What are the differential diagnoses for normocytic anemia?

Differential Diagnoses for Normocytic Anemia

Normocytic anemia (MCV 80-100 fL) is typically caused by hemorrhage, hemolysis, bone marrow failure, anemia of chronic inflammation, or renal insufficiency. 1

Primary Categories Based on Reticulocyte Response

The reticulocyte count is the critical first step in narrowing the differential diagnosis, as it distinguishes between production defects versus destruction or loss. 1, 2

Low Reticulocyte Index (<1.0): Decreased RBC Production

Anemia of Chronic Disease/Inflammation

• Most common cause of normocytic anemia in hospitalized patients 1
• Characterized by low serum iron, low TIBC, normal or elevated ferritin (>100 μg/L), and low transferrin saturation (<20%) 1, 2
• Inflammatory cytokines suppress endogenous erythropoietin production and directly inhibit erythropoiesis 1
• Check CRP and ESR to confirm inflammatory state 3, 1

Chronic Kidney Disease

• Develops when GFR falls below 20-30 mL/min 1, 2, 4
• Primary mechanism is erythropoietin deficiency 1, 4
• May show functional iron deficiency despite adequate stores 1, 2
• Measure serum creatinine and BUN; if creatinine ≥2 mg/dL with no other cause identified, anemia is likely due to EPO deficiency 1

Bone Marrow Failure/Infiltration

• Aplastic anemia presents with pancytopenia or other cytopenias 2, 5
• Myelodysplastic syndromes should be considered in older patients with unexplained normocytic anemia 2
• Bone marrow infiltration from malignancy (solid tumors or hematologic cancers) 1, 6
• Bone marrow aspiration and biopsy indicated when unexplained pancytopenia is present 1

Endocrine Disorders

• Hypothyroidism can cause normocytic anemia 2, 6
• Check TSH and free T4 2

Early or Combined Nutritional Deficiencies

• Early iron, B12, or folate deficiency may initially present as normocytic before morphological changes appear 1
• Combined deficiency states (iron plus B12/folate) may neutralize each other, resulting in normal MCV 3, 1
• High red cell distribution width (RDW) suggests underlying iron deficiency despite normal MCV 3, 1
• Check serum ferritin, transferrin saturation, vitamin B12, and folate levels 3, 1, 2

Riboflavin Deficiency

• Presents with normochromic, normocytic anemia and marrow aplasia 1
• Treat with riboflavin 5-10 mg/day 1

Medication-Induced

• NSAIDs, antibiotics, and other drugs can cause bone marrow suppression or hemolysis 1
• Comprehensive medication review is essential 1

High Reticulocyte Index (>1.0): Increased Destruction or Loss

Acute Blood Loss

• Cessation of bleeding is the primary focus 5
• Initial management with crystalloid fluids for hypovolemia 5
• Perform stool guaiac testing for occult gastrointestinal bleeding 1, 2
• In women, obtain detailed menstrual history 2
• Mass transfusion protocol if severe ongoing blood loss with hemodynamic instability 5

Hemolytic Anemia

• Diagnosed by signs of hemolysis: jaundice, hepatosplenomegaly, unconjugated hyperbilirubinemia, increased reticulocyte count, decreased haptoglobin 5
• Workup includes: LDH (elevated), haptoglobin (decreased), indirect bilirubin (elevated), direct antiglobulin test (Coombs test) 1, 2
• Peripheral smear may show schistocytes or other abnormal red cell morphology 2

Critical Diagnostic Pitfalls

Do not assume anemia of chronic disease without measuring iron studies, as 25-37.5% of patients with chronic kidney disease have concurrent iron deficiency 1. In the absence of inflammation, ferritin <30 μg/L indicates iron deficiency; with inflammation present, ferritin up to 100 μg/L may still represent iron deficiency 3, 1.

ESR is elevated by IVIG therapy, so use CRP rather than ESR to assess inflammation after IVIG treatment 3. CRP normalizes more quickly than ESR during resolution of inflammation 3.

Thrombocytopenia in normocytic anemia may indicate disseminated intravascular coagulation and is a risk factor for coronary artery abnormalities in specific clinical contexts 3.

Specific Clinical Contexts

Inflammatory Bowel Disease

• Major forms include iron deficiency anemia, anemia of chronic disease, and mixed anemia 3
• Minimum workup: CBC with RDW and MCV, reticulocyte count, differential blood count, serum ferritin, transferrin saturation, and CRP 3
• Patients with extensive small bowel resection or ileal Crohn's disease require more frequent assessment for B12 or folate deficiency 3