Glycogen Storage Disease

Type I
Von Gierke disease

Daryan Rahman
Contents
Introduction ........................................................................................................... 2
Etiology ................................................................................................................. 2
Pathophysiology .................................................................................................... 2
Histopathology ...................................................................................................... 2
History and Physical ............................................................................................. 3
Evaluation ............................................................................................................. 3
Treatment / Management ...................................................................................... 3
Differential Diagnosis ........................................................................................... 6
Complications ....................................................................................................... 6
References: ......................................................................................................... 7

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Introduction
Glycogen storage disease type I (GSD I), also known as Von Gierke disease, is
an inherited disorder caused by deficiencies of specific enzymes in the glycogen
metabolism pathway. It was first described by Von Gierke in 1929 who reported
excessive hepatic and renal glycogen in the autopsy reports of 2 children. It
comprises 2 major subtypes, GSD Ia and GSD Ib. In GSD Ia, there is a
deficiency of enzyme glucose-6-phosphatase (G6Pase) which cleaves glycogen
to glucose thus leading to hypoglycemia and lactic acidosis. Patients with GSD
1b have normal G6Pase enzyme activity but have a deficiency of the transporter
enzyme, glucose-6-phosphate translocase (G6PT). Patients present with
manifestations of hypoglycemia and metabolic acidosis typically around 3 to 4
months of age. In patients suspected of having the disease, genetic testing is the
investigation of choice to confirm the diagnosis. Dietary treatment prevents
hypoglycemia and improves the life expectancy of patients. However, to
prevent long-term complications such as hepatic adenomas and renal failure,
animal models of GSD I are being developed to study the disease more closely
and develop new treatment strategies such as gene therapy.

Etiology
GSD Ia results from mutations in the G6PC gene on chromosome 17q21 that
encodes for the G6Pase-a catalytic subunit. GSD Ib results from mutations in
the SLC37A4 gene on chromosome 11q23.3.

Pathophysiology
The enzyme G6Pase is primarily expressed in the liver, kidney, and intestine.
It has its active site on the luminal side of the endoplasmic reticulum (ER).
Glucose-6-phosphate translocase is responsible for translocating Glucose-6-
phosphate (G6P) from the cytoplasm into the ER lumen. The complex of
G6Pase and G6PT catalyzes the final step of both glycogenolysis and
gluconeogenesis for glucose production. Deficiency of either causes an
accumulation of glycogen and fat in the liver, kidney, and intestinal mucosa.

Histopathology
The availability of gene sequencing makes liver biopsy unnecessary. However,
a biopsy may be ordered by the gastroenterologist in view of hepatomegaly.
Histological evaluation of the liver shows hepatocytes filled with glycogen that
is periodic acid-Schiff positive and diastase sensitive.
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History and Physical
Some patients with GSD I may present with hypoglycemia and lactic acidosis in
the neonatal period. However, they are more likely to present at 3 to 6 months
of age with hepatomegaly and/or signs and symptoms of hypoglycemia,
including seizures. Symptoms of hypoglycemia appear with increased intervals
between feeds. Sometimes the infant may remain asymptomatic and would
present with an enlarged liver and protruding abdomen. Those left untreated
would develop an appearance similar to that seen in Cushing’s syndrome such
as short stature, round face, and full cheeks. They have a failure to thrive along
with delayed motor development. Cerebral damage resulting from recurrent
hypoglycemic episodes may lead to abnormal cognitive development. In
addition, patients with GSD Ib present with recurrent bacterial infections due to
neutropenia.

Evaluation
Initial laboratory findings in patients with GSD I will show hypoglycemia,
lactic acidosis, hyperuricemia, hypercholesterolemia, and hypertriglyceridemia.
Besides these, patients with GSD Ib will have neutropenia ranging from mild to
complete agranulocytosis. In a patient suspected with GSD I, glucagon
stimulation test should be avoided. It increases the risk of acute acidosis and
decompensation by causing a significant increase in blood lactate with little or
no increase in blood glucose concentration.
Instead of the invasive liver biopsy, noninvasive molecular genetic testing that
includes full gene sequencing of G6PC (GSD Ia) and SLC37A4 (GSD Ib) genes
is preferred for confirming the diagnosis. Sequence analysis has a detection rate
of up to 100% but may miss certain mutations of both G6PC and SLC37A4
genes. For such cases techniques such as quantitative PCR, long-range PCR,
multiplex ligation-dependent probe amplification, targeted array, or
comparative genomic hybridization analysis is employed.
The first choice to confirm the clinical suspicion of GSD I is a mutation
analysis. After excluding patients with neutropenia, complete G6PC sequencing
is performed. During the availability of liver biopsy tissue, G6Pase enzyme
activity is analyzed to confirm the diagnosis.

Treatment / Management
The main targets for the management of GSD I are the prevention of acute
metabolic derangement, prevention of acute and long-term complications,
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attainment of normal psychological development, and good quality of life. Diet
and lifestyle changes are made to prevent the primary concern of the disease,
hypoglycemia. Monitoring of blood glucose along with the laboratory
parameters should continue as with increasing growth, the child’s nutritional
needs change. Fasting should be avoided, and frequent small feeds rich in
complex carbohydrates along with fiber is recommended. Carbohydrates should
make up for 60% to 70% calories. Fructose and galactose are not metabolized to
glucose-6-phosphate due to the deficiency of the enzyme. Therefore, a diet low
in fructose and sucrose is recommended with limiting the intake of galactose
and lactose to one serving per day.
Initially, infants are fed soy-based, sugar-free formula on demand every 2 to 3
hours. With the increase in the infant’s sleep duration (longer than than 3 to 4
hours), it is important to avoid hypoglycemia during the overnight fast.
Awakening the infant every 3 to 4 hours to monitor blood glucose and giving
feeds is difficult. Therefore, it is important for the parents to be trained in
inserting a nasogastric (NG) tube or a G-tube should be placed surgically. This
allows the parents to administer feeds especially when the child is sick or
refuses to eat.
In patients with GSD I, cornstarch has been used for the treatment of
hypoglycemia as its slow digestion provides a steady release of glucose. This
maintains the glucose levels for longer periods of time. In young children, 1.6
gm of cornstarch per kg body weight every 3 to 4 hours is recommended. While
older children, adolescents, and adults, are given 1.7 to 2.5 gm of cornstarch per
kilogram body weight.
All patients with GSD I should wear a medical alert bracelet. Along with blood
glucose monitoring, a lactate meter can be a good tool to alert the parents
especially in times of emergency. Hypoglycemia should be treated immediately
with a fast-acting glucose source such as cornstarch or commercially prepared
glucose polymers or over-the-counter diabetic glucose tablets.
Patients with GSD Ib have an increased risk of infections at the surgical site for
G-tube due to neutropenia. Therefore granulocyte colony-stimulating factor (G-
CSF) is administered before placing a G-tube. The patients that receive G-CSF
need a complete blood count (CBC) evaluation monthly along with the
measurement of their spleen.
To avoid pump failures and occluded or disconnected tubing, bed-wetting
devices that detects formula spilling onto the bed, infusion pump alarms, safety
adapters, connectors, and tape for tubing is recommended as safety precautions.
Limiting foods rich in lactose and sucrose such as fruits, juice, and dairy puts a
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child at risk for nutritional deficiency. The child should be carefully assessed,
and diet should be supplemented with adequate micronutrients.
Oral citrate or bicarbonate is used to treat patients with persistent lactic acidosis.
These agents alkalinize the urine and reduce the risk of urolithiasis and
nephrocalcinosis. Allopurinol reduces uric acid levels preventing recurrent
attacks of gout. However, during an acute attack, Colchicine is preferred.
Hyperlipidemia has only shown a partial response to medical intervention with
statins, niacin, fibrates, and fish oil along with dietary interventions such as
consuming medium-chain triglyceride milk. Its resolution has been reported
with liver transplantation.
Starting from infancy, systemic blood pressure measurement should be checked
on every office visit while serum creatinine is evaluated every 3 to 6 months to
monitor renal function. Patients with persistent microalbuminuria should be
treated with an angiotensin-converting enzyme (ACE) inhibitor to prevent
worsening of renal function. An echocardiography is recommended every 3
years beginning after the first decade of life or earlier in the presence of
symptoms to screen for pulmonary hypertension.
Patients with GSD I have hepatomegaly universally due to fat and glycogen
deposition in the liver. The common liver lesions seen in patients with GSD Ia
include focal fatty infiltration, focal fatty sparing, focal nodular hyperplasia,
peliosis hepatis, hepatocellular adenoma (HCA), and hepatocellular carcinoma
(HCC). Therefore, a liver function test should be repeated every 6 to 12 months.
Liver transplantation is an option for patients with multifocal growing lesions
that do not respond to primary treatment.
As per guidelines for the management of GSD I published by the collaborative
European study, the following biomedical targets are recommended:
Preprandial blood glucose greater than 3.5 to 4.0 mmol/L (63 to 72 mg/dL)
Urine lactate/creatinine ratio less than 0.06 mmol/mmol
Serum uric acid concentration in high normal range for age
Venous blood base excess greater than - 5 mmol/L and venous blood
bicarbonate greater than 20 mmol/L (20 meq/L)
Serum triglyceride concentration less than 6 mmol/L (531 mg/dL)
Normal fecal alpha-1 anti-trypsin concentration for GSD Ib

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Differential Diagnosis
It is important to differentiate GSD I from other diseases that present with
hepatomegaly and or hypoglycemia.
GSD 0 (glycogen synthase deficiency)
GSD III (glycogen debranching enzyme deficiency)
GSD IV (branching enzyme deficiency)
GSD VI (hepatic phosphorylase deficiency)
GSD IX (hepatic form of phosphorylase kinase deficiency)
GSD XI (Fanconi-Bickel syndrome due to glucose transporter protein 2
deficiency)
Disorders of Gluconeogenesis (Fructose-1,6-bisphosphatase deficiency)
Primary liver disease (Hepatitis)
Niemann-Pick B disease
Gaucher disease
Hereditary fructose intolerance

Complications
Patients with GSD I may develop bleeding disorders from impaired platelet function. There is
also an increased risk of osteoporosis and fractures from vitamin D deficiency.
Therefore, routine monitoring of vitamin D levels along with dual-energy x-ray
absorptiometry (DXA) scans is recommended to monitor the bone density and
the need for vitamin D supplementation.
Renal failure may occur due to proximal renal tubular or renal glomerular
dysfunction. Erythropoietin (EPO) production is decreased with worsening of
renal function especially when the glomerular filtration rate (GFR) drops below
50 ml/min/1.73 m. Thus patients then develop anemia of chronic kidney disease
that may be further exacerbated by iron deficiency, chronic metabolic acidosis
or bleeding diathesis. Anemic patients are treated with EPO therapy after
screening them for iron deficiency and replenishing their iron stores. Patients
with uncontrolled blood lactate, serum lipids, and uric acid levels are also at an
increased risk for nephropathy that may need renal transplantation. Therefore,
an annual ultrasound examination of the kidneys is recommended after the first
decade of life.

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Severe hyperlipidemia and hypertriglyceridemia (greater than 1000 mg/dL)
increase the risk of xanthoma formation, acute pancreatitis, and early
atherosclerosis.
Other complications include menorrhagia and polycystic ovaries in females, and
gout from hyperuricemia.
Additionally, patients with GSD Ib have an increased risk of Crohn’s disease-
like enterocolitis and hypothyroidism.

References:

1. Carvalho PM, Silva NJ, Dias PG, Porto JF, Santos LC, Costa JM. Glycogen
Storage Disease type 1a - a secondary cause for hyperlipidemia: report of five
cases. J Diabetes Metab Disord. 2013 Jun 06;12(1):25

2.Raza M, Arif F, Giyanwani PR, Azizullah S, Kumari S. Dietary Therapy for

Von Gierke's Disease: A Case Report. Cureus. 2017 Aug 08;9(8):e1548.

3.Chou JY, Kim GY, Cho JH. Recent development and gene therapy for
glycogen storage disease type Ia. Liver Res. 2017 Sep;1(3):174-180.

4. McAdams AJ, Hug G, Bove KE. Glycogen storage disease, types I to X:

criteria for morphologic diagnosis. Hum Pathol. 1974 Jul;5(4):463-87.

5.Goldberg T, Slonim AE. Nutrition therapy for hepatic glycogen storage

diseases. J Am Diet Assoc. 1993 Dec;93(12):1423-30.

6.Rake JP, Visser G, Labrune P, Leonard JV, Ullrich K, Smit GP., European
Study on Glycogen Storage Disease Type I (ESGSD I). Guidelines for
management of glycogen storage disease type I - European Study on Glycogen
Storage Disease Type I (ESGSD I). Eur J Pediatr. 2002 Oct;161 Suppl
1:S112-9.

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