Glucose-6-Phosphatase Deficiency 

Glycogen is the stored form of glucose and serves as a tissue reserve for the body's glucose needs. It is composed of polymers of a 1-4 linked glucose, interrupted by a 1-6 linked branch point every 4-10 residues. Glycogen is formed in periods of dietary carbohydrate surplus and is broken down during starvation or periods of high glucose demand. Several inborn errors of glycogen metabolism have been described, and they result from mutations in genes that code for proteins involved in various steps of glycogen synthesis, degradation, or regulation. These disorders result in abnormal storage of glycogen, and hence the phrase glycogen storage diseases (GSDs).^[1]

Glucose-6-phosphatase (Glc-6-Pase) deficiency, also termed GSD type I or von Gierke disease, is a rare form of GSD. The hydrolysis and transport of glucose 6-phosphate requires a hydrolase and microsomal transporters, pyrophosphate and glucose. Type Ia results from a deficiency in the glucose 6-phosphate hydrolase activity, and makes up more than 80% of cases. Types Ib (glucose-6-phosphate transporter deficiency), Ic, and Id are allelic defects in the translocase associated with glucose-6-phosphatase.^[2]

Between meals, most tissues depend on glucose generated predominantly in the liver and kidney and distributed via the blood. The liver and the kidney are the primary organs responsible for blood glucose homeostasis in between meals. As alluded to earlier, glucose homeostasis is dependent upon the activity of the glucose-6-phosphatase (Glc-6-Pase)1 complex, which is composed of a glucose-6-phosphate transporter (Glc-6-PT) and a Glc-6-Pase catalytic unit. Glc-6-PT is a single copy gene (3–5) that is expressed ubiquitously.

Glycogenolysis results in the production of glucose-6-phosphate, which must then be dephosphorylated by Glc-6-Pase to yield free glucose that can be used by the body. In those with GSD the deficit can either be in the catalytic subunit (type Ia; von Gierke disease) or the G6P transporter (type Ib). In the former, enzyme is not expressed in liver, kidney, and intestine cells. This results in impaired generation of glucose from glycogen, thus resulting in fasting hypoglycemia, the prototype biochemical manifestation of this disease.

Glycogen and glucose-6-phosphate accumulate in the liver in GSD patients, as there is no effective alternative route for their metabolism, while glycogen synthesis continues normally in the postabsorptive stage. This results in characteristic hepatomegaly and on a diagnostic liver biopsy, sheets of swollen hepatocytes could be seen, typically arranged in a mosaic pattern with centrally placed nuclei. These cells have a clear cytoplasm as a result of all the glycogen within the cell being leached out by the process of fixation (using aqueous formalin).

Repetitive episodes of hypoglycemia leads to up-regulation of synthesis and transport of counterregulatory (stress) hormones, such as glucagon, cortisol, catecholamines, and growth hormone, with predictable metabolic effects. Muscle glycolysis is often up-regulated, resulting in high levels of pyruvate, lactate,^[3] and free fatty acid (FFA) being released into systemic circulation. In the liver, FFA partly undergoes conversion to acetyl CoA, which then enters the oxidative tricarboxylic (Krebs) acid cycle. Also, the fatty acids generated circulate as FFA or as triacylglycerol and may manifest as high serum levels of nonesterified fatty acid, triglyceride, or both.

Prolonged plasma retention of triglyceride-rich lipoproteins also promotes lipid deposition in lean tissue, such as liver, skeletal muscle, cardiac muscle, and pancreatic (islets of Langerhans) tissue, resulting in lipotoxicity, with deleterious tissue effects (steato-hepatitis, insulin resistance, cardiac contractile dysfunction, and pancreatic beta cell failure/insulin deficiency).

Hyperuricemia results from overproduction and underexcretion. Excessive urate is produced during the production of adenosine triphosphate (ATP) from adenosine 5'-diphosphate in a reaction that involves deamination of adenosine monophosphate to inosine, with resultant conversion to uric acid. This hyperuricemia is worsened by the excess lactate that competes with the uric acid for excretion by a common renal anion transporter.^[3]

Frequency

United States

The incidence of GSD I is 1 per 100,000 live births and inheritance is autosomal recessive.^[4] The glucose 6-phosphatase gene (G6PC) that encodes the hydrolase resides at 17q21 and that encoding glucose 6-phosphate translocase (G6PT) at 11q23 and mutations responsible for GSD I have been described in both type Ia and Ib patients.

International

Incidence in non-Ashkenazi Jews from North Africa may be as high as 1 case in 5420 persons.

Mortality/Morbidity

Prior to the advent of therapies such as continuous feeding and the use of cooked cornstarch, most individuals with GSD died young, usually as a result of hypoglycemia and other metabolic derangements. However, with prompt recognition of this condition in the perinatal period, effective therapy could be planned thus ensuring that most affected individuals are increasingly living up to adulthood.

• The majority of patients, even with treatment from childhood, have short stature. Their final adult height is often between the 5th and 10th percentiles when measured at age 18 years.
• Hepatomegaly is a universal finding. It is often accompanied by single or multiple hepatic adenomas that appear in the second decade of life and may grow quite large. In a case series of 37 patients, 75% had at least one hepatic adenoma. Malignant transformation of hepatic adenomas has been reported in several cases.
• Gouty arthritis is a commonly reported complication. Uric acid nephrolithiasis is also found in approximately 65% of patients.
• In patients with glycogen storage disease type Ia, serum triglyceride concentrations are markedly raised, whereas phospholipids and cholesterol levels may be raised moderately. In addition, both VLDL and LDL lipoprotein fractions are raised. Despite these abnormalities, endothelial vascular dysfunction and atherosclerosis seem to be rare in such patients. Trioche et al^[5] reported that serum apoE levels may be raised in individuals with GSD type Ia, perhaps as a result of increased hepatic synthesis and postulated that this could play an important role in counterbalancing the increased atherosclerosis risk associated with the lipid profile of patients with GSD Ia.
• Premature coronary vascular disease may be present and may be related in part to the lipid abnormality. Several reports indicate myocardial infarction in patients younger than 40 years that occurred because of advanced atherosclerosis. As more patients continue to live into their fourth and fifth decades, the increased relative risk of premature coronary disease in this population will become more clearly elucidated.
• Hypoglycemia may occur, but patients are frequently asymptomatic. However, it may be associated with any range of presentations, from seizure to coma and death.
• Proteinuria, hypertension, and chronic renal failure are common complications manifesting as focal segmental glomerulosclerosis and interstitial fibrosis. They may result from a chronic hyperfiltration injury (see Treatment).
• Osteopenia, osteoporosis, and bony fractures are presumed to be secondary to chronic excessive counterregulatory hormones. These features were probably underappreciated in earlier reported cohorts.
• Primary pulmonary hypertension has been reported in at least 6 people with G-6-phosphatase deficiency. This is presumed secondary to chronic acidosis or an unidentified vasoconstrictor that is supposed to be cleared by the liver. This is considered a rare complication.

Race

• Cases have been described in white persons, Hispanic persons, Asian persons, and non-Ashkenazi Jews. No official registries exist for this disorder.

Sex

• This is an autosomal recessive genetic disorder, males and females are equally affected.

Age

• This deficiency is usually diagnosed shortly after birth or during the first few months of life.
• Most complications, such as hepatic adenomas, renal disease, and osteopenia, occur in later life and are often detected in the second decade.