What is the most likely diagnosis and appropriate workup for a patient with normal hemoglobin and hematocrit, normal mean corpuscular volume, but low mean corpuscular hemoglobin and low mean corpuscular hemoglobin concentration?

Hypochromic Anemia with Normal MCV: Iron Deficiency Until Proven Otherwise

The most likely diagnosis is iron deficiency anemia, and you should immediately order serum ferritin and transferrin saturation to confirm the diagnosis. 1

Understanding the Laboratory Pattern

Your patient presents with a distinctive pattern that strongly suggests iron deficiency:

• Low MCH (24 pg) and low MCHC (29.6 g/dL) indicate hypochromia – meaning red blood cells contain insufficient hemoglobin despite normal cell size 1
• Normal MCV with reduced MCH/MCHC is characteristic of early or mild iron deficiency where hemoglobin synthesis is impaired before cell size becomes abnormal 1
• MCH is actually more reliable than MCV for detecting iron deficiency because it's less dependent on storage conditions and counting equipment, and decreases in both absolute and functional iron deficiency 1

This pattern occurs because iron deficiency first affects hemoglobin concentration within cells (lowering MCH and MCHC) before the cells themselves become smaller (lowering MCV). 1

Immediate Diagnostic Workup

First-Line Iron Studies

Order serum ferritin and transferrin saturation together as your initial diagnostic tests: 1, 2

• Ferritin <30 μg/L confirms iron deficiency in patients without inflammation 1
• Ferritin <45 μg/L provides optimal sensitivity and specificity for iron deficiency in routine practice 2
• Transferrin saturation <16-20% confirms insufficient circulating iron for erythropoiesis 1, 2

Critical Pitfall: Ferritin as an Acute Phase Reactant

Ferritin can be falsely elevated by inflammation, infection, malignancy, or liver disease despite true iron deficiency. 1 If ferritin appears normal (30-100 μg/L) but you still suspect iron deficiency:

• Check C-reactive protein (CRP) to assess for inflammation 1
• In the presence of inflammation, ferritin up to 100 μg/L may still indicate iron deficiency 1
• Transferrin saturation becomes more reliable than ferritin when inflammation is present 3, 1

Additional Useful Parameters

• Check RDW (red cell distribution width): Low MCV with RDW >14.0% suggests iron deficiency, while RDW ≤14.0% suggests thalassemia 1, 2
• Reticulocyte count: Should be low-normal in iron deficiency (inadequate bone marrow response due to lack of iron) 3

Differential Diagnosis to Consider

When Iron Studies Are Normal

If ferritin is >100 μg/L and transferrin saturation is normal, consider:

1. Thalassemia trait – particularly if MCV becomes low with normal iron studies and appropriate ethnic background (Mediterranean, Asian, African descent) 1, 2

   • Order hemoglobin electrophoresis 1, 2
   • Thalassemia typically shows MCV reduced out of proportion to anemia with normal RDW 1

2. Anemia of chronic disease – diagnosed when ferritin >100 μg/L AND transferrin saturation <20% 1

   • Look for underlying inflammatory conditions, malignancy, or chronic kidney disease 3, 1

3. Combined iron deficiency and anemia of chronic disease – suspect when ferritin is 30-100 μg/L with transferrin saturation <20% 1

Rare Genetic Causes (Only If Refractory to Treatment)

Do not pursue genetic testing initially. Only consider if patient fails to respond to oral iron therapy after 2-4 weeks: 1, 2

• IRIDA (iron-refractory iron deficiency anemia): Remarkably low transferrin saturation with low-normal ferritin, fails oral iron but may respond to IV iron 1, 2
• Sideroblastic anemia: May respond to pyridoxine (vitamin B6) 50-200 mg daily 1, 2

Investigating the Source of Iron Loss

Once iron deficiency is confirmed, you must identify the source of iron loss – do not simply treat with iron supplementation alone. 1, 2

In Adult Men and Non-Menstruating Women

Gastrointestinal blood loss is the most common cause and requires investigation: 1, 2

• Upper endoscopy with duodenal biopsies to exclude celiac disease (present in 2-3% of iron deficiency cases), gastric malignancy, NSAID gastropathy, and peptic ulcer disease 1, 2
• Colonoscopy to exclude colonic carcinoma, polyps, angiodysplasia, and inflammatory bowel disease 1, 2
• Men with hemoglobin <110 g/L warrant fast-track GI referral 1

In Premenopausal Women

Both menstrual blood loss AND gastrointestinal bleeding must be evaluated: 1

• Heavy menstrual bleeding is the most common cause in this population 1
• However, do not attribute iron deficiency solely to menstruation without GI evaluation if anemia is severe or refractory to treatment 1

Additional Causes to Assess

• Dietary inadequacy: Rare as sole cause in developed countries 1
• Malabsorption disorders: Celiac disease, H. pylori infection, autoimmune atrophic gastritis 1
• Chronic blood donation or frequent phlebotomy 1

Treatment Approach

First-Line: Oral Iron Supplementation

Start oral iron therapy immediately while diagnostic workup proceeds: 1, 2

• Ferrous sulfate 200 mg three times daily (or alternate-day dosing, which may have fewer side effects and similar efficacy) 1, 2
• Alternative formulations: Ferrous gluconate or ferrous fumarate if ferrous sulfate not tolerated 1, 2
• Adding ascorbic acid enhances iron absorption 2

Expected Response and Monitoring

Hemoglobin should rise ≥10 g/L within 2 weeks if iron deficiency is the cause – this therapeutic response confirms the diagnosis when iron studies are equivocal 1, 2

• Continue oral iron for at least 3 months after correction of anemia to replenish iron stores 2
• Monitor hemoglobin and ferritin at 3-month intervals for one year 2

When to Use Intravenous Iron

Consider IV iron if: 1, 2

• Malabsorption is present (celiac disease, inflammatory bowel disease, post-gastric bypass) 1, 2
• Patient cannot tolerate oral iron despite trying multiple formulations 1, 2
• No response to oral iron after 2-4 weeks with documented compliance 1, 2
• Expected hemoglobin increase of at least 2 g/dL within 4 weeks of IV iron 1, 2

Common Pitfalls to Avoid

1. Do not assume all microcytic anemia is iron deficiency – anemia of chronic disease, thalassemia, and sideroblastic anemia require different management 1, 2

2. Do not rely on ferritin alone in inflammatory states – add transferrin saturation to accurately diagnose iron deficiency 1

3. Do not overlook combined deficiencies – iron deficiency can coexist with B12 or folate deficiency, recognizable by elevated RDW 1, 2

4. Do not accept upper GI findings (esophagitis, gastritis, ulcer) as the sole cause without also examining the lower GI tract, because dual pathology is present in approximately 10-15% of patients 2

5. Do not delay GI investigation in adults with confirmed iron deficiency – occult malignancy must be excluded 1, 2