Von Gierke's Syndrome (Type I Glycogen Storage Disease)

Synonyms: GSD1

Von Gierke described the disease that bears his name in 1929.¹ There are 7 variations of glycogen storage disease (GSD) of which his is designated type I as it represents the largest group at about 25% of all GSD. He called it hepatonephromegalia glycogenica but in 1952 the association with glucose-6-phosphatase was described by Cori and Cori.² They had type III GSD named after them.

The disease has been further divided as the biochemistry has been elucidated. Glucose-6-phosphatase deficiency is the cause of type Ia and it should not be confused with glucose-6-phosphate dehydrogenase deficiency. There is a specific translocase deficiency in type Ib but they also have altered neutrophil functions predisposing them to gram-positive bacterial infections. Two other translocase deficiencies have been described to give types Ic and Id.

For practical purposes, there are 2 major forms. Type Ia has deficient glucose-6-phosphatase in the liver and type Ib has normal activity.

The abnormality has been located on gene map locus 17q21 for type Ia and 11q23 for type Ib. Type Ic has been mapped to 11q23-q24.2 and type Id to 11q23-q24.³

The condition is inherited as an autosomal recessive which means that both parents are carriers and the chance of a sibling being affected is 1 in 4. There is equal sex distribution and no racial difference in frequency.

There is an enzyme defect in glucose-6-phosphatase so that glucose-6-phosphate cannot be converted into free glucose but is metabolised to lactic acid or incorporated into glycogen. The liver and kidney are involved and hypoglycaemia is a major feature. Large quantities of glycogen are formed and stored in hepatocytes, renal and intestinal mucosa cells. Enlarged liver and kidneys are an important feature. Abnormalities of lipids may lead to xanthoma formation. Uric acid is often elevated and may cause clinical gout. Endogenous glucose production is not fully inhibited but in young people, production of free glucose reaches half that of healthy individuals, whilst adult patients may produce as much as two thirds of the normal amount of free glucose. Galactose, fructose, and glycerol are metabolised to lactate which is used in the brain as an alternative source of energy. The elevated blood lactate levels cause metabolic acidosis. Uric acid production is increased as glucagon levels are raised and there is competition with lactate for renal excretion.⁴

Presentation is usually soon after birth but can be a little later.

• Shortly after birth hypoglycaemia and lactic acidosis often cause convulsions.
• More moderate hypoglycaemia can cause irritability, pallor, cyanosis, hypotonia, tremors, loss of consciousness and apnoea.
• Some children have diarrhoea due to pseudocolitis.
• There is a characteristic rounded "doll's face" due to deposition of fat.
• During the first weeks of life the liver is normal in size but it enlarges, sometimes very considerably, and the mother may note abdominal enlargement.
• Growth is retarded and height is usually below the 3rd centile. Puberty is delayed but mental development is normal.
• Skin and mucous membranes may show eruptive xanthomas or gouty tophi on the extensor surfaces of the extremities. Uric acid arthropathy can develop.
• Altered platelet function can cause bleeding, especially epistaxis and this may result in iron deficiency anaemia.

Basic Tests

• Blood glucose and pH are usually low with elevated lactate, uric acid, triglyceride and cholesterol.
• Creatinine and urea may be raised if renal function is impaired.
• Lactic acidosis may simply be suggested by a high anion gap when electrolytes are measured.
• Older patients may show anaemia, neutropenia and proteinuria or at least microalbuminuria.

Special Tests

• Ultrasound should be used to assess and monitor the size of liver and kidneys and to detect possible hepatic adenomas and nephrocalcinosis.
• Glucagon does not cause a rise in glucose levels, but it does raise lactic acid levels.
• Oral galactose and fructose fail to increase glucose levels but plasma lactic acid levels increase.
• Glucose tolerance test progressively lowers lactic acid levels over several hours.

Tissue Diagnosis

• Definitive diagnosis involves assessment of glucose-6-phosphatase activity in fresh and frozen liver tissue specimens. To assess translocases, an open surgical liver biopsy is needed to obtain an adequate specimen.
• Histology shows increased amounts of normal glycogen, as well as fatty infiltration of the liver.
• Kidneys show glomerular hypertrophy. There is glomerulosclerosis and renal failure is a significant cause of morbidity and mortality.⁵

Diet and Lifestyle

• The main aim of treatment is to correct hypoglycaemia and maintain normoglycaemia. Young infants require a nasogastric tube overnight to deliver glucose. Older infants and children eat raw cornstarch to give slow release of glucose by day but nasogastric feeding by night is still required to prevent hypoglycaemia and associated metabolic problems. It is thought likely that preventing hypoglycaemia, that is especially a problem at night, will reduce complications.⁶
• Intake of fructose and galactose should be restricted as they do not increase glucose levels but it does increase lactic acid.
• Restriction of lipids is advised but statins are not used.
• Physical activity does not have to be restricted but rough games and contact sports should be avoided because of the bleeding tendency and the risk of rupture to an enlarged liver.

Drugs and Surgery

• Blood loss may require oral iron and uric acid levels may necessitate allopurinol. Treatment of hyperuricaemia and pyelonephritis protect renal function.
• Diazoxide to maintain blood glucose has been disappointing.
• Liver transplantation for primary disease or for hepatocellular carcinoma seems effective although the immunosuppresion may cause deterioration of renal function.⁷ Transplantation of hepatocytes appears to have had only temporary benefit.⁸

• Acute hypoglycaemia may be fatal or cause brain damage.
• Frequent infections in type Ib require intravenous therapy to correct hypoglycaemia and intravenous antibiotics to control infections.
• Bacterial infections and cerebral oedema are caused by prolonged hypoglycaemia and metabolic acidosis. Patients with type Ib are susceptible to bacterial infections including those of the CNS.
• Chronic metabolic lactic acidosis and changes in the proximal renal tubule cells can cause osteopenia and rickets with severe skeletal deformities or fractures. These impair mobility.
• Elevated uric acid causes a decrease in the glomerular function with proteinuria, haematuria, hypertension and chronic renal failure. Incomplete distal tubular acidosis sometimes causes hypercalciuria, nephrocalcinosis and renal stones.
• Older children and young adults require ultrasound assessment of the liver at least once a year.
• Hepatic adenomas usually develop in late teens and require careful follow-up in case of transformation to hepatocellular carcinoma although some tumours are embryonic hepatoblastomas. There is male to female ratio of 2:1 compared with a female preponderance that is usual in hepatocellular carcinoma. It is thought that adequate glucose feeding will reduce the risk of malignant change and may even reverse it.⁹ However, the policy is not infallible.¹⁰
• Liver transplantation is a final resort when conservative measures have failed or with malignant change of hepatic adenomas. It can improve quality of life with metabolic control and permit a catch up in growth but it does not prevent renal disease.¹¹
• Early death is usually caused by acute metabolic complications of hypoglycaemia or acidosis, bleeding and in patients with type Ib infections are a problem. Improving care and treatment have reduced the early mortality.
• Renal failure, hypertension or malignant change of hepatic adenomas may cause mortality in adolescents and young adults.

Survival to adulthood was previously rare but is now quite frequent. Long term follow up shows that problems are common.^12,13

• Hepatomegaly 100%. Often the hepatic edge is over 10cm below the costal margin.
• Short stature 90%. It is usually below the 3rd centile.
• Hepatic adenomas 75%
• Anaemia 81%
• Proteinuria or microalbuminuria 67%
• Renal calcification 65%
• Osteopenia, fractures or both 27%
• Raised uric acid 89%
• Raised serum cholesterol in 76% and triglycerides in 100%

Edgar Otto Conrad von Gierke was a German pathologist who was born in 1877 and died in 1945. He studied in Heidelberg, Breslau, and Berlin and spent a short while at the Cancer Institute in London. In 1910 he was appointed professor of bacteriology at the Technische Hochschule in Karlsruhe until his retirement in 1938. His work on the disease that bears his name was published in 1929.¹⁴