Iron Studies Decoder
Random iron panel pops up. Read the four arrows. Pick the anemia. The pattern is the test · memorize the table once and you own the bench question.
🏥 MCV Triage Station
Read the scenario, classify by MCV, then click to drill down to the diagnosis.
Defective nuclear division
Normal RBC size, not enough of them
Iron issues or thalassemia
MCV is the first triage gate on every anemia stem. <80 = microcytic → iron deficiency, thalassemia, anemia of chronic disease (late), lead, sideroblastic. 80·100 = normocytic → ask: hemolysis (retics up) or underproduction (retics down, BM, kidney, ACD)? >100 = macrocytic → ask: megaloblastic (B12, folate, drugs) or non-megaloblastic (liver, alcohol, hypothyroid, MDS, reticulocytosis)? The single number splits the entire workup tree · never start anemia from "what's the Hgb"; start from MCV + retics.
Clinical Images
The Villains: Key Diagnoses
Tap each card to reveal the crime file (key labs and clinical features).
Crime File
Crime File
Crime File
Crime File
Crime File
Crime File
Macrocytic Workup: Decision Tree
Follow the algorithm to reach the diagnosis.
Check for neuro sx, pernicious anemia Ab
No neuro sx. Check diet, methotrexate
Phenytoin blocks Ca + folate
TSH elevated or EtOH history
📈 Macrocytic Anemias (MCV >100)
Defective nuclear division slows down, RBCs become bigger
Macrocytic splits cleanly: megaloblastic (B12 or folate) vs non-megaloblastic. The smear tells you: hypersegmented neutrophils (>5 lobes) = megaloblastic. B12 vs folate · both give pancytopenia and macrocytosis, but only B12 deficiency causes subacute combined degeneration (posterior columns + corticospinal tracts → loss of vibration/proprioception + UMN signs). Folate gives no neuro findings. Pregnancy + macrocytic + no neuro = folate. Vegan or pernicious anemia + numb feet = B12. Give folate alone to a B12-deficient patient and you'll fix the anemia but accelerate the neuro damage.
B12 vs Folate: The Key Difference
| Feature | Vitamin B12 Deficiency | Folate Deficiency |
|---|---|---|
| Anemia Type | Megaloblastic | Megaloblastic |
| Neurologic Symptoms | YES - Subacute Combined Degeneration | NO - Never |
| Paresthesias | Dorsal columns affected | Not present |
| Elevated Homocysteine | YES | YES |
| Elevated Methylmalonate | YES (B12-specific) | NO |
| Most Common Cause | Type A Gastritis (Pernicious) | Overcooked vegetables |
🔴 Vitamin B12 Deficiency
Cofactors B12 Regulates:
- Malonyl-CoA Mutase - needed for fatty acid synthesis (can't build myelin without this)
- Homocysteine Methyl Transferase - converts homocysteine to methionine
Most Common Cause: Type A Gastritis (Pernicious Anemia)
- Autoimmune attack on stomach parietal cells
- Kills production of intrinsic factor (IF)
- B12 cannot be absorbed in terminal ileum without IF
- Results in megaloblastic anemia + neurologic damage
Neurologic Features (Subacute Combined Degeneration):
- Paresthesias (numbness/tingling) in feet
- Weakness progressing upward
- Loss of position sense (dorsal column pathology)
- Ataxia (uncoordinated movement)
Diagnosis Clue:
Elevated methylmalonate is pathognomonic for B12 deficiency (not seen in folate deficiency)
🟡 Folate Deficiency
Why Folate First?
Folate is the first vitamin to become depleted during periods of rapid cellular division because the body has minimal stores. Unlike B12 (which can be stored for years), folate reserves last only months.
Most Common Cause: Overcooked Vegetables
- Folate is destroyed by heat
- Excessively cooked food = no folate
- Causes megaloblastic anemia
- NO neurologic symptoms
Other Causes:
- Methotrexate (blocks folate metabolism)
- Malabsorption: Crohn's disease, celiac sprue, cystic fibrosis
- Rapid cell turnover (cancer, hemolysis)
Key Difference:
Folate deficiency causes anemia only. Never causes neurologic symptoms (no myelin damage).
Other Causes of Macrocytic Anemia
Hypothyroidism
Thyroid hormones are permissive for all body functions. Without them, everything slows down → including bone marrow. RBCs grow large but slowly.
Alcohol
Denatures all proteins. Impairs nuclear division directly. Also commonly causes folate deficiency (poor diet + malabsorption).
Chemotherapy
Drugs damage DNA and stop nuclear replication. Cytoplasm keeps growing → macrocytic cells.
⚠️ Anticonvulsant Drugs & Macrocytic Anemia
All anticonvulsants that cause macrocytic anemia block calcium and/or folate metabolism. Calcium is needed for microtubules during cell division.
→ Normocytic Normochromic Anemias
Normal MCV, Normal MCH → nothing wrong with the RBC itself, just not enough of them
Normocytic forks on reticulocyte count. Retics up (>2% corrected) = bone marrow is responding · you're losing or destroying RBCs (hemorrhage, hemolysis). Then ask: extravascular (spleen) vs intravascular (haptoglobin down, LDH up, hemoglobinuria). Retics down or inappropriately normal = marrow can't keep up · think kidney (low EPO), chronic disease, marrow failure (aplastic, MDS, infiltration), early iron deficiency. "Normocytic + retics 4% + indirect bili up + LDH 800 + haptoglobin undetectable" is intravascular hemolysis until proven otherwise. The retic count is the second triage gate after MCV.
Timeline-Based Normocytic Causes
Acute Hemorrhage (<4 days)
When a patient bleeds out suddenly, the body loses RBCs faster than it can replace them. Reticulocytes (immature RBCs) don't show up until day 3-4. Before that: normal RBC size, low count.
Chronic Disease (Early Phase, First 60 Days)
Infections, cancer, rheumatologic diseases trigger mild anemia by damping down erythropoietin (EPO). Before iron stores fully deplete (which takes months), the anemia is normocytic.
Renal Failure
Kidneys make erythropoietin (EPO). No kidneys = no EPO = bone marrow doesn't make RBCs.
Hypothyroidism (Again)
Thyroid hormones are required for EPO to work. Even if kidneys make EPO, without T3/T4 it's useless.
Bone Marrow Production Problems
Aplastic Anemia
Most Common Cause: Idiopathic (Autoimmune T-Cell Mediated)
In most cases, autoreactive T-cells attack and destroy hematopoietic stem cells. Marrow becomes replaced with fat and cannot make any blood cells (pancytopenia). Parvovirus B19 causes aplastic crisis in patients with chronic hemolysis (e.g., sickle cell), and pure red cell aplasia in immunocompromised patients, but it is NOT the most common cause of acquired aplastic anemia.
Other Causes:
- Chloramphenicol - antibiotic that's toxic to marrow
- Benzene - industrial chemical
- AZT - antiretroviral (older drugs, less used now)
- Vinblastine - chemotherapy agent
Myelofibrosis
Cancer of the bone marrow. Marrow becomes fibrotic (scarred, rigid) instead of making blood. RBCs can't be produced.
Fanconi Anemia
Genetic aplastic anemia (autosomal recessive DNA repair defect). ALL cell lines fail (pancytopenia, not just RBCs). Associated with physical anomalies including absent or hypoplastic thumbs and radius abnormalities. Increased cancer risk. Do NOT confuse with Diamond-Blackfan (pure RBC aplasia).
Diamond-Blackfan Syndrome
RBC aplasia + finger abnormality (classically triphalangeal thumb → thumb with 3 bones instead of 2).
🔴 Paroxysmal Nocturnal Hemoglobinuria (PNH)
Rare, acquired, life-threatening hemolytic anemia
Nocturnal = worse at night (concentrated urine makes hemoglobinuria visible).
Hemoglobinuria = peeing hemoglobin (pink/dark red urine).
The Anchor Story: RBCs are boats. The GPI anchor is the boat's anchor that keeps complement sharks away. Gene mutation = anchor fell off. Now the boat (RBC) gets attacked by complement sharks and sinks. No anchor = no protection.
Complement Attack Simulator
Watch how the GPI anchor (yellow) protects RBCs from complement attack.
CD55 (DAF) + CD59 (MAC inhibitor)
Complement can't attack
No CD55 or CD59
Complement destroys RBC
The Genetics
- Gene mutation in PIGA gene (X-linked)
- Loss of GPI anchor synthesis
- Without GPI anchor: CD55 (DAF - Decay Accelerating Factor) and CD59 (MAC inhibitor) can't attach to RBC surface
- Complement proteins (C3b, C5b-9) tag RBCs for destruction
- RBCs hemolyzed (destroyed)
Clinical Presentation
Fatigue Out of Proportion
Hemolysis is chronic but episodic. Patients are constantly exhausted because they're losing RBCs constantly.
Jaundice
Hemolysis releases bilirubin. Yellowing of skin and sclera.
Pink/Red Urine (Hemoglobinuria)
Hemoglobin gets filtered into urine. Concentrated in the morning (hence "nocturnal"). Not always at night → can happen anytime, despite the name.
Thrombosis in Unusual Sites
PNH has a weird tendency to cause clots in abnormal places:
- Hepatic vein thrombosis (Budd-Chiari syndrome)
- Portal vein thrombosis
- Cerebral vein thrombosis
- Mesenteric vein thrombosis
- Can cause MI or stroke despite young age
Diagnosis
Historical: Ham's Test
RBCs placed in a petri dish + complement + acid (decreased pH) → RBCs lyse (hemoglobinuria visible). Positive = PNH. But outdated.
Modern: Flow Cytometry (Gold Standard)
Detects absence of CD55 and CD59 on RBC surface. Much more sensitive and specific.
Treatment
Block the C5 protein of the complement system to prevent RBC destruction.
C5 Blockers (complement inhibitors):
- Eculizumab - IV infusion, first-line C5 blocker for PNH
- Ravulizumab - longer-acting C5 blocker, less frequent dosing
Decision Tree: Macrocytic Anemia Workup
Start with MCV. Click each branch to follow the workup algorithm.
Quiz: Test Your Knowledge
25 board-style vignettes covering macrocytic, normocytic, hemolytic, and PNH. Shuffled each session.