Lipids in hepatic glycogen storage diseases: pathophysiology, monitoring of dietary management and future directions

Abstract

Hepatic glycogen storage diseases (GSD) underscore the intimate relationship between carbohydrate and lipid metabolism. The hyperlipidemias in hepatic GSD reflect perturbed intracellular metabolism, providing biomarkers in blood to monitor dietary management. In different types of GSD, hyperlipidemias are of a different origin. Hypertriglyceridemia is most prominent in GSD type Ia and associated with long-term outcome morbidity, like pancreatitis and hepatic adenomas. In the ketotic subtypes of GSD, hypertriglyceridemia reflects the age-dependent fasting intolerance, secondary lipolysis and increased mitochondrial fatty acid oxidation. The role of high protein diets is established for ketotic types of GSD, but non-traditional dietary interventions (like medium-chain triglycerides and the ketogenic diet) in hepatic GSD are still controversial and necessitate further studies. Patients with these rare inherited disorders of carbohydrate metabolism meet several criteria of the metabolic syndrome, therefore close monitoring for cardiovascular diseases in ageing GSD patients may be justified.

Normoglycemic Ketonemia as Biochemical Presentation in Ketotic Glycogen Storage Disease

“…Hypoketosis has been reported before in GSD III patients (Seigel et al 2008;Clemente Touati et al 2012) et al 2010), in whom exogenous carbohydrate requirements are still relatively high (Derks and Van Rijn 2015). We speculate that, as a consequence of dietary management with frequent high-carbohydrate meals, there may have been a relatively high plasma insulin state together with high intracellular malonyl-CoA levels, physiologically inhibiting long-chain mitochondrial fatty acid oxidation at the level of carnitine palmitoyltransferase type I.…”

Liver Glycogen Phosphorylase Deficiency Leads to Profibrogenic Phenotype in a Murine Model of Glycogen Storage Disease Type VI

“…This study shows that Pygl ‐deficient mice following a fasting challenge display mild ketotic hypoglycemia along with reduced levels of serum metabolites, including triglyceride, cholesterol, and lactic acid, which can be substrates for GNG. Intriguingly, it has been suggested that elevated ketone bodies in ketotic GSDs reflect increased mitochondria fatty acid oxidation, which is elicited by GNG . Therefore, elevated blood ketone bodies and reduced levels of serum metabolites in fasted Pygl −/− mice raise the possibility that Pygl deficiency may induce GNG instead of defective glycogenolysis to compensate low glucose production in fasted periods, as suggested …”

A pediatric patient with glycogen storage disease type IA and Castleman disease

“…[1][2][3][4][5] The pathophysiology of these tumors has been related to the underlying metabolic disorder secondary to mutations in the G6PC gene. 3,6 Castleman disease is a rare lymphoproliferative disorder that has never been reported in association with GSD.…”

“…Patients with glycogen storage disease type IA (GSD‐IA) have a higher than average risk of developing various abdominal tumors . The pathophysiology of these tumors has been related to the underlying metabolic disorder secondary to mutations in the G6PC gene . Castleman disease is a rare lymphoproliferative disorder that has never been reported in association with GSD.…”

“…Castleman disease has not been reported in association with GSD; however, this group of metabolic diseases has been linked with hepatocellular adenomas, hepatoblastomas, and hepatocellular carcinomas . The underlying pathophysiology of cell proliferation in these tumors remains poorly understood; nevertheless, the metabolic amendment found in gluconeogenesis and glycogenolysis due to the absence of glucose‐6‐phosphatase has been proposed as a triggering mechanism of cellular overgrowth …”