In glucose-6-phosphatase deficiency (Von Gierke's disease/GSD Type 1), which metabolic pathways are SECONDARILY affected, and what clinical features result?

• A HMP shunt is blocked, causing hemolytic anemia; no lactic acidosis occurs
• B G6P accumulates, increasing glycogen synthesis and HMP shunt flux, causing hyperuricemia, hyperlipidemia, and lactic acidosis ✓
• C Glucose-6-phosphate accumulates, shunting into glycolysis (lactic acidosis), HMP shunt (excess ribose), glycogen synthesis (hepatomegaly), and pentosuria
• D Only glycogenolysis is impaired; gluconeogenesis remains intact providing adequate glucose

Explanation

G6P cannot be dephosphorylated to free glucose (for export/release), so it accumulates. Consequences: (1) excess glycogen synthesis → hepatomegaly, renomegaly; (2) increased glycolysis via PFK → lactic acidosis; (3) increased HMP shunt → excess ribose-5-phosphate → increased purine synthesis → hyperuricemia; (4) increased acetyl-CoA from pyruvate → increased fatty acid/VLDL synthesis → hyperlipidemia (hypertriglyceridemia). Clinical: hypoglycemia (cannot mobilize glucose), lactic acidosis, hyperuricemia (gout), hyperlipidemia, growth retardation.

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

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