Investigation and management of the hepatic glycogen storage diseases

Abstract

The glycogen storage diseases (GSD) comprise a group of disorders that involve the disruption of metabolism of glycogen. Glycogen is stored in various organs including skeletal muscle, the kidneys and liver. The liver stores glycogen to supply the rest of the body with glucose when required. Therefore, disruption of this process can lead to hypoglycaemia. If glycogen is not broken down effectively, this can lead to hepatomegaly. Glycogen synthase deficiency leads to impaired glycogen synthesis and consequently the liver is small. Glycogen brancher deficiency can lead to abnormal glycogen being stored in the liver leading to a quite different disorder of progressive liver dysfunction. Understanding the physiology of GSD I, III, VI and IX guides dietary treatments and the provision of appropriate amounts and types of carbohydrates. There has been recent re-emergence in the literature of the use of ketones in therapy, either in the form of the salt D,L-3-hydroxybutyrate or medium chain triglyceride (MCT). High protein diets have also been advocated. Alternative waxy maize based starches seem to show promising early data of efficacy. There are many complications of each of these disorders and they need to be prospectively surveyed and managed. Liver and kidney transplantation is still indicated in severe refractory disease.

Keywords: Glycogen storage disease (GSD); Glycosade; hepatomegaly; hypoglycaemia; ketones; lactate; medium chain triglyceride (MCT); next generation sequencing; waxy maize starch.

Figure 1

The pathways for synthesis and breakdown of glycogen as discussed in the text. Processes involved (A) glycogen synthase facilitates straight chain glucose polymer synthesis from glucose-1-phosphate molecules (via glucose uridyl-diphosphate); (B) glycogen branches formed by glycogen brancher enzyme; (C) glycogen debrancher action also cleaving off 1 molecule of glucose-1-phosphate; (D) glycogen phosphorylase cleaves glucose-1-phosphate molecule from straight chain glycogen; (E) glycogen phosphorylase activated by the phosphorylase kinase complex; (F) glucose isomerase converting glucose-1-phosphate to glucose-6-phosphate; (G) glucose-6-phosphate transport into endoplasmic reticulum (deficient in GSD Ib); (H) glucose is released by glucose-6-phosphatase (deficient in GSD Ia); (I) facilitated glucose transport across endoplasmic reticulum by SLC2A2 deficient in Fanconi-Bickel syndrome. GSD, glycogen storage disease.

Figure 2

Indicates fasting study of a patient with GSD III taking Glycosade^TM Note rise in lactate after carbohydrate is administered with concomitant suppression of beta-hydroxybutyrate (BOHB). This gradually rises at the end of the fast as the glucose level decreases. An acceptable therapeutic limit of fasting of 420 minutes with 40 g of Glycosade was prescribed for this patient. GSD, glycogen storage disease.

Figure 3

Biochemical profiles of some of the glycogen storage disorders discussed in the text. OGTT, oral glucose tolerance test.