What is the appropriate management for a 12-year-old patient presenting with morning hypoglycemia, elevated liver enzymes, normal Hemoglobin A1c (HbA1c), normal C-peptide, hyperuricemia, and hyperlipidemia?

Glycogen Storage Disease Type I (GSD-I) Management

This clinical presentation is highly consistent with Glycogen Storage Disease Type I (GSD-I), and management should focus on preventing hypoglycemia through frequent feedings with complex carbohydrates, cornstarch supplementation, and avoidance of fasting, with referral to a metabolic specialist for definitive diagnosis and comprehensive care. 1

Diagnostic Confirmation

The constellation of morning (fasting) hypoglycemia, hepatomegaly (implied by elevated liver enzymes), hyperuricemia, and hyperlipidemia with normal HbA1c and normal C-peptide is pathognomonic for GSD-I. 1

Key distinguishing features from other diagnoses:

• Normal C-peptide rules out endogenous hyperinsulinism (insulinoma, nesidioblastosis), which would show C-peptide >0.2 nmol/L during hypoglycemia 2, 3
• Normal HbA1c excludes diabetes mellitus as the primary pathology 1
• Elevated uric acid and lipids with fasting hypoglycemia strongly suggest a glycogen storage disorder rather than other causes of pediatric hypoglycemia 1

Critical laboratory findings at time of hypoglycemia in GSD-I include: 1

• Lactic acidosis (elevated blood lactate)
• Hyperuricemia
• Hypercholesterolemia and hypertriglyceridemia
• Elevated transaminases (AST/ALT often >500 IU/L in GSD-III, but can be elevated in GSD-I)
• Elevated beta-hydroxybutyrate (ketosis present, unlike hyperinsulinism)

Definitive diagnosis requires: 1

• Molecular genetic testing (targeted mutation analysis or comprehensive gene sequencing for G6PC gene)
• Avoid glucagon stimulation testing as it may worsen metabolic acidosis and cause acute decompensation 1

Immediate Management Priorities

Prevent hypoglycemia through dietary intervention: 1

1. Frequent feedings every 2-3 hours during the day with complex carbohydrates 1

2. Uncooked cornstarch supplementation:

   • Prevents overnight hypoglycemia by providing slow-release glucose
   • Typically 1.6-2.5 g/kg body weight given before bedtime 1
   • May require middle-of-night dose in younger children

3. Avoid fasting periods >3-4 hours during waking hours 1

4. Continuous overnight gastric drip feeding may be necessary if cornstarch alone is insufficient 1

Dietary restrictions: 1

• Restrict fructose and galactose intake (these cannot be converted to glucose in GSD-I)
• Avoid sucrose (table sugar) as it contains fructose
• Limit fruit and fruit juice consumption
• Lactose restriction may be needed (contains galactose)

Metabolic Complications Management

Hyperuricemia: 1

• Allopurinol therapy to prevent gout and uric acid nephropathy
• Target uric acid <6 mg/dL
• Monitor for kidney stones and renal function

Hyperlipidemia: 1

• Often improves with optimal glucose control
• Fibrate therapy may be considered if triglycerides remain >400 mg/dL fasting despite dietary management 1
• Avoid statins in children <10 years old 1

Hepatomegaly and elevated transaminases: 1

• Monitor for hepatic adenomas (develop in 16-75% of patients with GSD-I)
• Annual liver ultrasound starting in adolescence
• Alpha-fetoprotein monitoring for malignant transformation risk

Subspecialty Referral

Immediate referral to pediatric metabolic/genetic specialist or endocrinologist is mandatory for: 1

• Confirmation of diagnosis through genetic testing
• Individualized dietary prescription and cornstarch dosing
• Long-term monitoring for complications (hepatic adenomas, renal disease, osteoporosis, pulmonary hypertension)
• Growth and development monitoring

Multidisciplinary team should include: 1

• Metabolic geneticist or endocrinologist
• Metabolic dietitian experienced in GSD management
• Hepatologist (for adenoma surveillance)
• Nephrologist (for renal complications)

Critical Pitfalls to Avoid

Do NOT: 1

• Perform glucagon stimulation test (risk of severe metabolic decompensation)
• Delay treatment while awaiting genetic confirmation—begin dietary management immediately based on clinical presentation
• Restrict calories excessively (growth retardation is already a concern in GSD-I)
• Use metformin or other diabetes medications (this is NOT diabetes mellitus) 4

Do NOT confuse with GSD-III: 1

• GSD-III has more severe ketosis, less severe lactic acidosis
• GSD-III typically has normal uric acid and blood lactate
• GSD-III shows elevated creatine kinase (muscle involvement)
• Both can present with hepatomegaly and hypoglycemia, but biochemical profile differs

Monitoring Parameters

Regular monitoring should include: 1

• Fasting and postprandial glucose levels
• Growth parameters (height, weight)
• Liver function tests and hepatic imaging (ultrasound annually after adolescence)
• Renal function (creatinine, uric acid, urinalysis for proteinuria)
• Lipid profile
• Bone density (risk of osteoporosis)
• Blood pressure (risk of hypertension from renal disease)

Long-term Prognosis

With appropriate management: 1, 5

• Normal growth and development can be achieved
• Prevention of acute metabolic crises
• Reduced risk of long-term complications (hepatic adenomas, renal disease)
• Gene therapy shows promise in research settings but is not yet clinically available 5