Normal carbohydrate balance and maintenance of blood glucose levels Glycogen in the liver and (to a lesser degree) kidneys serve 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 add the G6P molecules to the ends of chains of glycogen (glycogen synthesis). Excess G6P is also shunted into the 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
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. 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 . 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 glycogenolysis and gluconeogenesis.
Pathophysiology The principal metabolic effects of deficiency of glucose-6-phosphatase are
hypoglycemia,
lactic acidosis,
hypertriglyceridemia, and
hyperuricemia. The
hypoglycemia of GSD I 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 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 gluconeogenic pathway to G6P. Accumulation of G6P inhibits the 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 acetyl-CoA 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.
Elevated lactate and lactic acidosis High levels of lactic acid in the blood are observed in all people with GSD I, 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 GSD I. 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 GSD I eliminates the possibility of lactic acidosis.
Elevated urate and complications High levels of
uric acid often present as a consequence of elevated lactic acid in GSD I patients. When lactate levels are elevated, blood-borne lactic acid competes for the same kidney tubular transport mechanism as urate, limiting the rate which 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 GSD I 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 GSD I 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 GSD I 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 GSD I,
cholesterol is typically only mildly elevated compared to other
lipids.
Hepatomegaly Impairment in the liver's ability to perform gluconeogenesis leads to clinically apparent
hepatomegaly. Without this process, the body is unable to liberate glycogen from the liver and convert it into blood glucose, leading to an accumulation of stored glycogen in the liver. Hepatomegaly from the accumulation of stored glycogen in the liver is considered a form of
non-alcoholic fatty liver disease. GSD I 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
glycogen at a limited rate. GSD I 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 glycogen 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. GSD Ib 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 GSD I remains unknown, despite ongoing research. The typical GSD I 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 GSD I range from 0% to 11%, with the latter figure representing more recent research. One reason for the increasing estimate is the growing population of GSD I patients surviving into adulthood when most adenomas develop. Treatment standards dictate regular observation of the liver by MRI or CT scan to monitor for structural abnormalities. Hepatic adenomas may be misidentified as
focal nodular hyperplasia in diagnostic imaging, though this condition is rare. However, hepatic adenomas in GSD I uniquely involve diffuse
Mallory hyaline deposition, which is otherwise commonly observed in focal nodular hyperplasia. Unlike common hepatic adenomas related to oral contraception, hemorrhaging in GSD I patients is rare. While the reason for the high prevalence of adenomas in GSD I is unclear, research since the 1970s has implicated serum
glucagon as a potential driver. In studies, patients who have been put on a dietary regimen to keep blood sugar in a normal range spanning 72 to 108 mg/dL (4.0 to 6.0 mmol/L) have shown a decreased likelihood of developing adenomas. Moreover, patients with well-controlled blood glucose have consistently seen a reduction in the size and number of hepatic adenomas, suggesting that adenomas may be caused by imbalances of hepatotropic agents like serum insulin and especially serum glucagon in the liver.
Osteopenia Patients with GSD I will often develop
osteopenia. The specific etiology of low bone mineral density in GSD is unknown, though it is strongly associated with poor metabolic control. Osteopenia may be directly caused by hypoglycemia or the resulting endocrine and metabolic sequelae. Improvements in metabolic control have consistently been shown to prevent or reverse clinically relevant osteopenia in GSD I patients. In cases where osteopenia progresses with age, bone mineral density in the ribs is typically more severe than in the vertebrae. In some cases bone mineral density T-score will drop below -2.5, indicating osteoporosis. There is some evidence that osteopenia may be connected with associated kidney abnormalities in GSD I, particularly glomerular hyperfiltration. The condition also seems responsive to calcium supplementation. In many cases bone mineral density can increase and return to the normal range given proper metabolic control and calcium supplementation alone, reversing osteopenia.
Kidney effects The kidneys are usually 10 to 20% enlarged with stored glycogen. In adults with GSD I, chronic
glomerular damage similar to
diabetic nephropathy may lead to
kidney failure. GSD I may present with various kidney complications. Renal tubular abnormalities related to hyperlactatemia are seen early in life, likely because prolonged lactic acidosis is more likely to occur in childhood. This will often present as
Fanconi syndrome with multiple derangements of renal tubular reabsorption, including tubular acidosis with bicarbonate and phosphate wasting. These tubular abnormalities in GSD I are typically detected and monitored by urinary calcium. Long term these derangements can exacerbate uric acid nephropathy, otherwise driven by hyperlactatemia. In adolescence and beyond, glomerular disease may independently develop, initially presenting as
glomerular hyperfiltration indicated by elevated urinary eGFR.
Splenomegaly Enlargement of the spleen (splenomegaly) is common in GSD I and has two primary causes. In GSD Ia, splenomegaly may be caused by a relation between the liver and the spleen which causes either to grow or shrink to match the relative size of the other, to a lessened degree. In GSD Ib, it is a side effect of the use of filgrastim to treat neutropenia.
Bowel effects Intestinal involvement can cause mild
malabsorption with greasy stools (
steatorrhea) but usually requires no treatment.
Infection risk Neutropenia is a distinguishing feature of GSD Ib, absent in GSD Ia. The
microbiological cause of neutropenia in GSD Ib is not well understood. Broadly, the problem arises from compromised cellular metabolism in the neutrophil, resulting in accelerated neutrophil apoptosis. The neutropenia in GSD is characterized by both a decrease in absolute neutrophil count and diminished neutrophil function. Neutrophils use a specific G6P metabolic pathway which relies on the presence of G6Pase-β or G6PT to maintain energy homeostasis within the cell. The absence of G6PT in GSD Ib limits this pathway, leading to
endoplasmic reticulum stress,
oxidative stress within the neutrophil, triggering premature apoptosis. It may cause clinically significant bleeding, especially
epistaxis. Additionally, GSD I patients may present with thrombocytopenia as a consequence of splenomegaly. In the setting of splenomegaly, various hematologic factors may be sequestered in the tissues of the spleen as blood is filtered through the organ. This can diminish levels of
platelets available in the bloodstream, leading to
thrombocytopenia.
Developmental effects Developmental delay is a potential secondary effect of chronic or recurrent hypoglycemia, but is at least theoretically preventable. Normal neuronal and muscle cells do not express glucose-6-phosphatase and are thus not impacted by GSD I directly. However, without proper treatment of hypoglycemia,
growth failure commonly results from chronically low insulin levels, persistent acidosis, chronic elevation of catabolic hormones, and
calorie insufficiency (or
malabsorption). The most dramatic developmental delays are often the cause of severe (not just persistent) episodes of hypoglycemia. ==Diagnosis==