GSDIa is a hereditary disease, caused by G6Pase catalytic subunit defected. The typical manifestation of this metabolic disorder includes hypoglycemia, hyperlipemia, hyperuricemia, and hyperlactacidemia. Blood lipid characteristics of GSDIa are high TC, TG, and LDL-C, and low HDL-C. Hyperlipemia is an important risk factor of cardiovascular and cerebrovascular diseases.
Hyperlipidemia in GSDIa patients is caused mainly by increased levels of acetyl-CoA and VLDL[12]. Previous studies lack large epidemiological data on blood lipid levels in patients with GSDIa. Furthermore, there is no large-scale study on serum lipid levels after using lipid-lowering drugs in GSDIa patients.
4.1 Lipid levels in GSDIa patients before intervention
The TC and TG levels in normal newborns are 1.7 mmol/L and 0.4 mmol/L, respectively. They both increase gradually after birth and remain at about 4.3 mmol/L from the age of about two years [13]. The normal value of blood lipid levels varies with age. The normal range values of TC, TG, HDL-C, and LDL-C in this study were based on the American NCEP Children's Expert Group report.
The mean level of TC in our study was 5.78 ± 3.07 mmol/L in 133 GSDIa patients, with 58.3% of them having hypercholesteremia. The mean level of TG was 8.32 ± 8.51 mmol/L in 142 GSDIa patients, with 98.6% of them having hypertriglyceridemia.
The incidence of hyperlipidemia is high in GSDIa patients. A previous study on 62 GSDI patients(53 GSDIa and nine GSDIb) showed that the mean levels of TC and TG were 6.18 ± 2.47 mmol/L and 11.17 ± 9.85 mmol/L, respectively, before treatment[14]. Another study, on 11 GSDIa patients, found the levels of TC and TG to range between 4.31–6.89 mmol/L and 16.26–69.09 mmol/L, respectively. However, the incidence of hyperlipemia was not reported in this study [15].
Thus, the level of hyperlipemia before treatment in our study is similar to what was previously reported. The incidence of hypertriglyceridemia is obviously higher than that of hypercholesteremia.
4.2. Lipid levels in GSDIa patient after raw cornstarch treatment
After raw cornstarch treatment in our study, 58.1% had hypercholesterolemia, and 98% had hypertriglyceridemia. It shows that the incidence of hypercholesterolemia and hypertriglyceridemia are still high, even after raw cornstarch treatment.
In the ESGSDI study, 41.3% of 233 GSDIa patients had hypercholesterolemia, and72.7% had hypertriglyceridemia[2]. Two other studies, on 37 and 41 GSDIa patients, respectively, found the incidence of hypercholesterolemia to range between 76 and 81.6% and the incidence of hypertriglyceridemia to range between 85.3 and 100%[16, 17]. As in our study, the incidence of hypertriglyceridemia was higher than that of hypercholesterolemia.
In a previous study, TC and TG have significantly decreased after raw cornstarch treatment in 62 GSDI patients(including 53 GSDIa patients)[14]. TC had decreased from 6.18 ± 2.47 mmol/L to 5.61 ± 1.84 mmol/L(P = 0.02) and TG had decreased from 11.17 ± 9.85 mmol/L to 6.81 ± 5.97 mmol/L(P = 0.01). In another study on 19 GSDI patients treated with nocturnal gastric tube infusion since they were one year old, lipid level decreased significantly but did not return to normal level[18].
In our study, after treatment with raw cornstarch, TG level had significantly decreased by 30 ± 50%(P < 0.05), while TC level did not change. Similar to the previous research, our study found that TG level could be decreased significantly by raw cornstarch treatment.
4.3 Comparison of lipid levels after treatment with lipid-lowering drugs
The lipid-lowering drugs used in this study were fibrates(fenofibrate and gemfibrozil) and atorvastatin. Previous studies had shown that secretion of very-low-density lipoprotein (VLDL) was normal, but its degradation rate had decreased in two GSDIa patients. This might reflect a decrease in LPL activity. In these two patients, TG had decreased by 50% following treatment with fibrates[19].
Previous studies showed that dyslipidemia in GSDIa patients is characterized by an increased level of VLDL and decreased LDLR metabolism. Furthermore, statins had been shown to have strong effects on lipid-lowering treatment in multiple studies, mainly on lowering VLDL remnants through the uptake of the LDL receptors. Thus, lipid levels can be substantially decreased by statins [20].
This study analyzed lipid metabolism in 30 GSDIa patients. The levels of TC and TG have improved after fibrates treatment, but changes did not reach the statistical significance level. TC and TG levels, however, could be significantly improved by atorvastatin treatment. TC in 11/15 patients(73.3%) has decreased back to a normal level. It is suggested that lipid metabolism could be improved following treatment with lipid-lowering drugs. We found that the therapeutic effect of atorvastatin was better than that of fibrates.TC could achieve a normal level in most patients following dietary control and treatment with raw cornstarch and atorvastatin.
4.4 The linear regression equation between TC and TG, and blood lipid control target
Pearson’s correlation test suggested that there is a positive correlation between TC and TG. TC and TG were found to be related at medium intensity. A regression equation was established for this relationship, TG = 1.63TC -2.86. The F-regression test was performed on the overall regression coefficient, showing a high significance level(P < 0.01),with the decision coefficient being R2 = 0.264.
The 2014 GSDI guidelines, published by the Genetics Society of the American Medical College, recommend maintaining a normal blood lipids range to reduce the risk of arteriosclerotic cardiovascular disease(ASCVD) and pancreatitis[7]. However, previous studies have shown that hyperlipidemia could be improved but not cured in GSDI patients[16]. The incidence rate of hypertriglyceridemia is obviously higher than that of hypercholesteremia, but the incidence of pancreatitis, the main complication of hypertriglyceridemia, is low. It is important to decrease the level of TC as it is considered a key factor leading to ASCVD [21]. After treatment with lipid-lowering drugs, TC has decreased to normal in most patients, but it was difficult to decrease TG to a normal level.
Because the complications of hyperlipidemia are caused mainly by TC, therefore, the TC level is the main target of lipid control in GSD patients. If TC is maintained at a normal level, TG do not have to be maintained normal and a certain degree of hypertriglyceridemia could be accepted. There is no need to further increase the dose of lipid-lowering drugs. Thereby, as long as the TC remains normal, we could set a TG target to allow a certain degree of hypertriglyceridemia. The lower bound of Chinese children's TC normal level (5.18 mmol/L[22]) was inserted into the established regression equation to obtain TG = 5.58 mmol/L. The prediction interval at 95% confidence level was − 3.28 ~ 14.37 mmol/L. We, therefore, targeted to keep TG level below 5.58 mmol/L. When this was achieved, a normal TC level could be maintained with no need for a further increase in lipid-lowering drug dosage.
Many studies had shown that it is difficult to control normal lipid levels in GSDIa patients. The aim is to maintain TC at a normal level while allowing a certain degree of hypertriglyceridemia. As long as TC could be maintained at a normal level, the TG level derived from this regression equation could be used as a reference for clinical treatment. Moreover, this was a retrospective study. A long follow-ups time is needed to observe differences in atherosclerosis incidence between patients with TG༞5.58 mmol/L and TG ≤ 5.58 mmol/L. Long-term treatment research is needed to confirm the feasibility of this control target.
The blood lipid levels in the NCEP standard are grouped by age. If we insert the normal values of TC in the different age groups into the regression equation, we could get their respective acceptable hypertriglyceridemia levels for different ages period.