Hyperlipidaemia does not impair vascular endothelial function in glycogen storage disease type 1a

doi:10.1016/0021-9150(94)90072-8

Atherosclerosis

Volume 110, Issue 1, 30 September 1994, Pages 95-100

https://doi.org/10.1016/0021-9150(94)90072-8 Get rights and content

Abstract

Patients with glycogen storage disease type I (GSD-1) often have marked hyperlipidaemia with abnormal lipoprotein profiles. This metabolic abnormality improves, but is not fully corrected, with dietary therapy and therefore these patients may be at high risk for the development of atherosclerosis. Endothelial dysfunction is an early event in atherogenesis and can be detected in children and young adults at high risk. We studied endothelial function, using a non-invasive ultrasonographic method, in the brachial arteries of 6 adult GSD-la patients (aged 23–33 years) with mean cholesterol of 7.9 mmol/l (range 4.7 to 14.6) and mean triglycerides of 9.1 mmol/l (range 4.1 to 21.3), and 12 age- and sex-matched normolipidaemic controls. Flow-mediated (endothelium-dependent) dilation was similar in patients and controls (8.2% vs. 10.5%; P = 0.20). Although the patient numbers are small, these results are consistent with the surprising lack of clinically evident atherosclerosis in GSD-1. The reasons these patients appear less susceptible to the damaging arterial effects of hyperlipidaemia are unknown. These results may have implications for others with secondary hyperlipidaemias.

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Cited by (40)

Glycogen storage disease type I patients with hyperlipidemia have no signs of early vascular dysfunction and premature atherosclerosis
2021, Nutrition, Metabolism and Cardiovascular Diseases
Citation Excerpt :
Similar observations have been published in 3 previous studies and are summarized in Table 1. Lee et al. found no evidence of atherosclerosis in 6 adult GSD Ia patients using a non-invasive ultrasonographic method to assess endothelial function in the brachial arteries [12]. Ubels et al. studied 9 adolescent GSD Ia patients at a mean age of 22.7 ± 3.4 years and found comparable IMT segments in both groups with even thinner segments in the patient group [6].
Glycogen storage disease type I (GSD I) is associated with hyperlipidemia, a known risk factor for premature atherosclerosis. Few studies have addressed endothelial dysfunction in patients with GSD I, and these studies yielded controversial results.
We investigated vascular dysfunction in a cohort of 32 patients with GSD I (26 GSD Ia, 6 GSD Ib, mean age 20.7 (4.8–47.5) years) compared to 32 age-, gender-, and BMI-matched healthy controls using non-invasive techniques such as quantification of carotid intima media thickness, retinal vessel analysis and 24 h-blood pressure measurements. In addition, early biomarkers of inflammatory and oxidative endothelial stress were assessed in blood. Although GSD I patients had a clearly proatherogenic lipid profile, increased oxidative stress, higher levels of high sensitivity C-reactive protein and increased lipoprotein associated phospholipase A2 activity, functional and structural parameters including carotid intima media thickness and retinal vessel diameters did not indicate premature atherosclerosis in this patient cohort. Blood pressure values and pulse wave velocity were comparable in patients and healthy controls, while central blood pressure and augmentation index were higher in GSD patients.
Our data suggest that GSD I is not associated with early vascular dysfunction up to the age of at least 20 years. Further studies are needed to elucidate the possibly protective mechanisms that prevent early atherosclerosis is GSD I. Longer follow-up studies are required to assess the long-term risk of vascular disease with increased oxidative stress being present in GSD I patients.
Diagnosis and management of glycogen storage disease type I: A practice guideline of the American College of Medical Genetics and Genomics
2014, Genetics in Medicine
This guideline is designed primarily as an educational resource for clinicians to help them provide quality medical services. Adherence to this guideline is completely voluntary and does not necessarily ensure a successful medical outcome. This guideline should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed toward obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this guideline. Clinicians also are advised to take notice of the date this guideline was adopted and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.
Glycogen storage disease type I (GSD I) is a rare disease of variable clinical severity that primarily affects the liver and kidney. It is caused by deficient activity of the glucose 6-phosphatase enzyme (GSD Ia) or a deficiency in the microsomal transport proteins for glucose 6-phosphate (GSD Ib), resulting in excessive accumulation of glycogen and fat in the liver, kidney, and intestinal mucosa. Patients with GSD I have a wide spectrum of clinical manifestations, including hepatomegaly, hypoglycemia, lactic acidemia, hyperlipidemia, hyperuricemia, and growth retardation. Individuals with GSD type Ia typically have symptoms related to hypoglycemia in infancy when the interval between feedings is extended to 3–4 hours. Other manifestations of the disease vary in age of onset, rate of disease progression, and severity. In addition, patients with type Ib have neutropenia, impaired neutrophil function, and inflammatory bowel disease. This guideline for the management of GSD I was developed as an educational resource for health-care providers to facilitate prompt, accurate diagnosis and appropriate management of patients.
A national group of experts in various aspects of GSD I met to review the evidence base from the scientific literature and provided their expert opinions. Consensus was developed in each area of diagnosis, treatment, and management.
This management guideline specifically addresses evaluation and diagnosis across multiple organ systems (hepatic, kidney, gastrointestinal/nutrition, hematologic, cardiovascular, reproductive) involved in GSD I. Conditions to consider in the differential diagnosis stemming from presenting features and diagnostic algorithms are discussed. Aspects of diagnostic evaluation and nutritional and medical management, including care coordination, genetic counseling, hepatic and renal transplantation, and prenatal diagnosis, are also addressed.
A guideline that facilitates accurate diagnosis and optimal management of patients with GSD I was developed. This guideline helps health-care providers recognize patients with all forms of GSD I, expedite diagnosis, and minimize adverse sequelae from delayed diagnosis and inappropriate management. It also helps to identify gaps in scientific knowledge that exist today and suggests future studies.
Ischemic stroke in an adult with glycogen storage disease type i
2010, Journal of Clinical Neuroscience
Citation Excerpt :
Marked hypertriglyceridemia and hypercholesterolemia from infancy are common features of GSD-I. Despite the high-risk lipid profile, GSD-I has not been shown definitively to cause premature atherosclerosis. Small studies found young adults with GSD-I to be no different from controls when evaluated for endothelium-dependent and independent arterial responses, blood pressure, ankle-brachial index, or intima-media thickness (IMT) of carotid and femoral arteries.3,4 Recently, the largest study to date assessed the development of atherosclerosis in GSD-I patients, with an average age of 23 years.5
Glycogen Storage Disease Type I (GSD-I) is a metabolic disorder characterized by deficiency of glucose-6-phosphatase resulting in ineffective glycogen metabolism to glucose. These patients frequently have hyperlipidemia, among many other metabolic derangements. There is no consensus regarding the risk of developing atherosclerosis. We report an adult male with GSD-I who presented with cerebral infarction and a history of prior ischemic stroke and multiple coronary stent placements. We suggest that patients with GSD-I do have an increased risk of atherosclerosis and its complications and predict that these complications will be seen more frequently since patients with GSD-I are living longer as a result of better treatment.
An association among iron, copper, zinc, and selenium, and antioxidative status in dyslipidemic pediatric patients with glycogen storage disease types IA and III
2010, Journal of Trace Elements in Medicine and Biology
Dyslipidemia in patients with glycogen storage disease types Ia (GSD Ia) and III (GSD III) does not lead to premature atherosclerosis. The aim of this study was to investigate the association among serum copper (Cu), zinc (Zn), iron (Fe), and selenium (Se) concentrations, and their carrier proteins: ceruloplasmin, albumin, and related antioxidant enzyme activities [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), paraoxonase (PON), and arylesterase (ARYL)] in 20 GSD Ia and 14 III patients compared to age and sex matched 20 healthy subjects. Erythrocyte oxidative stress was measured by erythrocyte thiobarbituric acid reactive substances (eTBARSs). Hypertriglyceridemia [333 (36–890) mg/dL] in GSD Ia and hypercholesterolemia with elevated LDL-cholesterol [188 (91–313) mg/dL] and decreased HDL-cholesterol [32(23–58) mg/dL] levels in GSD III were found. Serum Cu, Fe, and Zn showed no significant differences between groups. However, Se 60 (54–94), 81 (57–127) μg/L, ceruloplasmin 21 (10–90), 27 (23–65) μg/L, and albumin 2.4 (1.7–5.1), 2.8 (1.8–4.06) g/dL levels were decreased in GSD Ia and III groups, respectively, in comparison with the controls [Se 110 (60–136) μg/L, ceruloplasmin 72 (32–94) μg/L, and albumin 4.4 (4–4.8) g/dL)]. In spite of high oxidative stress in erythrocyte detected by elevated eTBARS/Hb levels in GSD group [674.8 (454.6–948.2) for GSD Ia, 636.3 (460.9–842.1) for GSD III, and 525.6 (449.2–612.6)], the activities of CAT, SOD, ARYL, and PON in GSD patients were not different from the controls. GPx activity was decreased in GSD Ia [3.7 (1.8–7.1) U/mL] and GSD III [4.2 (2.2–8.6) U/mL] compared with healthy controls [7.1 (2.9–16.2) U/mL].
In conclusion, this study supplied the data for trace elements, their carrier, and antioxidative enzymes in the patients with GSD Ia and III. The trace elements and anti-oxidative enzyme levels in GSD patients failed to explain the atherosclerotic escape phenomenon reported in these patients.
A monocentric pilot study of an antioxidative defense and hsCRP in pediatric patients with glycogen storage disease type IA and III
2009, Nutrition, Metabolism and Cardiovascular Diseases
Citation Excerpt :
Predominantly, pediatric patients with hepatic glycogen storage disease (GSD) have a raised lipid profile expressed as elevated triglyceride concentrations or mixed hyperlipidemia. In contrast to other diseases associated with exposure to cardiovascular risk factors at an early age, such as familial hypercholesterolemia,2 it has been shown that glycogen storage disease type Ia (GSD Ia) patients do not show any signs of endothelial dysfunction or premature atherosclerosis.3,4 Glycogen storage disease type Ia (von Gierke disease; OMIM + 232,200) is caused by a deficiency in glucose-6-phosphatase, which catalyzes the terminal step in both glycogenolysis and gluconeogenesis in the liver, kidney, and small intestine.5
Patients with glycogen storage disease type Ia (GSD Ia) and III (GSD III) do not develop premature atherosclerosis despite hyperlipidemia. The aim of the study was to investigate the oxidative–antioxidative conditions and high sensitivity C-reactive protein (hsCRP) levels in patients with glycogen storage disease type Ia and III.
We measured lipid profile and lipid peroxidation products in comparison with hsCRP and antioxidative status: trolox equivalent antioxidant capacity, total antioxidant activity, proteinaceous antioxidant enzymes (catalase, superoxide dismutase, paraoxonase, arylesterase), aqueous antioxidants (vitamin C, uric acid, bilirubin, total protein) and lipid-soluble antioxidants (alpha-tocopherol, beta-carotene). The study included 50 individuals: 22 with GSD Ia, 9 with GSD III, and 19 healthy subjects.
GSD Ia patients showed a marked hypertriglyceridemia, whereas GSD III patients demonstrated hypercholesterolemia with elevated LDL-cholesterol and decreased HDL-cholesterol levels. Lipid peroxidation levels increased in both GSD groups. The antioxidant activity elevated in GSD Ia group. No significant differences were found in the activities of antioxidant enzymes. Uric acid and alpha-tocopherol levels increased, however, vitamin C and beta-carotene reduced in both GSD groups. The hsCRP levels did not differ among the groups.
In summary our study revealed normal levels of hsCRP in spite of the dyslipidemic status in both GSD patients. The increased plasma antioxidative defense in GSD Ia might be attributed not only to the elevated uric acid but also to the supplemented vitamin E levels. These findings should motivate further investigations in the area of atherosclerotic escape of GSDs.
Vascular Dysfunction in Glycogen Storage Disease Type I
2009, Journal of Pediatrics
To determine cardiovascular disease risk in a larger cohort of patients with glycogen storage disease (GSD) I through the use of noninvasive measures of arterial function and anatomy.
Carotid intima media thickness (IMT), radial artery tonometry, and brachial artery reactivity were performed in 28 patients with GSD I (13F/15M, mean age 23 years) and 23 control subjects (19F/4M, mean age 23 years).
The primary outcome measure, mean left distal IMT was greater in the GSD cohort (0.500 ± 0.055 mm) than in the control group (0.457 ± 0.039 mm) (P = .002, adjusted for age, sex, and body mass index). Mean augmentation index measured by radial artery tonometry was higher in the GSD cohort (16.4% ± 14.0%) than in the control group (2.4% ± 8.7%) (P < .001). No significant difference was observed between mean brachial artery reactivity in the GSD cohort (6.3% ± 4.9% change) versus control subjects (6.6% ± 5.1% change) (P = .46).
GSD I is associated with arterial dysfunction evident by increased IMT and augmentation index. Patients with GSD I may be at increased risk for cardiovascular disease.

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Research paperHyperlipidaemia does not impair vascular endothelial function in glycogen storage disease type 1a

Abstract

Am. J. Clin. Nutr.

Clin. Chim. Acta.

Clin. Chim. Acta.

J. Pediatr.

J. Lipid. Res.

Lancet

J. Am. Coll. Cardiol.

Lancet

Lancet

J. Pediatr.

Am. J. Clin. Nutr.

The molecular basis of the type I glycogen storage diseases

BioEssays

Hepato-megalia glykogenica (glykogen spreicherkrankheit der leber and nieren)

Beitr. Pathol.

The hyperlipemias in disorders of carbohydrate metabolism: serial lipoprotein studies in diabetic acidosis with xanthomatosis and in glycogen storage disease

Metabolism

The serum apolipoprotein profile of patients with glucose-6-phosphatase deficiency

Pediatr. Res.

Research paper
Hyperlipidaemia does not impair vascular endothelial function in glycogen storage disease type 1a