Von Gierke Disease (Glycogen Storage Disease Type I)

1. Introduction / Definition

2. Biochemical Background: Normal Role of Glucose-6-Phosphatase

• During fasting, the liver breaks down stored glycogen (glycogenolysis) and synthesizes new glucose (gluconeogenesis)
• Both pathways produce glucose-6-phosphate (G6P)
• G6Pase hydrolyzes G6P → free glucose + inorganic phosphate
• Free glucose is then released into the bloodstream via GLUT2

3. Subtypes

4. Pathogenesis

1. G6P accumulates in the cytoplasm
2. Excess G6P is shunted into glycolysis → increased lactate → lactic acidosis
3. G6P is also shunted into the pentose phosphate pathway → increased ribose-5-phosphate → increased PRPP → purine overproduction → hyperuricemia
4. Excess glucose-6-phosphate promotes glycogen synthesis → massive hepatic and renal glycogen accumulation
5. Increased fat synthesis and decreased lipolysis → hyperlipidemia (hypertriglyceridemia, elevated LDL)
6. Hypoglycemia occurs because neither glycogenolysis nor gluconeogenesis can release free glucose from G6P

5. Clinical Features

A. Infancy / Early Childhood

• Hepatomegaly - marked enlargement of the liver (glycogen and lipid accumulation)
• Renomegaly (kidney enlargement)
• Hypoglycemic seizures - fasting for as little as 3-4 hours triggers severe hypoglycemia
• Failure to thrive, stunted growth / short stature
• Doll-like facies with round (fat) cheeks
• Protuberant abdomen due to massive hepatomegaly

B. Metabolic Abnormalities

C. Additional Features in GSD-Ib

• Chronic neutropenia and functional neutrophil/monocyte deficiencies
• Recurrent bacterial infections
• Ulceration of the oral and intestinal mucosae

D. Adult Complications (Untreated)

• Gout (hyperuricemia)
• Hepatic adenomas - benign liver tumors that may rarely undergo malignant transformation to hepatocellular carcinoma (HCC)
• Renal disease - focal segmental glomerulosclerosis, tubulointerstitial atrophy, proteinuria
• Renal Fanconi syndrome - aminoaciduria, phosphaturia, low-molecular-weight proteinuria, bicarbonaturia
• Nephrocalcinosis / calcium kidney stones
• Osteoporosis
• Pulmonary hypertension (rare)

6. Diagnosis

Laboratory Findings

• Fasting hypoglycemia (blood glucose < 40 mg/dL)
• Elevated lactate (lactic acidemia)
• Elevated uric acid (hyperuricemia)
• Elevated triglycerides and cholesterol
• Normal or low insulin levels

Glucagon Stimulation Test

• Glucagon injection normally raises blood glucose by mobilizing liver glycogen
• In Von Gierke disease: flat or paradoxical response (blood glucose rise < 4 mmol/L), because G6P cannot be converted to free glucose

Liver Biopsy (Histology)

• Marked hepatomegaly with glycogen-laden hepatocytes (PAS positive, diastase sensitive)
• Intranuclear glycogen
• Large lipid vacuoles (steatosis)
• Mild or no fibrosis

Molecular / Genetic Testing

• DNA testing for mutations in G6PC (GSD-Ia) or SLC37A4 (GSD-Ib) - this is now the preferred confirmatory test
• Enzyme activity assay on fresh liver biopsy

7. Treatment

Dietary Management

• Frequent feedings (every 3-4 hours) to prevent fasting hypoglycemia
• Uncooked cornstarch (raw cornstarch): slowly digested, releases glucose gradually - a single dose (1.75-2.5 g/kg) at bedtime can maintain serum glucose above 3.9 mmol/L for 7+ hours
• Nasogastric continuous glucose infusion at night (especially in infants)
• Low-fructose, low-galactose diet (these sugars cannot bypass the G6Pase block and worsen lactic acidosis)

Pharmacological Treatment

• Allopurinol - to reduce hyperuricemia and gout
• Lipid-lowering agents - for hyperlipidemia
• Citrate supplementation - to correct acidosis and reduce kidney stone risk
• ACE inhibitors - for renal protection in patients with proteinuria
• G-CSF (granulocyte colony-stimulating factor) - in GSD-Ib to correct neutropenia

Surgical / Organ Replacement

• Liver transplantation - corrects hepatic enzyme deficiency and hypoglycemia; does not fully correct renal disease
• Kidney transplantation - performed for renal failure but does not correct the hypoglycemia

Monitoring Goals (European Study on GSD-I Guidelines)

• Preprandial blood glucose > 3.5-4.0 mmol/L (60-70 mg/dL)
• Serum uric acid in high-normal range
• Venous bicarbonate > 20 mmol/L
• Serum triglycerides < 6.0 mmol/L
• BMI within 2 SD of normal

8. Prognosis

• Life expectancy has improved considerably with treatment
• Untreated patients have severe metabolic derangements, growth failure, and early death
• Treated patients often develop late complications such as hepatic adenomas, renal disease, gout, and osteoporosis
• Adenomas require surveillance due to rare risk of HCC

9. Summary Table

1. Von Gierke = G6Pase deficiency = GSD Type I
2. The "LHHU" mnemonic for metabolic features: Lactic acidosis, Hypoglycemia, Hyperuricemia, Hyperlipidemia (Uricemia)
3. Glucagon test shows a flat response (pathognomonic)
4. Treatment cornerstone = uncooked cornstarch + frequent feeds
5. Hyperuricemia mechanism = increased PRPP via pentose phosphate pathway + lactic acid competing with urate at renal tubules