High childhood serum triglyceride concentrations associate with hepatocellular adenoma development in patients with glycogen storage disease type Ia

Abstract

Background & aims: Glycogen storage disease type Ia (GSDIa) is an inborn error of carbohydrate metabolism caused by pathogenic variants in the glucose-6-phosphatase catalytic subunit 1 (G6PC1) gene and is associated with hepatocellular adenoma (HCA) formation. Data on risk factors for HCA occurrence in GSDIa are scarce. We investigated HCA development in relation to sex, G6PC1 genotype, and serum triglyceride concentration (TG).

Methods: An observational study of patients with genetically confirmed GSDIa ≥12 years was performed. Patients were categorised for sex; presence of 2, 1, or 0 predicted severe G6PC1 variant (PSV); and median TG during childhood (<12 years; stratified for above/below 5.65 mmol/L, i.e. 500 mg/dl).

Results: Fifty-three patients (23 females) were included, of which 26 patients developed HCA at a median (IQR) age of 21 (17-25) years. At the age of 25 years, 48% of females and 30% of males had developed HCA (log-rank p = 0.045). Two-thirds of patients with GSDIa carried 2 PSVs, 20% carried 1, and 13% carried none. Neither the number of PSVs nor any specific G6PC1 variants were associated with HCA occurrence. Childhood TG was 3.4 (3.0-4.2) mmol/L in males vs. 5.6 (4.0-7.9) mmol/L in females (p = 0.026). Childhood TG >5.65 mmol/L was associated with HCA development at younger age, compared with patients with childhood TG <5.65 mmol/L (18 vs. 33 years; log-rank p = 0.001). Cox regression analysis including TG, sex, and TG-sex interaction correction revealed childhood TG >5.65 mmol/L as an independent risk factor for HCA development (hazard ratio [HR] 6.0; 95% CI 1.2-29.8; p = 0.028).

Conclusions: In patients with GSDIa, high childhood TG was associated with an increased risk of HCA, and earlier onset of HCA development, independent of sex-associated hypertriglyceridaemia, and G6PC1 genotype.

Lay summary: Glycogen storage disease type Ia (GSDIa) is a rare, inherited metabolic disease that can be complicated by liver tumours (hepatocellular adenomas), which in turn may cause bleeding or progress to liver cancer. Risk factors associated with hepatocellular adenoma formation in patients with GSDIa are largely unknown. In our study, we found that high serum triglyceride concentrations during childhood, but not specific genetic variants, were associated with increased risk of hepatocellular adenoma diagnosis later in life.

Keywords: Benign neoplasm; G6PC1, glucose-6-phosphatase catalytic subunit 1; G6Pase, glucose-6-phosphatase; GSDIa, glycogen storage disease type Ia; Glucose-6-phosphatase triglycerides; Glycogen storage disease type Ia; HCA, hepatocellular adenoma; HR, hazard ratio; Hepatic adenoma; MRI, magnetic resonance imaging; Metabolic disorder; PSV, predicted severe variant; TG, serum triglyceride concentration.

Graphical abstract

Fig. 1

Flowchart of inclusion of the study population. G6PC1, glucose-6-phosphatase catalytic subunit 1; GSDIa; glycogen storage disease type Ia; HCA, hepatocellular adenoma.

Fig. 2

Schematic overview of G6PC1 with number of observed variants and occurrence of HCA at each site. No specific G6PC1 variant was associated with HCA formation. The G6PC1 active site is defined as amino acids 83, 119, 170, and 176. G6PC1, glucose-6-phosphatase catalytic subunit 1; HCA, hepatocellular adenoma; ER lumen, endoplasmatic reticulum lumen.

Fig. 3

Kaplan–Meier survival analysis for time to HCA occurrence in patients with GSDIa. (A) Total cohort. (B) Stratified by treatment era. (C) Stratified by sex. (D) Stratified by G6PC1 variant severity. Levels of significance: p values noted (log-rank test). G6PC1; glucose-6-phosphatase catalytic subunit 1; HCA, hepatocellular adenoma; GSDIa, glycogen storage disease type Ia; PSV, predicted severe variant.

Fig. 4

Longitudinal median childhood TG in patients with GSDIa per patient per 6 months. (A) Stratified for sex. (B) Stratified for diagnosis of HCA. Horizontal lines represent median TGs per moment of measurement. Levels of significance: ∗p <0.05; ^p <0.01 (Mann–Whitney U test). GSDIa, glycogen storage disease type Ia; HCA, hepatocellular adenoma; TG, serum triglyceride concentration.

Fig. 5

Influence of median childhood TG on HCA occurrence in patients with GSDIa, with patients clustered according to childhood TG above or below 5.65 mmol/L (500 mg/dl). (A) Kaplan–Meier survival analysis for time to HCA occurrence, stratified by median childhood TG above/below 5.65 mmol/L. Levels of significance: p values noted (log-rank test). (B) Cox regression analysis including sex and median childhood TG (model 1). Levels of significance: p values noted (Cox regression analysis). (C) Cox regression analysis including sex, median childhood TG, and interaction term for sex and median childhood TG (model 2). Levels of significance: p values noted (Cox regression analysis). GSDIa, glycogen storage disease type Ia; HCA, hepatocellular adenoma; TG, serum triglyceride concentration.