AUTHOR INFORMATION

Section 1 of 12

Authored by Karl S Roth, MD, Chair, Professor, Department of Pediatrics, Creighton University School of Medicine

Karl S Roth, MD, is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Association for the Advancement of Science, American College of Nutrition, American Pediatric Society, American Society for Clinical Nutrition, American Society of Nephrology, Association of American Medical Colleges, Medical Society of Virginia, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research, and Southern Society for Pediatric Research

Edited by Edward Kaye, MD, Vice President of Clinical Research, Genzyme Corporation; Robert Konop, PharmD, Director, Clinical Account Management, Ancillary Care Management, Inc; Hagop Youssoufian, MSc, MD, Medical Director, Adjunct Associate Professor, Clinical Discovery Department, Bristol-Myers Squibb; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Karl S Roth, MD
Editor's Email:	Edward Kaye, MD

eMedicine Journal, October 14 2005, VOLUME 6, Number 10

INTRODUCTION

Section 2 of 12

Background: In 1929, von Gierke provided the initial description of glycogen-storage disease type I (GSD I) from autopsy reports of 2 children whose large livers contained excessive glycogen. (He also reported similar findings in the kidneys.) Both children had frequent nosebleeds before their deaths, consistent with histories documented in today's patients.

In 1952, Cori and Cori reported 6 similar patients. Two had almost total deficiency of hepatic glucose-6-phosphatase, whereas the remaining 4 had normal enzyme activity. These authors recognized that defects in the enzymology of hepatic GSD might cause a heterogeneous group of disorders. However, the mystery of patients with these clinical symptoms despite normal phosphatase activity remained unsolved until 1978, when Narisawa et al identified a defect in intracellular transport of the enzyme substrate.

In recognition of the original clinical description of the disease, the type I Cori classification has been preserved; GSD type Ia (GSD Ia) designates the true enzyme defect, and GSD type Ib (GSD Ib) designates the intracellular transport defect. Because free glucose is the product of the hepatic glucose-6-phosphatase reaction, either type leads to accumulation of liver glycogen, accompanied by fasting hypoglycemia. Hepatomegaly, the natural consequence of glycogen accumulation, is the clinical hallmark of the disease.

Pathophysiology: The liver loses its capacity as a glucose-homeostatic organ because of a fundamental inability to release free glucose. GSD I (subtypes Ia and Ib) is one of the few genetic-biochemical causes of newborn hypoglycemia. The usual homeostatic mechanism cannot halt the rapid drop in blood glucose levels that normally occurs over the first several hours after birth (reflecting consumption of maternal glucose); the decrease continues. This decrease in circulating glucose can be precipitous, resulting in no measurable blood level. Seizures, cyanosis, and apnea may ensue. In the older child, repeated episodes of hypoglycemia may result in brain damage, as measured on performance testing and assessment of brainstem auditory evoked potentials.

In the hepatocyte, the glycogen catabolic machinery responds normally to stimuli caused by hypoglycemia (eg, neural, hormonal), ending in a flood of glucose-6-phosphate that cannot be released from the cell. However, glucose-6-phosphate is also the substrate for glycolysis and produces lactate. Lactate exits the hepatocyte, causing clinically significant lactic acidemia in proportion to the degree of stimulus for glycogen breakdown. The accumulation of lactic acid in blood can cause true acidosis with a large anion gap, a characteristic of GSD I.

The immense increase in the intracellular phosphorylated intermediate compounds of glycolysis concurrently inhibits rephosphorylation of adenine nucleotides, activating the nucleic acid degradation pathway and resulting in increased uric acid, the end product. Hyperuricemia can reach levels that require use of xanthine oxidase inhibitors to prevent nephrolithiasis. Nephrolithiasis secondary to increased uric acid is a constant threat to the patient whose disease is poorly controlled.

Severe hypoglycemia stimulates epinephrine secretion, which activates lipoprotein lipase and release of free fatty acids. These fatty acids are transported to the liver, where they are used for triglyceride synthesis and are exported as very-low-density lipoprotein (VLDL), which is elevated in these patients. Paradoxically, even in the face of hypoglycemia, patients with GSD I do not develop significant ketosis because the abundance of acetyl coenzyme A (CoA) derived from glycolysis activates the acetyl CoA carboxylase enzyme that produces malonyl CoA in the first step of fatty acid synthesis. Because malonyl CoA inhibits transport of fatty acid into the mitochondrion, beta-oxidation of fatty acids for energy to support the hypoglycemic cells does not occur. This causes a continuing drop in blood glucose levels and explains the absence of ketone bodies.

Nosebleeds experienced by the patients in von Gierke's report probably resulted from the bleeding tendency characteristic of GSD Ia and Ib. This tendency resembles von Willebrand disease and suggests alterations in membrane glycoprotein synthesis. Although such changes have been found, no definitive explanation addresses how these alterations actually cause defective platelet aggregation.

In GSD Ib, patients are susceptible to gram-positive infections. Neutrophils from patients with GSD Ib have a significantly impaired respiratory-burst response to stimuli compared with type Ia neutrophils. Because the respiratory burst generates superoxide, which is a major defense against gram-positive organisms, a defect in this response would be expected to render the neutrophils susceptible, causing neutropenia and diminishing the individual's resistance to infection. There is evidence to suggest that microsomal transport of glucose-6-phosphate has a role in antioxidant protection of the neutrophil; therefore, a genetic defect in the transporter could impair cellular function and lead to apoptosis.

Growth is generally impaired in patients with type I GSD, though most patients' growth can be improved with good dietary therapy. However, a subset of patients exists whose growth remains unimproved by treatment; the endocrine parameters of growth in this group are not measurably different from the larger number of patients.

Several studies have also documented a decreased bone mineral density in some, but not all patients with GSD type I. One such investigation reported no correlation between bone mineral density and turnover markers, indicating an uncoupling of bone turnover in GSD patients.

For many years, it has remained unclear why children with GSD type I so often have severe anemia in the absence of renal function compromise. Some have recently proposed a central role of hepcidin production by hepatic adenomas in GSD type I. Hepcidin is a peptide hormone that is also a key regulator of the egress of cellular iron; in excess, it may interfere with intestinal iron transport as well as iron release from macrophages.

Although extremely rare, subtypes Ic and Id have occurred. Individuals with these forms probably have unusual mutations in the translocase gene (11q23).

Frequency:

• In the US: The lack of newborn screening precludes reliable estimates of the incidence. The only estimates are for glycogen storage disorders as a group, which suggest an incidence of 1 case per 20,000-25,000 births. GSD I is unlikely to occur more frequently than 1 case in 50,000 infants.

  In an odd quirk, clinical symptoms of biotinidase deficiency in patients with underlying GSD type Ia have been associated with marked elevations in biotinidase levels on serum assay. However, mass screening for biotinidase deficiency does not reveal elevated activity.

Mortality/Morbidity: The affected newborn is at risk for all neonatal hypoglycemic complications. (Older children under treatment may experience symptoms identical to those listed below with impending hypoglycemia.)

• Hypoglycemic complications are entirely nonspecific and include the following:
  
  
  • Twitching
    
    
  • Cyanosis
    
    
  • Seizures
    
    
  • Irritability
    
    
  • Apathy
    
    
  • Hypotonia
    
    
  • Hypothermia
    
    
  • Apnea
    
    
  • Coma (may be secondary to cerebral edema from combined hypoglycemia and hypoxia secondary to hypoglycemic seizures)

• Long-term consequences of glycogen storage include the following:
  
  
  • Hepatic adenomas
    
    
  • Hepatocellular carcinoma
    
    
  • Progressive renal insufficiency
    
    
  • Hyperuricemic nephrocalcinosis
    
    
  • Hyperlipidemic xanthomas
    
    
  • Short stature
• Hypoglycemic brain damage

• In GSD Ib, secondary consequences of neutrophilic abnormalities include multiple and recurrent infections, brain abscess, and pseudocolitis.

Sex: GSD Ia and Ib occur with equal frequency in both sexes.

Age: As genetic disorders, both types are present at conception, with clinical onset at birth.

CLINICAL

Section 3 of 12

History:

• Initial symptoms of neonatal hypoglycemia occur shortly after birth, and episodes do not respond to glucagon administration. Symptoms include the following:
  • Tremors

  • Irritability

  • Cyanosis

  • Seizures

  • Apnea

  • Coma



• Older infants may present with the following:
  • Frequent lethargy

  • Difficult arousal from overnight sleep

  • Tremors

  • Overwhelming hunger

  • Poor growth

  • Apparent increase in abdominal girth, although extremities appear thin

  • A doll-like facial appearance caused by adipose tissue deposition in the cheeks



• Young children with GSD Ia may experience nosebleeds.



• Young children with GSD Ib may have frequent otitides, gingivitis, and boils.



• Symptoms of severe hypoglycemia in patients of all ages are likely to follow any illness that causes mild anorexia or fasting (eg, viral gastroenteritis).



• In middle childhood, affected patients may manifest evidence of rickets and anemia.



• Patients with GSD Type Ib at all ages may be affected by a Crohn-like ileocolitis (pseudocolitis). The severity of the primary disorder is not correlated with the intestinal symptoms.

Physical:

• Affected infants are healthy at birth, though some are born with an enlarged liver.


• • Careful abdominal examination is mandatory for any neonate with hypoglycemia.
  
  
  
  • Abdominal protuberance develops early because of massive hepatomegaly.
  
  
  
  • No splenomegaly occurs.
  
  
  
  • The liver is firm and uniform in consistency in early life but may become nodular with the development of adenoma.
  
  
  
• The patient may present with poor growth, short stature, and rachitic changes.



• Gingivitis and compromised dentition may be present.



• Xanthoma may be found on extensor surfaces, such as the elbows and knees.



• Ultrasonographic evaluation may show large kidneys in affected patients of all ages. Proteinuria may accompany this finding.



• In addition to hypoglycemia, an increased plasma lactate value is a characteristic laboratory finding in a symptomatic newborn with GSD I. The increased lactate originates from the flooding of the glycolytic pathway by glucose-6-phosphate, which is derived from breakdown of glycogen but which cannot be cleaved to free glucose and is released into blood.

Causes:

• GSD Ia and Ib are autosomal recessive genetic traits caused by mutations at loci 17q21 and 11q23, respectively.



• GSD Ia is caused by deficient activity of the enzyme glucose-6-phosphatase, representing at least 14 distinct allelic variants.



• GSD Ib is caused by deficiency of glucose-6-phosphate translocase, which is responsible for importing glucose-6-phosphate from the cytosol to the interior of the microsome, thus bringing substrate into contact with enzyme. To date, allelic variation in this disorder has not been explored.

DIFFERENTIALS

Section 4 of 12

Biotinidase Deficiency
Constitutional Growth Delay
Crohn Disease
Epistaxis
Fructose 1-Phosphate Aldolase Deficiency (Fructose Intolerance)
Glycogen-Storage Disease Type I
Glycogen-Storage Disease Type II
Glycogen-Storage Disease Type III
Glycogen-Storage Disease Type IV
Glycogen-Storage Disease Type V
Glycogen-Storage Disease Type VI
Growth Failure
Growth Hormone Deficiency
Hepatoblastoma
Hepatocellular Carcinoma
Liver Tumors
[Metabolic Bone Disease]

Other Problems to be Considered:

Niemann-Pick disease, type A (classic infantile form)
Type 1 hyperlipoproteinemia

WORKUP

Section 5 of 12

Lab Studies:

• The initial laboratory workup should include blood glucose with electrolytes. If the blood glucose concentration is low, electrolyte results may permit calculation of an increased anion gap, which suggests lactic acidemia.



• Studies of liver function, plasma uric acid, and urinary creatinine clearance are essential.

• Perform a CBC and differential.


• • In GSD Ia, the WBC count is generally within reference ranges because the defect does not affect leukocyte function.

  • In contrast, GSD Ib causes chronic granulocytopenia due to the impaired function of the neutrophils, particularly in relation to gram-positive organisms.
  
  
  
• Perform a coagulation profile to include bleeding time tests.

Imaging Studies:

• Ultrasonography of liver and kidneys may be useful.


• • Abdominal ultrasonography can enable reasonable estimates of liver and kidney size. These estimates are especially useful during treatment of chronic GSD because the relative size of the liver is expected to diminish with growth of the child.
  
  
  
  • Ultrasonography may also be useful late in the clinical course to provide a baseline for evaluating nodules.
  
  
  
• Bone-density studies may be useful in middle childhood to identify patients who may have diminished bone density in adolescence.

Other Tests:

• Glucagon administration produces no hyperglycemic response, though it markedly increases the plasma lactic acid level.



• Oral (PO) administration of galactose 1.75 g/kg causes no change in blood glucose values, though plasma lactic acid levels markedly increase.

Procedures:

• Always directly measure glucose-6-phosphatase activity in the liver before and after detergent treatment of the homogenate, especially when activity appears to be within the reference ranges before treatment.



• Open biopsy is usually needed to obtain sufficient tissue for this assay; therefore, measure all other parameters before the procedure is performed.

TREATMENT

Section 6 of 12

Medical Care:

• Diagnostic evaluation is performed most safely in a hospital, especially in infants, because of the potential for severe hypoglycemia. Many untreated children will have been admitted often by a hematologist or gastroenterologist for the diagnosis of massive hepatomegaly.



• Young infants require continuous nasogastric (NG) tube feedings to sustain blood sugar levels.


• • Older children usually can be switched to raw cornstarch feedings, which sustain blood glucose values for 4-6 hours.
  
  
  
  • Large quantities of raw cornstarch may be necessary, because overall utilization of this material is impaired in patients compared with healthy control subjects.
  
  
  
• Pay scrupulous attention to the dental and oral health of patients with GSD Ib to reduce incidence of infection.



• Any intercurrent infection that causes decreased intake requires intravenous (IV) glucose support until resolution.

Surgical Care:

• Surgery is usually unnecessary after initial diagnosis by means of open liver biopsy.



• Promptly attend to any skin infection in patients with GSD Ib because deep-tissue extension requiring surgical debridement and plastic reconstruction may develop.



• In older children with GSD Ib, cautiously evaluate abdominal pain for pseudocolitis.



• Perform annual ultrasonographic surveillance for hepatic adenomas, which may require surgical removal.

Consultations:

• Biochemical genetics specialist



• Nephrologist

Diet:

• Diet, the mainstay of therapy for both types of GSD I, requires close monitoring and adjustment by a highly specialized nutritionist.



• The fundamental principle of diet management for these patients is maintenance of a steady-state balance between circulating glucose and existing glycogen stores. Consequently, a chief aim is to avoid excessive carbohydrates and calories while supplying adequate calories and protein for growth.



• Because of the triglyceridemia characteristic in this disorder, counsel the patient to avoid high lipid intake.



• Most biochemical parameters can be substantially normalized and liver size can be reduced by approaching glucose homeostasis by means of overnight feeding.



• Overnight NG feedings should be administered only by a pump equipped with an alarm in case of flow interruption.



• When pancreatic amylase reaches sufficient activity in children older than 2-3 years, overnight feeding usually is replaced by raw cornstarch at bedtime and very early morning hours.

Activity:

• Instruct the patient to avoid all contact sports because of the propensity for infection and bleeding, as well as the potential for liver damage.



• Encourage the patient to engage in all other physical activities up to individual limits. Personal limitations should be the basis for participation in school activities.

MEDICATION

Section 7 of 12

GSD Ia has no specific medication requirement beyond prophylactic PO iron and prompt treatment of intercurrent infections (which might interrupt PO intake).

Regarding GSD Ib, in addition to prophylactic PO iron and prompt treatment of intercurrent infections, weekly administration of granulocyte colony-stimulating factor (GCSF) is critical. GCSF is now standard therapy to prevent or reduce incidences of serious infection. GCSF also may delay or prevent pseudocolitis symptoms.

Drug Category: Trace elements -- These are inorganic substances found in small amounts in the tissues and required for various metabolic processes.

Drug Name	Iron sulfate (Feosol) -- Nutritionally essential inorganic substance.
Adult Dose	60 mg (as elemental iron) PO qd
Pediatric Dose	1-2 mg/kg/d (as elemental iron) PO; not to exceed 15 mg/d
Contraindications	Documented hypersensitivity; hemochromatosis, hemosiderosis, or hemolytic anemias
Interactions	Ascorbic acid enhances absorption; interferes with tetracycline absorption; milk, cereal, tea, coffee, eggs, dietary fiber, and antacids impair absorption
Pregnancy	A - Safe in pregnancy
Precautions	Gastrointestinal upset; iron toxicity observed with ingestion of large amount and can be fatal, especially in children; parenteral (IV) administration may cause several reactions including headaches, malaise, fever, generalized lymphadenopathy, arthralgia, and urticaria; can cause severe anaphylaxis, phlebitis at infusion site

Drug Category: Colony stimulating factors -- These agents act as hematopoietic growth factors that stimulate the development of granulocytes. They are used to treat or prevent neutropenia when patients are receiving myelosuppressive cancer chemotherapy and to reduce neutropenia associated with bone marrow transplantation. These drugs are also used to mobilize autologous peripheral blood progenitor cells for bone marrow transplantation and to manage chronic neutropenia.

Drug Name	Filgrastim (G-CSF, Neupogen) -- GCSF that activates and stimulates production, maturation, migration, and cytotoxicity of neutrophils.
Adult Dose	5 mcg/kg SC qwk
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Synergistic effects with interleukin-3 (increase megakaryocyte and platelet production)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Do not use 12-24 h before or 24 h after cytotoxic chemotherapy because increases sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy; do not admix with sodium chloride; caution in gout and psoriasis; adverse effects include fever, bone pain, and flu-like symptoms

FOLLOW-UP

Section 8 of 12

Further Inpatient Care:

• Conditions that reduce PO intake require IV glucose to maintain blood sugar and to avoid complications of severe hypoglycemia.

Further Outpatient Care:

• Close nutritional and biochemical genetic follow-up is critical, especially during initial and pubertal growth periods.



• Patients should be seen by subspecialists at least every 6 months.

In/Out Patient Meds:

• No medications are required for GSD Ia.



• Patients with GSD Ib require GCSF on a weekly basis.

Transfer:

• Consider transferring any patient who is admitted for any reason other than routine IV fluid administration for blood glucose support.

Complications:

• Severe hypoglycemia, cerebral edema, coma, death



• Hepatic adenoma and/or adenocarcinoma



• Glomerular hyperfiltration and glomerulosclerosis



• Brain damage



• Severe anemia



• Growth failure

Prognosis:

• Patients receiving proper treatment should have a reasonable life span.

Patient Education:

• Teach parents of infants how to insert an NG feeding tube.



• Teach family members how to test blood glucose levels.



• Teach family members and older children how to recognize signs of impending hypoglycemia.



• Provide intensive nutritional education to patients so they can assist in their own dietary control as early as possible.



• For excellent patient education resources, visit eMedicine’s Ear, Nose, and Throat Center. Also, see eMedicine’s patient education article Nosebleeds.

MISCELLANEOUS

Section 9 of 12

Medical/Legal Pitfalls:

• Percutaneous liver biopsy in an unrecognized patient with postoperative hemorrhage



• Administration of steroid or other symptomatic therapy in a hypoglycemic newborn who suffers hypoglycemic damage after discharge



• Failure to distinguish GSD Ia from Ib, resulting in administration of GCSF to a patient with GSD Ia, which can cause life-threatening or disfiguring infection



• Failure to maintain adequate surveillance for hepatic adenomas

TEST QUESTIONS

Section 10 of 12

CME Question 1: Which of the following signs and symptoms clinically distinguishes glycogen-storage disease type Ia (GSD Ia) from type Ib (GSD Ib)?

A: Bleeding tendency due to platelet dysfunction
B: Severity of hypoglycemia
C: Development of glomerulosclerosis
D: Neutrophilic dysfunction
E: None of the above

The correct answer is D: In GSD Ib, patients have increased susceptibility to gram-positive infections. Neutrophils from patients with GSD Ib show clinically significant impairment in respiratory-burst response to stimuli compared with type Ia neutrophils. Because the respiratory burst generates superoxide, a major defense against gram-positive organisms, a defect in this response would be expected to render the neutrophils susceptible, cause neutropenia, and diminish the individual`s resistance to infection.

CME Question 2: What is the aim of nutritional therapy in the treatment of glycogen storage disease type I (GSD I)?

A: Prevention of hypoglycemia
B: Reduction in liver size
C: Improvement of growth
D: Retardation of glycogen synthesis
E: All of the above

The correct answer is E: Nutritional therapy should aim to do all of the above. The fundamental principle of diet management for patients with GSD I is maintenance of a steady-state balance between circulating glucose and existing glycogen stores. Consequently, a chief aim is to avoid excessive carbohydrates and calories while supplying adequate calories and protein for growth.

Pearl Question 1 (T/F): In addition to hypoglycemia, increased plasma lactate is a key laboratory finding in a symptomatic newborn with glycogen-storage disease type I (GSD I).

The correct answer is True: Increased plasma lactate level is a characteristic of GSD I. The increased lactate value originates from the flooding of the glycolytic pathway by glucose-6-phosphate, which is derived from breakdown of glycogen but which cannot be cleaved to free glucose and released into blood.

Pearl Question 2 (T/F): Glucagon is an appropriate emergency treatment for hypoglycemia in glycogen-storage disease type I (GSD I).

The correct answer is False: An intravenous (IV) bolus of glucose is the appropriate step. Because of the biochemical nature of the defect, glucagon elicits no response.

Pearl Question 3 (T/F): Glomerulosclerosis is the primary risk factor for the kidney in patients with glycogen-storage disease type I (GSD I).

The correct answer is False: Because of the characteristic elevation of blood uric acid, nephrolithiasis secondary to uric acid also is a constant threat to the patient whose disease is poorly controlled.

Pearl Question 4 (T/F): The WBC count in a patient with glycogen-storage disease type Ia (GSD Ia) is likely to be within reference ranges.

The correct answer is True: In GSD Ia, the WBC count generally is within reference ranges because the defect does not affect leukocyte function. In contrast, glycogen-storage disease type Ib (GSD Ib) causes chronic granulocytopenia because of the impaired function of the neutrophils, particularly in relation to gram-positive organisms.

PICTURES

Section 11 of 12

Caption: Picture 1. Microsome is shown in relation to the substrate, glucose-6-phosphate, which has been released from cytosolic glycogen. This substrate is transferred across the microsomal membrane by the protein translocase, where by glucose-6-phosphatase acts on it to release free glucose and inorganic phosphate. Patients with glycogen-storage disease type Ia are genetically deficient in glucose-6-phosphate activity, while those affected with glycogen-storage disease type Ib lack translocase.
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BIBLIOGRAPHY

Section 12 of 12

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• Roe TF, Thomas DW, Gilsanz V, et al: Inflammatory bowel disease in glycogen storage disease type Ib. J Pediatr 1986 Jul; 109(1): 55-9[Medline].
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• Visser G, Rake JP, Labrune P, et al: Granulocyte colony-stimulating factor in glycogen storage disease type 1b. Results of the European Study on Glycogen Storage Disease Type 1. Eur J Pediatr 2002 Oct; 161 Suppl 1: S83-7[Medline].
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