# Clinical Cases: Megaloblastic and Hemolytic Anemias

## Case 1: Pernicious Anemia with Neurologic Manifestations

### Patient Presentation
**Demographics:** 68-year-old female

**Chief Complaint:** Progressive fatigue, numbness in feet, and unsteady gait for 6 months

**History of Present Illness:**
The patient reports gradually worsening fatigue and shortness of breath. Over the past 4 months, she has developed numbness and tingling in both feet that has progressed to involve her lower legs. She has noticed difficulty with balance and has fallen twice. Family members report she has become more forgetful. She has a history of vitiligo and hypothyroidism. She follows a regular diet including meat and dairy products.

**Physical Examination:**
- Vital signs: BP 118/72, HR 88, RR 18, Temp 36.8C
- General: Pale, elderly woman with mild lemon-yellow skin tinge
- HEENT: Scleral icterus, smooth beefy-red tongue (glossitis)
- Cardiac: II/VI systolic flow murmur
- Neurologic:
  - Decreased vibration sense at ankles bilaterally
  - Decreased proprioception in toes
  - Positive Romberg sign
  - Broad-based gait with positive heel-to-toe difficulty
  - Deep tendon reflexes: 3+ at knees (brisk)
  - Babinski sign positive bilaterally

### Workup and Results

**Complete Blood Count:**
- WBC: 4,200/uL (low normal)
- Hemoglobin: 7.8 g/dL (severely low)
- MCV: 118 fL (markedly elevated)
- MCH: 38 pg (elevated)
- Platelets: 125,000/uL (low)
- Reticulocyte count: 0.5% (inappropriately low)

**Peripheral Blood Smear:**
- Macro-ovalocytes
- Hypersegmented neutrophils (6+ lobes seen)
- Anisocytosis and poikilocytosis
- Occasional nucleated red blood cells

**Additional Labs:**
- LDH: 1,850 U/L (markedly elevated)
- Indirect bilirubin: 2.4 mg/dL (elevated)
- Haptoglobin: 45 mg/dL (low normal)
- Vitamin B12: 82 pg/mL (severely low, normal 200-900)
- Folate: 15 ng/mL (normal)
- Methylmalonic acid (MMA): 3,200 nmol/L (markedly elevated)
- Homocysteine: 48 umol/L (elevated)

**Immunologic Testing:**
- Anti-intrinsic factor antibodies: Positive
- Anti-parietal cell antibodies: Positive

### Clinical Image

![Megaloblastic Anemia - Hypersegmented Neutrophil](case_01_image.jpg)

*Peripheral blood smear findings in megaloblastic anemia showing characteristic macro-ovalocytes and hypersegmented neutrophils with nuclear-cytoplasmic asynchrony.*

### Diagnosis
**Pernicious Anemia with Subacute Combined Degeneration of the Spinal Cord**

Diagnostic criteria met:
- Macrocytic anemia with MCV > 100 fL
- Low vitamin B12 with elevated MMA (confirms tissue deficiency)
- Positive anti-intrinsic factor antibodies (highly specific for pernicious anemia)
- Neurologic findings of posterior and lateral column involvement
- Associated autoimmune conditions (vitiligo, hypothyroidism)

### Treatment Plan
1. **Urgent B12 replacement:**
   - Cyanocobalamin 1000 mcg IM daily x 7 days
   - Then weekly x 4 weeks
   - Then monthly maintenance indefinitely

2. **Monitoring during treatment:**
   - Watch for hypokalemia (potassium shifts into new RBCs)
   - Reticulocyte count should peak at days 5-7
   - Hemoglobin rises within 1-2 weeks

3. **Long-term care:**
   - Lifelong B12 replacement (cannot be cured)
   - Upper endoscopy to screen for gastric carcinoma/carcinoid
   - Monitor neurologic symptoms (may take 6+ months to improve, may be irreversible)

### Teaching Points
1. B12 deficiency causes neurologic damage that folate deficiency does not
2. Subacute combined degeneration affects posterior columns (vibration, proprioception) and lateral columns (upper motor neuron signs)
3. Neurologic manifestations can occur without significant anemia
4. Elevated MMA distinguishes B12 deficiency from folate deficiency (both elevate homocysteine)
5. Anti-intrinsic factor antibodies are highly specific (but not sensitive) for pernicious anemia
6. The elevated LDH reflects ineffective erythropoiesis with intramedullary hemolysis
7. Treatment must begin promptly to prevent irreversible neurologic damage

---

## Case 2: Warm Autoimmune Hemolytic Anemia

### Patient Presentation
**Demographics:** 42-year-old female

**Chief Complaint:** Sudden onset of fatigue, jaundice, and dark urine for 5 days

**History of Present Illness:**
The patient was in her usual state of health until 1 week ago when she developed an upper respiratory infection. She then noticed progressive fatigue, yellowing of her eyes, and dark "cola-colored" urine. She denies any new medications, recent travel, or family history of anemia or jaundice.

**Physical Examination:**
- Vital signs: BP 110/65, HR 108, RR 20, Temp 37.4C
- General: Pale, icteric woman in mild distress
- HEENT: Scleral icterus, conjunctival pallor
- Cardiac: Tachycardic, III/VI systolic flow murmur
- Abdomen: Splenomegaly (3 cm below costal margin), no hepatomegaly
- Skin: Jaundice, no petechiae or rashes

### Workup and Results

**Complete Blood Count:**
- WBC: 12,400/uL (elevated)
- Hemoglobin: 6.8 g/dL (severely low, was 13.2 g/dL 6 months ago)
- MCV: 105 fL (elevated due to reticulocytosis)
- Platelets: 235,000/uL (normal)
- Reticulocyte count: 14% (markedly elevated)
- Absolute reticulocyte count: 420,000/uL

**Hemolysis Labs:**
- LDH: 680 U/L (elevated)
- Total bilirubin: 5.2 mg/dL (elevated)
- Indirect bilirubin: 4.6 mg/dL (elevated)
- Haptoglobin: < 10 mg/dL (undetectable)
- Urinalysis: Urobilinogen elevated, no hemoglobinuria

**Peripheral Blood Smear:**
- Polychromasia (reticulocytes)
- Spherocytes present
- No schistocytes or sickle cells
- Nucleated RBCs present

**Direct Antiglobulin Test (Coombs):**
- DAT: Positive
- Monospecific: IgG positive, C3 negative

**ANA:** Weakly positive (1:80)

### Diagnosis
**Warm Autoimmune Hemolytic Anemia (AIHA)**

Key diagnostic features:
- Evidence of hemolysis: elevated LDH, indirect bilirubin, undetectable haptoglobin
- Elevated reticulocyte count (appropriate marrow response)
- Positive DAT with IgG (characteristic of warm AIHA)
- Spherocytes on smear (from partial phagocytosis)
- Extravascular hemolysis pattern (splenomegaly, no hemoglobinuria)

### Treatment Plan
1. **First-line therapy:**
   - Prednisone 1 mg/kg/day (60-80 mg daily)
   - Folic acid 1 mg daily
   - Monitor hemoglobin every 2-3 days initially

2. **Transfusion if needed:**
   - Transfuse for symptomatic anemia or hemoglobin < 7 g/dL with symptoms
   - Blood may be "least incompatible" - transfuse anyway if clinically needed

3. **If steroid-refractory (no response by 3 weeks):**
   - Rituximab (anti-CD20)
   - Consider splenectomy for refractory cases

4. **Workup for secondary causes:**
   - Evaluate for underlying lymphoproliferative disorder
   - Complete autoimmune workup (lupus panel)

### Teaching Points
1. Warm AIHA involves IgG antibodies that opsonize RBCs for splenic destruction
2. The DAT (direct Coombs test) is positive for IgG +/- C3
3. Spherocytes form when splenic macrophages remove portions of antibody-coated membrane
4. The MCV may be elevated due to reticulocytosis (reticulocytes are larger than mature RBCs)
5. Undetectable haptoglobin is the most sensitive marker for hemolysis
6. Always look for underlying causes: lymphoma, CLL, lupus, drugs
7. Transfusion should not be withheld for life-threatening anemia despite difficulty crossmatching

---

## Case 3: Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency

### Patient Presentation
**Demographics:** 25-year-old African American male

**Chief Complaint:** Sudden onset of fatigue, dark urine, and yellowing eyes for 2 days

**History of Present Illness:**
The patient was recently diagnosed with a urinary tract infection and started on trimethoprim-sulfamethoxazole 5 days ago. Two days ago, he noticed sudden fatigue, back pain, and passage of very dark urine. He has never had similar episodes. His family history is notable for a brother who had a "blood problem" after taking an antimalarial medication.

**Physical Examination:**
- Vital signs: BP 105/60, HR 115, RR 22, Temp 37.8C
- General: Pale, icteric, ill-appearing young man
- HEENT: Scleral icterus, conjunctival pallor
- Cardiac: Tachycardic, flow murmur
- Abdomen: Mild splenomegaly
- Skin: Jaundice

### Workup and Results

**Complete Blood Count:**
- Hemoglobin: 7.2 g/dL (was 14.5 g/dL baseline)
- MCV: 95 fL (normal)
- Reticulocyte count: 8% (elevated)
- WBC: 14,200/uL (elevated)

**Hemolysis Labs:**
- LDH: 1,250 U/L (markedly elevated)
- Total bilirubin: 6.8 mg/dL
- Indirect bilirubin: 6.1 mg/dL
- Haptoglobin: < 10 mg/dL (undetectable)
- Urinalysis: Hemoglobinuria present (intravascular hemolysis)

**Peripheral Blood Smear:**
- Bite cells (degmacytes)
- Blister cells
- Polychromasia
- Heinz bodies seen on supravital staining

**Direct Antiglobulin Test:** Negative

**G6PD Level:** 2.1 U/g Hb (low, normal 4.6-13.5)
*Note: May be falsely normal during acute episode due to young RBC predominance*

### Diagnosis
**G6PD Deficiency with Acute Hemolytic Crisis (Drug-Induced)**

Key diagnostic features:
- Acute intravascular hemolysis following oxidant drug exposure
- Bite cells and Heinz bodies characteristic of oxidant damage
- Negative DAT excludes immune hemolysis
- G6PD level low (confirm 2-3 months after acute episode)
- X-linked inheritance pattern suggested by family history

### Treatment Plan
1. **Immediate management:**
   - Stop the offending drug (TMP-SMX)
   - IV fluid hydration to maintain urine output and prevent AKI
   - Transfusion if symptomatic or hemoglobin critically low
   - Alternative antibiotic for UTI (nitrofurantoin is also contraindicated)

2. **Prevention:**
   - Provide patient with list of drugs and foods to avoid
   - Avoid: sulfonamides, dapsone, primaquine, nitrofurantoin, fava beans
   - Consider medical alert bracelet

3. **Follow-up:**
   - Repeat G6PD level 2-3 months after acute episode
   - Genetic counseling for X-linked inheritance
   - Screen family members at risk

### Teaching Points
1. G6PD deficiency is the most common enzyme deficiency worldwide (X-linked)
2. G6PD is needed to maintain glutathione in reduced form to protect against oxidant damage
3. Oxidant stress (drugs, infection, fava beans) triggers acute hemolysis
4. Bite cells form when Heinz bodies are "pitted out" by splenic macrophages
5. G6PD level may be falsely normal during acute crisis (reticulocytes have higher G6PD)
6. Repeat testing 2-3 months later when RBC population normalizes
7. Hemolysis is self-limited as older, more deficient cells are destroyed first