiency. Ferritin up to 100 μg/L may still represent iron deficiency when inflammation is present. 2

Distinguishing Anemia of Chronic Disease from Iron Deficiency

Without Active Inflammation:

• Iron deficiency: Ferritin <30 μg/L, low transferrin saturation (<16-20%), elevated RDW 2
• Anemia of chronic disease: Ferritin >100 μg/L, transferrin saturation <20% 2

With Active Inflammation:

• Iron deficiency: Ferritin <100 μg/L, low transferrin saturation 2
• Anemia of chronic disease: Ferritin >100 μg/L, transferrin saturation <20% 2
• Mixed picture: Ferritin 30-100 μg/L indicates combined iron deficiency and anemia of chronic disease 2

The MCV pattern in anemia of chronic disease is typically normocytic (50-70% of cases) or mildly microcytic, with normal or low reticulocyte count. 2, 3

Pathophysiology Context

Anemia of chronic disease results from inflammatory cytokines (TNF, IL-1, IL-6, interferon) that upregulate hepatic hepcidin production, which blocks ferroportin and traps iron in reticuloendothelial macrophages, creating functional iron deficiency for erythropoiesis despite adequate total body iron stores. 2, 3, 4 These same cytokines suppress erythropoietin production and directly inhibit bone marrow erythropoiesis. 3, 4, 5

Treatment Algorithm

Step 1: Optimize the Underlying Disease

The presence of anemia of chronic disease is a clear indicator of active disease, and optimization of treatment for the underlying condition must precede any other intervention. 2 In inflammatory conditions, controlling disease activity with appropriate anti-inflammatory or immunosuppressive therapy often improves hemoglobin levels independent of iron supplementation. 2

Step 2: Address Iron Deficiency Component

• If ferritin <100 μg/L with inflammation (or <30 μg/L without): Administer intravenous iron supplementation 2
• Oral iron should be avoided in active inflammation as it promotes microbial growth, inhibits T-cell immunity, and is poorly absorbed due to hepcidin-mediated blockade 5
• Intravenous iron is preferred for moderate to severe anemia or active inflammatory disease 6

Step 3: Consider Erythropoiesis-Stimulating Agents (ESAs)

ESAs should only be considered after optimizing disease treatment and providing intravenous iron, with insufficient response to both interventions. 2

• Target hemoglobin: Not above 12 g/dL 2
• FDA warning: ESAs increase risk of death, myocardial infarction, stroke, and thromboembolism when targeting hemoglobin >11 g/dL in chronic kidney disease 7
• Use the lowest dose sufficient to reduce transfusion requirements 7

Step 4: Transfusion Criteria

Red blood cell transfusion should be considered when hemoglobin is below 7 g/dL, or above this threshold if symptoms (dyspnea, angina, tachycardia) or particular risk factors (cardiovascular disease, ongoing bleeding) are present. 2

• Transfusions must be followed by intravenous iron supplementation to address the underlying deficiency 2
• Transfusions are a temporary measure and do not correct the underlying pathology 2

Additional Considerations

Vitamin Deficiencies:

If MCV is elevated (macrocytosis), measure vitamin B12 and folate levels, as deficiencies can coexist with anemia of chronic disease, particularly in inflammatory bowel disease with ileal involvement or resection. 2 These deficiencies should be corrected to avoid compounding the anemia. 2

Monitoring:

• During active disease: Check complete blood count and CRP at regular intervals based on disease severity 2
• After initiating treatment: Monitor hemoglobin weekly until stable 7
• Assess iron stores (ferritin, transferrin saturation) before and during ESA therapy 7

Common pitfall: Assuming all anemia in chronic disease is purely inflammatory. Always evaluate for concurrent true iron deficiency, vitamin deficiencies, medication effects (azathioprine, sulfasalazine causing hemolysis or macrocytosis), renal insufficiency, or occult bleeding. 2, 6