A 32-year-old man from rural Maharashtra presents with hypopigmented macules on his face and trunk for 6 months. Slit-skin smear shows 4+ acid-fast bacilli. He is started on multidrug therapy (MDT) for lepromatous leprosy. After 2 weeks of treatment with rifampicin, dapsone, and clofazimine, he develops acute hemolytic anemia with jaundice, dark urine, and reticulocytosis of 12%. His baseline G6PD status was not checked. Which antileprotic agent is most likely responsible for this adverse effect?

Explanation

## Diagnosis: Dapsone-Induced Hemolytic Anemia in G6PD Deficiency ### Clinical Context The patient presents with acute hemolytic anemia (jaundice, dark urine, elevated reticulocytosis) occurring early in antileprotic therapy. The temporal relationship to MDT initiation and the hemolytic picture are key. ### Mechanism of Dapsone Toxicity **Key Point:** Dapsone is a sulfone that undergoes N-acetylation and generates reactive metabolites (nitroso compounds and hydroxylamine derivatives) that cause oxidative stress on red blood cells. **High-Yield:** In G6PD-deficient individuals, the pentose phosphate pathway is impaired, reducing NADPH availability. This severely limits the cell's ability to regenerate reduced glutathione (GSH), making RBCs vulnerable to oxidative damage from dapsone metabolites. ### Why Dapsone? | Feature | Dapsone | Rifampicin | Clofazimine | |---------|---------|-----------|-------------| | **Hemolysis risk** | Very high (esp. G6PD deficiency) | Minimal | Minimal | | **Onset** | 1–3 weeks | Rare | Rare | | **Mechanism** | Oxidative stress via metabolites | Enzyme induction | Slow accumulation | | **Severity** | Can be severe/fatal | — | — | **Clinical Pearl:** Dapsone-induced hemolysis is dose-dependent and can occur even in non-G6PD individuals at high doses, but is catastrophic in G6PD deficiency. A baseline G6PD assay before starting dapsone is standard practice in endemic areas (Africa, Mediterranean, Southeast Asia, India). ### Management - Immediate cessation of dapsone - Supportive care: transfusion if Hb < 7 g/dL - Consider alternative: ofloxacin or minocycline as replacement in MDT regimen - G6PD testing and genetic counseling **Mnemonic: DAPSONE HEMOLYSIS = **D**ose-dependent, **A**cetylation-derived metabolites, **P**entose phosphate impairment (G6PD), **S**evere in deficiency, **O**xidative stress, **N**itroso compounds, **E**arly onset** [cite:KD Tripathi 8e Ch 50]