80 - NIMS MEDICINE february 2009 paper - 5

5q: most characteristic finding in Von Gierke's disease or glycogen storage disease type 1 is ?

a. fasting hypoglycemia
b. hypouricemia
c. alkalosis
d. none

answer: a . fasting hypoglycemia .

The principal metabolic effects of deficiency of glucose-6-phosphatase or von gierke's disease are:

* hypoglycemia
* lactic acidosis
* hypertriglyceridemia
* hyperuricemia

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.