A 28-year-old woman of South Indian origin presents with jaundice, dark urine, and fatigue for 3 days. She reports a recent upper respiratory tract infection treated with cotrimoxazole. On examination, she is icteric with splenomegaly. Laboratory findings show: Hb 7.2 g/dL, reticulocyte count 12%, total bilirubin 4.8 mg/dL (indirect 4.2 mg/dL), LDH 680 IU/L, haptoglobin <10 mg/dL. Peripheral blood smear shows spherocytes and polychromasia. Direct antiglobulin test (DAT) is negative. What is the most likely diagnosis?

Explanation

## Clinical Presentation & Diagnosis This patient has acute hemolysis triggered by an oxidative stress (cotrimoxazole exposure) in a genetically predisposed individual. ### Key Diagnostic Features **High-Yield:** The combination of: - Acute hemolysis following a **drug trigger** (cotrimoxazole is a classic G6PD precipitant) - **Negative DAT** (rules out immune-mediated hemolysis) - **Spherocytes on smear** (seen in both hereditary spherocytosis AND G6PD crises due to oxidative membrane damage) - **South Indian ethnicity** (G6PD deficiency is endemic in Mediterranean, African, and Asian populations including South India) - **Female patient** (G6PD is X-linked; females are typically heterozygous carriers and usually asymptomatic, but can manifest disease if homozygous or if extreme X-inactivation skewing results in predominantly G6PD-deficient red cells) ### Why G6PD Deficiency Fits Best 1. **Drug-induced trigger:** Cotrimoxazole (a sulfonamide-trimethoprim combination) is a well-known oxidative stressor that precipitates hemolysis in G6PD-deficient individuals by generating reactive oxygen species that overwhelm the pentose phosphate pathway. 2. **Negative DAT:** Definitively excludes autoimmune hemolytic anemia; G6PD hemolysis is entirely non-immune in mechanism. 3. **Acute presentation:** G6PD crises are typically acute and self-limited, resolving in 7–10 days as older RBCs (with lower residual enzyme activity) are selectively destroyed and replaced by younger reticulocytes (with higher G6PD activity). 4. **Spherocytes:** Oxidative damage to the RBC membrane causes cross-linking of spectrin and loss of membrane surface area, producing spherocytes and bite cells (keratocytes) on smear. **Clinical Pearl:** **Osmotic fragility** is characteristically abnormal (increased) at baseline in **hereditary spherocytosis** but is typically **normal in acute G6PD crisis**; the two should not be conflated. Definitive diagnosis of G6PD deficiency requires a **G6PD enzyme assay**, which should ideally be performed **after the acute episode resolves** — during active hemolysis, the preferential destruction of older, enzyme-depleted cells and the surge of young reticulocytes (which have higher G6PD levels) can produce a falsely normal result. *(KD Tripathi, Essentials of Medical Pharmacology; Williams Hematology)* ### Differential Reasoning | Feature | G6PD Deficiency | Hereditary Spherocytosis | Autoimmune HA | MAHA | |---------|-----------------|--------------------------|---------------|------| | DAT | Negative | Negative | **Positive** | Negative | | Drug/oxidant trigger | **Yes** | No | No | No | | Osmotic fragility | Normal (baseline) | **Abnormal (baseline)** | Normal | Normal | | Schistocytes | No | No | No | **Yes** | | Family history | X-linked recessive | Autosomal dominant | No | Underlying disease | **Key Point:** A **negative DAT with acute hemolysis** narrows the differential to non-immune causes (G6PD, hereditary spherocytosis, MAHA, or other enzyme defects). The **drug/oxidant trigger** and **South Indian ethnic background** make G6PD deficiency the most likely diagnosis here, with hereditary spherocytosis less likely given the absence of a lifelong history and the clear precipitant.