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Case details

A 12- year-old girl who had a grossly enlarged abdomen reported to OPD . She had a history of frequent episodes of weakness, sweating and pallor that were eliminated by eating. Her development had been slow; she sat at the age of 1 year, walked unassisted at the age of 2 years, and was doing poorly in the school.

Physical examination revealed normal blood pressure,temperature and a normal pulse rate but a sub normal weight (23 Kg).The liver was enlarged, firm and was descended in to pelvis. The spleen was not palpable,nor were the kidneys. The remainder of the physical examination was within the normal limits.

Laboratory investigation report revealed, low blood glucose, low p H, high lactate, triglycerides, ketones and high free fatty acids. The liver biopsy revealed high glycogen content. Hepatic glycogen structure was normal. The enzyme assay performed on the biopsy tissue revealed very low glucose-6- phosphatase levels.

What is the probable diagnosis?

What is the possible treatment for this patient?

Case details

The girl is suffering from Von –Gierke’s disease. The clinical picture, biochemical findings, hypoglycemia and increased Hepatic Glycogen stores are all characteristic of Von –Gierke’s disease.

Von –Gierke’s disease

Glycogen storage disease (GSD) type I, is also known as Von Gierke’s disease or hepatorenal Glycogenesis. Von Gierke  described the first patient with GSD type I in 1929.

Basic concept- Glycogen is a readily mobilised storage form of glucose. It is a very large, branched polymer of glucose residues that can be broken down to yield glucose molecules when energy is needed. Most of the glucose residues in glycogen are linked by α-1,4-glycosidic bonds. Branches at about every tenth residue are created by α-1, 6-glycosidic bonds. 

Figure-1- showing structure of Glycogen
Glycogen is not as reduced as fatty acids are and consequently not as energy rich.

Why do animals store any energy as glycogen? Why not convert all excess fuel into fatty acids? 

Glycogen is an important fuel reserve for several reasons-

1)  The controlled break down of glycogen and release of glucose increase the amount of glucose that is available between meals. Hence, glycogen serves as a buffer to maintain blood-glucose levels.

2)   Glycogen’s role in maintaining blood-glucose levels is especially important because glucose is virtually the only fuel used by the brain, except during prolonged starvation.

3)  Moreover, the glucose from glycogen is readily mobilised and is therefore a good source of energy for sudden,strenuous activity.

4)  Unlike fatty acids, the released glucose can provide energy in the absence of oxygen and can thus supply energy for anaerobic activity.

The two major sites of glycogen storage are the liver and skeletal muscle. The concentration of glycogen is higher in the liver than in muscle (10% versus 2% by weight), but more glycogen is stored in skeletal muscle overall because of its much greater mass. Glycogen is present in the cytosol in the form of granules ranging in-

 Figure-2- showing glycogen granules

-diameter from 10 to 40 nm .In the liver,glycogen synthesis and degradation are regulated to maintain blood-glucose levels as required to meet the needs of the organism as a whole. In contrast,in muscle, these processes are regulated to meet the energy needs of the muscle itself.

An Overview of Glycogen Metabolism

Glycogen degradation and synthesis are relatively simple biochemical processes.

Glycogen degradation consists of three steps:

 (1) The release of glucose 1-phosphate from glycogen,

(2) The remodelling of the glycogen substrate to permit further degradation, and

 (3) The conversion of glucose 1-phosphate into glucose 6-phosphate for further metabolism. (See Figure-2)

The glucose 6-phosphate derived from the breakdown of glycogen has three fates –

(a) It is the initial substrate for Glycolysis,

(b) It can be processed by the pentose phosphate pathway to yield NADPH and ribose derivatives; and

(c) It can be converted into free glucose for release into the bloodstream.

 This conversion takes place mainly in the liver and to a lesser extent in the intestines and kidneys.


 Figure -3- Showing glycogen degradation and the fate of glucose-6- phosphate.

Glycogen synthesis -requires an activated form of glucose, uridine diphosphate glucose (UDP-glucose), which is formed by the reaction of UTP and glucose 1-phosphate. UDP-glucose is added to the nonreducing end of glycogen molecules. Branching takes place after the addition of at least 12 glucose residues. As is the case for glycogen degradation, the glycogen molecule must be remodeled for continued synthesis.

The regulation of these processes is quite complex. Several enzymes taking part in glycogen metabolism allosterically respond to metabolites that signal the energy needs of the cell. These allosteric responses allow the adjustment of enzyme activity to meet the needs of the cell in which the enzymes are expressed. Glycogen metabolism is also regulated by hormonally stimulated cascades that lead to the reversible phosphorylation of enzymes, which alters their kinetic properties. Regulation by hormones allows glycogen metabolism to adjust to the needs of the entire organism. By both these mechanisms,glycogen degradation is integrated with glycogen synthesis. 

Figure-4 – showing an overview of glycogen metabolism

 Pathophysiology of Von –Gierke’s disease

Because of insufficient G6Pase activity,G6P cannot be converted into free glucose, but G6P is metabolised to lactic acid or incorporated into glycogen. In this way, large quantities of glycogen are formed and stored as molecules with normal structure in the cytoplasm of hepatocytes and renal and intestinal mucosa cells; therefore, enlarged liver and kidneys dominate the clinical presentation of the disease.

The chief biochemical alteration is hypoglycemia, while secondary abnormalities are hyperlactatemia, metabolic acidosis, hyperlipidemia, and hyperuricemia.

Hypoglycemia– The deficiency of G6Pase blocks the process of glycogen degradation and gluconeogenesis in the liver, preventing the production of free glucose molecules. As a consequence, patients with GSDtype I have fasting hypoglycemia. Hypoglycemia inhibits insulin secretion and stimulates glucagon and cortisol release.

Hyperlactatemia and acidosis– Undegraded G6P is metabolised to lactate, which is used in the brain as an alternative source of energy. The elevated blood lactate levels cause metabolic acidosis.

Hyperuricemia– Blood uric acid levels are raised because of the increased endogenous production and reduced urinary elimination caused by competition with the elevated concentrations of lactate, which should be excreted.

Hyperlipidemia– Elevated endogenous triglyceride synthesis and diminished lipolysis causes hyperlipidemia. Triglycerides increase the risk of fatty liver infiltration, which contributes to the enormous amount of liver enlargement. Despite significantly elevated serum triglyceride levels in patients, vascular lesions and atherosclerosis are rare complications.


Patients with GSD type I account for 24.6%of all patients with GSD.


Type I glycogen storage disease is an autosomal recessive disorder .As with other genetically determined diseases,GSD type 1 develops during conception, yet the first signs of the disease may appear at birth or later.

 Clinical Manifestations

o  The earliest signs of the disease may develop shortly after birth and are caused by hypoglycemia and lactic acidosis.

o   Convulsions are a leading sign of disease.

o    Frequently,symptoms of moderate hypoglycemia, such as irritability,pallor, cyanosis, hypotonia, tremors, loss of consciousness, and apnoea, are present.

o   A leading sign of GSD type I is enlargement of the liver and kidneys. During the first weeks of life, the liver is normal size. It enlarges gradually thereafter, and in some patients, it even reaches the pubic symphysis. Enlargement of the abdomen due to hepatomegaly can be the first sign noted by the patient’s mother.

o   The patient’s face is characteristically reminiscent of a doll’s face (rounded cheeks due to fat deposition).

o   Mental development proceeds normally.

o   Growth is retarded and children affected with GSD type I never gain the height otherwise expected from the genetically determined potential of their families. The patient’s height is usually below the third percentile for their age. The onset of puberty is delayed.

o   Late complications of disease are renal function disturbance , renal stones, tubular defects, and hypertension, mainly in patients older than 20 years. Renal function deterioration progresses to terminal insufficiency,requiring dialysis and transplantation.

o   Skin and mucous membrane changes include the following:

  • Eruptive xanthomas develop on the extensor surfaces of the extremities.
  • Tophi or gouty arthritis may occur. Uric tophi often have the same distribution as xanthomas.
  • Many patients bleed easily, particularly from the nose. This tendency is a result of altered platelet function due to the platelets’ lower adhesiveness. Frequent and, occasionally, prolonged epistaxis may cause anaemia. At times, the bleeding may be so severe that blood transfusions are required.


Laboratory Investigations

GSD type I: Serum glucose and blood pH levels are frequently decreased, while the serum lactate, uric acid,triglyceride, and cholesterol levels are elevated. Urea and creatinine levels might be elevated when renal function is impaired. The following laboratory values should be obtained:

  • Serum glucose and electrolyte levels (Higher anion gap may suggest lactic acidosis.)
  • Serum lactate level
  • Blood pH
  • Serum uric acid level
  • Serum triglyceride and cholesterol levels
  • Gamma glutamyl transferase level (Liver dysfunction)
  • CBC and differential (eg, anaemia, leucopenia, neutropenia)
  • Coagulation- Bleeding and clotting time
  • Urinalysis for aminoaciduria, proteinuria, and microalbuminuria in older patients
  • Urinary excretion levels of uric acid and calcium
  • Serum alkaline phosphatase, calcium, phosphorus, urea, and creatinine levels.

Imaging Studies

  • In GSD type I, liver and kidney ultrasonography should be performed for follow-up of organomegaly.
  •  Abdominal CT scanning or MRI is advised whenever the lesions are large, poorly defined, or are growing rapidly.

Other Tests

  • Glucagon and epinephrine tests do not cause a rise in glucose levels, but plasma levels of lactic acid are raised.
  • Orally administered galactose and fructose (1.75 g/kg) do not increase glucose levels, but plasma lactic acid levels do increase.
  • Glucose tolerance test (1.75 g/kg PO) progressively lowers lactic acid levels over several hours after the administration of glucose.


Most children with GSD type I are admitted to the hospital to make a final diagnosis, to manage hepatomegaly or hypoglycemia.

 Because no specific treatment is available,symptomatic therapy is very important.


 The primary goal of treatment is to correct hypoglycemia and maintain a normoglycemic state. The normoglycemic state can be achieved with overnight nasogastric infusion of glucose, parental nutrition, or per oral administration of raw corn starch. Glucose molecules are continuously released by hydrolysis of corn starch in the digestive tract over 4 hours following its intake. The intake of fructose and galactose should be restricted because it has been shown that they can not be converted to glucose but they do increase lactic acid production. Limited intake of lipids is advisable for the existing hyperlipidemia.


·     No specific drug treatment is recommended for GSD type I. Appropriately treat concurrent infections with antibiotics.

·     Allopurinol (Zyloprim),a xanthine oxidase inhibitor, therapy can reduce uric acid levels in the bloodand prevent occurrence of gout and kidney stones in adult life.

·    Hyperlipidemia can be reduced by lipid-lowering drugs (eg, 3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA]reductase inhibitors, fibric acid derivatives).

·     In patients with renal lesions,microalbuminuria can be reduced with Angiotensin-converting enzyme (ACE)inhibitor therapy. In addition to their antihypertensive effects, ACE inhibitors are renoprotective and reduce albuminuria. Nephrocalcinosis and renal calculi can be prevented with citrate therapy.

·  Additionally, for patients with GSD type I,the future may bring Adeno-associated virus vector – mediated gene therapy,which may result in curative therapy,


  • Bacterial infections and cerebral oedema are caused by prolonged hypoglycemia and metabolic acidosis.
  • Long-term complications encompass growth retardation, hepatic adenomas with a high rate of malignant change, xanthomas, gout, and renal dysfunction. Long-term complications result from metabolic disturbances, mostly hypoglycemia.
  • Acute hypoglycemia may be fatal, and long-term complications include irreversible damage to the CNS.
  • Early death usually caused by acute metabolic complications (eg, hypoglycemia, acidosis) or  bleeding in the course of various surgical procedures


 The prognosis is better than in the past provided that all the available dietary and medical measures are implemented.

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