Glucose-6-Phosphatase Deficiency Workup

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

Laboratory Studies

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  • 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 plasma glucose 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

    • 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.

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Imaging Studies

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  • Hepatic ultrasonography [11]

    • Ultrasonography 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, ultrasonographic 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 ultrasonographic 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 ultrasonography: Findings indicate that up to 65% of patients have evidence of renal stones or calcinosis upon ultrasonographic 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.

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Other Tests

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  • 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.

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Procedures

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  • 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.

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Histologic Findings

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

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