What are the typical presentations of Von Gierke disease?

Clinical Presentation of Von Gierke Disease (Glycogen Storage Disease Type I)

Von Gierke disease (GSD type I) classically presents with hypoglycemia, hepatomegaly, growth retardation, and characteristic biochemical abnormalities including lactic acidosis, hyperlipidemia, and hyperuricemia. 1

Initial Presentation and Key Features

Early Manifestations

• Symptomatic hypoglycemia: Often appears when feeding intervals increase (e.g., when infant starts sleeping through the night)
  • Blood glucose may decrease to <40 mg/dl within 3-4 hours of feeding 1
  • Presents with tremors, seizures, lethargy, and in severe cases, coma
• Hepatomegaly: Massive liver enlargement is a hallmark feature
  • Often noted during routine physical examination by 3-6 months of age
  • Creates protuberant abdomen 1, 2
• Nephromegaly: Kidney enlargement is common and helps distinguish from other GSDs 1
• Distinctive facial features: Round "doll-like" face with full cheeks and cushingoid appearance 1, 3
• Hyperpnea: Due to lactic acidosis, may mimic pneumonia 1

Growth and Development

• Failure to thrive and short stature
• Delayed motor development
• Cognitive development usually normal unless recurrent severe hypoglycemia causes cerebral damage 1

Biochemical Abnormalities

• Hypoglycemia: Severe fasting hypoglycemia is the hallmark feature
• Lactic acidosis: Often pronounced, leading to metabolic acidosis
• Hyperlipidemia: Serum often appears cloudy or milky
  • Very high triglyceride concentrations
  • Increased phospholipids and LDL cholesterol
  • Decreased HDL cholesterol 1
• Hyperuricemia: Due to impaired renal clearance 1, 2
• Elevated free fatty acids: Markedly increased 1
• Mild to moderate elevation of liver enzymes 3

Subtype Differences

• GSD type Ia (80% of cases): Deficiency of glucose-6-phosphatase (G6Pase) 2, 4
• GSD type Ib (20% of cases): Deficiency of glucose-6-phosphate transporter (G6PT) with additional features:
  • Neutropenia and impaired neutrophil function
  • Recurrent bacterial infections
  • Oral and intestinal mucosal ulcerations
  • Inflammatory bowel disease 1, 2

Long-Term Complications

Hepatic Complications

• Development of liver adenomas with increasing age
• Risk of malignant transformation to hepatocellular carcinoma 1, 2

Renal Complications

• Proximal renal tubular dysfunction
• Glomerular hyperfiltration leading to proteinuria
• Progressive renal insufficiency potentially requiring transplantation 1, 2, 5

Hematologic Complications

• Bleeding diathesis due to platelet dysfunction
• Recurrent epistaxis, easy bruising, menorrhagia in females 1
• Anemia, especially in patients with hepatic adenomas 1

Other Complications

• Decreased bone mass, osteoporosis, and fractures 1
• Vitamin D deficiency 1
• Polycystic ovaries in females after 4 years of age 1
• Pulmonary hypertension 1, 6
• Risk of early atherosclerosis and ischemic stroke 1
• Acute pancreatitis in patients with severe hypertriglyceridemia 1

Diagnostic Considerations

The diagnosis is based on:

• Clinical presentation
• Characteristic biochemical abnormalities
• Molecular genetic testing of G6PC (GSD Ia) or SLC37A4 (GSD Ib) genes
• Liver biopsy (becoming less common with advances in genetic testing) 1, 2

Key Pitfalls to Avoid

1. Delayed diagnosis: Hypoglycemia may be mild and go unrecognized until complications develop
2. Misdiagnosis as other liver disorders: Ultrasound findings can be similar to other GSDs and liver storage disorders
3. Overlooking renal involvement: Nephromegaly is a distinguishing feature from other GSDs
4. Failure to recognize GSD Ib: Neutropenia and infections may be the predominant presentation
5. Inadequate monitoring: Long-term complications require vigilant surveillance

Early recognition and appropriate dietary management are crucial to prevent hypoglycemia, improve growth, and minimize long-term complications in patients with Von Gierke disease.