A 4-month-old infant presents with severe fasting hypoglycemia, hepatomegaly, and lactic acidosis. Biochemical analysis reveals elevated pyruvate and lactate levels. A genetic defect in the enzyme marked **D** in the gluconeogenesis pathway diagram is suspected. Which of the following best explains why this infant cannot maintain blood glucose during fasting, despite intact upstream gluconeogenic enzymes?

Explanation

## Why Glucose-6-phosphatase deficiency is right The enzyme marked **D** (glucose-6-phosphatase) catalyzes the FINAL and rate-limiting step of gluconeogenesis and glycogenolysis — the dephosphorylation of glucose-6-phosphate to free glucose. This enzyme is located in the endoplasmic reticulum membrane and is expressed ONLY in liver and kidney. When deficient (Von Gierke disease / GSD type Ia), glucose-6-phosphate accumulates in hepatocytes but cannot be released into the bloodstream as free glucose, resulting in severe fasting hypoglycemia from infancy. The accumulated glucose-6-phosphate is shunted into alternative pathways: glycogen synthesis (causing hepatomegaly), glycolysis (producing lactate and causing lactic acidosis), and the pentose phosphate pathway (producing NADPH for fatty acid synthesis, causing hyperlipidemia). This is the classic presentation described in Harper 32e Ch 20 and Robbins 10e Ch 6. ## Why each distractor is wrong - **Pyruvate carboxylase deficiency**: This would block the FIRST committed step of gluconeogenesis (pyruvate → oxaloacetate). However, pyruvate carboxylase deficiency is rare and causes a different clinical picture (neurological symptoms, normal or low lactate). The clinical vignette here — severe hypoglycemia with elevated lactate and hepatomegaly — is pathognomonic for glucose-6-phosphatase deficiency. - **PEPCK deficiency**: This would block the second step (oxaloacetate → phosphoenolpyruvate). While this would impair gluconeogenesis, PEPCK deficiency is extremely rare and does not cause the classic Von Gierke presentation. Moreover, the question specifically anchors on enzyme **D**, not enzyme **B**. - **Fructose-1,6-bisphosphatase deficiency**: This blocks the third step of gluconeogenesis. While deficiency causes fasting hypoglycemia and lactic acidosis, it does NOT cause hepatomegaly or the characteristic glycogen accumulation seen in Von Gierke disease, because the block occurs earlier in the pathway. **High-Yield:** Glucose-6-phosphatase is the ONLY enzyme that releases free glucose from liver and kidney — muscle lacks it, so muscle glycogen cannot contribute to blood glucose. Deficiency = Von Gierke disease = severe fasting hypoglycemia + hepatomegaly + lactic acidosis + hyperuricemia. [cite: Harper 32e Ch 20; Robbins 10e Ch 6]