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Lipid Status and Linear Relationship Between Total Cholesterol and Triglycerides in Glycogen Storage Disease Type Ia

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Lipid Status and Linear Relationship Between Total Cholesterol and Triglycerides in Glycogen Storage Disease Type Ia Lipid Status and Linear Relationship Between Total Cholesterol and Triglycerides in Glycogen Storage Disease Type Ia Zhenjie Zhang Peking Union Medical College Hospital Yuheng Yuan Heidelberg University Mingsheng Ma Peking Union Medical College Hospital Yuehui Hong Peking Union Medical College Hospital Zhixing Sun Peking Union Medical College Hospital Yiwen Xu Peking Union Medical College Hospital Zhengqing Qiu ( [email protected] ) Peking Union Medical College Hospital Research Keywords: Glycogen storage disease type Ia, lipid metabolism, atorvastatin Posted Date: July 22nd, 2020 DOI: https://doi.org/10.21203/rs.3.rs-46912/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Loading [MathJax]/jax/output/CommonHTML/fonts/TeX/fontdata.js Page 1/9 Abstract Background Glycogen storage disease type Ia(GSDIa) is a glucose metabolic disorder disease. GSDIa patients are characterized by hypoglycemia, hepatomegaly, hyperlipidemia, and hyperlactacidemia. This study aims to review the lipid status, explore lipid treatment targets, and assess preferable lipid-lowering drugs. Methods Clinical data on GSDIa patients’ characteristics were collected. Diet control and raw cornstarch treatment were used to maintain normal blood glucose and lipid level. Some patients were given lipid-lowering drugs. We compared the lipid levels before and after each treatment. Results A total of 163 GSDIa patients were enrolled in this study. The lipid level was assessed 773 times. After treatment with raw cornstarch, TG level has signicantly decreased by 30 ± 50%(P < 0.001). There was no change in TC level. Thirty patients regularly took atorvastatin or brates for more than one year. The therapeutic effect of atorvastatin was better than brates. The total cholesterol(TC) was positively correlated with TG after treatment, resulting in the following regression equation: TG = 1.63*TC-2.86. Conclusion Patients with GSDIa have signicant abnormalities in blood lipid metabolism. We found that there was a linear correlation between TC and TG, which was TG = 1.63*TC-2.86. Because the complications of hyperlipidemia are caused mainly by TC, thereby, as long as the TC remains normal, we could set a TG target to allow a certain degree of hypertriglyceridemia. The bound of Chinese Children's TC normal level (5.18 mmol/L) was used in the established regression equation to obtain TG = 5.58 mmol/L. We, therefore, targeted to keep TG level below 5.58 mmol/L. This study found that the therapeutic effect of atorvastatin was better than brates. 1. Background Glycogen storage disease type 1 (GSDI, OMIM 232200) is a glucose metabolic disorder caused by glucose-6-phosphatase (G6Pase) deciency. The incidence of GSDI is about 1/100 000[1], of which GSDIa accounts for 80%[2]. Because the last step of glycogenolysis and gluconeogenesis is affected, GSDI patients present with severe hypoglycemia. Besides, patients also present with hyperlipidemia, hyperuricemia, hyperlactacidemia, and growth and development retardation[3]. The main therapeutic approaches are dietary control and raw cornstarch treatment. Raw cornstarch can maintain a normal glucose production rate, thus avoiding hypoglycemia and reducing secondary metabolic complications. G6Pase is mainly located in the liver. It is composed of glucose-6-phosphatase catalytic subunit (G6PC) and glucose-6-phosphate transporter(G6PT)[4]. G6PC hydrolyzes G6P into glucose and phosphate. The G6PC active site is located in the endoplasmic reticulum, into which G6P is transported by G6PT[5][6]. Mutations in G6PC are the cause of GSDIa. Untreated GSDIa patients usually show signicant lipid metabolism disorder, which includes elevated triglyceride(TG) and total cholesterol(TC),and decreased low- and high-density lipoprotein-cholesterol(LDL-C and HDL-C, respectively)[7]. Although hyperlipidemia in GSDIa patients is prevalent and severe, studies on lipid status in GSDIa patients are extremely rare. Most reported studies are case reports, ignoring treatment status and genotyping. Currently, there is neither recommendation for lipid-lowering drugs nor denite treatment targets for GSDIa patients. To date, this is the most extensive retrospective single-center study of lipid metabolism in GSDIa patients. In this study, we reviewed the status of lipid metabolism in GSDIa patients, aiming to reveal their lipid status, explore the lipid treatment targets, and identify preferable lipid-lowering drugs. 2. Methods 2.1 Patients The study includes 163 GSDIa patients, referred to the Pediatric Department of Peking Union Medical College Hospital between July 1985 and April 2017. Most patients were followed-up once a year. All the patients presented with development retardation, hepatomegaly, fasting hypoglycemia, hyperlipidemia, hyperlactacidemia, and elevated liver enzymes. The diagnosis was conrmed when a mutation was found in the G6PC gene. Dietary control and raw cornstarch treatment were used to maintain normal blood glucose and lipid levels. General guidelines for dosing raw cornstarch included 1.6 g of raw cornstarch per kilogram of body weight (ideal body weight) every 3–4 hours for young children, and 1.7–2.5 g raw cornstarch/kg every 4–5 hours (sometimes 6 hours) for older children, adolescents, and adults. Some patients with severe hyperlipidemia were treated with lipid-lowering drugs. Thirty of the study participants regularly took atorvastatin or brates (fenobrate or gembrozil) for more than one year. They were divided into an atorvastatin group and a brates group. According to the diagnostic criteria of hyperlipidemia in the American National Cholesterol Education Program (NCEP) Children's Experts Group[8], the data were divided into ve age groups: 0–4 y, 5–9 y, 10–14 y, 15–19 y, and greater than 20 years old. Loading [MathJax]/jax/output/CommonHTML/fonts/TeX/fontdata.js Page 2/9 The participants’ mean values for each age group were used as the outcome. The change in the patients’ lipid value is relatively fast and becomes stable several months after initiation of treatment. Therefore, each patient was counted as one case in each age group. This can be considered as reecting on the level of the last one or two years. We focused on the control level of each age group, so the data of any patient in the different age groups are independent of each other. 2.2 General Examination Trained examiners used standardized protocols. All participants were instructed to fast for ve hours before venipuncture. Compliance was determined by an interview on the morning of the examination. Laboratory evaluations for all patients included TC, TG, HDL-C, and LDL-C. 2.3 Diagnostic criteria of hyperlipidemia Lipid levels were related to age and sex, and were assessed following the American NCEP Children's Expert Group guidelines. The blood lipid levels were grouped by age, as indicated above. The normal range of TC, TG, HDL-C, and LDL-C in our study was based on previously reported values [8]. For patients older than 18 years, the diagnostic criteria followed the 2016 Chinese Guideline for the Management of Dyslipidemia in Adults[9]. The normal ranges for TC, TG, LDL-C and HDL-C are presented in Table 1. Table 1 The classication standard of TC, TG, LDL-C and HDL-C in patients of all ages in this study TC[mg/dl(mmol/L)] TG[mg/dl(mmol/L)] Age(year-old) Sex 0–4 5–9 10–14 15–19 > 20 0–4 5–9 10–14 Appropriate M < 176(4.56) < < < 170(4.40) < 200 < 69(0.78) < 67(0.76) < 80(0. level 180(4.66) 178(4.61) (5.20) F < 177(4.58) < < < 177(4.58) < 79(0.89) < 73(0.82) < 93(1. 184(4.77) 179(4.64) Critical high M 177209 181209 179208 171203 200240 69102 67104 80129 level F 178206 185211 180207 178209 79115 73108 93135 Hyperlipidemia M > 209(5.41) > > > 203(5.26) ≥ 240 > 102(1.15) > 104(1.18) > 129(1 209(5.41) 208(5.39) (6.20) F > 206(5.34) > > > 209(5.41) > 115(1.30) > 108(1.22) > 135(1 211(5.46) 207(5.36) LDL-C[mg/dl(mmol/L)] HDL-C[mg/dl(mmol/L)] Age(year-old) Sex 5–9 10–14 15–19 > 20 5–9 10–14 15–19 Appropriate M < < 112(2.90) < 112(2.90) < 130(3.40) > 50(1.30) > 47(1.22) > 40(1.04) level 106(2.75) F < < 113(2.93) < 114(2.95) > 48(1.24) > 46(1.19) > 44(1.14) 118(3.06) Critical high M 106133 112136 112134 130160 39 ~ 50 38 ~ 47 31 ~ 40 level F 118144 113140 114141 37 ~ 48 38 ~ 46 36 ~ 44 Hyperlipidemia M > > 136(3.52) > 134(3.47) ≥ 160(4.10) < 39(1.01) < 38(0.98) < 31(0.80) 133(3.44) F > > 140(3.63) > 141(3.65) < 37(0.96) < 38(0.98) < 36(0.93) 144(3.73) The normal range of TC, TG, LDL-C and HDL-C in children are reference The NCEP Children's Experts Group in the United States The normal range of TC, TG, LDL-C and HDL-C in patients aged 18 or over are reference 2016 Chinese guideline for the management of dyslipidemia in adults In this article, we want to set a cut-off point for severe hypertriglyceridemia. Acute pancreatitis is the main complication of hyperlipidemia. In the glycogen storage disease (GSD) medical guidelines published by the American College of Medical Sciences in 2014, it was suggested that pancreatitis might occur in GSD patients with TG higher than 11 mmol/L. Therefore, TG ≥ 11 mmol/L was considered as a cut-off point for severe hypertriglyceridemia[7]. 2.4 Statistical methods All data were divided into six groups by age: 0–1, 2–4, 5–9, 10–14, 15–19 and greater than 20 years. The data were analyzed with SPSS 24.0.0.0.
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