Markedly Elevated Serum Transaminases in Glycogen Storage Disease Type III

Abstract

Glycogen storage disease type III (GSD III) is an autosomal recessive metabolic disorder that is caused by the deficiency of the glycogen-debranching enzyme. Presenting problems often include hepatomegaly, elevated transaminases, hyperlipidemia, mild hypoglycemia, and failure to thrive. We describe a patient who developed marked elevation in serum transaminases (alanine aminotransferase [ALT] > 2000 IU/L), without evidence of significant hepatocellular necrosis or liver dysfunction. A 17-month-old girl presented to our emergency department with acute vomiting and diarrhea. Physical examination revealed hepatosplenomegaly (liver and spleen 6 and 2 cm below the costal margins, respectively). Her weight and height were at the 75th percentile. Laboratory tests showed elevated transaminases: ALT 408 IU/L (reference range <40 IU/L), aspartate aminotransferase (AST) 328 IU/L (reference range <40 IU/L), gamma-glutamyl transpeptidase (gGTP) 53 IU/L (reference range 8–78 IU/L), and total bilirubin 0.3 mg/dL (reference range <1.0 mg/dL). Initial workup revealed unremarkable acetaminophen level, creatine phosphokinase (CPK), coagulation studies, hepatitis virus panel, thyroid function tests, ceruloplasmin, α-1 antitrypsin phenotype, auto-immune studies, and liver ultrasound. Although the symptoms of acute gastroenteritis improved, her transaminases remained elevated. Additional history revealed that the patient had episodes of shakiness, crankiness, and vomiting in the morning before eating breakfast. Fasting laboratory studies revealed hypoglycemia (glucose 55 mg/dL [reference range 70–110 mg/dL] and hyperlipidemia (triglyceride 316 mg/dL [reference range 28–153 mg/dL] and cholesterol 188 mg/dL [reference range 75–200]). Given the clinical picture, a suspicion for GSD III arose, so genetic studies of peripheral blood DNA were undertaken. Although genetic studies were pending, the patient experienced a sudden spike in transaminases on routine testing (ALT 2104 IU/L, AST 1441 IU/L) without any signs of illness or other laboratory abnormalities (total bilirubin 0.5 mg/dL, direct bilirubin 0.2 mg/dL (0.1–0.4), gGTP 142 IU/L, prothrombin time 12.6 seconds (11.5–16.1 seconds), albumin 4.2 g/dL (3.8–5.4 g/dL), and CPK 71 IU/L (29–168 IU/L). A liver biopsy was performed to exclude other etiologies aside from GSD III for this elevation of transaminases. The biopsy revealed enlarged hepatocytes with abundant glycogen-rich material (Fig. 1), and enzymatic analysis of liver tissue revealed absent debranching enzyme activity (0 μmol/min/g tissue [control 0.31 ± 0.1 μmol/min/g tissue]), supporting the diagnosis of GSD III. Of note, there was minimal evidence of hepatocellular injury or inflammation. Subsequently, genetic studies revealed heterozygous mutations in the amylo-1,6-glucosidase (AGL) gene, including a nonsense mutation, c.2590C>T (R864X), previously reported to be causative for GSD type III (1–3), and a potentially pathological missense mutation in a highly conserved tyrosine residue, c.1484A>G (Y495C), not previously associated with GSD type III. During the ensuing 2 years, her serum transaminase levels remained elevated between 300 and 500 IU/L (Fig. 2). Her other biochemical markers of liver disease have remained unremarkable, and she has not developed any clinical stigmata of advanced liver disease. FIGURE 1 Microscopic appearance of GSD III. Left, The hepatocytes are plant-like with clear cytoplasm and prominent cell membranes. The nuclei are small and uniform. Scattered glycogenated nuclei are seen. No cholestasis or significant inflammation is present ... FIGURE 2 Clinical course of GSD III. Serum transaminase levels over time are shown.