Glycogen storage disease type I pathophysiology: Difference between revisions
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==Pathophysiology== | ==Pathophysiology== | ||
===Normal carbohydrate balance and maintenance of blood glucose levels=== | ===Normal carbohydrate balance and maintenance of blood glucose levels=== | ||
[[Glycogen]] 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), and to add the G6P molecules to the ends of chains of glycogen (glycogen synthesis). Excess G6P is also shunted into production of [[triglyceride]]s and exported for storage in [[adipose tissue]] as [[fat]]. | [[Glycogen]] 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), and to add the G6P molecules to the ends of chains of glycogen (glycogen synthesis). Excess G6P is also shunted into production of [[triglyceride]]s 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 glycogen in the form of G6P. This process is termed [[glycogenolysis]]. The G6P remains within the liver cell unless the phosphate is cleaved by glucose-6-phosphatase. This [[dephosphorylation]] reaction produces free glucose and free PO<sub>4</sub> [[anion]]s. 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. Glycogenolysis can supply the glucose needs of an adult body for 12-18 hours. | 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 glycogen in the form of G6P. This process is termed [[glycogenolysis]]. The G6P remains within the liver cell unless the phosphate is cleaved by [[glucose-6-phosphatase]]. This [[dephosphorylation]] reaction produces free glucose and free PO<sub>4</sub> [[anion]]s. 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. Glycogenolysis 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 acid]]s (mainly [[alanine]]), [[free fatty acid]]s, and [[lactic acid]]. Free fatty acids from triglycerides are converted to [[ketone]]s, 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 glycogenolysis, is the dephosphorylation of G6P by glucose-6-phosphatase to free glucose and PO<sub>4</sub>. | 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 acid]]s (mainly [[alanine]]), [[free fatty acid]]s, and [[lactic acid]]. Free fatty acids from triglycerides are converted to [[ketone]]s, 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 glycogenolysis, is the dephosphorylation of G6P by glucose-6-phosphatase to free glucose and PO<sub>4</sub>. | ||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Pathophysiology
Normal carbohydrate balance and maintenance of blood glucose levels
Glycogen 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), and to add the G6P molecules to the ends of chains of glycogen (glycogen 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 glycogen in the form of G6P. This process is termed glycogenolysis. The G6P remains within the liver cell unless the phosphate is cleaved by glucose-6-phosphatase. This dephosphorylation reaction produces free glucose and free PO4 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. Glycogenolysis 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 glycogenolysis, is the dephosphorylation of G6P by glucose-6-phosphatase to free glucose and PO4.
Thus glucose-6-phosphatase mediates the final, key, step in both of the two main processes of glucose production during fasting. In fact the effect is amplified because the resulting high levels of glucose-6-phosphate inhibit earlier key steps in both glycogenolysis and gluconeogenesis.
Pathophysiology of the metabolic effects of glucose-6-phosphatase deficiency
The principal metabolic effects of deficiency of glucose-6-phosphatase are:
The hypoglycemia of GSD I is termed "fasting", or "post-absorptive", meaning that it occurs after completion of digestion of a meal-- usually about 4 hours later. This inability to maintain adequate blood glucose levels during fasting results from the combined impairment of both glycogenolysis and gluconeogenesis. Fasting hypoglycemia is often the most significant problem in GSD I, 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 gluconeogenenic 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 GSD I, 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 glucose is impaired. Triglyceride levels in GSD I 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 GSD I 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.