What is the most likely diagnosis and appropriate workup for a patient with a low red blood cell count (3.99 ×10⁶/µL), macrocytosis (mean corpuscular volume 99.7 fL), normal mean corpuscular hemoglobin and concentration, and an elevated red‑cell distribution width (15.9%)?

Diagnostic Assessment of Borderline Anemia with Macrocytosis and Elevated RDW

This patient has borderline anemia with high-normal MCV (approaching macrocytosis) and elevated RDW, which most likely represents early nutritional deficiency—particularly vitamin B12 or folate deficiency—or early iron deficiency in evolution, and requires immediate iron studies, vitamin B12, and folate levels to establish the diagnosis. 1

Understanding the CBC Pattern

The laboratory values reveal several critical findings:

• RBC 3.99 × 10⁶/µL is at the lower limit of normal, indicating borderline anemia 2
• MCV 99.7 fL is high-normal, approaching the macrocytic threshold of 100 fL, which suggests evolving macrocytosis 1
• Elevated RDW 15.9% (normal <14.0%) indicates significant variation in red blood cell size, reflecting a mixed population of cells 2
• Normal MCH and MCHC suggest normochromic cells on average, though the elevated RDW indicates heterogeneity 2

This combination—near-macrocytic MCV with elevated RDW—is highly characteristic of nutritional deficiencies, particularly B12 or folate deficiency in early stages. 1, 3 The elevated RDW reflects the coexistence of normal older cells with newly produced abnormal cells. 2

Most Likely Diagnoses

Primary Consideration: Vitamin B12 or Folate Deficiency

Vitamin B12 or folate deficiency is the most likely diagnosis given the high-normal MCV trending toward macrocytosis combined with elevated RDW. 1, 3 Research demonstrates that 24.1% of macrocytosis cases are due to B12 deficiency, and notably, 20.9% of B12-deficient patients present with isolated macrocytosis without frank anemia. 3

The elevated RDW is particularly significant because megaloblastic conditions characteristically show higher RDW values compared to other causes of macrocytosis. 3 This patient's pattern suggests the bone marrow is already producing megaloblastic cells, but anemia has not yet fully developed.

Secondary Consideration: Early Iron Deficiency

While less typical with this MCV, early iron deficiency cannot be excluded. Iron deficiency can present with normal or high-normal MCV early in its course, with elevated RDW being one of the earliest markers. 2, 1 The combination of low MCV and RDW >14.0% typically indicates iron deficiency, but this patient's MCV is not yet low. 2

Other Possibilities

• Alcohol use accounts for 36.5% of macrocytosis cases and should be assessed through history 3
• Medication-related macrocytosis represents 12.9% of cases 3
• Mixed deficiency states (combined B12/folate and iron deficiency) can produce this pattern with competing effects on MCV 1

Essential Diagnostic Workup

Immediate Laboratory Tests Required

1. Iron studies (serum ferritin, transferrin saturation, total iron-binding capacity) to assess for absolute or functional iron deficiency 2, 1

2. Vitamin B12 level to evaluate for B12 deficiency, which can cause irreversible neurologic damage if untreated beyond 3 months 1, 4

3. Folate level to assess for folate deficiency 1, 4

4. Reticulocyte count (absolute or corrected) to evaluate bone marrow response and determine if erythropoiesis is appropriately increased 2, 1

Interpretation Thresholds

• Serum ferritin <30 μg/L confirms iron deficiency in the absence of inflammation 1
• Transferrin saturation <15-16% supports iron deficiency 2, 1
• Low reticulocyte count suggests impaired red cell production from nutritional deficiency or bone marrow dysfunction 2
• Elevated reticulocyte count would suggest hemolysis or recent blood loss 2

Critical Clinical Considerations

Urgent Evaluation for Blood Loss

If iron deficiency is confirmed, investigate for gastrointestinal bleeding immediately, particularly in adult men and postmenopausal women, as this is the most common cause. 2, 1 Obtain stool guaiac testing and consider endoscopic evaluation. 2, 1

Vitamin B12 Deficiency Warning

Do not treat with folic acid alone without first checking B12 levels. 4 Folic acid supplementation can mask B12 deficiency by correcting the anemia while allowing irreversible neurologic damage to progress. 4 Vitamin B12 deficiency that progresses beyond 3 months can produce permanent degenerative spinal cord lesions. 4

Assessment for Inflammation

Ferritin can be falsely elevated in inflammatory states, chronic disease, malignancy, or liver disease. 1 If ferritin is elevated but iron deficiency is still suspected clinically, consider measuring C-reactive protein to assess for inflammation. 1

Clinical Pitfalls to Avoid

• Do not dismiss borderline values: This patient may have early-stage deficiency that will progress to overt anemia if untreated. Macrocytosis should be evaluated even without frank anemia. 3

• Do not assume single etiology: Mixed deficiencies (e.g., combined B12 and iron deficiency) can occur and may produce confusing CBC patterns with competing effects on MCV. 1

• Do not delay B12 assessment: Neurologic complications from B12 deficiency can develop before severe anemia and may be irreversible. 4

• Consider medication history: Many drugs cause macrocytosis, including methotrexate, anticonvulsants, and antiretrovirals. 3

• Assess alcohol intake: Chronic alcohol use is the most common cause of macrocytosis (36.5% of cases) and should be specifically queried. 3