What are the likely causes and appropriate work‑up for an adult with normocytic anemia (hemoglobin ≈9.7 g/dL, hematocrit ≈31 %, red blood cell count ≈3.2 million/µL, mean corpuscular volume ≈95–100 fL) and low‑normal white blood cell count (white blood cell count ≈3.8 ×10³/µL)?

Normocytic Anemia with Low-Normal WBC: Diagnostic Approach

This patient has moderate normocytic anemia (hemoglobin 9.6–9.8 g/dL) with borderline low MCHC (30.2–31.5 g/dL), requiring immediate gastrointestinal evaluation to exclude occult malignancy, followed by systematic assessment for anemia of chronic disease, chronic kidney disease, or combined iron deficiency. 1

Immediate Mandatory Investigation

In a patient with persistent anemia and low-normal WBC, gastrointestinal blood loss and occult malignancy must be excluded first, regardless of symptoms. 1

• Upper endoscopy with small bowel biopsies is required to exclude gastric cancer, peptic ulcer disease, angiodysplasia, and celiac disease (which affects 2–3% of iron-deficient patients). 2, 1
• Colonoscopy must be performed to exclude colonic cancer, polyps, inflammatory bowel disease, and other bleeding sources. 1
• The borderline low MCHC (30.2–31.5 g/dL) suggests possible hypochromia, which can indicate iron deficiency even when MCV appears normal. 2

Essential Laboratory Work-Up

Iron Studies (First Priority)

• Serum ferritin <30 μg/L confirms absolute iron deficiency in the absence of inflammation. 2, 1
• Ferritin 30–100 μg/L with inflammation suggests combined iron deficiency and anemia of chronic disease. 2, 1
• Ferritin >100 μg/L with transferrin saturation <20% indicates anemia of chronic disease alone. 2, 1
• Transferrin saturation <16–20% signals insufficient circulating iron for erythropoiesis. 2, 1

Critical pitfall: Ferritin is an acute-phase reactant and can be falsely normal or elevated during inflammation, infection, malignancy, or liver disease despite true iron deficiency. 2 However, ferritin >150 μg/L essentially excludes absolute iron deficiency even with concurrent inflammation. 2

Additional Required Tests

• Reticulocyte count distinguishes impaired red cell production (low/normal reticulocytes) from hemolysis or acute blood loss (elevated reticulocytes). 1, 3, 4
• C-reactive protein (CRP) assesses for anemia of chronic disease, which typically presents with normocytic anemia, low serum iron, and elevated inflammatory markers. 2, 1, 5
• Serum creatinine and estimated GFR evaluate for chronic kidney disease, which produces normocytic/normochromic anemia that worsens as GFR declines. 1, 3
• Vitamin B12 and folate levels exclude nutritional deficiencies that can present with normocytic anemia or mask microcytosis in combined deficiencies. 6, 1, 7
• Peripheral blood smear identifies morphologic abnormalities not apparent from indices alone, including signs of hemolysis, dysplasia, or infiltrative processes. 6, 1

Differential Diagnosis Based on Laboratory Pattern

If Ferritin <30 μg/L (or <100 μg/L with inflammation) AND Transferrin Saturation <20%

• Diagnose iron deficiency anemia and initiate oral iron supplementation after completing GI evaluation. 2, 1
• The low-normal MCHC supports this diagnosis, as MCH and MCHC are more sensitive markers for iron deficiency than MCV alone. 2
• Combined deficiencies (iron plus B12/folate) can result in normal MCV while MCH and MCHC remain low. 2

If Ferritin >100 μg/L AND Transferrin Saturation <20%

• Diagnose anemia of chronic disease and focus treatment on identifying and managing the underlying inflammatory condition. 2, 1, 5
• Consider malignancy, autoimmune disease, chronic infection, or inflammatory bowel disease as potential causes. 6, 5

If Ferritin 30–100 μg/L

• Suspect combined iron deficiency and anemia of chronic disease. 2, 1
• Consider a therapeutic trial of iron while concurrently investigating and managing inflammatory disease. 2

If Reticulocyte Count is Elevated

• Evaluate for hemolysis with unconjugated bilirubin, haptoglobin, lactate dehydrogenase, and direct Coombs test. 3, 4
• Assess for acute blood loss with stool guaiac testing and clinical evaluation for occult bleeding. 1, 4

If Reticulocyte Count is Low/Normal

• Consider bone marrow infiltration, aplastic anemia, or myelodysplastic syndrome, particularly given the low-normal WBC count. 6, 3, 4
• Bone marrow biopsy may be indicated if initial work-up is unrevealing and anemia persists. 6

Special Considerations for Low-Normal WBC

• The WBC count of 3.8 × 10³/μL (at lower limit of normal) combined with persistent anemia raises concern for bone marrow pathology, including myelodysplastic syndrome, aplastic anemia, or marrow infiltration. 6, 3
• If initial work-up excludes common causes and anemia persists, bone marrow examination should be strongly considered. 6

Treatment Algorithm

Treatment should be deferred until the underlying cause is identified, as the etiology dictates appropriate management. 1

1. If iron deficiency is confirmed: Initiate oral iron supplementation after GI evaluation; therapeutic response within 3 weeks confirms diagnosis. 2, 1
2. If anemia of chronic disease is diagnosed: Address the underlying inflammatory condition. 1, 5
3. If CKD-related anemia is present: Iron therapy should be considered first, then erythropoietin if anemia persists despite adequate iron stores. 6, 1, 3
4. If malignancy is detected: Treatment of the underlying malignancy will often correct the anemia. 1