Dataset Information

Estimation of Health Utility Scores for Glycogen Storage Disease Type Ia.

ABSTRACT:

Background

Glycogen Storage Disease Type Ia (GSDIa) is a rare genetic metabolic disorder characterized by hypoglycemia, hepatomegaly, growth failure, and possible seizures/death. Patients frequently consume cornstarch to maintain blood glucose. Evidence demonstrating the impact of GSDIa on health-related quality of life (HRQoL) is lacking. This study aims to understand the burden of GSDIa by obtaining utility values for economic appraisals.

Methods

A targeted literature review and interviews with experts (n = 4) and caregivers (n = 4) informed the development of health state vignettes describing different GSDIa severities by age and level of hypothetical treatment (i.e., gene therapy) response. Health states reflecting caregivers' experiences were also developed. A convenience sample of the UK general public completed a time trade-off (TTO) exercise. Scores conceptually varied from 0 (dead) to 1 (full health). States were also rated using a visual analog scale (VAS) and the EQ-5D-5L. Data were descriptively summarized.

Results

One hundred participants completed the exercise (male: 48%; mean age: 42 years). Scores were lowest for the adolescent pre-treatment state (TTO = 0.38). Large increments in HRQoL were observed for the response (adult: TTO = 0.86; child: TTO = 0.84) and complete response (adult and child: TTO = 0.94) hypothetical treatment response states. Caregiver values were lowest for the pre-treatment state (TTO = 0.57) and highest for the complete response state (TTO = 0.95). VAS and EQ-5D-5L scores followed a similar pattern.

Conclusion

This study found an HRQoL burden on GSDIa patients and caregivers, with potential large improvement from a hypothetical treatment. These findings may be useful for families, clinicians, regulatory agencies, and in therapy economic evaluations.

SUBMITTER: Kruger E

PROVIDER: S-EPMC10333147 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Publications

Estimation of Health Utility Scores for Glycogen Storage Disease Type Ia.

Kruger Eliza E Aggio Daniel D de Freitas Hayley H Lloyd Andrew A

PharmacoEconomics - open 20230411 4

<h4>Background</h4>Glycogen Storage Disease Type Ia (GSDIa) is a rare genetic metabolic disorder characterized by hypoglycemia, hepatomegaly, growth failure, and possible seizures/death. Patients frequently consume cornstarch to maintain blood glucose. Evidence demonstrating the impact of GSDIa on health-related quality of life (HRQoL) is lacking. This study aims to understand the burden of GSDIa by obtaining utility values for economic appraisals.<h4>Methods</h4>A targeted literature review and ...[more]

PMID: 37039966

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Project description:Glycogen storage disease type Ia (GSDIa) is a rare, inherited glucose-6-phosphatase-α (G6Pase-α) deficiency-induced carbohydrate metabolism disorder. Although hyperlipidemia is a hallmark of GSDI, the extent of lipid metabolism disruption remains incompletely understood. Lipidomic analysis was performed to characterize the serum lipidome in patients with GSDIa, by including age- and sex-matched healthy controls and age-matched hypercholesterolemic controls. Metabolic control and dietary information biochemical markers were obtained from patients with GSDIa. Patients with GSDIa showed higher total serum lysophosphatidylcholine (Fold Change, (FC) 2.2, P < 0.0001), acyl-acyl-phosphatidylcholine (FC 2.1, P < 0.0001), and ceramide (FC 2.4, P < 0.0001) levels and bile acid (FC 0.7, P < 0.001), acylcarnitines (FC 0.7, P < 0.001), and cholesterol esters (FC 1.0, P < 0.001) than those of healthy controls, and higher di- (FC 1.1, P < 0.0001; FC 0.9, P < 0.01) and triacylglycerol (FC 6.3, P < 0.0001; FC 3.9, P < 0.01) levels than those of healthy controls and hypercholesterolemic subjects. Both total cholesterol and triglyceride values correlated with Cer (d16:1/22:0), Cer (d18:1/20:0), Cer (d18:1/20:0(OH)), Cer (d18:1/22:0), Cer (d18:1/23:0), Cer (d18:1/24:1), Cer (d18:2/22:0), Cer (d18:2/24:1). Total cholesterol also correlated with Cer (d18:1/24:0), Cer (d18:2/20:0), HexCer (d16:1/22:0), HexCer (d18:1/18:0), and Hex2Cer (d18:1/20:0). Triglyceridelevels correlated with Cer (d18:0/24:1). Alanine aminotransferase values correlated with Cer (d18:0/22:0), insulin with Cer (d18:1/22:1) and Cer (d18:1/24:1), and HDL with hexosylceramide (HexCer) (d18:2/23:0). These results expand on the currently known involvement of lipid metabolism in GSDIa. Circulating Cer may allow for refined dietary assessment compared with traditional biomarkers. Because specific lipid species are relatively easy to assess, they represent potential novel biomarkers of GSDIa.

Project description:Background: Glycogen storage disease type Ia (GSD Ia), also known as von Gierke disease, is the most common glycogen storage disorder. It is caused by the deficiency of glucose-6-phosphatase, the enzyme that catalyzes the final step of gluconeogenesis and glycogenolysis. The accumulation of glucose-6-phosphate leads to increased glycogen and triglyceride levels in the liver. Patients with GSD Ia can develop steatohepatitis, cirrhosis, and increased risk for hepatocellular adenomas and carcinomas. We previously showed that animal models of GSD Ia had defective autophagy and dysfunctional mitochondria. In this study, we examined the effect of VK2809, a liver-specific thyroid hormone receptor β agonist, on hepatic steatosis, autophagy, and mitochondrial biogenesis in a mouse model of GSD Ia. Methods: G6pc-/--deficient (GSD Ia) mice were treated with VK2809 or vehicle control by daily intraperitoneal injection for four days. The hepatic triglyceride and glycogen were determined by biochemical assays. Autophagy and mitochondrial biogenesis were measured by Western blotting for key autophagy and mitochondrial markers. Results: VK2809 treatment decreased hepatic mass and triglyceride content in GSD Ia mice. VK2809 stimulated hepatic autophagic flux as evidenced by increased microtubule-associated protein light chain 3-II (LC3B-II), decreased p62 protein levels, activation of AMP-activated protein kinase (AMPK), inhibition of the mammalian target of rapamycin (mTOR) signaling, enhancement of protein levels of ATG5-ATG12, and increased lysosomal protein expression. VK2809 also increased the expression of carnitine palmitoyltransferase 1a (CPT1α) and fibroblast growth factor 21 (FGF21), as well as mitochondrial biogenesis to promote mitochondrial β-oxidation. Conclusions: In summary, VK2809 treatment decreased hepatic triglyceride levels in GSD Ia mice through its simultaneous restoration of autophagy, mitochondrial biogenesis, and β-oxidation of fatty acids. Liver-specific thyromimetics represent a potential therapy for hepatosteatosis in GSD Ia as well as nonalcoholic fatty liver disease.

Project description:A deficiency in glucose-6-phosphatase-α (G6Pase-α) in glycogen storage disease type Ia (GSD-Ia) leads to impaired glucose homeostasis and metabolic manifestations including hepatomegaly caused by increased glycogen and neutral fat accumulation. A recent report showed that G6Pase-α deficiency causes impairment in autophagy, a recycling process important for cellular metabolism. However, the molecular mechanism underlying defective autophagy is unclear. Here we show that in mice, liver-specific knockout of G6Pase-α (L-G6pc-/-) leads to downregulation of sirtuin 1 (SIRT1) signaling that activates autophagy via deacetylation of autophagy-related (ATG) proteins and forkhead box O (FoxO) family of transcriptional factors which transactivate autophagy genes. Consistently, defective autophagy in G6Pase-α-deficient liver is characterized by attenuated expressions of autophagy components, increased acetylation of ATG5 and ATG7, decreased conjugation of ATG5 and ATG12, and reduced autophagic flux. We further show that hepatic G6Pase-α deficiency results in activation of carbohydrate response element-binding protein, a lipogenic transcription factor, increased expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), a lipid regulator, and suppressed expression of PPAR-α, a master regulator of fatty acid β-oxidation, all contributing to hepatic steatosis and downregulation of SIRT1 expression. An adenovirus vector-mediated increase in hepatic SIRT1 expression corrects autophagy defects but does not rectify metabolic abnormalities associated with G6Pase-α deficiency. Importantly, a recombinant adeno-associated virus (rAAV) vector-mediated restoration of hepatic G6Pase-α expression corrects metabolic abnormalities, restores SIRT1-FoxO signaling, and normalizes defective autophagy. Taken together, these data show that hepatic G6Pase-α deficiency-mediated down-regulation of SIRT1 signaling underlies defective hepatic autophagy in GSD-Ia.

Dataset Information

Estimation of Health Utility Scores for Glycogen Storage Disease Type Ia.

Background

Methods

Results

Conclusion

Publications

Estimation of Health Utility Scores for Glycogen Storage Disease Type Ia.

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