A 32-year-old woman with hereditary fructose intolerance (HFI) presents with severe hypoglycaemia and hepatomegaly after consuming fruit juice. Which metabolic intermediate accumulates in HFI and best explains the clinical findings, distinguishing it from galactosaemia?

Explanation

## Hereditary Fructose Intolerance (HFI) vs Galactosaemia: Metabolic Distinction ### Pathophysiology of HFI **Enzyme Defect:** Aldolase B (fructose-1-phosphate aldolase) deficiency **Metabolic Block:** ``` Fructose → [Fructokinase] → Fructose-1-phosphate ⚠ [Aldolase B deficiency] → ACCUMULATION ``` **Consequences of F-1-P Accumulation:** 1. **ATP Depletion** - F-1-P sequestration traps inorganic phosphate (Pi) - ↓ Available Pi for ATP synthesis - Hepatocyte energy crisis → cell death 2. **Inhibition of Gluconeogenesis** - F-1-P inhibits aldolase A (gluconeogenic enzyme) - ↓ Glucose production → severe hypoglycaemia - Fasting hypoglycaemia is **hallmark** of HFI 3. **Hepatotoxicity** - ATP depletion → hepatocyte necrosis - Cirrhosis if fructose exposure continues - Hepatomegaly from fatty infiltration ### Pathophysiology of Galactosaemia **Enzyme Defect:** Galactose-1-phosphate uridyltransferase (GALT) deficiency (classic galactosaemia) **Metabolic Block:** ``` Galactose → [Galactokinase] → Galactose-1-phosphate ⚠ [GALT deficiency] → ACCUMULATION ``` **Consequences of Galactose-1-P Accumulation:** 1. **Cataracts** (infantile onset) - Galactose reduced to galactitol (via aldose reductase) - Galactitol accumulates in lens (osmotically active) - Osmotic swelling → lens opacification 2. **Intellectual Disability** (if untreated) - Galactose-1-P toxic to CNS - Impaired myelination 3. **Hepatomegaly & Cirrhosis** - Similar ATP depletion mechanism as HFI - But **cataracts are pathognomonic** for galactosaemia ### Comparison Table | Feature | HFI | Galactosaemia | |---------|-----|---------------| | **Enzyme defect** | Aldolase B | GALT | | **Accumulating metabolite** | Fructose-1-phosphate | Galactose-1-phosphate | | **Primary clinical sign** | Severe hypoglycaemia (fasting) | Infantile cataracts | | **Hepatic injury** | Cirrhosis (ATP depletion) | Cirrhosis (ATP depletion) | | **Trigger** | Fructose/sucrose ingestion | Lactose (galactose) ingestion | | **Intellectual disability** | Rare | Common (if untreated) | | **Cataracts** | Absent | Present (reversible if early) | **Key Point:** The **accumulating metabolite** is the key discriminator: - **HFI** = Fructose-1-phosphate ↑ → ATP depletion → hypoglycaemia + hepatotoxicity - **Galactosaemia** = Galactose-1-phosphate ↑ → cataracts + intellectual disability (+ hepatotoxicity) **High-Yield:** In NEET PG, HFI is tested as a cause of **fasting hypoglycaemia in infants/children** after introduction of fruits or sucrose. Galactosaemia is tested as a cause of **neonatal cataracts** (classic triad: cataracts, hepatomegaly, intellectual disability). **Clinical Pearl:** A child presenting with **hypoglycaemia + hepatomegaly after fruit juice** → think HFI. A newborn with **cataracts + hepatomegaly** → think galactosaemia. The metabolic intermediate explains both the pathophysiology and the clinical phenotype. **Mnemonic:** **HFI = Hypoglycaemia + Fructose-1-P**; **Galactosaemia = Galactose-1-P + Glaucome (cataracts)**