Normal carbohydrate balance and maintenance of blood glucose levels<unk>  in liver and (to a lesser degree) kidneys serves as a form of stored, rapidly accessible glucose, so that the blood glucose level can be maintained between meals. For about 3 hours after a carbohydrate-containing meal, high insulin levels direct liver cells to take glucose from the blood, to convert it to glucose-6-phosphate (G6P) with the enzyme glucokinase, and to add the G6P molecules to the ends of chains of<unk> <unk>  synthesis). Excess G6P is also shunted into production of triglycerides and exported for storage in adipose tissue as fat. When digestion of a meal is complete, insulin levels fall, and enzyme systems in the liver cells begin to remove glucose molecules from strands of<unk>  in the form of G6P. This process is termed<unk> olysis. The G6P remains within the liver cell unless the phosphate is cleaved by glucose-6-phosphatase. This dephosphorylation reaction produces free glucose and free anions. The free glucose molecules can be transported out of the liver cells into the blood to maintain an adequate supply of glucose to the brain and other organs of the body.<unk> olysis can supply the glucose needs of an adult body for 12–18 hours. When fasting continues for more than a few hours, falling insulin levels permit catabolism of muscle protein and triglycerides from adipose tissue. The products of these processes are amino acids (mainly alanine), free fatty acids, and lactic acid. Free fatty acids from triglycerides are converted to ketones, and to acetyl-CoA. Amino acids and lactic acid are used to synthesize new G6P in liver cells by the process of gluconeogenesis. The last step of normal gluconeogenesis, like the last step of<unk> olysis, is the dephosphorylation of G6P by glucose-6-phosphatase to free glucose and . Thus glucose-6-phosphatase mediates the final, key, step in both of the two main processes of glucose production during fasting. The effect is amplified because the resulting high levels of glucose-6-phosphate inhibit earlier key steps in both<unk> olysis and gluconeogenesis. Pathophysiology The principal metabolic effects of deficiency of glucose-6-phosphatase are hypoglycemia, lactic acidosis, hypertriglyceridemia, and hyperuricemia. Map of effects in<unk> a from non-functioning glucose-6-phosphatase. The hypoglycemia of<unk>  is termed "fasting", or "post-absorptive", usually about 4 hours after the complete digestion of a meal. This inability to maintain adequate blood glucose levels during fasting results from the combined impairment of both<unk> olysis and gluconeogenesis. Fasting hypoglycemia is often the most significant problem in<unk> , and typically the problem that leads to the diagnosis. Chronic hypoglycemia produces secondary metabolic adaptations, including chronically low insulin levels and high levels of glucagon and cortisol. Lactic acidosis arises from impairment of gluconeogenesis. Lactic acid is generated both in the liver and muscle and is oxidized by NAD+ to pyruvic acid and then converted via the gluconeogenic pathway to G6P. Accumulation of G6P inhibits conversion of lactate to pyruvate. The lactic acid level rises during fasting as glucose falls. In people with<unk> , it may not fall entirely to normal even when normal glucose levels are restored. Hypertriglyceridemia resulting from amplified triglyceride production is another indirect effect of impaired gluconeogenesis, amplified by chronically low insulin levels. During fasting, the normal conversion of triglycerides to free fatty acids, ketones, and ultimately acetyl-CoA is impaired. Triglyceride levels in<unk>  can reach several times normal and serve as a clinical index of "metabolic control". Hyperuricemia results from a combination of increased generation and decreased excretion of uric acid, which is generated when increased amounts of G6P are metabolized via the pentose phosphate pathway. It is also a byproduct of purine degradation. Uric acid competes with lactic acid and other organic acids for renal excretion in the urine. In<unk>  increased availability of G6P for the pentose phosphate pathway, increased rates of catabolism, and diminished urinary excretion due to high levels of lactic acid all combine to produce uric acid levels several times normal. Although hyperuricemia is asymptomatic for years, kidney and joint damage gradually accrue. Elevated lactate and lactic acidosis High levels of lactic acid in the blood are observed in all people with<unk> , due to impaired gluconeogenesis. Baseline elevations generally range from 4 to 10 mol/mL, which will not cause any clinical impact. However, during and after an episode of low blood sugar, lactate levels will abruptly rise to exceed 15 mol/mL, the threshold for lactic acidosis. Symptoms of lactic acidosis include vomiting and hyperpnea, both of which can exacerbate hypoglycemia in the setting of<unk> . In cases of acute lactic acidosis, patients need emergency care to stabilize blood oxygen, and restore blood glucose. Proper identification of lactic acidosis in undiagnosed children presents a challenge, since the first symptoms are typically vomiting and dehydration, both of which mimic childhood infections like gastroenteritis or pneumonia. Moreover, both of these common infections can precipitate more severe hypoglycemia in undiagnosed children, making diagnosis of the underlying cause difficult. As elevated lactate persists, uric acid, ketoacids, and free fatty acids further increase the anion gap. In adults and children, the high concentrations of lactate cause significant discomfort in the muscles. This discomfort is an amplified form of the burning sensation a runner may feel in the quadriceps after sprinting, which is caused by a brief buildup of lactic acid. Proper control of hypoglycemia in<unk>  entirely eliminates the possibility for lactic acidosis. Elevated urate and complications High levels of uric acid often present as a consequence of elevated lactic acid in<unk>  patients. When lactate levels are elevated, blood-borne lactic acid competes for the same kidney tubular transport mechanism as urate, limiting the rate that urate can be cleared by the kidneys into the urine. If present, increased purine catabolism is an additional contributing factor. Uric acid levels of 6 to 12 mg/dl (530 to 1060 umol/L) are common among<unk>  patients, if the disease is not properly treated. In some affected people, the use of the medication allopurinol is necessary to lower blood urate levels. Consequences of hyperuricemia among<unk>  patients include the development of kidney stones and the accumulation of uric acid crystals in joints, leading to kidney disease and gout, respectively. Hyperlipidemia and plasma effects Elevated triglycerides in<unk>  result from low serum insulin in patients with frequent prolonged hypoglycemia. It may also be caused by intracellular accumulation of glucose-6-phosphate with secondary shunting to pyruvate, which is converted into Acetyl-CoA, which is transported to the cytosol where the synthesis of fatty acids and cholesterol occurs. Triglycerides above the 3.4 mmol/L (300 mg/dL) range may produce visible lipemia, and even a mild pseudohyponatremia due to a reduced aqueous fraction of the blood plasma. In<unk> , cholesterol is typically only mildly elevated compared to other lipids. Hepatomegaly Hepatomegaly with enlarged liver visible in red crosshairs and extending downward. Impairment in the liver's ability to perform gluconeogenesis leads to clinically apparent hepatomegaly. Without this process, the body is unable to liberate<unk>  from the liver and convert it into blood glucose, leading to an accumulation of stored<unk>  in the liver. Hepatomegaly from the accumulation of stored<unk>  in the liver is considered a form of non-alcoholic fatty liver disease.<unk>  patients present with a degree of hepatomegaly throughout life, but severity often relates to the consumption of excess dietary carbohydrate. Reductions in the mass of the liver are possible, since most patients retain residual hepatic function that allows for the liberation of stored<unk>  at a limited rate.<unk>  patients often present with hepatomegaly from the time of birth. In fetal development, maternal glucose transferred to the fetus prevents hypoglycemia, but the storage of glucose as<unk>  in the liver leads to hepatomegaly. There is no evidence that this hepatomegaly presents any risk to proper fetal development. Hepatomegaly in GSD type I generally occurs without sympathetic enlargement of the spleen.<unk> b patients may present with splenomegaly, but this is connected to the use of filgrastim to treat neutropenia in this subtype, not comorbid hepatomegaly. Hepatomegaly will persist to some degree throughout life, often causing the abdomen to protrude, and in severe cases may be palpable at or below the navel. In GSD-related non-alcoholic fatty liver disease, hepatic function is usually spared, with liver enzymes and bilirubin remaining within the normal range. However, liver function may be affected by other hepatic complications in adulthood, including the development of hepatic adenomas. Hepatic adenomas The specific etiology of hepatic adenomas in<unk>  remains unknown, despite ongoing research. The typical<unk>  patient presenting with at least one adenoma is an adult, though lesions have been observed in patients as young as fourteen. Adenomas, composed of heterogeneous neoplasms, may occur individually or in multiples. Estimates on the rate of conversion of a hepatocellular adenoma into hepatocellular carcinoma in<unk>  range from 0% to 11%, with the latter figure representing more recent research. One reason for the increasing estimate is the growing population of<unk>  patients surviving into adulthood,
Glycogen storage disease type I
Glycogen storage disease type 0
Glycogen storage disease type V
Glycogen storage disease type VI
Essential fructosuria
Inborn errors of carbohydrate metabolism
Aspartylglucosaminuria
Familial dysbetalipoproteinemia