What is the likely diagnosis and recommended evaluation and treatment for a patient with low hemoglobin, normal mean corpuscular volume, and low serum iron?

Low Hemoglobin with Normal MCV and Low Iron

This presentation most likely represents early iron deficiency anemia or anemia of chronic disease (with or without concurrent iron deficiency), and you should immediately order serum ferritin and transferrin saturation to distinguish between these diagnoses. 1

Most Likely Diagnosis

Iron deficiency anemia is the most common cause of anemia worldwide and frequently presents with normal MCV in early stages before microcytosis develops. 1, 2 The key diagnostic feature here is that:

• Mean corpuscular hemoglobin (MCH) decreases before MCV in iron deficiency, making MCH a more sensitive early marker than MCV itself. 1
• Normal MCV with low iron suggests you are catching iron deficiency in its early phase, before the red cells have become frankly microcytic. 2
• Low hemoglobin concentration (MCHC) often accompanies iron deficiency even when MCV remains normal, indicating hypochromic red cells. 2

The differential diagnosis also includes:

• Anemia of chronic disease (ACD), which typically presents with normocytic anemia and low serum iron. 3, 2
• Combined iron deficiency and ACD, particularly common in inflammatory conditions like inflammatory bowel disease. 3

Essential Diagnostic Workup

First-Line Tests (Order Immediately)

Serum ferritin is the single most powerful test for diagnosing iron deficiency. 1 Interpretation depends critically on inflammatory status:

• Ferritin <30 μg/L confirms iron deficiency in patients without inflammation. 3, 1, 2
• In the presence of inflammation, ferritin up to 100 μg/L may still indicate iron deficiency. 3, 1
• Ferritin >150 μg/L essentially excludes absolute iron deficiency even with concurrent inflammation. 1

Transferrin saturation <16-20% indicates insufficient circulating iron for erythropoiesis. 3, 1

Obtain C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) to assess for inflammation, as this changes ferritin interpretation. 2

Measure reticulocyte count to evaluate bone marrow response—a low/normal count indicates impaired erythropoiesis while an elevated count suggests hemolysis or blood loss. 2

Distinguishing Iron Deficiency from Anemia of Chronic Disease

The diagnostic criteria for anemia of chronic disease are: serum ferritin >100 μg/L AND transferrin saturation <20%. 3

If serum ferritin is between 30-100 μg/L, suspect combined iron deficiency and anemia of chronic disease. 3

Critical Pitfalls to Avoid

Ferritin is an acute phase reactant and can be falsely normal or elevated during inflammation, infection, malignancy, or liver disease despite true iron deficiency. 1 This is the most common diagnostic error—do not rule out iron deficiency based solely on "normal" ferritin if inflammation is present.

In patients with combined nutritional deficiencies (iron plus B12/folate), MCV may appear normal while MCH and MCHC remain low, masking both deficiencies. 1 Therefore, if iron studies are equivocal, consider checking vitamin B12 and folate levels, especially if the red cell distribution width (RDW) is elevated. 2

Normal iron studies with persistent normocytic anemia warrant hemoglobin electrophoresis to exclude thalassemia trait, particularly in patients of Mediterranean, African, Middle Eastern, or Southeast Asian descent. 1

Investigation for Underlying Cause

Once iron deficiency is confirmed, you must identify the source:

In adult men and postmenopausal women with iron deficiency, gastrointestinal blood loss is the most common cause and mandates endoscopic evaluation to exclude malignancy. 1, 2

In premenopausal women, assess menstrual blood loss as the primary cause. 1

Obtain small bowel biopsies during upper endoscopy, as 2-3% of patients with iron deficiency anemia have celiac disease. 1

Treatment Approach

For confirmed iron deficiency anemia, first-line treatment is oral iron supplementation. 1, 4 Recent evidence suggests intermittent dosing is as effective as daily dosing with fewer side effects. 4

A therapeutic response to 3 weeks of oral iron supplementation (rising hemoglobin and reticulocyte count) confirms the diagnosis when other tests are equivocal. 1

Reserve intravenous iron for patients who cannot tolerate oral iron, cannot absorb it (malabsorption syndromes), or require rapid repletion (preoperative optimization, severe symptomatic anemia). 1, 2

If anemia of chronic disease is diagnosed, treat the underlying inflammatory condition; erythropoietin therapy may be considered in specific situations such as chronic kidney disease. 2

Algorithmic Approach

1. Order serum ferritin, transferrin saturation, CRP, and reticulocyte count immediately. 1, 2

2. If ferritin <30 μg/L (or <100 μg/L with inflammation) AND transferrin saturation <20%:

   • Diagnose iron deficiency anemia
   • Investigate underlying cause (GI evaluation in men/postmenopausal women, assess menstrual losses in premenopausal women)
   • Start oral iron supplementation 3, 1

3. If ferritin >100 μg/L AND transferrin saturation <20%:

   • Diagnose anemia of chronic disease
   • Treat underlying inflammatory condition 3

4. If ferritin 30-100 μg/L:

   • Suspect combined iron deficiency and anemia of chronic disease
   • Consider trial of iron supplementation while treating underlying condition 3

5. If iron studies are normal:

   • Check vitamin B12 and folate levels
   • Consider hemoglobin electrophoresis for thalassemia trait
   • Evaluate for hemolysis if reticulocyte count is elevated 1, 2