Microcytic Anemias
Master the MCV-based approach to anemia diagnosis and management
Anemia sorting hat · Macrocytic / Normocytic · Hemolytic · IDA workup
Opening Vignette
A 42-year-old man presents with fatigue, dyspnea on exertion, and angular cheilitis. Labs show Hgb 9 g/dL, MCV 62 fL, RBC 5.8. Serum iron 20 mcg/dL, ferritin 8 ng/mL, TIBC 480 mcg/dL. What's the diagnosis?
Clinical Images
Understanding MCV-Based Classification
+ TIBC
HIGH TIBC
<15?
Low/Nml TIBC
High+ESR up?
Normal TIBC
MCV / RBC
The Corpuscular Approach
Measures the size of RBCs. <80 is microcytic (small cells). Directly reflects hemoglobin production capacity.
Amount of hemoglobin per RBC. Low in microcytic anemias (impaired Hgb production).
Calculated as MCH ÷ MCV. Usually low in microcytic disease (except hereditary spherocytosis).
Low in production problems (iron deficiency, chronic disease, lead). HIGH in hemolysis or acute bleeding.
Most common category overall. Low MCV with low MCH indicates impaired hemoglobin synthesis. RBCs are small and pale on smear (target cells). The bone marrow is struggling to make adequate hemoglobin.
Iron Deficiency Anemia
Iron Deficiency Anemia (IDA)
Low serum iron, low ferritin🔑Ferritin under 12 = virtually diagnostic for IDA. Ferritin is an acute-phase reactant, so it can be falsely normal during inflammation. If in doubt, check both ferritin AND TIBC., HIGH TIBC🔑TIBC = "empty seats on the iron bus." High TIBC means tons of transferrin sitting empty, waiting for iron. Body is so desperate it made more buses. (transferrin elevated because body is desperately hunting for iron). Microcytic, hypochromic smear with target cells.
Iron stores depleted → iron-binding capacity exceeded → iron can't get incorporated into heme → RBCs produced are small and pale.
Ferritin <30 ng/mL is virtually diagnostic. Target cells on smear. Angular cheilitis and koilonychia (spoon nails) with chronic deficiency.
Ferritin can be falsely NORMAL in concurrent inflammation/malignancy. Check both ferritin AND iron/TIBC. Also: IDA does NOT cause thrombocytosis; that's chronic disease anemia's move.
Until age 21: Poor dietary intake. Middle age: IBD (especially Crohn's). After age 40: Mucosal bleeding (males: colon cancer; females: endometrial). Always colonoscope a middle-aged man with IDA.
Ferrous iron (ferrous sulfate, ferrous fumarate, ferrous gluconate) with vitamin C to enhance absorption. PO preferred; IV for intolerance. Expect Hgb rise 1-2 g/dL per month. Always investigate the cause (GI bleed, poor intake, malabsorption).
Anemia of Chronic Disease
Anemia of Chronic Disease (ACD)
Low serum iron, ferritin NORMAL or INCREASED, LOW TIBC (opposite of IDA!). This distinction is critical on the board.
Any chronic disease >3 weeks triggers inflammation → ↑ hepcidin🔑Hepcidin = the iron gatekeeper. It blocks ferroportin on gut cells and macrophages, trapping iron inside. The body hides iron from bacteria during infection, but also from its own red cells. Chronic inflammation = permanent hepcidin spike. (IL-6 mediated) → hepcidin blocks ferroportin → iron trapped in macrophages → can't get to marrow even though stores are full → low serum iron with high ferritin.
RBCs die in 60-90 days (not from bleeding or hemolysis; just normal lifespan). Ferritin and TIBC direction OPPOSITE to iron deficiency. Mild reticulocytosis but inadequate.
Ferritin is normal/high (inflammation), not low. TIBC is low, not high. Students who only memorize "low iron, low ferritin" will miss this. The KEY DIFFERENTIATOR is ferritin direction.
Infections (TB, endocarditis), autoimmune (RA, SLE), malignancy, renal disease, heart failure. Any condition lasting weeks to months.
Treat the underlying disease. ESA (erythropoietin) for selected patients (especially CKD, cancer). Iron supplementation is usually ineffective (iron trapped, not deficient).
Lab Interpreter: Spot the Diagnosis
Interactive Lab Detective
Click on a case to see labs light up. Then choose the diagnosis:
Case 1: 38-year-old woman with fatigue and GI bleeding history
Case 2: 55-year-old man with RA, anemia, normal GI workup
Case 3: 6-year-old with developmental delay, living in old house, basophilic stippling on smear
Lab Comparison Table
| Finding | Iron Deficiency | Chronic Disease | Lead Poisoning |
|---|---|---|---|
| Serum Iron | LOW | LOW | NORMAL |
| Ferritin | LOW (<30) | NORMAL/HIGH | NORMAL |
| TIBC | HIGH (>350) | LOW (<280) | NORMAL |
| FEP | NORMAL | NORMAL | HIGH |
| Smear | Target cells | Target cells, RBC indexes acceptable | Basophilic stippling |
Villain Flip Cards
Each microcytic villain has a lab signature. Tap to flip and expose the pattern.
- Ferritin: <12 (empty stores)
- TIBC: >400 (body screaming for iron)
- Serum iron: LOW
- RDW: HIGH (uneven cell sizes)
- Smear: pencil cells, hypochromic, target cells
- Rx: ferrous sulfate + vit C. Find the bleed.
- Ferritin: HIGH or normal (iron trapped)
- TIBC: LOW (not even searching)
- Serum iron: LOW
- MCV: normal or mildly low
- Context: RA, TB, malignancy, CKD >3 weeks
- Rx: treat underlying disease. Iron won't help.
- Iron studies: ALL NORMAL
- RBC count: HIGH (more small cells)
- RDW: Normal (cells uniformly small)
- Smear: target cells
- Confirm: hemoglobin electrophoresis
- Pitfall: if iron is low, it's still thalassemia + IDA
- FEP: HIGH (protoporphyrin accumulates)
- Serum iron: Normal (iron is there, just blocked)
- TIBC: Normal
- Smear: basophilic stippling (lead)
- BM biopsy: ringed sideroblasts
- Lead specific: developmental delay, wrist drop, gum lines
- Smear: sickled cells, target cells
- Hgb electrophoresis: HbSS only (no HbA)
- Reticulocytes: HIGH (chronic hemolysis)
- LDH: HIGH, indirect bili HIGH
- Dactylitis: first crisis in infancy
- Rx: hydroxyurea (raises HbF), prophylactic PCN
- MCHC: HIGH (unique to spherocytosis)
- MCV: Low or normal
- Smear: spherocytes (no central pallor)
- Osmotic fragility: positive
- Family history: positive
- Rx: splenectomy (curative) + folate + vaccinations first
The Microcytic Workup Algorithm
Answer each step before the next branch reveals. This is how you work up a real patient.
Lead Poisoning
Lead Poisoning
Normal serum iron, normal or reduced TIBC, HIGH free erythrocyte protoporphyrin (FEP). Basophilic stippling on smear (RBCs with basophilic inclusions).
Lead blocks Delta-ALA Dehydratase (early step) and Ferrochetolase (late step in heme synthesis) → protoporphyrin accumulates → can't incorporate iron into heme → microcytic, hypochromic RBCs.
Basophilic stippling🔑Basophilic stippling = blue dots in the red cell from precipitated RNA. The ribosomal RNA that should have been cleared out is stuck because the heme synthesis enzymes are blocked. Lead = stuck ribosomes = blue polka dots. (RBCs packed with precipitated ribosomes/RNA). Elevated FEP is the confirmatory test. Normal serum iron (unlike IDA), so the lab pattern is distinct.
Easy to confuse with iron deficiency if you only look at MCV. But serum iron and TIBC are normal in lead poisoning. FEP differentiates. Also: lead causes BASOPHILIC STIPPLING, not target cells.
Children eating peeling paint in old buildings (lead paint). Also occupational exposure (battery workers, miners). Chronic toxicity affects CNS (developmental delay, encephalopathy), kidneys, GI tract.
Remove source of exposure. Chelation therapy (EDTA, dimercaprol, succimer) if blood lead >45 mcg/dL or symptomatic. Iron supplementation won't help (iron isn't the problem; heme synthesis is blocked).
Thalassemia Syndromes
Alpha-Thalassemia
4 alpha-globin genes total. Each deletion incrementally worsens disease.
Silent carrier. Normal labs, no symptoms. Only detectable if you look.
Alpha-thalassemia trait. Microcytic anemia, mild ± symptoms. RBC count often disproportionately high relative to Hgb (RBC/Hgb ratio useful for diagnosis).
Hemoglobin H disease. Moderate anemia, splenomegaly, symptoms. Forms Hb H (β4 tetramers). More microcytic. Hemolytic component.
Hydrops Fetalis (Hemoglobin Bart = γ4). Incompatible with life in utero. Fetal death or severe hemolytic disease at birth.
Loss of alpha chain → excess beta chains precipitate → hemolysis. No alpha → only beta available → Hb H or Bart forms. Microcytic because fewer normal globin chains.
Trait: observation, genetic counseling. Hb H disease: transfusion support PRN, folate supplementation, splenectomy if hypersplenism. Prenatal testing critical for at-risk couples.
Beta-Thalassemia
2 beta-globin genes total. Mutations reduce or abolish beta production.
Beta-thalassemia trait (carrier). Microcytic anemia, asymptomatic or mild symptoms. Elevated Hb A2 and Hb F on electrophoresis (compensation). Normal or elevated bilirubin due to turnover.
Beta-thalassemia major (Cooley anemia). Severe anemia, jaundice at 6 months (when Hb F switches off and only abnormal beta available). Requires transfusions. Extramedullary hematopoiesis.
Beta-thalassemia trait: ↑ Hb A2 (>3.5%), ↑ Hb F.🔑Hb A2 > 3.5% = beta-thalassemia trait on electrophoresis. The body compensates for less beta by making more delta chains (which form Hb A2 = alpha2-delta2). Think: beta's down, delta's up. Beta-thalassemia major: Hb A2 + Hb F only, NO Hb A (normal). This electrophoresis pattern is diagnostic.
At birth, Hb F (fetal, made from gamma chains) protects. At 6 months, gamma → beta switch occurs. If beta is defective, suddenly only Hb A2 (α2δ2) and Hb F remain. Severe anemia and hypoxia result.
Trait: observation. Major: chronic transfusions, iron chelation (transfusions overload iron), folate. Splenectomy if hypersplenism. Bone marrow/gene therapy curative but high-risk.
Interactive: Thalassemia Gene Deletion Counter
Explore Thalassemia Severity
Click gene buttons to delete them and see how phenotype changes:
Alpha-Thalassemia (4 genes normal)
Beta-Thalassemia (2 genes normal)
Sickle Cell Disease & Trait
Sickle Cell Disease (HbSS)
Homozygous point mutation: Glu → Val at codon 6 of beta-globin chain. Results in Hb S (Hemoglobin Sickle).
Hb S polymerizes under low O2 → distorts RBC shape into sickle → vaso-occlusion → tissue necrosis. Hemolysis due to RBC fragility.
Dactylitis (painful swelling of hands/feet) in infancy. Vaso-occlusive crises (acute, severe bone pain), acute chest syndrome, splenic sequestration, priapism.
Protects against malaria (heterozygote advantage). Intracellular sickling seen on blood smear. High reticulocyte count (chronic hemolysis). Elevated indirect bilirubin.
Hydroxyurea (↑ Hb F, ↓ sickling). Prophylactic penicillin (asplenia/functional). Pain management, hydration, transfusion support for crises. Screen for complications (stroke, osteonecrosis, retinopathy, nephropathy).
Don't confuse Sickle Cell Disease with Sickle Cell Trait. Trait is heterozygous (AS), generally benign, asymptomatic. Disease is homozygous (SS), severe.
Sickle Cell Trait (HbAS)
Heterozygous: one normal β, one sickle β. Usually asymptomatic. Diagnosed incidentally on screening.
Painless hematuria (medullary necrosis from sickling in renal medulla). Cells may sickle only under extreme hypoxia (altitude, unpressurized aircraft). Generally normal lifespan.
Hb electrophoresis shows Hb S + Hb A. No symptoms, normal RBC indices, normal hemolysis markers.
Genetic counseling (if both parents carry S, risk of SS disease is 25%). Advise avoiding extreme hypoxia. No specific treatment needed.
Other Microcytic Anemias
Hemoglobin C Disease (HbCC)
Homozygous: Glu → Lys at codon 6 (same position as sickle). Results in Hb C.
Hb C is less soluble → crystals form in RBCs → hemolysis. Much milder than sickle cell.
Mild hemolytic anemia, jaundice, splenomegaly. Microinfarcts but far fewer than sickle. Target cells on smear (not sickle cells). Chronic hemolysis.
Recognize as microcytic anemia with hemolysis. Distinguish from sickle by pattern on Hb electrophoresis and smear findings (target cells, not sickled cells). Milder clinical course.
Sideroblastic Anemia
RBCs with iron-laden mitochondria (visible on Prussian Blue stain). Failure to incorporate iron into heme despite available iron.
Hereditary (X-linked, rare, positive family history). Acquired (myelodysplasia, drugs like isoniazid). Acquired much more common on board exams.
Prussian Blue stain shows ringed sideroblasts (iron granules ringing the nucleus). Microcytic or normocytic depending on severity. Variable hemoglobin content.
Defect in heme synthesis machinery (often ALAS1, mitochondrial enzyme). Iron can't get incorporated → accumulates in mitochondria. RBCs produced are ineffective.
Hereditary: pyridoxine (vitamin B6) may help some patients. Acquired: treat underlying condition (stop offending drug, treat MDS). Transfusion support and iron chelation as needed.
Special Case: Hereditary Spherocytosis
Hereditary Spherocytosis (Microcytic Hyperchromic)
THE ONLY microcytic anemia with HIGH MCHC. This is your board clue. All others have low or normal MCHC.
Defect in RBC membrane proteins (spectrin, ankyrin, band 3) → RBC loses discoid shape → becomes dense sphere → trapped in splenic cords → hemolyzed. Intrinsic RBC defect, not external.
Low MCV, HIGH MCHC, high reticulocytes, high indirect bilirubin, hyperkalemia (RBCs burst, K+ releases). Osmotic fragility test positive.
Spherocytes (dense, small, dark RBCs without central pallor). Not target cells. This is the diagnostic clue on microscopy.
Positive family history + hemolytic anemia + spherocytes + hyperkalemia = this diagnosis. Easy to miss if you're only looking at MCV. Remember: "Spherocytes = Spherocytosis" unless there's another reason (autoimmune, transfusion, burns).
Folate supplementation (chronic hemolysis demands it). Splenectomy (removes the site of hemolysis) curative or near-curative. Prophylactic vaccinations before splenectomy.
Memory Hooks (Tap to Reveal)
Iron Deficiency Labs Mnemonic
Chronic Disease Labs Mnemonic
Lead Poisoning Clue
Thalassemia Genes Rule
Sickle vs. Trait
Spherocytosis: The Exception
Beta-Thalassemia Major: The 6-Month Rule
Decision Tree: Microcytic Anemia Workup
Board-Style Walkthrough
25 original vignettes. One at a time. Shuffle restarts fresh.
Board-Style Walkthrough
Original board-style vignettes. Shuffled, never-repeat, full explanations for every choice.