A patient has a red blood cell count of 5.42 ×10⁶/µL (high), hemoglobin of 11.4 g/dL (low), hematocrit 38% (normal), mean corpuscular volume of 70 fL (low), mean corpuscular hemoglobin of 21 pg (low), mean corpuscular hemoglobin concentration of 30 g/dL (low), and red cell distribution width of 16.2% (high). What is the most likely diagnosis and what initial investigations and treatment should be pursued?

Microcytic Anemia with Elevated RDW: Iron Deficiency vs. Thalassemia Trait

This patient has classic iron deficiency anemia, characterized by microcytic hypochromic red cells (low MCV, MCH, MCHC), elevated RDW indicating heterogeneous cell populations, and a compensatory elevated RBC count. 1

Most Likely Diagnosis

Iron deficiency anemia is the primary diagnosis, based on the following pattern:

• Low MCV (70 fL) with low MCH (21 pg) and low MCHC (30 g/dL) indicates microcytic hypochromic anemia, most commonly caused by iron deficiency. 2, 1
• Elevated RDW (16.2%) is highly characteristic of iron deficiency, reflecting the mixture of normal-sized older red cells and progressively smaller, iron-deficient newer cells in circulation. 1, 3
• The elevated RBC count (5.42 × 10⁶/µL) despite low hemoglobin represents a compensatory bone marrow response attempting to maintain oxygen-carrying capacity by producing more cells, even though each cell contains less hemoglobin. 4

Critical Differential: Thalassemia Trait

Thalassemia trait must be excluded, as it also presents with microcytic anemia but requires different management:

• The RDW/RBC ratio is the most reliable discriminator: Calculate RDW/RBC = 16.2/5.42 = 2.99. A value >3.3 suggests iron deficiency, while <3.3 suggests thalassemia trait. 4
• In this case, the ratio of 2.99 is borderline and does not definitively exclude thalassemia, particularly given the markedly elevated RBC count which is more typical of thalassemia. 4
• However, the elevated RDW strongly favors iron deficiency over thalassemia trait, as thalassemia typically produces uniform microcytosis with normal or only mildly elevated RDW. 4, 3

Initial Diagnostic Workup

Order the following tests immediately to confirm iron deficiency and exclude other causes:

Essential First-Line Tests

• Serum ferritin: Ferritin <30 μg/L confirms iron deficiency in the absence of inflammation; ferritin <15 μg/L is diagnostic. 1, 5
• Transferrin saturation (TSAT): TSAT <15-20% supports iron deficiency and is less affected by inflammation than ferritin. 2, 1, 5
• C-reactive protein (CRP): Needed to interpret ferritin, as ferritin is an acute-phase reactant and can be falsely elevated with inflammation. 2, 1
• Absolute reticulocyte count: Evaluates bone marrow response; a low or inappropriately normal count indicates impaired red cell production despite anemia. 2, 1, 5

Additional Tests to Consider

• Peripheral blood smear: Look for hypochromic microcytic cells, pencil cells (characteristic of iron deficiency), and target cells (which would suggest thalassemia). 1
• Hemoglobin electrophoresis: If iron studies are normal or borderline, obtain hemoglobin electrophoresis to exclude thalassemia trait, particularly in patients of Mediterranean, African, Middle Eastern, or Southeast Asian descent. 1
• Vitamin B12 and folate levels: Exclude combined deficiencies, though less likely given the microcytic pattern. 1, 5

Investigation for Underlying Cause

Iron deficiency in adults always requires investigation for the source of blood loss:

• In premenopausal women: Obtain detailed menstrual history, including frequency, duration, and heaviness of periods (number of pads/tampons per day, presence of clots). 5
• In men and postmenopausal women: Gastrointestinal bleeding is the most common cause and requires endoscopic evaluation (upper endoscopy and colonoscopy) to exclude malignancy. 1
• Dietary assessment: Evaluate for restrictive diets (vegetarian/vegan), but do not presume dietary insufficiency as the sole cause without confirming with iron studies. 5
• Assess for malabsorption: History of celiac disease, inflammatory bowel disease, or gastric surgery. 2

Treatment Approach

If Iron Deficiency is Confirmed

Initiate oral iron supplementation as first-line therapy:

• Ferrous sulfate 325 mg (65 mg elemental iron) once daily to three times daily, taken between meals on an empty stomach for optimal absorption. 5
• Recent evidence supports intermittent dosing (every other day or three times weekly) as equally effective with fewer gastrointestinal side effects. 6
• Expect hemoglobin to increase by approximately 1-2 g/dL every 2-4 weeks with appropriate treatment. 1, 7
• Continue iron supplementation for 3-6 months after hemoglobin normalizes to replenish tissue iron stores. 5
• Reticulocyte count should increase within 1 week of starting therapy, indicating bone marrow response. 7

If Oral Iron Fails or is Not Tolerated

Consider intravenous iron for patients who cannot tolerate, cannot absorb, or do not respond to oral iron:

• Intravenous iron is preferred over continued oral therapy in these situations, with contemporary formulations having rare allergic reactions. 6
• Parenteral iron should be reserved for patients who cannot tolerate or absorb oral preparations, or when rapid repletion is needed. 1

If Thalassemia Trait is Diagnosed

Do not treat with iron supplementation, as thalassemia trait does not respond to iron and excessive iron can accumulate:

• Thalassemia trait requires no specific treatment but genetic counseling if planning pregnancy. 2
• Anemia is not a characteristic of hemochromatosis or thalassemia trait; finding anemia in these conditions should prompt investigation for other causes. 2

Monitoring Response to Treatment

Repeat complete blood count after 4-8 weeks to confirm response:

• Hemoglobin should increase by 1-2 g/dL every 2-4 weeks. 1, 7
• MCV, MCH, and MCHC will gradually normalize as iron-replete red cells replace iron-deficient cells. 1
• RDW may initially increase further as new normal-sized cells mix with existing microcytic cells, then gradually normalize. 3
• If no response after 4 weeks, reassess diagnosis: Consider thalassemia trait, ongoing blood loss exceeding replacement, malabsorption, or non-compliance. 1

Common Pitfalls to Avoid

• Do not rely on MCV alone: Iron deficiency can present with normal MCV in early stages, and the elevated RDW is often the first clue. 1, 5
• Do not accept ferritin alone in patients with inflammation: Use TSAT to confirm iron deficiency, as ferritin can be falsely elevated in chronic disease, malignancy, or liver disease. 2, 1, 5
• Do not overlook combined deficiencies: Iron deficiency can coexist with B12/folate deficiency, masking macrocytosis and presenting with normal MCV but elevated RDW. 7, 8
• Do not presume dietary insufficiency as the sole cause: Always confirm with iron studies and investigate for pathologic blood loss. 5
• Do not treat empirically without confirming the diagnosis: Thalassemia trait will not respond to iron and requires different counseling. 1
• Do not ignore the borderline RDW/RBC ratio: If iron studies are normal, hemoglobin electrophoresis is mandatory to exclude thalassemia trait. 4