A girl presented with an important growth retardation, hepatomegaly, fasting hypoglycemia, lactic acidosis, increased serum cholesterol, triglycerides and uric acid, and increased liver glycogen (7.5%). There was no rise in blood glucose after IV galactose or fructose, but glucagon gave a delayed response. Type Ib glycogen storage disease was suggested by the low normal activity of glucose-6-phosphatase (G-6-Pase) which reached 1.8 units/g (normal, 2 to 10 units/g) and the normal activity of other glycogenolytic enzymes, measured in homogenates prepared in H2O from previously frozen liver tissue. After portacaval shunt (PCS), height increased by 29 cm in 3 years. Serum cholesterol decreased from 618 to 216 mg/dl, and triglycerides decreased from 890 to 116 mg/dl. During an oral glucose tolerance test, peak values for glucose (mg/dl) and insulin (μunits/ml) were, respectively, 210 and 50 before and 280 and 90 after PCS. Sixty min after the IV administration of a tracer dose of [2-3H;U-14C]glucose, the3H/14C ratio in blood glucose decreased to 24% of its initial value indicating a functional G-6-Pase (mean ± S.E. in control subjects: 59% ± 7; in type la CSD: 92% ± 3). The activity of G-6-Pase measured as described above increased to 3.8 units/g of liver 1 year after PCS and 7.85 units/g of liver after 3 years. At that time, a simultaneous assay of the enzyme in a fresh, previously not frozen liver biopsy, homogenized in 0.25 M sucrose, revealed only about 29% of the activity of the same sample prepared in H2O (mean ± S.E. in three controls: 95.8% ± 8.9).SpeculationThe higher than normal utilization of [2-3H;U-14C]glucose observed after portacaval shunt hi this patient suggests that besides the postulated defect of the microsomal glucose-6-phos-phate transport system (19), other hitherto unexplored pathogenetic mechanisms should be investigated, including the regulation of the synthesis of glucose-6-phosphatase, to explain the unpaired degradation of glycogen hi type Ib glycogen storage disease.