What is the best approach to manage a patient with microcytic hypochromic red blood cells (RBCs)?

Management of Microcytic Hypochromic RBCs

The first-line approach is to confirm iron deficiency anemia with serum ferritin and transferrin saturation, then treat with oral ferrous sulfate 200 mg three times daily for at least three months after hemoglobin normalizes, while simultaneously investigating the underlying cause of iron loss. 1, 2, 3

Initial Diagnostic Workup

Measure serum ferritin as the single most useful test:

• Ferritin <15 μg/L confirms absent iron stores 1, 3
• Ferritin <30 μg/L indicates low body iron stores 1, 3
• Use a cut-off of 45 μg/L for optimal sensitivity and specificity in practice 1, 2, 3
• Ferritin >150 μg/L makes iron deficiency unlikely 1

Add transferrin saturation (TSAT) to the workup:

• TSAT is more sensitive than hemoglobin alone for detecting iron deficiency 1, 2, 3
• TSAT <16-20% suggests iron deficiency 1

Use RBC indices to differentiate causes:

• Low MCV with RDW >14.0% strongly suggests iron deficiency anemia 1, 2, 3
• Low MCV with RDW ≤14.0% suggests thalassemia minor 1, 2
• Mean corpuscular hemoglobin (MCH) is more reliable than MCV because it's less dependent on storage conditions 1

First-Line Treatment for Iron Deficiency

Oral iron supplementation is the standard treatment:

• Ferrous sulfate 200 mg (65 mg elemental iron) three times daily 1, 2, 3
• Continue for at least three months after hemoglobin normalizes to replenish iron stores 1, 2, 3
• Do not crush or chew tablets 4

Alternative formulations if ferrous sulfate is not tolerated:

• Ferrous gluconate or ferrous fumarate 1, 3
• Add ascorbic acid (vitamin C) to enhance iron absorption 1, 3

Expected response to confirm diagnosis:

• Hemoglobin should rise ≥10 g/L (≥1 g/dL) within 2 weeks 1, 2, 3
• Expect at least 2 g/dL increase within 4 weeks 1, 2, 3

Monitoring Protocol

Follow hemoglobin and iron studies systematically:

• Check at 2 weeks, 4 weeks, 3 months 2, 3
• Then every 3 months for the first year 1, 2, 3
• Then annually thereafter 2, 3
• Provide additional oral iron if hemoglobin or MCV falls below normal 1, 3

Investigation of Underlying Cause

In adults with confirmed iron deficiency, investigate the source of iron loss:

• Men with Hb <110 g/L or non-menstruating women with Hb <100 g/L warrant fast-track GI referral 1
• Consider investigation at any level of anemia with confirmed iron deficiency, especially with more severe degrees 1
• Evaluate for gastrointestinal blood loss (melena, hematochezia, occult bleeding) 1
• Screen for celiac disease if malabsorption is suspected 1
• Consider H. pylori infection or autoimmune atrophic gastritis if treatment failure occurs 1

When to Consider Genetic Disorders

Red flags that should prompt genetic testing:

• Family history of anemia 2
• Anemia refractory or incompletely responsive to iron supplementation 2
• Neurologic disease or skin photosensitivity 2
• Extreme microcytosis (MCV <70) 1
• Elevated ferritin and/or TSAT, or low TSAT combined with low-normal ferritin (>20 mg/L) 2

Key genetic disorders to consider:

Iron-Refractory Iron Deficiency Anemia (IRIDA):

• Very low TSAT with low-to-normal ferritin and failure to respond to oral iron 1, 2, 3
• Requires intravenous iron (iron sucrose or iron gluconate) repeatedly—oral iron is ineffective 2, 3
• Do not use oral iron for IRIDA as it delays appropriate treatment 2

X-linked Sideroblastic Anemia (ALAS2 defects):

• Initial treatment with pyridoxine (vitamin B6) 50-200 mg daily 5, 1, 2
• If responsive, continue lifelong maintenance at 10-100 mg daily 5, 1, 2
• Occasionally high doses up to 300 mg per day may be considered in overweight, active, or elderly patients 5

SLC11A2 (DMT1) defects:

• Treat with oral iron supplementation and/or erythropoietin (EPO) and/or erythrocyte transfusions based on individual needs 5, 1
• Monitor iron status to detect toxic iron loading early 5
• MRI of the liver should be considered since normal serum ferritin does not exclude liver iron loading 5, 1

STEAP3 defects:

• Treat with erythrocyte transfusions in combination with EPO 5, 1
• Manage systemic iron loading with chelation therapy 5, 1

SLC25A38 defects:

• Hematopoietic stem cell transplantation (HSCT) is the only curative option 5, 1
• Symptomatic treatment includes erythrocyte transfusions and chelation therapy 5, 1

ABCB7 defects:

• Presents with mild microcytic anemia and ataxia in males 5
• Treatment of mild anemia is not indicated 5
• X-linked inheritance pattern requires family counseling 5

When to Use Intravenous Iron

Consider IV iron if oral therapy fails:

• Malabsorption confirmed (celiac disease, inflammatory bowel disease) 1, 2
• Expected hemoglobin increase of at least 2 g/dL within 4 weeks 1, 2
• Use iron sucrose or iron gluconate 1, 3

Critical Pitfalls to Avoid

Do not assume all microcytic anemia is iron deficiency:

• Anemia of chronic disease, thalassemia, and sideroblastic anemia must be differentiated to avoid unnecessary iron therapy 1, 2
• Order hemoglobin electrophoresis if microcytosis with normal iron studies, appropriate ethnic background, or MCV disproportionately low relative to degree of anemia 1

Do not overlook combined deficiencies:

• Iron deficiency can coexist with B12 or folate deficiency 1, 2

In genetic sideroblastic anemias, iron overload is more dangerous than the anemia itself:

• Unrecognized tissue iron loading can cause severe morbidity and mortality 2
• Monitor ferritin and do not exceed 500 mg/L to avoid iron overload risk 1

Failure to respond to oral iron within 2-4 weeks mandates investigation:

• Consider non-compliance, ongoing blood loss, malabsorption, or genetic disorders 1, 2

In inflammatory states, ferritin up to 100 μg/L may still be consistent with iron deficiency:

• Add TSAT to differentiate iron deficiency from anemia of chronic disease 1