Patient: Miguel Santos, 3-year-old male

Key Salient Features

1. Precipitating Trigger

• Exposure to naphthalene mothballs 2 days prior - a well-known oxidative stressor that triggers hemolysis in G6PD-deficient individuals.

2. Classic Triad of Presentation

3. Hemodynamic Compromise

• HR 148/min (tachycardia), RR 32/min (tachypnea) - signs of compensatory response to severe anemia.
• Soft grade 2/6 systolic flow murmur (high-output state from anemia).
• BP 96/60 mmHg - borderline hypotension, indicating significant cardiovascular stress.

4. CBC Findings - Severe Hemolytic Anemia

• Hb 6.2 g/dL (normal 11.5-13.5) - critically low.
• Reticulocyte count 8.2% (normal 0.5-1.5%) - brisk regenerative response confirming hemolysis, not bone marrow failure.
• MCV 89 fL - normocytic (rules out iron deficiency or thalassemia as primary cause).
• WBC and platelets normal - no pancytopenia (rules out aplastic anemia).

5. Peripheral Smear - Pathognomonic Findings

• Bite cells and blister cells - characteristic of oxidative RBC damage (splenic pitting of Heinz bodies).
• Heinz bodies on supravital stain - denatured hemoglobin precipitates; pathognomonic of G6PD deficiency/oxidative hemolysis.
• Polychromasia - confirms active reticulocytosis.
• No spherocytes - helps distinguish from hereditary spherocytosis.
• No schistocytes - rules out microangiopathic hemolytic anemia (TTP/HUS).

6. Hemolysis Markers

7. The Diagnostic Pitfall - G6PD Assay "Normal" During Crisis

• G6PD assay reads "Normal/borderline" despite the diagnosis being G6PD deficiency.
• Explanation: During an acute episode, reticulocytes and young RBCs (which have higher G6PD activity) dominate the circulation - the most G6PD-deficient older cells have already been destroyed. This creates a falsely normal result.
• Repeat testing 4-8 weeks after the acute episode is needed for a reliable result.

8. Family History - X-linked Inheritance

• Maternal uncle with "yellow eyes" as a baby - consistent with X-linked recessive transmission. Miguel likely inherited the deficient gene from his carrier mother.

9. Splenomegaly (~2 cm)

• Spleen palpable below the left costal margin - reflects active phagocytosis of damaged RBCs (extravascular hemolysis component as well).

10. Renal Function Intact

• Creatinine 0.4 mg/dL (normal) - despite hemoglobinuria, acute kidney injury has not yet developed. This remains a risk requiring monitoring.

Summary Diagnosis

Learning Objectives - Full Explanation

LO 1: Prioritized Differential Diagnosis for Acute Anemia + Jaundice in a Child

Framework: Is the jaundice prehepatic, hepatic, or posthepatic?

• In Miguel's case: elevated indirect bilirubin + normal liver enzymes + cola urine = prehepatic (hemolytic) cause.

Prioritized Differential:

LO 2: Pathophysiology of Oxidative Hemolysis in G6PD Deficiency

Normal RBC Antioxidant Defense:

Glucose → G6P → [G6PD enzyme] → 6-phosphogluconate + NADPH
                                       ↓
                              NADPH → Glutathione reductase
                                       ↓
                   Oxidized Glutathione (GSSG) → Reduced Glutathione (GSH)
                                       ↓
                GSH + Glutathione Peroxidase → neutralizes H₂O₂ → H₂O

What happens in G6PD Deficiency:

1. G6PD enzyme is deficient or unstable → insufficient NADPH produced.
2. Without NADPH, glutathione cannot be regenerated in reduced form (GSH).
3. RBCs become unable to neutralize reactive oxygen species (H₂O₂, superoxides).
4. Oxidative stress (from naphthalene, drugs, infection, fava beans) overwhelms the defense.
5. Hemoglobin is oxidized → denatured Hb precipitates as Heinz bodies (visible on supravital staining with methyl violet).
6. Heinz bodies are "bitten out" by splenic macrophages → bite cells and blister cells on smear.
7. Oxidized RBC membrane becomes rigid → cells are destroyed → intravascular + extravascular hemolysis.

Clinical correlation:

• Hemoglobinuria (cola urine) = free Hb released into plasma and filtered by kidney = intravascular hemolysis.
• Jaundice = unconjugated bilirubin from RBC breakdown.
• Splenomegaly = the spleen removing damaged cells (extravascular component).
• Reticulocytosis (8.2%) = bone marrow compensating by pushing out new RBCs.

LO 3: Interpreting CBC, Peripheral Smear, Hemolysis Markers - Including the G6PD Assay Pitfall

CBC Interpretation:

Peripheral Smear Findings:

Hemolysis Markers:

The G6PD Assay Pitfall - Exam Favorite!

• G6PD deficiency affects older RBCs most - their enzyme half-life is much shorter (GdA- variant: half-life only 13 days vs. 60 days for normal G6PD).
• During an acute hemolytic crisis, the oldest, most G6PD-deficient cells are preferentially destroyed first.
• What remains in circulation are the young reticulocytes and newly released RBCs, which still have near-normal G6PD activity.
• Reticulocytes have significantly higher G6PD activity than mature RBCs.
• Result: the assay is measuring cells with relatively higher enzyme levels → false normal reading.

LO 4: Distinguishing G6PD Deficiency from AIHA, Hereditary Spherocytosis, and Thalassemia

Targeted Comparison Table:

• Positive DAT = AIHA
• Negative DAT with spherocytes = Hereditary Spherocytosis
• Negative DAT with bite cells/Heinz bodies + oxidant trigger = G6PD deficiency

LO 5: Acute Management Plan + Prevention in the Philippine Setting

Acute Management:

• Remove the naphthalene/mothballs from the environment.
• Avoid any further oxidant exposure (see trigger list below).

• IV access, cardiac monitoring (HR 148, compensated but at risk).
• Supplemental O₂ if SpO₂ drops.
• IV fluids to maintain renal perfusion and flush free hemoglobin from tubules (preventing acute kidney injury from hemoglobinuria).
• Monitor urine output closely - hemoglobinuria can cause acute tubular necrosis.

• Hb of 6.2 g/dL with tachycardia, tachypnea, and flow murmur = transfusion indicated.
• Most G6PD-deficient episodes are self-limiting once the trigger is removed; however, severe acute anemia requires packed RBC transfusion.
• Target Hb >8-10 g/dL in symptomatic child.

• Serial Hb, reticulocyte count.
• Creatinine monitoring (AKI risk from hemoglobinuria).
• The hemolytic episode in G6PD A- variant is typically self-limiting because only the older RBCs are maximally deficient; once those are destroyed, the remaining young cells have enough enzyme to withstand oxidant stress.

• Repeat G6PD assay 4-8 weeks after the acute episode.
• Genetic counseling referral.

Prevention Strategies:

• The Philippines includes G6PD deficiency in its Expanded Newborn Screening Program (Republic Act 9288), which screens for G6PD along with other metabolic conditions.
• Miguel's mother recalls screening was done but lost the card - this is the real-world challenge.
• In Southeast Asia, the prevalent variant is G6PD Viangchan (Class II - severe); in the Philippines, G6PD Mahidol and G6PD Union are also found. These variants have very low enzyme activity (as low as 0-10% of normal), making clinical disease more severe than the milder G6PD A- variant seen in African populations.
• Early detection through NBS allows trigger avoidance from infancy, preventing hemolytic crises.

• G6PD is X-linked recessive - the gene is on the X chromosome (Xq28).
• Miguel is an affected male - he has only one X chromosome carrying the deficient gene (hemizygous).
• His mother is an obligate carrier (her brother also had jaundice as a baby).
• Counseling points:
  • All sons of a carrier mother have a 50% chance of being affected.
  • All daughters of a carrier mother have a 50% chance of being carriers.
  • Daughters can be symptomatic if homozygous or if X-inactivation (lyonization) is unfavorable.
  • Fathers with G6PD deficiency will pass the gene to all daughters (who become carriers) but none of their sons (since sons receive the Y chromosome from dad).
• Screen siblings, especially male siblings.

Summary Map

TRIGGER (Naphthalene)
       ↓
G6PD Deficiency → ↓NADPH → ↓GSH → Cannot neutralize oxidative stress
       ↓
Hb oxidized → Heinz bodies → Bite/blister cells
       ↓
Intravascular hemolysis → Hemoglobinuria (cola urine)
Extravascular hemolysis → ↑Indirect bilirubin (jaundice)
       ↓
Hb 6.2, Reticulocytes 8.2%, LDH↑, Haptoglobin↓, DAT negative
       ↓
G6PD assay falsely NORMAL (reticulocytes dominate) → Repeat in 4-8 weeks
       ↓
Management: Remove trigger, IV fluids, pRBC transfusion, monitor kidneys
Prevention: Trigger avoidance, NBS, genetic counseling