glucose-6-phosphate dehydrogenase deficiency

**Pathophysiology** - G6PD is the rate-limiting enzyme of the hexose monophosphate (pentose phosphate) shunt. It converts glucose-6-phosphate to 6-phosphogluconolactone and generates NADPH. - NADPH keeps glutathione in its reduced form (GSH, via glutathione reductase). GSH detoxifies H2O2 (via glutathione peroxidase). - RBCs have no mitochondria and depend entirely on the HMP shunt for NADPH. With G6PD deficiency, oxidative stress denatures hemoglobin, which precipitates as **Heinz bodies**. Splenic macrophages remove the Heinz bodies, leaving **bite cells** (degmacytes). The result is both extravascular and some intravascular hemolysis.

**Genetics/Epidemiology** - X-linked recessive. Males are mainly affected, and heterozygous females have variable expression because of lyonization. - It is the most common enzymatic disorder of RBCs. - Variants: - **G6PD A- (African type):** Mild. The enzyme is unstable, so older RBCs are affected. Hemolysis is self-limited because young RBCs retain activity. - **G6PD Mediterranean:** More severe, with markedly reduced enzyme activity in all RBCs. It is common in people of Middle Eastern, Mediterranean, and South Asian descent. - Heterozygote advantage: it confers partial protection against *Plasmodium falciparum* malaria, similar to sickle cell trait.

**Triggers (oxidant stressors)** - Infections, which are the most common trigger. - Fava beans (favism, more typical of the Mediterranean variant). - Drugs: primaquine, dapsone, sulfonamides (TMP-SMX), nitrofurantoin, rasburicase, methylene blue, chloroquine/quinidine (variant dependent), and high-dose aspirin. - Naphthalene (mothballs). - Mnemonic: "Hemolysis IS D PAIN": Infection, Sulfa, Dapsone, Primaquine, Aspirin, Isoniazid, Nitrofurantoin.

**Clinical Presentation** - Usually asymptomatic until an oxidant trigger. Hemolysis then begins 1-3 days after exposure. - Acute hemolytic anemia with fatigue, jaundice, dark urine (hemoglobinuria), back pain, and splenomegaly (sometimes). - Neonatal jaundice is also seen, and in severe cases it can lead to kernicterus.

**Labs** - Anemia with elevated LDH, indirect bilirubin, and reticulocyte count. Haptoglobin is decreased. - Peripheral smear: **Heinz bodies** (seen with supravital stain such as crystal violet) and **bite cells**. - Negative Coombs test (non-immune hemolysis). - Diagnosis: quantitative G6PD enzyme assay. **Test after the acute episode (about 2-3 months later).** Testing during hemolysis can give a false-normal result because older, enzyme-deficient RBCs have been destroyed and reticulocytes (with high G6PD) predominate.

**Management** - Avoid triggers and treat the underlying infection. - Supportive care: hydration, and transfusion for severe anemia. - Folate supplementation is sometimes used with chronic hemolysis.

**High-yield comparisons** - Heinz bodies are also seen in alpha-thalassemia (HbH). - Pyruvate kinase deficiency is the other classic RBC enzyme deficiency, but it is autosomal recessive and causes decreased ATP, rigid RBCs, and echinocytes (burr cells). - Hereditary spherocytosis is Coombs negative with spherocytes and increased MCHC, but with no Heinz bodies. - Methemoglobinemia can also be provoked by oxidants, and methylene blue treatment is dangerous in G6PD deficiency. - Chronic granulomatous disease (NADPH oxidase deficiency) is a separate NADPH-related defect. It impairs the phagocyte respiratory burst, not RBC oxidative protection.