Glycogen storage disease type Ia: linkage of glucose, glycogen, lactic acid, triglyceride, and uric acid metabolism

Abstract

A female presented in infancy with hypotonia, undetectable serum glucose, lactic acidosis, and triglycerides >5000 mg/dL. The diagnosis of type 1A glycogen storage disease was made via the result of a liver biopsy, which showed increased glycogen and absent glucose-6-phosphatase enzyme activity. The patient was treated with dextrose administered orally, which was replaced by frequent feedings of cornstarch, which resulted in an improvement of her metabolic parameters. At age 18 years of age, she had marked hypertriglyceridemia (3860 mg/dL) and eruptive xanthomas and was treated with fenofibrate, atorvastatin, and fish oil. At age 29 years she was noted to have multiple liver adenomas, severe anemia, and hyperuricemia. Aggressive cornstarch therapy was commenced with a goal of maintaining her blood glucose levels >75 mg/dL and lactate levels <2 mmol/L. After 15 months on this regimen, her lipids levels (measured in mg/dL) off all medications were as follows: total cholesterol 222, triglycerides 179, high-density lipoprotein cholesterol 32, and calculated low-density lipoprotein cholesterol 154. Her weight was stable with a body mass index of 24.8 kg/m(2). Her liver adenomas had decreased in size, and her anemia and hyperuricemia had improved. She was homozygous for the R83C missense mutation in G6PC. Our data indicate that optimized metabolic control to maintain blood glucose levels >75 mg/dL is critical in the management of this disease.

Figure 1. Overview of the Interrelationships of Glucose, Lactate, Triglyceride, Uric Acid, and Glygogen Metabolism in the Liver

UDP-glucose is uridine diphosphoglucose. Steps in the process are catalyzed by: 1. hexokinase/glucokinase, 2. glucose-6-phosphatase (G6Pase), 3. phosphoglucomutase, 4. glycogen synthase, 5. branching enzyme, 6. glycogen phosphorylase, and 7. debranching enzyme (figure as modified from references 7 and 8). In glycogen storage disease type Ia there is a block in the conversion of glucose-6-phosphate to glucose due to a deficiency of glucose-6-phosphatase. This block results in markedly enhanced conversion of glucose-6-phosphate to: 1) to pyruvate and lactate; 2) to pyruvate and then to acetyl-CoA, fatty acids and finally to triglycerides; 3) to ribose-5-phosphate and then to uric acid; or to 4) to glucose-1-phosphate, then to UDP-glucose, then to amylopectin, and then to glycogen. The excess production of lactate, triglycerides, uric acid, and glycogen can be diminished by the administration of exogenous cornstarch (glucose polymer) on a regular and prescribed basis.