What is the diagnosis and treatment for a patient with a decreased anion gap (6), hypochromic microcytic anemia (decreased Hemoglobin (HGB), Hematocrit (HCT), Mean Corpuscular Hemoglobin (MCH), and Mean Corpuscular Hemoglobin Concentration (MCHC))?

Hypochromic Microcytic Anemia with Low Anion Gap

The most likely diagnosis is iron deficiency anemia, and you should initiate oral iron supplementation (ferrous sulfate 200 mg three times daily) while investigating the underlying cause, particularly gastrointestinal blood loss in adult men and post-menopausal women. 1, 2

Understanding the Clinical Picture

The combination of decreased hemoglobin, hematocrit, MCH, and MCHC indicates hypochromic microcytic anemia. 1 The low anion gap (6) is an important clue that often goes unrecognized—it can occur with severe hypoalbuminemia or paraproteinemia, but in the context of microcytic anemia, it may reflect laboratory artifact or concurrent metabolic disturbances. 2

MCH is actually more reliable than MCV for detecting iron deficiency because it is less dependent on storage conditions and counting equipment, and it decreases in both absolute and functional iron deficiency. 1, 2 This makes your laboratory findings particularly significant for iron deficiency.

Diagnostic Workup

Essential First-Line Tests

• Serum ferritin is the single most powerful test for iron deficiency, with levels <15 μg/L indicating absent iron stores and <30 μg/L indicating low body iron stores. 1, 2
• Transferrin saturation <16-20% indicates insufficient circulating iron for erythropoiesis. 2
• Critical pitfall: Ferritin is an acute phase protein and can be falsely normal or elevated during inflammation, infection, malignancy, or liver disease despite true iron deficiency. 1, 2 However, ferritin >150 μg/L essentially excludes absolute iron deficiency even with concurrent inflammation. 1, 2

When Iron Studies Are Equivocal

• In inflammatory conditions, a ferritin cut-off of 45 μg/L provides optimal trade-off between sensitivity (specificity 0.92) for detecting iron deficiency. 1
• If ferritin is 30-100 μg/L in the presence of inflammation, consider combined iron deficiency and anemia of chronic disease. 2
• A therapeutic trial of oral iron for 2-4 weeks with repeat hemoglobin measurement can confirm iron deficiency when other tests are equivocal—expect hemoglobin rise ≥10 g/L within 2 weeks if iron deficiency is present. 2, 3

Rule Out Alternative Diagnoses

• Obtain hemoglobin electrophoresis if iron studies are normal, particularly in patients of Mediterranean, African, Middle Eastern, or Southeast Asian descent, as thalassemia causes MCV reduced out of proportion to anemia severity. 1, 2
• In thalassemia, MCV is typically more severely reduced relative to the degree of anemia compared to iron deficiency. 1
• Consider sideroblastic anemia if microcytosis and hypochromia persist despite normal iron studies and negative hemoglobin electrophoresis. 1

Treatment Algorithm

Immediate Management

• Start oral iron supplementation: Ferrous sulfate 200 mg three times daily (or equivalent elemental iron 150-200 mg daily). 2
• Continue iron therapy for 3 months total to replenish stores, even after hemoglobin normalizes. 2, 3
• Monitor hemoglobin, MCH, and MCHC after 2-4 weeks—expect hemoglobin rise ≥10 g/L if responding appropriately. 2, 3

Investigate the Underlying Cause

• In adult men and post-menopausal women with confirmed iron deficiency, gastrointestinal evaluation is mandatory as GI blood loss is the most common cause. 2
• The British Society of Gastroenterology recommends investigation at any level of anemia in the presence of iron deficiency, though the case is stronger with more severe degrees of anemia (Hb <110 g/L in men or <100 g/L in non-menstruating women). 1
• Obtain small bowel biopsies during upper endoscopy as 2-3% of patients with iron deficiency anemia have celiac disease. 2

When to Consider Parenteral Iron

• Malabsorption documented on endoscopy or biopsy. 4
• Iron losses exceeding maximal oral replacement capacity. 4
• True intolerance to oral iron (not just minor GI upset). 4
• Inflammatory bowel disease where oral iron may be poorly tolerated. 3

Monitoring After Treatment

• Repeat CBC after 2-4 weeks of iron therapy to confirm response. 2, 3
• After correction, monitor CBC at 3-month intervals for one year, then after another year. 3
• If no response to oral iron after 3 weeks, reconsider diagnosis—possibilities include ongoing blood loss, malabsorption, anemia of chronic disease, or misdiagnosis. 2, 5

Critical Pitfalls to Avoid

• Do not rely on hemoglobin and hematocrit alone—normal ranges do not exclude iron deficiency, as they decrease only when severe iron depletion is present. 6 Many cases of early iron deficiency are missed when CBC is ordered without iron studies. 6
• Do not assume normal iron studies exclude iron deficiency in the presence of inflammation. 1, 2
• Do not stop iron supplementation when hemoglobin normalizes—continue for 3 months to replenish stores. 2, 3
• Do not overlook the low anion gap—while investigating the anemia, also evaluate for hypoalbuminemia or other causes of low anion gap that may indicate serious underlying pathology. 2