What is the recommended work-up for anemia of chronic disease?

Work-up for Anemia of Chronic Disease

Begin the diagnostic work-up with a complete blood count (CBC) with red cell indices, reticulocyte count, iron studies (serum iron, TIBC, ferritin, transferrin saturation), and inflammatory markers (CRP or ESR) to differentiate anemia of chronic disease from other causes and identify coexisting iron deficiency. 1, 2

Initial Laboratory Assessment

Essential First-Line Tests

• CBC with differential and red cell indices to characterize the anemia morphologically—anemia of chronic disease is typically normocytic and normochromic, though it can become microcytic as the disease progresses 3, 4, 5

• Reticulocyte count (corrected for degree of anemia) to assess bone marrow response—a low or inappropriately normal reticulocyte count indicates impaired erythropoiesis characteristic of anemia of chronic disease 3, 1

• Complete iron panel including:

  • Serum iron (typically low in anemia of chronic disease) 3, 6
  • Total iron binding capacity/TIBC (low to normal, distinguishing it from iron deficiency where TIBC is elevated) 3, 7, 6
  • Transferrin saturation (calculated from serum iron and TIBC; typically low but >15-16% in pure anemia of chronic disease) 3, 7
  • Serum ferritin (normal to elevated in anemia of chronic disease, reflecting adequate or increased iron stores) 3, 4, 6

• Inflammatory markers (CRP or ESR) to confirm the presence of chronic inflammation and interpret ferritin levels, as ferritin is an acute phase reactant that can be falsely elevated by inflammation 7, 2, 4

Distinguishing Anemia of Chronic Disease from Iron Deficiency

Key Diagnostic Features

The critical distinction lies in iron parameters, as these conditions frequently coexist:

• Pure anemia of chronic disease: Low serum iron, low-normal TIBC, normal-to-elevated ferritin (typically >100 μg/L), transferrin saturation >16%, and elevated inflammatory markers 3, 4, 6

• Coexisting iron deficiency: Ferritin <30 μg/L without inflammation or <100 μg/L with elevated CRP, transferrin saturation <15-20%, and elevated TIBC 3, 7, 2

• Functional iron deficiency (common in chronic disease): Adequate total body iron stores but insufficient iron availability for erythropoiesis, suggested by ferritin >100 μg/L but transferrin saturation <20% 3, 7

Important Caveat

In patients with inflammatory conditions, ferritin levels up to 100 μg/L may still indicate iron deficiency despite appearing "normal," because inflammation artificially elevates ferritin 7, 2. Always interpret ferritin in the context of CRP levels.

Additional Work-up Based on Clinical Context

Screen for Other Reversible Causes

• Vitamin B12 and folate levels if macrocytosis is present (MCV >100 fL) or in high-risk patients (inflammatory bowel disease, ileal resection, malabsorption, elderly) 3, 2

• Thyroid function tests (TSH) as hypothyroidism causes normocytic anemia that mimics anemia of chronic disease and is easily correctable 3

• Stool guaiac test for occult gastrointestinal bleeding if any suggestion of iron deficiency or unexplained worsening of anemia 3

• Renal function (serum creatinine, eGFR) as chronic kidney disease commonly causes anemia through erythropoietin deficiency, and work-up should be initiated when hemoglobin falls below 12 g/dL in men or 11 g/dL in women with CKD 3, 1

When to Measure Erythropoietin Levels

Do not routinely measure serum erythropoietin levels in patients with chronic disease and normocytic anemia, as EPO levels are rarely elevated in the setting of kidney dysfunction and the test does not guide clinical decision-making 3, 1. The diagnosis of EPO deficiency is clinical, based on the presence of chronic disease (particularly CKD with creatinine ≥2 mg/dL) and exclusion of other causes 3.

Algorithmic Approach to Work-up

Step 1: Confirm Anemia and Classify Morphologically

• Obtain CBC with indices
• Classify as microcytic (MCV <80), normocytic (MCV 80-100), or macrocytic (MCV >100) 1, 2

Step 2: Obtain Iron Studies and Inflammatory Markers

• Serum iron, TIBC, ferritin, transferrin saturation
• CRP or ESR 7, 1, 2

Step 3: Interpret Results in Context

• Low iron + low TIBC + elevated ferritin + elevated CRP = anemia of chronic disease 4, 6
• Low iron + elevated TIBC + low ferritin = iron deficiency anemia 3, 2
• Both patterns present = mixed anemia (treat iron deficiency first) 3, 7

Step 4: Assess Reticulocyte Response

• Low/normal reticulocyte count confirms hypoproliferative anemia 3, 1
• Elevated reticulocyte count suggests hemolysis or bleeding (pursue alternative diagnosis) 3, 2

Step 5: Screen for Specific Reversible Causes

• Check B12/folate if macrocytic or high-risk patient 3, 2
• Check TSH in all patients (common, easily treatable) 3
• Check renal function if not already known 3, 1
• Stool guaiac if any suggestion of GI blood loss 3

Critical Pitfalls to Avoid

• Never assume normal ferritin excludes iron deficiency in inflammatory states—ferritin <100 μg/L with elevated CRP may still indicate iron deficiency requiring treatment 7, 2

• Do not delay iron studies to check other tests first—iron deficiency is the most common coexisting condition and must be identified immediately 7

• Avoid starting empiric iron supplementation without confirming the diagnosis—iron studies must be obtained before treatment, and in anemia of chronic disease, iron supplementation alone is ineffective and potentially harmful 6, 8

• Do not overlook combined deficiencies—patients with chronic disease frequently have multiple contributing factors (iron, B12, folate, renal insufficiency) that require simultaneous assessment 3, 1, 2

• Remember that anemia of chronic disease can become microcytic over time—do not assume all microcytic anemia is iron deficiency; check the complete iron panel and inflammatory markers 4, 5