What is the likely diagnosis and recommended work‑up/management for a 10‑year‑old boy with recurrent abdominal pain, intermittent transaminase elevations (~100 U/L), CK ~5 000 U/L, LDH ~500 U/L, and normal haptoglobin?

Likely Diagnosis: Muscle Disease (Not Primary Liver Disease)

This 10-year-old boy has a primary muscle disorder causing markedly elevated CK (5000 IU/L), with the transaminase elevations (ALT/AST in the 100s) representing "leakage" from damaged muscle tissue rather than true hepatocellular injury. The normal haptoglobin excludes hemolysis, and the clinical picture—recurrent abdominal pain with intermittently normal enzymes—strongly suggests an underlying metabolic myopathy, most likely Glycogen Storage Disease Type III (GSD III) given his age and presentation pattern. 1

Why This is Muscle Disease, Not Liver Disease

• The CK elevation of 5000 IU/L is the critical diagnostic clue: AST and ALT are both present in skeletal muscle, and when muscle injury occurs, these enzymes leak into the bloodstream alongside CK. 1

• AST is significantly less liver-specific than ALT because it exists in high concentrations in cardiac muscle, skeletal muscle, kidneys, brain, and red blood cells—making muscle injury a common cause of "elevated liver enzymes." 2

• The magnitude of CK elevation (5000 IU/L) far exceeds what would be expected from liver disease alone, and this degree of elevation is diagnostic of rhabdomyolysis or chronic myopathy. 3, 4

• Normal haptoglobin excludes hemolysis as a cause of the enzyme elevations, narrowing the differential to muscle or liver pathology. 1

Most Likely Diagnosis: Glycogen Storage Disease Type III

GSD III (debrancher enzyme deficiency) classically presents in childhood with hepatomegaly, hypoglycemia, growth retardation, and progressive myopathy—though muscle symptoms in childhood are often mild or absent initially. 5

Key Features Supporting GSD III:

• Intermittent transaminase elevations are characteristic because the liver involvement in GSD III fluctuates with metabolic stress (fasting, illness, exercise). 5

• Recurrent abdominal pain may reflect hepatomegaly (which can cause discomfort) or metabolic derangements during fasting states. 5

• Elevated CK with mild-to-moderate transaminase elevations is the typical laboratory pattern: 80% of children with GSD IIIa have subtle motor delays, and CK can be elevated even when muscle symptoms are minimal. 5

• LDH elevation (500 IU/L) reflects both muscle and liver glycogen accumulation; LDH is released from damaged muscle and is a sensitive (though nonspecific) marker for Pompe disease and other glycogen storage disorders. 5

• The age (10 years) fits the natural history: GSD III often presents in early childhood with hepatic features, and muscle involvement becomes more apparent in adolescence and adulthood. 5

Recommended Diagnostic Work-Up

Immediate Laboratory Testing:

1. Repeat CK, AST, ALT, and LDH to confirm the pattern and establish a baseline for monitoring. 1

2. Fasting glucose and lactate to assess for hypoglycemia and lactic acidosis, which are common in GSD III during fasting states. 5

3. Comprehensive metabolic panel including albumin, bilirubin, and INR to assess synthetic liver function—if these are normal, liver transplantation is not indicated even if cirrhosis is present histologically. 5

4. Urine glucose tetrasaccharide (Glc4): This is a sensitive (though nonspecific) marker for Pompe disease and other glycogen storage disorders; it can be elevated in GSD III and helps narrow the differential. 5

5. Abdominal ultrasound to assess for hepatomegaly, hepatic steatosis, and structural liver abnormalities. Imaging should be performed at baseline and then every 12–24 months in pediatric GSD III patients. 5

Definitive Diagnostic Testing:

• Enzyme assay for debrancher enzyme activity in cultured fibroblasts (from skin biopsy) or muscle biopsy is the gold standard for diagnosing GSD III. 5

• Genetic testing for AGL gene mutations confirms the diagnosis and can distinguish GSD IIIa (liver + muscle involvement) from GSD IIIb (liver only). 5

• Muscle biopsy (if performed) will show glycogen accumulation and can be used for enzyme assay and histological confirmation. 5

Rule Out Alternative Diagnoses:

• Pompe disease (GSD II): Check acid alpha-glucosidase (GAA) enzyme activity if there is any suspicion of cardiomyopathy or respiratory muscle weakness. Pompe disease typically presents with higher CK elevations (up to 2000 IU/L in late-onset cases) and can mimic GSD III. 5

• Other metabolic myopathies: Consider McArdle disease (GSD V), Tarui disease (GSD VII), or mitochondrial myopathies if exercise intolerance or recurrent rhabdomyolysis is prominent. 5

• Rhabdomyolysis: Although CK of 5000 IU/L meets the threshold for rhabdomyolysis (≥5× upper limit of normal ≈ 1000 IU/L), the intermittent nature of symptoms and lack of acute renal failure suggest chronic myopathy rather than acute rhabdomyolysis. 3, 4, 6

Management and Monitoring

Nutritional Management (Cornerstone of GSD III Treatment):

• Frequent meals with complex carbohydrates to prevent hypoglycemia and reduce hepatic glycogen accumulation. 5

• High-protein diet (25–30% of total calories) to provide alternative fuel substrates and reduce reliance on glycogen. 5

• Cornstarch supplementation (1.5–2.5 g/kg) at bedtime to maintain euglycemia overnight. 5

Hepatic Monitoring:

• Laboratory testing every 6–12 months: AST, ALT, PT, bilirubin, and albumin to monitor for progression to cirrhosis or end-stage liver failure. 5

• Abdominal imaging every 12–24 months (ultrasound in pediatric patients; CT/MRI in older patients) to monitor for hepatocellular adenomas or malignant transformation. 5

• MELD score calculation if there is evidence of synthetic dysfunction (elevated bilirubin, prolonged INR, low albumin)—though liver transplantation is not indicated unless synthetic function is severely impaired. 5

Musculoskeletal Monitoring:

• Serial CK measurements to track muscle disease progression. 5

• Physical therapy assessment for motor delays, hypotonia, or weakness—80% of children with GSD IIIa have gross motor function below the 25th percentile for age. 5

• Cardiac evaluation (ECG, echocardiogram) to screen for hypertrophic cardiomyopathy, which can develop in GSD IIIa. 5

Avoid Common Pitfalls:

• Do not pursue extensive hepatic evaluation (including liver biopsy) until CK has been checked—this prevents misdiagnosis of primary liver disease and unnecessary invasive procedures. 1

• Do not assume normal ALT excludes significant muscle disease—many children with GSD III have only mildly elevated transaminases despite significant muscle involvement. 2

• Do not overlook cardiac involvement—hypertrophic cardiomyopathy can develop in GSD IIIa and requires regular monitoring. 5

• Do not recommend contact sports or aggressive upper-extremity weight-bearing activities (cartwheels, climbing) in children with hepatomegaly and muscle weakness, as these increase the risk of liver injury and joint damage. 5

Prognosis and Long-Term Outlook

• Hepatic manifestations often improve with age: Many children with GSD III experience resolution or improvement of hepatomegaly and transaminase elevations during adolescence, though cirrhosis can develop in some cases. 5

• Muscle involvement typically worsens in adulthood: Proximal and distal weakness, atrophy, and cardiomyopathy become more prominent in the third and fourth decades of life. 5

• Liver transplantation corrects hepatic disease but does not address muscle or cardiac manifestations—it is reserved for patients with end-stage liver failure and preserved synthetic function is not an indication for transplant. 5

• Overall prognosis is favorable with appropriate management: Most patients with GSD III have a normal lifespan if metabolic control is maintained and cardiac complications are monitored. 5