Glycogen Storage Disease Type I - Journal of Gastrointestinal and ...

Glycogen storage disease type I
Glycogen Storage Disease Type I - between Chronic Ambulatory
Follow-up and Pediatric Emergency
Evelina Moraru 1 , Oana Cuvinciuc 1 , Luiza Antonesei 1 , Doina Mihãilã 2 , Laura Bozomitu 3 , Tania Rusu 1 , Bogdan Stana 1 ,
Paula Sacaci 1 , Ana Luchian 1 , Livia Bratu 5 , Alice Popescu 4 , Ozkan Mircan 3 , Dan Moraru 3
1) 2 nd Clinic of Pediatrics. 2) Morphopathology Laboratory. 3) 3 rd Clinic of Pediatrics. 4) Pediatrics Outpatient Clinic, “Sf.
Maria” Emergency Hospital for Children, Iasi. 5) Private Outpatient Clinic, Roman
Abstract
Background and aims. To describe the characteristics
of patients with type I glycogenosis, the presentation types,
the main clinical signs, the diagnostic criterias and also the
disease outcomes on long term follow-up. Methods. The
study group consisted of 6 patients (medium age 3 years 6
months) admitted in hospital between 2001 and 2005 and
followed-up for 1 to 5 years. The sex ratio was 1:1. Results.
The referral reasons varied from hepatomegaly incidentally
discovered (3 of 6 patients) to abdominal pain (4 of 6
patients), growth failure (3 of 6 patients), symptoms of
hypoglycemia (3 of 6 patients), recurrent epistaxis (1 patient).
Hepatomegaly was present in all cases. Biological profile:
hypoglycemia, increased transaminase values, hypertriglyceridemia,
lactic acidosis, normal uric acid levels. Two
patients had neutropenia and other two had increased
glomerular filtration rate. Liver biopsy showed glycogenladen
hepatocytes and markedly increased fat. Four patients
had type Ia and 2 patients type Ib glycogenosis. The therapy
consisted of: diet, ursodeoxycholic acid, granulocyte
colony-stimulating factor, broad spectrum antibiotics for
those with type Ib glycogenosis. The follow-up parameters
were clinical, biological, imaging. Metabolic interventions
and antiinfectious therapy were necessary. All patients are
alive, two of them on the waiting list for liver transplantation.
Conclusions. Glycogen storage disease type I is a rare
condition, but with possible life-threatening consequences.
It has to be kept in mind whenever important hepatomegaly
and/or hypoglycemia are present.
Key words
Glycogen storage disease type I - hypoglycemia -
children - hepatomegaly
J Gastrointestin Liver Dis
March 2007 Vol.16 No 1, 47-51
Address for correspondence: Prof. Evelina Moraru
Spitalul de Urgenþã pt.Copii
“Sf. Maria”
Str. Vasile Lupu 62
Iaºi, Romania
E-mail: emoraru@iasi.mednet.ro
Introduction
Glycogen storage disease type I (GSD I) is part of a rare
group of inherited diseases characterized by enzyme defects
that affect the glycogen synthesis and degradation cycle.
GSD I is more appropriately considered a defect in
gluconeogenesis, as the enzyme defect blocks the formation
of glucose not only from glycogen stores, but also from
glucose precursors (lactate, aminoacids) (1). There are two
subtypes of type I glycogen storage disease, both having
autosomal recessive transmission: type Ia is the most
common, characterized by a defect in glucose-6-phosphatase
(an enzyme found only in the liver, kidney and
intestinal mucosa) activity, and type Ib, caused by a defect
in microsomal transport of glucose-6-phosphate (2). Given
the fact that there are no newborn screening programs for
this disorder, there are no reliable estimates for the incidence
of GSD I, but it is unlikely that it occurs more frequently
than 1 case in 100 000 infants (3). Besides the clinical findings
of massive hepatomegaly, enlarged kidneys and growth
failure, the biologic picture of GSD I is very complex,
characterized by hypoglycemia, lactic acidosis, hyperlipidemia,
moderate increase in transaminase levels,
hyperuricemia, and also neutropenia or neutrophil
dysfunction in type Ib GSD. The hepatic and renal injury is
chronic, emphasizing the need for long-term follow-up.
There is a high variability in the course of the disease,
including the possibility of hepato-carcinoma, making
therapeutic decisions vary from simple dietary measures to
liver or hepatocyte transplantation (4). Life expectancy in
GSD-1 has improved considerably. Its relative rarity implies
that no metabolic centre has experience of a large series of
patients. Experience with long-term management and followup
at each centre is limited (5).
The aims of this study are to establish the characteristics
of patients with GSD I, to describe the presentation types
and the main clinical signs, to evaluate the diagnostic
criterias (clinical, biological and histological) and also the
disease outcomes regarding growth, liver function and
metabolic profile on long term follow-up. The importance of
establishing practical guidelines for long term follow-up is

48
Moraru et al
emphasized by the serious and potential life-threatening
complications of the disease.
Material and methods
The study group consisted of 6 patients aged 1 year 3
months to 6 years 5 months (mean age 3 years 6 months) at
diagnosis, admitted in our clinic between 2001 and 2006 and
periodically reevaluated for 1 to 5 years. The sex ratio was
1:1. There was no consanguinity of the parents of these
children, nor was there any known shared pedigree between
the 6 cases, all of whom lived in different regions of
Moldavia.
The inclusion criterias were:
1. clinical: hepatomegaly; growth failure; no muscular
symptoms and signs;
2. biological: hypoglycemia early in fasting (3-4 hours
after meals); normal insulin / glycemia ratio; little or no
glycemic response to glucagon; lactic acidosis; normal
values of creatinine kinase;
3. histological: markedly increased fat and glycogen in
hepatocytes.
Results
The clinical information for each of the 6 cases is shown
in Table I.
The first presentation in our clinic was due to different
reasons. Two patients were referred for investigation of a
hepatomegaly incidentally discovered at physical
examination in the context of an acute pathologic condition.
The other patients referred as follows: abdominal pain
accompanied by increased abdominal girth (Fig.1) (4 cases),
growth failure (3 cases), symptoms of hypoglycemia with
early morning awakenings for feeding and an increased
appetite, episodes of fatigue and decreased energy that
improved after feeding, unexplained somnolence, sweating
(2 cases), recurrent epistaxis (1 case). Two of the cases had
a positive history of frequent bacterial infections (recurrent
mouth ulcers, otitides, boils, pneumonias).
The physical findings constantly included hepatomegaly
of different degrees, from moderate to massive, with a liver
Table I Clinical information for cases 1 – 6
Fig.1 Case 3: female, 2 yrs 1 month old, dolllike
facies, short stature, increased abdominal
girth, liver span 18 cm.
span between 14 and 22 cm. In five cases the patients had
doll-like facies (Fig.1), four patients had growth failure, four
patients had excessive sweating, and two had ketotic breath.
The hematological parameters showed mild irondeficiency
anemia in three cases and moderate neutropenia
in the two cases associated with frequent bacterial infections
(cases 4 and 6).
The serum biochemical profiles of the 6 children are
summarized in Table II. All of them had elevated liver
transaminase levels, although of varying severity.
Case Age at Sex Reason for referral Physical findings
diagnosis
1 15 mo F asymptomatic hepatomegaly Liver span 14 cm, ketotic breath
incidentally discovered
2 19 mo M Suspected recurrent hypoglycemia; Liver span 16 cm, doll-like facies,
increased abdominal girth, abdominal pain ketotic breath
3 2 yr 1 mo F Asymptomatic hepatomegaly incidentally Liver span 18 cm, doll-like facies,
discovered.
short stature
4 4 yr 10 mo F Short stature; increased abdominal girth, Liver span 18 cm, doll-like facies, short stature
abdominal pain
5 4 yr 10 mo M Short stature, increased abdominal girth, Liver span 22 cm, doll-like facies, short stature
abdominal pain, recurrent epistaxis
6 6 yr 5 mo M Suspected recurrent hypoglycemia; Liver span 20 cm, doll-like facies, short stature

Glycogen storage disease type I 49
Table II Serum biochemical profile on presentation
Case Fasting ALP, U/L AST, U/L ALT, U/L GGT, U/L Total Cholesterol Triglycerides
glucose bilirubin (120 – 230 (20-130
mg/dl) mg/dl)
1 0.28 g/l X1.5 NV X 6 NV X 5 NV N N 268 340
2 0.45 g/l N X 4 NV X 5 NV N N 327 280
3 0.33 g/l N X 12 NV X 11 NV X 4 NV N 339 1100
4 0.42 g/l N X 5 NV X 4 NV X 2 NV N 275 570
5 0.38 g/l N X 2 NV X 3 NV N N 324 740
6 0.44 g/l N X 3 NV X 3 NV N N 306 620
ALP alkaline phosphatase, AST aspartate aminotransferase, ALT alanin aminotransferase, GGT gammaglutamyl transpeptidase, NV
normal value
Random blood glucose levels varied between severe
hypoglycemia and normal values, and the glycemic profile
correlated to feeding schedule showed the occurrence of
hypoglycemia within 3 to 4 hours after meals in all cases.
The patients underwent fasting challenges that were
concurrent with these findings. The oral glucose tolerance
test showed inappropriate (small) glycemic rise in all cases.
We assessed the insulin levels, correlated to the glycemia
values, finding low levels of insulinemia and appropriate
values of insulin/glycemia ratios in all cases. The glucagon
test showed a glycemia rise of 15 – 25 % in two cases, and
no glycemic response in 4 cases. This helped us to
distinguish GSD I from GSD III, in which patients often
have an increased serum glucose after glucagon
administration, with the exception of prolonged fasting, when
patients with GSD III lose their ability to respond to
glucagon. Having no access to enzymatic diagnosis in our
country, those analyses have been strong arguments for
the clinical type of GSD. The results of the fasting challenges
are shown in Table III.
Table III Results of initial fasting challenge
Time to Fasting challenge Time to
Case hypogly- Glucagon response lactic
cemia in fed state acidosis
1 3.0 Negative Positive
2 3.5 Negative Positive
3 3.5 Negative Positive
4 4 Glycemia rise of 15% Positive
5 3 Negative Positive
6 3.5 Glycemia rise of 25% Positive
In the evaluation protocol we included the assessment
of hypoglycemia consequences on the central nervous
system. Clinically, all patients were within normal for age
regarding psychomotor development. The EEG showed no
changes consistent with brain damage. The psychological
evaluation was also normal.
Imaging studies consisted of ultrasonographic
evaluation and CT scan. Ultrasonography showed marked
homogeneous hepatomegaly with intense hyperechogenicity,
no splenic abnormalities; the kidneys were enlarged
in three cases (age between 4 and 7 years), all of them also
having increased glomerular filtration rate. There were no
signs of portal hypertension in any of the cases. The CT
scan was performed in 3 cases, showing massive
homogeneous enlargement of the liver, with low contrast
enhancement.
Three cases had delayed bone maturation.
The percutaneous liver biopsy showed glycogen-laden
hepatocytes in PAS staining in all cases, establishing the
diagnosis of GSD (Fig.2). Sudan stain showed markedly
increased fat in the liver. There was no evidence of fibrosis
in the liver tissue. The bone marrow showed no pathologic
elements in any of the cases.
The association of massive liver enlargement, rapid onset
of hypoglycemia 3 to 4 hours after meals, elevated lactic
acid levels and marked hypertriglyceridemia was considered
sufficient to establish the diagnosis of GSD Ia in four cases,
The triglyceride values were elevated in all cases but at
different degrees: 200 – 500 mg/dl in 2 cases, 500 – 1000 mg/
dl in 3 cases, and more than 1000 mg/dl in one case, accompanied
by prolonged bleeding time due to impaired platelet
function as a consequence of hypertriglyceridemia (1).
Uric acid levels were normal at diagnosis in all patients.
The lactate levels increased dramatically with hypoglycemia
and glucagon administration and decreased following
administration of glucose. Ketosis was quantified in urine
at 1+ in 4 cases and 2+ in 2 cases. Four of the patients (cases
3-6) had increased glomerular filtration rate, with normal
blood urea nitrogen. The youngest patients had no evidence
of renal involvement at admission.
Fig.2 Case 3: Liver tissue, optic microscopy: glycogen laden
hepatocytes (PAS stain).

50
and Ib in those two cases associated with frequent bacterial
infections and neutropenia (cases 4 and 6) (1,21,22). In these
two cases, although they had no suggestive symptoms, we
performed also colonoscopy and colonic mucous biopsies
to identify the eventual changes consistent with inflammatory
bowel disease that is often associated with glycogen
storage disease type Ib (6,7,22). We found no such changes.
Therapeutic approach
The mainstay of therapy in all cases consisted of dietary
measures including a pattern of frequent carbohydrate
feedings; administration of 2 g/kg of uncooked cornstarch
suspensions (1,8,9,20) every 6 hours was effective in
avoiding hypoglycemia symptoms in all children. However,
during follow-up, in spite of this measure, there were still
low glycemic values in the morning, but no accompanying
symptoms.
Data about the development of premature atherosclerosis
in young adult GSD I patients are very scarce. Even though
in familial hypercholesterolemia or familial combined
hyperlipidemia, a comparable degree of hyperlipidemia is
associated with cardiovascular morbidity and mortality at
early age, studies showed that GSD type Ia is not associated
with premature atherosclerosis, despite the longstanding
dyslipidaemia and microalbuminuria (10). Little is known
about possible vascular protective mechanisms against the
dyslipidaemia in GSD Ia. The diminished platelet aggregation
(11) can be only partly protective (12). Recently, a decreased
susceptibility of in vitro oxidation of VLDL cholesterol has
been found (13). The renal deleterious effects of
dyslipidaemia are, however, an argument for lipid-lowering
measures, including drug treatment (14,15,20). We
considered it prudent to advise our patients to avoid high
lipid intake, and we recommended omega-3 fatty acids
supplements (fish oil) for their effect of decreasing
triglycerides and VLDL levels in hypertriglyceridemic
subjects, with a concomitant increase in HDL. Omega-3 fatty
acids lower plasma triglycerides by inhibiting VLDL and
apolipoprotein B-100 (16) synthesis, and in conjunction with
transcription factors, target the genes governing cellular
triglyceride production and those activating oxidation of
excess fatty acids in the liver. Inhibition of fatty acid
synthesis and increased fatty acid catabolism reduce the
amount of substrate available for triglyceride production
(17). We also recommended dietary restrictions on fructose
and galactose and supplemented the diet with calcium and
multivitamins (1).
All patients received treatment with ursodeoxycholic
acid (15 mg/kg body weight) for its hepatoprotective effects
and its intervention in cholesterol metabolism.
Those patients with type Ib GSD received also broad
spectrum antibiotics, and one of them received granulocyte
colony-stimulating factor (GCSF) 5 μg/kg twice per week for
a period of two years, and the median neutrophil counts
increased significantly to normal values and simultaneously
there was a slight decrease in median leukocyte and platelet
Moraru et al
counts, and the number and severity of infections decreased.
As a complication of the treatment, a mild splenomegaly
occurred.
Evolution during follow-up
The patients were followed-up in our clinic for a period
of 1 to 5 years. The follow-up parameters were clinical (the
amount of catch-up growth under appropriate carbohydrate
supplementation, the liver span, psychological evaluation),
biological (neutrophil count, glycemic profile, transaminase
levels, lipid profile, uric acid levels, renal function
parameters), imaging (for early detection of focal hepatic
lesions and renal changes).
One of the four patients with short stature had a
satisfactory growth rate, reaching normal values for age
after two years of treatment. The other three patients
remained under normal values for age. Cases 1 and 2 that
showed normal values of the anthropometric measurements
for age at diagnosis also had a satisfactory growth rate.
Liver span decreased in four cases by 10-15 % and increased
by 10-15% in the other two cases. There were no signs of
brain damage or any deterioration in cognitive functions or
delay in psychomotor achievements.
Despite the dietary measures, there was poor control of
the glycemic values in cases 2 and 3, with frequent moderate
hypoglycemia during the night and in the morning
accompanied by sweating, tremor, irritability/apathy. In the
other 4 cases there was good glycemia control, with rare
episodes of hypoglycemia accompanying acute diseases
with low oral intake that required intravenous glucose
support and prompt metabolic intervention until resolution.
Transaminase levels remained moderately to mildly
increased, with the exception of case 3 that maintained moderate
to high levels for a period of one year of follow-up
(Fig3).
Fig.3 Transaminase values during follow-up.
Cholesterol and triglyceride values normalized in case 1
and remained slightly to moderately increased in the other 4
cases.
Uric acid was high after 3 and 4 years, respectively, in
cases 3 and 2, and normal in all the other cases. We used
allopurinol 10 mg/kg/day divided in three doses.

Glycogen storage disease type I 51
There were no signs of renal function impairment in any
of the patients during follow-up, and case 2 showed also
renal enlargement and high glomerular filtration rate after 3
years of follow-up.
Ultrasonographic evaluation was performed during
every check-up (18) and there were no focal liver changes
suggestive for adenoma or hepatocellular carcinoma.
Because of the massive hepatomegaly accompanied by
poor glycemic control, cases 2 and 3 are on the waiting list
for liver transplantation (20-22).
As a new hope for the etiologic treatment of the disease,
recent data of genetic research on animal models
demonstrated that a single administration of a recombinant
adenovirus vector can alleviate the clinical manifestations
of GSD type Ia, suggesting that this disorder in humans can
potentially be corrected by gene therapy (19).
Conclusions
Glycogen storage disease type I is a rare condition, but
it has to be kept in mind for differential diagnosis whenever
confronted with hepatomegaly and/or hypoglycemia. It is
important to look for hypoglycemia even in the absence of
suggestive clinical signs, as the high levels of lactate can
serve as an alternative fuel for the brain.
The profound alteration of carbohydrate homeostasis
with its consequences on acid-base balance can lead to lifethreatening
situations that need prompt metabolic
intervention; patients with GSD type Ib require special
attention because of the high risk of sepsis.
Long term complications of GSD type I require complete
periodic reevaluation.
Hepatic transplantation is indicated in cases in which
there is no sufficient metabolic control, in children who
develop multiple adenomas and when hepatomegaly is
massive.
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