Glycogen storage disease type Ia is an autosomal recessive disorder caused by a deficiency of glucose-6-phosphatase activity (7
). Mutations in the G6PC gene cause a defect in the catalytic subunit of the enzyme (8
). The case reported here was homozygous for a C to T substitution in the G6PC gene resulting in the substitution of arginine with cysteine at position 83 of the amino acid sequence (a previously reported mutation) (8
). This defect causes an inability to convert glucose-6-phosphate to glucose, resulting in abnormal flux through the glycolytic pathway leading to increased production of pyruvate, which is converted to either lactate or triglycerides via acetyl CoA and fatty acids (see as modified and taken from reference 7
). Glucose-6-phosphate can also be converted to uric acid via the pentose phosphate pathway, as well as to glycogen via glucose-1-phosphate, UDP-glucose, and amylopectin (see ) (7
). Therefore, unless patients with type 1 GSD regularly receive adequate amounts of exogenous glucose, they rapidly develop severe hypoglycemia, marked hypertriglyceridemia, hyperuricemia, and elevated lactate levels. The marked hypertriglyceridemia in this disease is related to enhanced de novo lipogenesis due to increased conversion of glucose-6-phosphate to triglycerides as shown in (11
Overview of the Interrelationships of Glucose, Lactate, Triglyceride, Uric Acid, and Glygogen Metabolism in the Liver
As an infant, the patient was documented to have serum triglycerides over 5,000 mg/dl, and at age 18 years she developed eruptive xanthomas with serum triglyceride levels of 3,860 mg/dl. At that time, she was receiving inadequate cornstarch therapy, and treatment with atorvastatin, fenofibrate, and fish oil maintained her triglycerides below 500 mg/dl. However, with better metabolic control that maintained her blood glucose levels > 75 mg/dl, off all medications she was able to reduce her triglyceride levels to 179 mg/dl. However, her latest value was 433 mg/dl, suggesting that her dietary regimen may not have been as optimal at the time of this latest sampling. Nevertheless, the data indicate that this form of therapy can be very effective in suppressing her de novo lipogenesis and hypertriglyceridemia, and is preferable to statin or fibrate therapy.
At the time of her latest sampling, we documented that she clearly had an elevated LDL cholesterol and small dense LDL cholesterol level. Our measurements of sterols indicated very striking suppression of cholesterol synthesis and some decrease in markers of cholesterol absorption, findings not previously reported in this disease. This suppression of cholesterol synthesis may be due to the increased shunting of fatty acids into the triglyceride pathway in this disease, and a resultant suppression of liver cholesterol production. In addition her elevated levels of apoB and LDL are probably due to delayed fractional clearance of LDL and down regulation of her hepatic LDL receptor activity. This latter effect may be due to excess liver glycogen and lipid storage, which may also account for her markedly elevated CRP level. As illustrated in this case adequate and careful supplementation with uncooked cornstarch (a slowly digested glucose polymer) results in marked improvement in triglyceride and uric acid levels, as well as improvement in liver adenomas over time.
Another clinically significant problem in these patients is anemia. The reason for the severe anemia in glycogen storage disease type Ia has now been clarified. Weinstein and colleagues have reported that patients with glycogen storage disease type Ia and large hepatic adenomas have a microcytic anemia associated with low iron levels, which is refractory to iron therapy. This anemia is linked to the presence of hepatic adenomas, and adenoma resection or liver transplantation has been associated with a return to normal hemoglobin levels (12
). The anemia that develops in these patients appears to be an effect of aberrant expression of hepcidin by the adenomas. Hepcidin is a peptide produced in the liver that is detectable in serum and urine. Hepcidin binds and internalizes a protein known as MTP1 that facilitates iron absorption in the intestine, rendering it dysfunctional (15
). A dramatic increase in hepcidin mRNA expression has been observed in glycogen storage disease patients with adenomas compared with other patients who had unaffected liver tissue. Our patient's severe anemia was probably related to her liver adenomas. More optimal metabolic control decreased her adenoma size, probably decreased hepcidin levels, and significantly decreased the severity of her anemia. Confirmation for this concept of the role of liver hepcidin comes from studies in mice in which hepcidin gene expression has been knocked out or where human hepcidin has been overexpressed using transgenic mice (15
There are 14 types of glycogen storage diseases, which have been classified based on their enzyme deficiencies (see ). Hyperlipidemia is seen in types 0, I, III, VI and IX, but is most prominent in type Ia. In glycogen storage disease type III, VI and IX, hyperlipidemia is thought to be mainly due hypoglycemia and activation of glucose counterregulation resulting in increased fatty acid flux from adipose tissue to the liver to provide an alternative source of fuel. In contrast, in glycogen storage disease type Ia, the severe hypertriglyceridemia is due to lack of conversion of glucose-6-phosphate to glucose (step 2, ), resulting in excess glucose-6-phosphate being shunted towards pyruvate, lactate, triglyceride, uric acid, and glycogen production (7
The novel features in this case, not previously reported, are the suppression of markers of cholesterol synthesis (lathosterol) and absorption (beta-sitosterol and campesterol), presumably because of increased endogenous triglyceride production. Other novel features previously unreported include documentation of increased levels of non-HDL cholesterol, apoB, LDL cholesterol, small dense LDL cholesterol, and decreased levels of HDL cholesterol, apoA-I, and apoA-I in large alpha-1 migrating HDL, all abnormalities observed in patients with hypertriglyceridemia (her levels were 433 mg/dl at the time of these evaluations). A third set of novel features reported here are the markedly elevated CRP levels, with normal levels of LpPLA2, indicating excess lipid storage in the liver, but not in peripheral macrophages.
What is clear is that in patients with glycogen storage disease type Ia it is very important to achieve metabolic control by maintaining serum glucose levels > 75 mg/dl throughout the day and night, which improves the hypertriglyceridemia, hyperuricemia, lactic acidosis, and anemia, and decreases the size of the liver adenomas (7
). Referral to a specialized center is recommended to optimize therapy. This rare disorder clearly demonstrates the linkage between glucose, triglyceride, lactic acid, uric acid, and glycogen metabolism.