Anemia

Microcytic Anemia

Distinguish iron deficiency from thalassemia and inflammatory iron restriction, recognize sideroblastic anemia and lead exposure, and use the smear, iron studies, RBC indices and hemoglobin testing appropriately.

Audience: internal medicine residents Last reviewed: July 2026

Bedside approach

Answer these questions first

Is iron deficiency present? Review ferritin, TSAT, serum iron, TIBC, inflammation and the clinical risk of blood loss or malabsorption.
Is the RBC count relatively preserved? Marked microcytosis with a normal or increased RBC count may suggest thalassemia trait.
What does the smear show? Hypochromia, target cells, anisopoikilocytosis, basophilic stippling and dimorphic populations may redirect testing.
Could inflammation be masking iron deficiency? Ferritin may be normal or elevated during inflammation despite restricted iron availability or concurrent absolute deficiency.
Is there a toxin or medication exposure? Review lead, alcohol, zinc, copper, isoniazid, linezolid, chloramphenicol and other marrow-toxic exposures.
Is this lifelong or newly acquired? Prior CBCs, family history, ancestry, pregnancy screening and prior hemoglobin testing help distinguish inherited from acquired causes.

Urgent escalation

  • Hemodynamic instability or active major bleeding
  • Severe symptomatic anemia or ischemic symptoms
  • Pregnancy with severe anemia or suspected major hemoglobinopathy
  • Neurologic or gastrointestinal symptoms with possible lead poisoning
  • Progressive pancytopenia, blasts or marked dysplasia
  • Severe congenital anemia or transfusion dependence

1. Initial evaluation

  1. Confirm microcytosis and review previous hemoglobin, MCV, RDW and RBC count.
  2. Obtain an absolute reticulocyte count and inspect the peripheral smear.
  3. Check ferritin, serum iron, TIBC or transferrin, and transferrin saturation.
  4. Evaluate blood loss, diet, gastrointestinal disease, menstruation, pregnancy, malabsorption and prior surgery.
  5. When iron deficiency is not established, consider hemoglobin analysis, inflammatory disease, lead testing and sideroblastic anemia.
  6. Escalate to genetic or marrow testing when the clinical pattern remains unexplained.

2. Common laboratory patterns

Feature Iron deficiency Thalassemia trait Inflammatory iron restriction
Ferritin Usually reduced Usually normal unless iron deficiency coexists Often normal or increased
Serum iron Reduced Often normal Reduced
TIBC or transferrin Often increased Usually normal Often reduced or normal
TSAT Reduced Usually normal unless deficiency coexists Reduced
RBC count Often reduced or normal Often normal or increased relative to hemoglobin Usually reduced or normal
RDW Often increased May remain relatively uniform Variable
Smear Hypochromia and anisopoikilocytosis Target cells and marked microcytosis Usually nonspecific
These patterns overlap. Do not diagnose thalassemia from the CBC alone or exclude iron deficiency solely because ferritin is not low during inflammation.

3. Iron deficiency

Iron deficiency remains the most common acquired cause of microcytic anemia. The diagnostic work should identify both the deficiency and its cause.

Common causes

  • Menstrual or obstetric blood loss
  • Gastrointestinal blood loss
  • Reduced dietary intake
  • Pregnancy or increased physiologic demand
  • Celiac disease or other malabsorption
  • Bariatric or gastrointestinal surgery
  • Frequent blood donation or phlebotomy

Use the dedicated Iron Deficiency guide for ferritin and TSAT interpretation, replacement selection and monitoring.

Iron deficiency may be normocytic early. Conversely, profound thalassemia-related microcytosis can occur with only mild anemia.

4. Thalassemia and hemoglobin disorders

When to suspect thalassemia trait

  • Microcytosis out of proportion to the degree of anemia
  • Normal or relatively increased RBC count
  • Longstanding microcytosis
  • Family history or ancestry associated with hemoglobin variants
  • Normal iron stores
  • Target cells on smear
  • Failure to improve with appropriate iron replacement

Testing approach

  • Confirm iron status first.
  • Order hemoglobin analysis when beta-thalassemia or a variant is suspected.
  • Recognize that alpha-thalassemia trait may have normal routine hemoglobin analysis.
  • Consider molecular testing when alpha-thalassemia or another inherited disorder remains likely.
  • Offer genetic counseling when reproductive implications are relevant.
Iron deficiency can reduce HbA2 and complicate beta-thalassemia-trait interpretation. Correct established iron deficiency and interpret the result with hematology or laboratory guidance when needed.

Interactive tool

Mentzer index

The Mentzer index is a rough screening clue calculated as MCV divided by RBC count. It is not sufficiently accurate to replace iron studies, hemoglobin analysis or genetic testing.

Enter the MCV and RBC count.

Traditional heuristic: below 13 may favor thalassemia trait; above 13 may favor iron deficiency. Mixed disease, pregnancy, age, transfusion and other disorders reduce reliability.

5. Inflammatory iron restriction

Inflammation raises hepcidin, reduces intestinal iron absorption and limits release of stored iron. Serum iron and TSAT may be low even though ferritin is normal or elevated.

Clinical settings

  • Chronic infection
  • Autoimmune or inflammatory disease
  • Malignancy
  • Chronic kidney disease
  • Critical illness
Absolute iron deficiency and inflammatory restriction frequently coexist. Interpret ferritin, TSAT, inflammatory context and treatment response together.

6. Sideroblastic anemia

Sideroblastic anemia results from impaired heme synthesis with pathologic mitochondrial iron accumulation in erythroid precursors. The MCV may be low, normal or high depending on the cause.

Acquired causes and associations

  • Myelodysplastic neoplasm with ring sideroblasts
  • Alcohol
  • Vitamin B6 deficiency
  • Copper deficiency or excess zinc
  • Lead exposure
  • Isoniazid
  • Linezolid
  • Chloramphenicol

Supporting findings

  • Increased serum iron, ferritin or TSAT
  • Dimorphic RBC population
  • Basophilic stippling or Pappenheimer bodies
  • Progressive cytopenias or dysplasia
  • Ring sideroblasts on marrow iron stain
Ring sideroblasts are a marrow finding and do not automatically establish a specific diagnosis. Interpret them with morphology, medications, nutrient status, cytogenetics and molecular testing.

7. Lead exposure

Exposure clues

  • Old paint, renovation or contaminated dust
  • Battery manufacture or recycling
  • Metal work, welding, smelting or firing ranges
  • Imported pottery, cosmetics, spices or traditional remedies
  • Occupational exposure brought into the home
  • Abdominal pain, constipation, neuropathy or cognitive symptoms

Evaluation

  • Measure a venous blood lead concentration.
  • Identify and terminate the exposure source.
  • Assess CBC, iron status, kidney function and neurologic symptoms.
  • Consult poison control, occupational medicine or medical toxicology for clinically significant exposure.
  • Use chelation only through established toxicology guidance.
Basophilic stippling may support the diagnosis but may be absent. Blood lead testing—not smear morphology—confirms exposure.

8. When to consider marrow or genetic evaluation

  • Persistent unexplained microcytosis with adequate iron stores
  • Progressive or multilineage cytopenias
  • Dimorphic smear or suspected sideroblastic anemia
  • Peripheral dysplasia or circulating blasts
  • Iron overload with microcytic anemia
  • Strong inherited pattern with nondiagnostic hemoglobin analysis
  • Severe childhood or transfusion-dependent anemia

9. Resident summary

  1. Start with ferritin, TSAT, RBC count, RDW and the smear.
  2. Investigate the cause whenever iron deficiency is present.
  3. Marked microcytosis with a preserved RBC count suggests thalassemia but does not prove it.
  4. Correct iron deficiency before overinterpreting HbA2.
  5. Alpha-thalassemia trait may have normal routine hemoglobin analysis.
  6. The Mentzer index is a screening clue, not a definitive test.
  7. Increased iron stores with microcytosis should raise concern for sideroblastic or inherited iron-utilization disorders.
  8. Confirm suspected lead exposure with a blood lead concentration.

10. Knowledge check

Question 1

A patient has MCV 64 fL, mild anemia, normal ferritin and a relatively increased RBC count. Which diagnosis should be considered?

Question 2

Which statement about the Mentzer index is most accurate?

Question 3

A patient with inflammatory disease has low serum iron, low TSAT and ferritin 180 ng/mL. What is the best interpretation?

Question 4

A patient has abdominal pain, neuropathy, microcytic anemia and basophilic stippling after occupational battery exposure. What test confirms exposure?

References

  1. Cappellini MD, et al. Inherited microcytic anemias. ASH Education Program. 2020. Open article
  2. Cazzola M. Ineffective erythropoiesis and its treatment. Blood. 2022. Open article
  3. Cazzola M, Invernizzi R. Diagnosis and treatment of sideroblastic anemias. ASH Education Program. 2015. Open article
  4. World Health Organization. Guideline for clinical management of exposure to lead. 2021. WHO guideline
  5. Centers for Disease Control and Prevention. Thalassemia. CDC resource
  6. American Society of Hematology. Hemoglobin electrophoresis in sickle-cell disease. ASH resource

Educational disclaimer

This guide is intended for clinician education and does not replace local laboratory methods, hematology consultation, toxicology guidance, genetic counseling, institutional protocols or individualized clinical judgment. Severe anemia, significant lead poisoning and suspected major hemoglobinopathies require appropriate local escalation.