A 3-month-old infant presents with hepatomegaly, hypoglycemia, and elevated blood lactate after fasting. Liver biopsy shows glycogen accumulation. Enzyme activity assay reveals deficiency of glucose-6-phosphatase. Which biochemical consequence directly explains the fasting hypoglycemia in this condition?

• A Impaired glycogenolysis due to blocked phosphorylase activation
• B Defective gluconeogenesis owing to absent phosphoenolpyruvate carboxykinase
• C Inability to release free glucose from glucose-6-phosphate into the circulation ✓
• D Excess insulin secretion triggered by high hepatic glucose-6-phosphate

Explanation

Glucose-6-phosphatase deficiency (GSD type Ia, von Gierke disease) prevents the terminal dephosphorylation of glucose-6-phosphate to free glucose in the liver. Both glycogenolysis and gluconeogenesis are intact but produce glucose-6-phosphate, which cannot be converted to glucose for export, causing severe fasting hypoglycemia. The accumulated glucose-6-phosphate is shunted into glycolysis generating excess lactate (lactic acidosis) and into the HMP shunt. Insulin excess is not the mechanism; rather, hypoglycemia suppresses insulin.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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