What are the possible diagnoses for a patient with a low red blood cell (RBC) count and normal iron studies?

Differential Diagnosis of Low RBC Count with Normal Iron Studies

The most likely diagnoses are anemia of chronic disease, thalassemia trait, chronic kidney disease, or hemolytic anemia—each requiring specific diagnostic tests to differentiate. 1

Primary Diagnostic Considerations

Thalassemia Trait

• Microcytosis disproportionate to the degree of anemia strongly suggests thalassemia, where the MCV is typically reduced more than expected for the hemoglobin level. 1
• Order hemoglobin electrophoresis immediately in patients with microcytosis and normal iron studies, particularly those of Mediterranean, African, Middle Eastern, or Southeast Asian descent. 1
• Beta-thalassemia trait shows elevated HbA2 (>3.5%), while alpha-thalassemia trait typically shows a normal electrophoresis pattern. 1

Anemia of Chronic Disease (ACD)

• ACD presents with low serum iron BUT normal or elevated ferritin (typically >100 μg/L), distinguishing it from iron deficiency. 2, 3
• The transferrin saturation is usually low (<20%), but the total iron binding capacity (TIBC) is normal or low, unlike iron deficiency where TIBC is elevated. 2
• Look for underlying inflammatory conditions, autoimmune diseases, malignancy, or chronic infections. 3
• Ferritin acts as an acute phase reactant—apparently normal ferritin levels (12-100 μg/L) may mask coexistent iron deficiency in inflammatory states; a cutoff of 45 μg/L provides better sensitivity/specificity. 1

Chronic Kidney Disease

• Anemia in CKD is typically normocytic and normochromic with inappropriately low erythropoietin production for the degree of anemia. 2
• Check serum creatinine and estimated GFR to assess renal function. 3
• The anemia correlates with severity of kidney dysfunction and responds to erythropoietin therapy. 2

Hemolytic Anemia

• Elevated reticulocyte count (corrected for anemia) indicates active red cell destruction or blood loss. 2
• Order direct Coombs test for autoimmune hemolytic anemia, LDH, indirect bilirubin, and haptoglobin. 4
• Consider hereditary spherocytosis, G6PD deficiency, or paroxysmal nocturnal hemoglobinuria based on clinical context. 4

Critical Diagnostic Algorithm

Step 1: Verify iron studies are truly normal

• Confirm the panel includes serum ferritin, transferrin saturation, and TIBC—not just serum iron alone. 1
• Remember that ferritin <45 μg/L may indicate iron deficiency even if technically "normal" (>12 μg/L), especially with inflammation. 1

Step 2: Examine the MCV

• Microcytic (MCV <80 fL): Order hemoglobin electrophoresis for thalassemia trait. 1
• Normocytic (MCV 80-100 fL): Check reticulocyte count, creatinine, and inflammatory markers. 2, 3
• Macrocytic (MCV >100 fL): Measure vitamin B12 and folate levels. 2, 4

Step 3: Check reticulocyte count

• Low reticulocyte count: Suggests decreased production (ACD, CKD, bone marrow disorders). 3
• High reticulocyte count: Indicates hemolysis or recent blood loss. 2

Step 4: Assess for chronic disease

• Measure inflammatory markers (CRP, ESR) if ACD suspected. 3
• Screen for malignancy, autoimmune disease, or chronic infection based on clinical presentation. 3

Common Pitfalls to Avoid

• Do not assume normal ferritin excludes iron deficiency in inflammatory conditions—the acute phase response can falsely elevate ferritin. 1
• Failure to obtain hemoglobin electrophoresis in appropriate ethnic backgrounds leads to unnecessary gastrointestinal investigations when thalassemia trait is the actual diagnosis. 1
• Do not rely solely on hemoglobin and hematocrit—these decrease only with severe iron depletion and can miss early deficiency states. 5
• Combined deficiencies (e.g., iron plus folate) may mask microcytosis, presenting as normocytic anemia with elevated red cell distribution width (RDW). 2

Additional Diagnostic Tests

• Bone marrow examination remains the gold standard for assessing iron stores when biochemical tests are equivocal, though rarely needed. 2
• Stool guaiac testing should be performed if any suspicion of occult gastrointestinal blood loss exists, even with normal iron studies. 2
• Consider myelodysplastic syndromes or other bone marrow disorders if pancytopenia or abnormal white blood cell/platelet counts are present. 4