Glucose-6-Phosphatase Deficiency Treatment & Management

Updated: Jan 03, 2012
  • Author: Lawrence C Wolfe, MD; Chief Editor: George T Griffing, MD  more...
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Treatment

Medical Care

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  • 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. [12]

    • 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 ultrasonographic 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. [13] 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 ultrasonographic 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 μ mol/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.

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Surgical Care

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  • 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.

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Consultations

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  • 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

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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.

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Activity

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  • 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.

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