What causes normocytic, normochromic anemia with normal blood cell morphology and no evidence of bone marrow disorders?

Differential Diagnosis of Normocytic, Normochromic Anemia with Normal Blood Cell Morphology

The most likely causes of normocytic, normochromic anemia with normal peripheral blood morphology and no evidence of bone marrow infiltration are anemia of chronic inflammation, early chronic kidney disease, acute blood loss (if recent), hemolysis (if compensated), or medication-related bone marrow suppression—requiring reticulocyte count as the critical next step to distinguish between decreased RBC production versus increased destruction/loss. 1

Systematic Diagnostic Approach

Step 1: Obtain Reticulocyte Index (RI)

The reticulocyte count corrected for degree of anemia is the essential starting point to determine the mechanism 2:

• Low RI (<1.0-2.0): Indicates decreased RBC production, suggesting 2:

  • Anemia of chronic inflammation (most common in this presentation)
  • Early chronic kidney disease with erythropoietin deficiency
  • Early nutritional deficiencies (iron, B12, folate) before morphologic changes appear
  • Medication-induced bone marrow suppression
  • Early bone marrow failure syndromes

• High RI (>2.0): Indicates normal/increased RBC production with peripheral destruction or loss, suggesting 2:

  • Acute hemorrhage (within days, before iron depletion causes microcytosis)
  • Hemolytic anemia (compensated, maintaining normal morphology initially)

Step 2: Essential Laboratory Workup

Perform comprehensive testing to identify treatable causes 1:

• Iron studies: Serum ferritin, transferrin saturation (TSAT), serum iron, TIBC 1

  • Anemia of chronic disease: Ferritin >100 μg/L with TSAT <20% 1
  • Absolute iron deficiency: Ferritin <30 μg/L (or <100 μg/L if inflammation present), TSAT <16% 2, 1

• Renal function: Serum creatinine and estimated GFR 2, 1

  • Anemia develops when GFR <20-30 mL/min due to erythropoietin deficiency 1
  • If creatinine ≥2 mg/dL and no other cause identified, erythropoietin deficiency is likely 1

• Inflammatory markers: CRP and ESR 1

  • Elevated levels support anemia of chronic inflammation 1

• Vitamin B12 and folate levels 2, 1

  • Combined deficiencies can present with normal MCV initially 1

Step 3: Directed Investigation Based on Initial Results

If reticulocyte count is LOW (decreased production):

• Review medications carefully for bone marrow suppressants (NSAIDs, antibiotics, chemotherapy agents, hydroxyurea, diphenytoin) 2, 1

• Evaluate for occult blood loss with stool guaiac testing, as gastrointestinal bleeding can present before iron stores are depleted 1

• Consider riboflavin deficiency (rare), which causes normochromic, normocytic anemia with marrow aplasia; responds to 5-10 mg/day supplementation 1

If reticulocyte count is HIGH (increased destruction/loss):

• Investigate for hemolysis 2, 1:

  • Indirect and direct bilirubin (elevated indirect bilirubin)
  • Haptoglobin (decreased)
  • LDH (elevated)
  • Direct antiglobulin test/Coombs test
  • Examine for jaundice and hepatosplenomegaly

• Evaluate for acute hemorrhage with focused history on recent bleeding events and stool guaiac 1

• Check for DIC if thrombocytopenia is present 1

Step 4: Consider Bone Marrow Examination Only When Indicated

Bone marrow aspiration and biopsy are rarely contributive in normocytic anemia with normal peripheral blood morphology and should be reserved for specific scenarios 3:

• Unexplained pancytopenia or other cytopenias 1
• Concern for infiltrative process despite normal peripheral smear
• Failure to identify cause after comprehensive noninvasive workup
• Progressive anemia despite treatment of identified causes

Research shows that in "idiopathic" normocytic anemia after thorough noninvasive evaluation, bone marrow examination reveals abnormalities in <10% of cases, with excellent prognosis during follow-up 3.

Most Common Causes in Clinical Practice

Anemia of Chronic Inflammation (Most Likely)

This is the most common cause of normocytic, normochromic anemia with normal morphology 4, 5, 6:

• Mechanism: Inflammatory cytokines suppress erythropoietin production and directly inhibit erythropoiesis, while also causing functional iron deficiency 1, 6
• Laboratory pattern: Low serum iron, low TIBC, ferritin >100 μg/L, TSAT <20% 1
• Management: Focus on treating the underlying inflammatory condition 6

Chronic Kidney Disease

Second most common cause when renal function is impaired 1, 5:

• Develops when GFR falls below 20-30 mL/min 1
• Primary mechanism: Erythropoietin deficiency 1
• Important caveat: 25-37.5% of CKD patients have concurrent iron deficiency, so never assume anemia of CKD without checking iron studies 1

Acute Blood Loss (Recent)

Can present as normocytic before iron stores are depleted 5:

• Timing: Within days of bleeding event, before microcytosis develops
• Key finding: Elevated reticulocyte count 2
• Management: Identify and stop bleeding source; crystalloid resuscitation for hypovolemia 5

Critical Pitfalls to Avoid

• Do not assume anemia of chronic disease without measuring iron studies, as up to 37.5% have concurrent iron deficiency requiring different treatment 1

• Do not confuse statistical thresholds with disease states: Hemoglobin <12 g/dL (women) or <13 g/dL (men) are population-based WHO definitions, not absolute biological boundaries 1

• Do not rush to bone marrow biopsy: The yield is extremely low (<10%) when peripheral blood morphology is normal and comprehensive noninvasive workup has been performed 3

• Do not overlook medication review: Many commonly prescribed drugs cause bone marrow suppression or hemolysis 1

• Monitor high RDW in normocytic anemia: May indicate underlying iron deficiency despite normal MCV 1