Von Gierke's Disease

1. DEFINITION AND CLASSIFICATION

• Definition: Autosomal recessive disorder of carbohydrate metabolism caused by defects in the glucose-6-phosphatase (G6Pase) system, leading to impaired glycogenolysis and gluconeogenesis.
• Classification:
  • Type Ia: Deficiency of the catalytic subunit of glucose-6-phosphatase-α (G6PC). Accounts for ~80% of cases.
  • Type Ib: Deficiency of the glucose-6-phosphate translocase (G6PT), affecting transport of G6P into the ER. Caused by SLC37A4 mutations.
• Affected Tissues: Liver, kidney, and intestinal mucosa.

2. ETIOLOGY AND GENETICS

• Inheritance: Autosomal Recessive.
• Gene Loci:
  • GSD Ia: G6PC gene on chromosome 17q21.
  • GSD Ib: SLC37A4 gene on chromosome 11q23.
• Pathophysiology:
  • Primary Defect: Inability to convert Glucose-6-Phosphate (G6P) to Glucose.
  • Metabolic Consequences:
    • Hypoglycemia: Failure of hepatic glucose output during fasting (blockade of both glycogenolysis and gluconeogenesis).
    • Lactic Acidosis: Accumulated G6P is shunted into glycolysis.
    • Hyperuricemia: G6P shunted to Pentose Phosphate Pathway → increased purine synthesis/degradation + decreased renal clearance of urate due to lactate competition.
    • Hyperlipidemia: G6P enters glycolysis → increased Acetyl CoA → increased lipogenesis (triglycerides/cholesterol).

3. CLINICAL FEATURES

• Presentation: Typically presents at 3–6 months of age (when feeding intervals increase or weaning occurs). rarely neonatal hypoglycemia.
• General Appearance:
  • "Doll-like" facies: Fat cheeks, round face.
  • Short stature/growth retardation.
  • Thin extremities with truncal obesity.
  • Protuberant abdomen (massive hepatomegaly).
• Hepatic:
  • Massive hepatomegaly (universal).
  • NO Splenomegaly (Important distinguishing feature from GSD types III, IV, VI, IX).
• Renal: Bilateral renomegaly (nephromegaly) due to glycogen storage.
• GSD Type Ib Specific Features:
  • Neutropenia: Cyclical or chronic; often associated with neutrophil dysfunction.
  • Recurrent Infections: Otitis media, skin abscesses, pneumonia.
  • Inflammatory Bowel Disease (IBD): Crohn-like enterocolitis (bloody diarrhea, failure to thrive).

4. BIOCHEMICAL INVESTIGATIONS

• Hypoglycemia: Severe, fasting (often <50 mg/dL).
• Lactic Acidosis: High anion gap metabolic acidosis; lactate levels rise significantly during fasting.
• Hyperlipidemia:
  • Massive hypertriglyceridemia (plasma may appear "milky" or lipemic).
  • Elevated cholesterol (VLDL, LDL).
• Hyperuricemia: Present even in young children.
• Liver Function Tests:
  • Transaminases (AST/ALT): Usually normal or mildly elevated (unlike GSD III/IV where they are significantly high).
  • Glucagon Stimulation Test: Administration of glucagon results in NO rise in glucose but a marked rise in lactate. (Historical utility; rarely done now).

5. DIAGNOSIS

• Gold Standard: Molecular Genetic Testing (Multigene panel or single-gene sequencing for G6PC and SLC37A4).
• Liver Biopsy (Historical):
  • Histology: Distended hepatocytes with glycogen and fat (steatosis). No fibrosis (unlike GSD III/IV).
  • Enzyme Assay: Absent G6Pase activity. Not routine anymore.
• Imaging: Ultrasound shows massive hepatomegaly (uniform echogenicity) and renomegaly.

6. LONG-TERM COMPLICATIONS

• Hepatic:
  • Hepatic Adenomas: Develop in 2nd/3rd decade. Risk of hemorrhage.
  • Hepatocellular Carcinoma (HCC): Risk of malignant transformation of adenomas.
• Renal:
  • Hyperfiltration (early) → Microalbuminuria → Proteinuria.
  • Focal Segmental Glomerulosclerosis (FSGS) → Renal failure.
  • Nephrocalcinosis and renal stones (due to hypercalciuria/hypocitraturia).
• Metabolic/Other:
  • Gout: Due to chronic hyperuricemia.
  • Pancreatitis: Secondary to severe hypertriglyceridemia.
  • Osteopenia/Osteoporosis: Low bone mineral density; increased fracture risk.
  • Polycystic Ovaries: Common in females; fertility usually preserved.
  • Pulmonary Hypertension: Rare late complication.

7. MANAGEMENT

Goal: Maintain normoglycemia (Blood glucose >70 mg/dL) to suppress metabolic derangements.

A. Dietary Management

• Infants: Continuous nocturnal nasogastric (NG) drip feeding (glucose polymer or sucrose-free formula). Frequent daytime feeds (q 2-3 hours).
• Children/Adults (Uncooked Cornstarch - UCCS):
  • Acts as a slow-release glucose source.
  • Dose: 1.6 to 2.5 g/kg body weight every 4–6 hours.
  • Modified Starch: Glycosade (waxy maize starch) allows longer fasting (overnight) in older children/adults.
• Restrictions:
  • Avoid Fructose (fruit/juice) and Galactose (dairy/lactose) as they cannot be converted to glucose and worsen lactate accumulation.
  • Avoid Sucrose.

B. Pharmacotherapy

• Hyperuricemia: Allopurinol (Xanthine oxidase inhibitor).
• Hyperlipidemia: Statins (HMG-CoA reductase inhibitors) or Fibrates (for triglycerides).
• Renal Protection: ACE inhibitors (Enalapril/Lisinopril) for microalbuminuria/proteinuria. Citrate supplementation for nephrocalcinosis prevention.
• GSD Ib Specific:
  • G-CSF (Filgrastim): To treat neutropenia and prevent infections.
  • Empagliflozin (SGLT2 inhibitor): Emerging therapy for neutropenia/neutrophil dysfunction in GSD Ib (removes toxic metabolites like 1,5-anhydroglucitol).
  • Vitamin E: Antioxidant support for neutrophil function.

C. Surgical Management

• Liver Transplantation:
  • Curative for metabolic defects (corrects hypoglycemia).
  • Indicated for multiple adenomas, HCC, or poor metabolic control.
  • Does not reverse renal disease.
• Kidney Transplantation: For end-stage renal disease.

8. PROGNOSIS

• Survival has improved dramatically with dietary management.
• Major morbidity arises from long-term complications (renal failure, hepatic adenomas).
• Normal adult height and puberty are achievable with strict metabolic control.