High childhood serum triglyceride concentrations associate with hepatocellular adenoma development in patients with
Martijn P D Haring1, Fabian Peeks2, Maaike H Oosterveer3
1Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Insights
High childhood triglycerides increase hepatocellular adenoma (HCA) risk in glycogen storage disease type Ia (GSDIa). This finding is independent of G6PC1 genotype and sex, highlighting TG as a key factor for HCA development.
Area of Science:
- Metabolic disorders
- Genetics
- Hepatology
Background:
- Glycogen storage disease type Ia (GSDIa) is an inherited metabolic disorder linked to hepatocellular adenoma (HCA) formation.
- Risk factors for HCA in GSDIa patients are not well-established.
- This study investigates GSDIa, G6PC1 genotype, sex, and triglyceride levels as potential HCA risk factors.
Purpose of the Study:
- To identify risk factors for hepatocellular adenoma (HCA) development in patients with Glycogen storage disease type Ia (GSDIa).
- To investigate the association of GSDIa with sex, G6PC1 genotype, and serum triglyceride (TG) levels in relation to HCA occurrence.
Main Methods:
- Observational study including genetically confirmed GSDIa patients aged 12 years and older.
- Patients were categorized by sex, number of predicted severe G6PC1 variants (PSV), and childhood median triglyceride (TG) levels (< or > 5.65 mmol/L).
- Statistical analyses included log-rank tests and Cox regression to assess HCA development risk.
Main Results:
- Hepatocellular adenoma (HCA) developed in 26 of 53 GSDIa patients by a median age of 21 years.
- Females had a higher incidence of HCA by age 25 (48% vs. 30%).
- High childhood triglycerides (>5.65 mmol/L) were an independent risk factor for HCA development (HR 6.0), associated with earlier onset (18 vs. 33 years).
Conclusions:
- High childhood serum triglyceride concentrations are associated with an increased risk and earlier onset of hepatocellular adenoma (HCA) in GSDIa patients.
- This association is independent of G6PC1 genotype and sex-specific hypertriglyceridemia.
- Serum triglyceride levels during childhood are a significant predictor of HCA development in GSDIa.
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.
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