AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

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). 

Glucose-6-phosphatase (Glc-6-Pase) deficiency is a rare form of GSD, also termed as GSD 1  or von Gierke disease. The hydrolysis and transport of glucose 6-phosphate requires a hydrolase and microsomal transporters, pyrophosphate and glucose. Type Ia is due to a deficiency in the glucose 6-phosphate hydrolase activity, and comprises 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.¹

Pathophysiology

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 comprised 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, and free fatty acid (FFA) being released  into systemic circulation. In the liver, FFA partly undergo conversion to acetyl CoA, which then enters the oxidative tricarboxylic (Krebs) acid cycle. Also, the fatty acids generated circulate as free fatty acid (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 pancreas (islets of Langerhans) resulting in lipotoxicity with deleterious tissue effects (steato-hepatitis, insulin resistance, cardiac contractile dysfunction, and pancreatic beta cell failure/insulin deficiency).

Hyperuricemia results from both overproduction and underexcretion. Excessive urate is produced during the production of 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.

Frequency

United States

The incidence of GSD I is 1 per 100,000 live births and inheritance  is autosomal recessive.² 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 al³ reported that serum apoE  levels may be raised in individuals with GSD type 1a, 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.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

It is usually diagnosed in first year of life. However, long-term care requires repeated documentation of symptoms to assess glycemic control and screen for complications.

• Parental consanguinity is an important factor because the disease is autosomal recessive. It is more likely to appear in consanguineous families.
• Family history that includes one member with known GSD type Ia increases the likelihood of other kindred being affected and warrants careful evaluation of all newborns in the family.
• Hypoglycemia may be symptomatic or asymptomatic. The lack of symptoms may be related to efficient usage of acetyl coenzyme A through the Krebs metabolic pathway.
• Failure to thrive is a common but nonspecific presentation.
• Patients have delayed pubertal onset and development.
• Seizures may occur because of hypoglycemia but not because of an underlying CNS disorder.
• Patients may have abdominal pain from hepatomegaly, uric acid nephrolithiasis, or pancreatitis.
• Hematuria (stone disease) may be observed.
• Bony pain or fracture, especially vertebral compression fractures from osteopenia, may be reported.
• Patients may have joint symptoms (gouty arthritis).
• Patients may have evidence of recurrent bacterial infections. These can be observed in association with GSD type Ib, which may otherwise appear identical to GSD type Ia.

Physical

In a report from the collaborative European Study on Glycogen Storage Disease Type I, patients (GSD Ia and GSD Ib) presented at a median age of 6 months (range 1 d to 12 y) and 4 months (range 1 d to 4 y), respectively.⁴ This study reported the  following features, from most to least common:

• Protruding abdomen — 83%
• Metabolic derangement — 71%
• Growth failure — 25%
• Recurrent infections — 3% in GSD Ia, 41% in GSD Ib
• Muscular hypotonia — 13%
• Delayed psychomotor development — 7%

Hepatomegaly is often the first clue to diagnosis and in the first year of life; asymptomatic hepatomegaly may be the only finding. Typically, no associated jaundice, ascites, or splenomegaly is present. The liver enlargement may be massive, with the lower border extending down to the pelvis in older patients. Hepatic adenomas are frequent and should be specifically sought during palpation. When present, they may give the liver a lumpy texture. They may even be tender, especially if any recent hemorrhage has occurred within the mass. The absence of palpable adenomas does not exclude their presence; it simply underlines the importance of hepatic imaging tests. Documenting the size of the liver and adenomas over time is important. This information can prove to be a good indicator of therapeutic response and can indicate the need for further investigation and management.

Height and growth velocity are usually subnormal, and pubertal development is usually delayed. This is thought to be a consequence of chronic disease and a chronic catabolic state similar to malnutrition. Usually, bone age is delayed and insulinlike growth factor 1 levels are subnormal. Abnormal growth patterns may be ameliorated by good, long-term compliance and control with treatment regimens. Serial documentation of height and pubertal stage may be used as surrogate markers for overall disease control.

Patients may have a tendency toward central adiposity (rounded abdomen). Following blood pressure levels regularly is key to the early diagnosis of renal insufficiency.

Physical signs of hyperlipidemia may be present, especially as xanthomas, which may be seen over the elbows, knees, shins, and possibly as eruptions over the buttocks.

Joint examination may reveal signs of hyperuricemia, including acute gouty arthritis or tophaceous gouty deposits. Spinal examination may document the presence of a deformity or pain over any of the vertebral bodies as a clue to potential osteoporotic fracture.

Some patients have an increased tendency to bruising or bleeding. The presence of recurrent bacterial skin infections may be a clue to the diagnosis of GSD type Ib, which is otherwise clinically identical to GSD type Ia.

Cardiac examination may reveal signs of pulmonary hypertension, including high jugular venous pressure, loud P₂, right ventricular heave, tricuspid regurgitation, or right-sided S₃.

Causes

• The gene for G-6-phosphatase has been cloned, and, to date, more than 17 different mutations have been reported in unrelated, affected patients.
• Certain mutations have been suggested to be characteristic in specific ethnic groups, and early work indicates that specific mutations may predict a patient's therapeutic response or predilection for developing hepatic adenomas.
• Many more studies are needed to clarify the issue of predictive associations in genetic testing.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

GSD type IX (liver phosphorylase kinase deficiency)

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Liver enzymes
• • Levels may be mildly elevated in 50% of patients.
  • Aspartate aminotransferase and alanine aminotransferase levels are typically 37-150 U/L, and alkaline phosphatase levels may be 140-660 U/L.
  • Higher elevations of alkaline phosphatase indicate the need to consider alternative or additional obstructive liver pathology.
• Hemoglobin
• • Up to 80% of affected patients have indices consistent with anemia associated with a chronic disease.
  • Hemoglobin values are 105-120 g/L.
• Plasma glucose
• • The level is characteristically low (<4 mmol/L or 70 mg/dL) in the fasting state.
  • This is one of the main markers used to assess the adequacy of therapy.
• Plasma lactate and bicarbonate
• • The plasma lactate level is always elevated, often higher than 6 mmol/L. It does not always normalize, even with appropriate therapy. It is also used as a key marker of metabolic control.
  • Plasma bicarbonate values may be low due to buffering of plasma organic acids and lactate, but they may be further lowered in the presence of renal tubular dysfunction that can occur in older patients.
• Uric acid: Evaluations reveal that the urate level is elevated in more than 50% of patients, with levels often 140-880 µmol/L (2.3-14.7 mg/dL).
• Plasma lipids
• • Total cholesterol levels are increased in 75% of cases, usually 5-14 mmol/L (195-545 mg/dL), and triglyceride values are elevated in all patients, sometimes as high as 49 mmol/L (4083 mg/dL).
  • These abnormalities may also persist to some degree, even with proper therapy.
• Creatinine: The serum creatinine level remains within the reference range until renal function is compromised, often years after a detectable change in creatinine clearance or urinary protein levels.
• Creatinine clearance
  • Values can be quite variable.
  • Early associated nephropathy may manifest as an increased clearance rate, suggestive of hyperfiltration.
  • As injury progresses, the creatinine clearance rate may decline to normal, and, eventually, reduced clearance is observed.
• Urinary protein
  • Up to 61% of young adults with GSD type Ia have some abnormality in urinary protein excretion.
  • This abnormality may range from microalbuminuria to frank proteinuria greater than 1 g/d.
  • The presence of proteinuria may signal the presence of renal disease and contribute to its progression.
• Serum alpha-fetoprotein
• • This is commonly used as a tumor marker for hepatocellular carcinoma.
  • The level should be checked and followed in any patient with known hepatic adenomas, especially if a change occurs in their appearance.
  • Overall sensitivity and specificity of the test in this context is not known. Many case reports exist of hepatic adenomas that show malignant changes without a rise in serum alpha-fetoprotein values. The results from this test are not likely to be sensitive and should not be relied upon as the sole, determining evaluation.

Imaging Studies

• Hepatic ultrasound
• • Ultrasound of the liver is important for both diagnosis and monitoring of long-term response to therapy.
  • Most patients with GSD have an increase in liver echogenicity ranging from mild to severe. Interestingly, among all patients with GSD, most showing a severe increase in echogenicity have GSD type Ia or Ib, as opposed to GSD type VI or IX, which tend to only show mild increases in echogenicity. Therefore, ultrasound images may have a minor role in suggesting the type of GSD present.
  • Hepatic adenomas may appear hypodense, isodense, or hyperdense depending on the degree of surrounding fatty infiltration of the liver.
  • Serial ultrasound examinations are considered the best way to monitor changes in the size or appearance of hepatic adenomas.
  • Importantly, note that abnormalities of portal venous flow, esophageal varices, or splenomegaly are very rarely found unless a secondary disease process is present.
  • Also, no relationship has been demonstrated between liver echogenicity and the adequacy of metabolic control.
• Renal ultrasound: Findings indicate that up to 65% of patients have evidence of renal stones or calcinosis upon ultrasound examination, which is important for determining treatment of hyperuricemia.
• CT and MRI with contrast
• • These more costly imaging studies are more sensitive and specific for detecting changes in the appearance or size of adenomas.
  • They may particularly help detect hemorrhage or malignant degeneration.
  • T1-weighted images often show adenomas to be isointense or hyperintense and may demonstrate a thin fibrous capsule.
  • T2-weighted images are usually hyperintense in appearance.
  • Importantly, note that both adenomas and hepatocellular carcinomas may have a fibrous capsule, fat deposition, necrosis, and hemorrhage. Therefore, biopsy of the lesion remains the criterion standard to diagnose malignancy.
• Bone age
• • Assessments should be performed for a baseline value and then periodically until the end of puberty.
  • Typically, bone age is delayed compared to chronologic age.
  • With improved metabolic control or definitive control with liver transplantation, further growth potential exists and an improvement in delayed bone age is possible.
• Bone density: Generally, bone mineral densitometry studies are inadequate. However, if fractures are present or if antiresorptive therapy is planned, obtaining a baseline bone density value at the age of puberty and following the measurements periodically is reasonable.

Other Tests

• Response to glucagon or epinephrine
• • Patients who lack G-6-phosphatase are not able to produce glucose from glycogenolysis.
  • They have fasting hypoglycemia that is unresponsive to exogenous glucagon or epinephrine administration.
  • If anything, their lactic acidosis may become worse.
• Response to galactose or fructose
• • Galactose and fructose are normally converted to glucose by way of glucose-6-phosphate.
  • When G-6-phosphatase is lacking, administering galactose or fructose (as lactose or sucrose) aggravates the lactic acidosis without raising the blood glucose level.
• Genetic testing
• • The gene for G-6-phosphatase has been cloned and DNA testing is now possible, which is especially useful for family screening.
  • Nevertheless, at least for index cases, liver biopsy remains the criterion standard for diagnosis.

Procedures

• Liver biopsy
• • Typically, liver biopsy findings demonstrate higher than 4% glycogen content and an abundance of normally structured glycogen.
  • G-6-phosphatase activity is very low or completely absent.
  • Liver biopsy of adenomas may be indicated to help exclude malignant transformation in patients with a liver mass that has changed in size or displayed new features such as necrosis, hemorrhage, or calcification that possibly indicate malignant degeneration.

Histologic Findings

Even following resection of hepatic adenomas, the presence of tumor necrosis may make differentiating a malignant and nonmalignant hepatic tumor difficult.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Hyperlipidemia
  • Patients with GSD type Ia typically have very high serum triglyceride levels with modest elevations of total cholesterol and low-density lipoprotein cholesterol and low levels of high-density lipoprotein cholesterol.
  • The etiology of this dyslipidemia is thought to be increased hepatic lipogenesis. However, some evidence also indicates that the cause is decreased triglyceride clearance due to diminished hepatic lipoprotein lipase activity.
  • Although this lipid profile is considered atherogenic in the general population, patients with GSD type Ia may not have the same risk. Nevertheless, myocardial infarction at a young age or acute pancreatitis warrants attention.
  • Compliance with appropriate dietary therapy is the first line of treatment.
  • The recommended diet is comprised of 15-20% fats, equally distributed among saturated and nonsaturated, and daily cholesterol intake of less than 200 mg/d.
  • This improves the hypertriglyceridemia in most patients and may decrease the total cholesterol level by 18-25%.
• Persistent hyperlipidemia
  • If hyperlipidemia persists despite maximal dietary measures, initiating a trial of drug therapy is reasonable.
  • Reports suggest that fibrates and niacin may decrease triglyceride levels by up to 30%, but this effect may not be sustained long-term.
  • Additionally, the use of fish oil supplements (eicosapentaenoic acid, 10 g/1.73 m²/d) has been shown to lower triglyceride levels by an average of 49% when used for a 3-month period.
  • Statins and bile acid sequestrant resins are probably contraindicated because they may exacerbate the hypertriglyceridemia.
  • An obvious need exists for more long-term studies of drug therapy in this setting.
• Hepatic adenomas
  • Single or multiple hepatic adenomas are observed in up to 80% of patients.
  • Although they have been seen in patients as young as 3 years, they usually appear during the second or third decade.
  • These adenomas bear a remarkable similarity to pharmacologic estrogen-induced hepatic adenomas, and several hypotheses exist about their development mechanism. Mitochondrial B-oxidation of fatty acids is thought to be inhibited by excess malonyl coenzyme A (due to G-6-phosphatase deficiency), which decreases carnitine palmitoyltransferase I and increases extramitochondrial fatty acid oxidation. This process may be significant in oncogenesis.
  • Given the pathophysiologic similarity to estrogen-induced hepatic adenomas, affected patients should use oral contraceptive pills with caution or not at all.
• Hepatic adenoma prevention and treatment
  • Evidence about using strict dietary control of glucose, lipids, and lactate to prevent adenoma formation and promote regression is conflicting. Reports indicate that many cases may not respond to dietary therapy.
  • Monitor hepatic adenomas with biannual or yearly ultrasound examinations. Serum alpha-fetoprotein values should also be measured serially as a potential marker of malignant transformation, which may occur in 11% of adenomas.
  • Adenomas may cause symptoms such as pain or vomiting. An acute onset of pain may indicate hemorrhage into the tumor capsule.
  • Adenomas that show signs of growth, hemorrhage, necrosis, calcification, or elevated alpha-fetoprotein levels should be referred for definitive diagnosis (ie, via biopsy or resection).
  • Once the determination has been made that aggressive therapy is warranted for symptom control, hemorrhage control, or to exclude malignancy, a decision must be made between localized resection or orthotopic liver transplant. A liver transplant has the added benefit of correcting the underlying metabolic defect, but it also means a lifetime of immunosuppression and its associated risks. However, either way, patients require life-long medical therapy.
  • Patients must be informed of the potential risks and benefits of each therapy so that they can make the most appropriate decision.
• Renal disease
  • Renal disease associated with G-6-phosphatase deficiency was previously thought to manifest mainly as renal enlargement upon ultrasound examination or hematuria from uric acid stones. However, the initial change in affected patients has been shown to be hyperfiltration, which is a nephropathy similar to diabetes.
  • This increase in the glomerular filtration rate is not observed at birth, but it is present in up to 50% of patients by age 1 year.
  • After several years, progressive proteinuria can be observed that sometimes develops into the nephrotic range. This may be found in up to 70% of patients older than 10 years.
  • Along with the proteinuria, a progressive decline in creatinine clearance and the onset of hypertension may occur.
  • Eventually, dialysis-dependent renal failure occurs approximately 12 years after the first appearance of proteinuria.
  • Most deaths from renal failure occur in older patients who did not receive aggressive dietary management from birth or who did not comply with therapy.
  • Although several theories have been suggested, the exact mechanism of the hyperfiltration is unknown.
• Renal disease management
  • Proper methods to manage associated renal disease are still quite uncertain.
  • Probably the most important factor for preventing renal deterioration is patient compliance with a dietary therapy that maintains euglycemia and reduces hyperlipidemia and counterregulatory hormone excess.
  • Controlling hyperuricemia helps prevent uric acid stones and uric acid nephropathy.
  • If hypertension develops, it should be aggressively controlled to delay the progression of renal damage.
  • The main question remains whether angiotensin-converting enzyme inhibitors decrease hyperfiltration and proteinuria and delay the progression or appearance of overt renal failure, as is observed in diabetes.
  • A reduction in proteinuria has been observed in a few patients treated on an experimental basis, but no formal trials have been published to answer this question. In the absence of any contraindications, it is probably a reasonable choice in the presence of hypertension.
• Hyperuricemia
  • Debate exists regarding when to initiate therapy to treat hyperuricemia.
  • Most clinicians begin when an affected patient has an episode of acute gouty arthritis, uric acid nephrolithiasis, or gouty tophi. However, initiating therapy in asymptomatic patients who have serum urate levels greater than 420 µmol/L (7 mg/dL) also may be reasonable.
  • Treatment usually consists of a dietary review to ensure compliance and 100-300 mg allopurinol daily. Allopurinol should never be started during an acute attack of gout because it may exacerbate the arthritis.
  • Any patient with hyperuricemia should maintain appropriate body weight and limit ethanol consumption.
• Metabolic bone disease
  • Osteopenia and osteoporosis are being increasingly identified in patients with G-6-phosphatase deficiency, but the exact mechanism has not been identified.
  • One possible cause is poor dietary calcium intake and increased urinary calcium excretion without a concomitant rise in 25-vitamin D, parathyroid hormone, or skeletal alkaline phosphatase. This represents an inappropriate response to a negative calcium balance.
  • Compared to age-matched controls, bone mineral content and bone densitometry may be reduced, even in patients as young as 3 years.
  • No clinical trials have been performed on the management of osteoporosis in this population, but it would seem prudent to ensure that the prescribed diet contains adequate calcium and vitamin D. Hopefully, future trials will address the question of antiresorptive therapy such as bisphosphonates.

Surgical Care

• Gastrostomy feeding tube
• • Placement facilitates overnight, continuous drip feedings.
  • Feeding tubes are usually placed shortly after diagnosis, but some clinicians delay placement until age 6-12 months if the diagnosis is made at birth.
  • Pay careful attention to ensure a healthy insertion site, and treat any infection early.
• Liver resection and transplantation
• • Symptomatic hepatic adenomas or possible malignant mass transformation may require resection or liver transplant.
  • On occasion, liver transplantation has been advocated when maximal dietary therapy fails to give metabolic control and normal growth. This is controversial because of the life-long risks incurred by immunosuppression.
  • Available data indicate that patients with GSD type Ia who received a liver transplant have normal metabolic balance, which allows catch-up growth and improves quality of life.
  • Evidence indicates that renal disease (focal segmental glomerulosclerosis) is not prevented or corrected by liver transplantation.

Consultations

• Dietitian with experience in inherited metabolic diseases
• Endocrinologist or gastroenterologist for primary care or to specifically manage lipids, feeding, adequacy of metabolic control, and hepatomegaly, among other aspects
• Nephrologist to help monitor or treat patients with deteriorating renal function or heavy proteinuria
• General or transplant surgeon

Diet

Dietary therapy is the cornerstone of managing GSD. The goal is to provide a diet that supplies a constant amount of glucose during the day and night, while also providing all the essential nutrients for normal growth. At the same time, avoid overfeeding and possible excessive weight gain.

Dietary therapy usually begins in the hospital and requires expert help from an experienced dietitian. The diet may require frequent modification to maximize compliance and metabolic control, while taking the changing nutritional requirements of the growing child into account.

• Three basic dietary modalities
• • Institute frequent feedings of glucose polymer solutions.
  • Use gastric drip-feeding through an enteral feeding tube.
  • Feed uncooked cornstarch, which is a complex carbohydrate that undergoes slow intestinal hydrolysis and provides a constant source of glucose over several hours.
• Infants and young children
• • Studies have shown that maximal metabolic control by maintaining euglycemia and suppressing lactic acidosis can be achieved by giving glucose at a rate of 8-9 mg/kg/min.
  • This may be accomplished with glucose polymer feeds such as Nutramigen given every 2-3 hours around the clock.
  • Alternatively, overnight gastric drip feeds using an enteral pump may be initiated via a gastrostomy tube.
  • Initially, frequently monitor blood glucose and lactate levels to help solidify the most appropriate feeding regimen. The goal is a blood glucose level greater than 4 mmol/L (71 mg/dL) and a lactate level of 4-6 mmol/L.
• Older children
• • After approximately age 2 years, children's glucose requirements decrease to 5-7 mg/kg/min, and their diet should be adjusted appropriately to avoid overfeeding.
  • At this time, uncooked cornstarch may be introduced because pancreatic enzymes are most likely made in sufficient amount to digest the cornstarch.
  • Uncooked starch may be given during or after meals 3 times a day in a dose of 1.5-2 g/kg/meal.
• Adolescents and adults
• • After the pubertal growth spurt, nighttime glucose requirements decrease to 3-4 mg/kg/min. Diets should be adjusted accordingly.
  • Additionally, at this time, overnight drip feeds may possibly be replaced with an uncooked starch portion at bedtime, with or without a second portion in the middle of the night.
  • One study found that a dose of cornstarch of 1.76 ±0.41 g/kg at bedtime allowed up to 7 hours of euglycemic metabolic control in most patients. However, some patients required a second portion after 5 hours.
  • Either way, this regimen allows for a long duration of uninterrupted sleep with good control and no enteral feeding requirements.
• Compliance with appropriately prescribed therapy may be expected to minimize growth and pubertal delay, improve hyperlipidemia, prevent osteopenia, and possibly have a role in preventing or shrinking hepatic adenomas.

Activity

• Encourage patients to maintain a healthy, active lifestyle. This may be beneficial in preventing the excessive weight gain that occurs in some patients. However, remember that exercise may aggravate hypoglycemia, which should be reflected in the dietary plan.
• If massive hepatomegaly or adenomas are present, avoiding contact sports or activities with a risk of abdominal injury may be prudent to protect the liver or avoid hemorrhage into an adenoma.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medication therapy should be primarily directed toward controlling hyperlipidemia and hyperuricemia. However, note that most literature in this area consists of case reports. No randomized controlled trials, aside from dietary therapy, have been performed.

Drug Category: Hypouricemics

Used in the treatment of hyperuricemia, gout, and uric acid nephrolithiasis.

Drug Category: Hypolipidemics

Hyperlipidemia, especially hypertriglyceridemia, is thought to be a risk factor for acute pancreatitis and contributes to the development of atherosclerotic vascular disease.

Drug Name	Niacin (vitamin B-3)
Description	Suppresses hepatic synthesis of very low-density lipoprotein and LDL cholesterol, subsequently lowering triglyceride and total cholesterol levels.
Adult Dose	100 mg PO tid, increasing gradually to 1 g tid as tolerated
Pediatric Dose	100-300 mg PO divided tid
Contraindications	Documented hypersensitivity; active liver disease or unexplained significant increases in AST and ALT; large doses, especially when administered in SR form, are associated with severe hepatotoxicity patients who have a definite and recent history of peptic ulcer disease (can reactivate ulcers)
Interactions	Cutaneous vasodilation may be a problem if high dose used with peripheral dilators such as nitroglycerine; taking aspirin 30-60 min before first dose of day may help alleviate prostaglandin-mediated adverse effects of niacin (eg, flushing, itching); clonidine may inhibit niacin-induced flushing
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in gallbladder disease or diabetes and those predisposed to gout; monitor blood glucose levels; may elevate uric acid levels; pregnancy category C when used in doses greater than RDA

Drug Name	Gemfibrozil (Lopid)
Description	Lowers serum triglyceride and total cholesterol levels while increasing HDL cholesterol levels. Mechanism of action is thought to be decreased hepatic lipogenesis.
Adult Dose	600 mg PO bid 30 min ac
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; gallbladder disease, renal or hepatic insufficiencies
Interactions	May potentiate effects of warfarin; monitor closely if coadministered with lovastatin therapy
Pregnancy	X - Contraindicated in pregnancy
Precautions	Discontinue if no reduction in triglyceride levels is observed after 3 mo of therapy; monitor for abnormal elevation of ALT, AST, LDH, bilirubin, and alkaline phosphatase serum levels; incidence of myositis is higher among patients with renal impairment

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Immediately after diagnosis, the family must receive as much information as possible about the rationale and goals of dietary therapy.
• Parents should feel comfortable with the diet plan and how it will be administered.
• They also must become familiar with the operation of the overnight feeding pump.
• Importantly, give instructions on detecting and emergently treating hypoglycemia.

Further Outpatient Care

• Frequent follow-up is required after diagnosis and management therapy. This helps ensure that the goal of 24-hour euglycemia with normalization of lactate and acidosis is being met.
• Once a patient is on a stable dietary regimen, follow-up may be less frequent but not less than every 6 months.

In/Out Patient Meds

• Gemfibrozil may be considered for hypertriglyceridemia that is unresponsive to dietary therapy.
• Allopurinol helps control hyperuricemia.

Transfer

• A multidisciplinary team experienced with inborn errors of metabolism should handle the initial diagnosis.
• Hypertriglyceridemic pancreatitis, especially if severe or unstable, requires transfer to an appropriate care facility.
• Large, symptomatic, or worrisome hepatic masses with or without hemorrhage may warrant transfer to a center with a liver transplant program.

Deterrence/Prevention

• Given the complexity of management, use of a patient flow chart is advisable to keep track of the multiple variables and indices of treatment. These include the following:
• • Height
  • Weight
  • Growth velocity
  • Pubertal stage
  • Blood glucose
  • Lactate
  • Urate
• The patient should purchase and use a home glucometer to regularly document glycemic control, especially if symptomatic from hypoglycemia.

Complications

• Numerous tests must be performed periodically to screen and monitor for the progression of any complications. These should be part of the flow sheet and include the following:
• • Cholesterol and triglyceride levels
  • Liver enzyme values
  • Creatinine level
  • Creatinine clearance rate
  • Twenty-four–hour urinary protein measurements
  • Alpha-fetoprotein level
  • Bone age determination
  • Abdominal ultrasound examination
  • Bone density measurements

Prognosis

• Prognosis is strongly related to early diagnosis and good life-long compliance with appropriately prescribed and monitored diet therapy.
• Screening for complications may be useful in some cases, but no long-term clinical trials have investigated most nondietary interventions.
• As patients with this disorder live longer, understanding the long-term natural history and better assessing prognosis will become possible.

Patient Education

• Recognition and emergency treatment of hypoglycemia
• Rationale and mechanics of diet therapy (eg, continuous 24-h glucose supply)
• Importance of adhering to dietary therapy to attain normal growth and development
• Importance of regular follow-up to allow frequent reassessment of dietary needs and screening for complications
• Avoiding pharmacologic estrogen preparations, especially in the presence of liver tumors
• Importance of tight supervision and good metabolic control for any pregnancy
• Risks related to having another affected child
• For excellent patient education resources, visit eMedicine's Cholesterol Center and Statins Center. Also, see eMedicine's patient education articles High Cholesterol, Cholesterol FAQs, and Atorvastatin (Lipitor).

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Patients, especially young patients and their families, should receive careful instructions on the importance of monitoring, detecting, and correcting hypoglycemia in order to minimize the risk of long-term brain injury from hypoglycemic episodes.
• Maintaining a high index of suspicion for malignant degeneration of hepatic adenomas that show any change over time is important.
• Although whether using estrogen compounds contributes to adenoma growth in this situation remains unknown, patients with known hepatic adenomas should not use estrogen-containing oral contraceptives.
• Family members of an affected individual should be offered genetic counseling before contemplating pregnancy.

Special Concerns

• Pregnancy
• • Although rare, if a patient has dietary control good enough to allow pubertal development and ovulation, pregnancy is a possibility.
  • In addition to genetic counseling, such patients should be referred to a high-risk pregnancy center for management.
  • Close attention to metabolic control, especially during the first trimester, is important for fetal organogenesis.
  • Avoiding hypoglycemia at any time during pregnancy is important. A severe episode may result in fetal death. The risk of hypoglycemia may be lower in the third trimester because of increased insulin resistance, but rapid fetal growth may increase the glucose requirements and subsequently provoke hypoglycemia. Some clinicians prefer the reintroduction of overnight gastric drip feeds to ensure adequate glucose supply, but no evidence indicates that this regimen is superior to oral uncooked cornstarch every 5 hours overnight.
  • If betamethasone is used for fetal lung maturity, serum lactate levels may rise, presumably from the stimulation of gluconeogenesis.
  • Although a theoretical concern, no reports exist of hepatic adenoma development during the estrogen stimulation of pregnancy.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: May 18, 2007