不同方案治疗糖代谢异常的非酒精性脂肪肝疗效分析及血清FGF21变化

【作者】 颜红梅；

【导师】 高鑫；

【作者基本信息】 复旦大学 ， 内科学， 2011， 博士

【摘要】 第一部分盐酸吡格列酮与盐酸小檗碱治疗伴糖代谢异常的非酒精性脂肪肝性肝病随机开放对照临床试验目的：评价盐酸吡格列酮及盐酸小檗碱治疗伴糖代谢异常(IFG/IGT/新诊断DM)的非酒精性脂肪性肝病(NAFLD)患者的疗效与安全性。方法：符合条件受试者173位被随机分至三组：A组(单纯生活方式干预组,n=59)、B组(生活方式干预组+吡格列酮15mg qd,n=56)、C组(生活方式干预+小檗碱0.5g tid组,n=58),共治疗16周。研究主要终点为：血糖水平[空腹血糖(FBG)、2h血糖(2hBG)、HbAlc]；血脂(TC、TG、HDL-c、LDL-c)；肝酶(ALT、AST、γ-GT)水平的改善；次要终点为：质子磁共振波谱方法(1H MRS)评估治疗前后肝脏脂肪含量(HFC)变化。结果：一、各组基线数据差异无统计学意义,包括性别、年龄、BMI、腰围、WHR、血压等；二、主要终点：治疗后血糖变化：1)单纯生活方式干预组FBG下降0.00±0.90mmol/L(P>0.05),2hBG下降0.80±2.3 mmol/L(P>0.05),HbAlc下降0.11±0.82%(P<0.05)；2)吡格列酮组FBG下降0.43±1.19 mmol/L(P<0.05),2hBG下降3.00±3.31 mmol/L(P<0.05),HbAlc下降0.55±0.59%(P<0.05)；3)小檗碱组FBG下降0.51±1.38 mmol/L(P<0.05)2hBG下降2.34±3.36 mmol/L (p<0.05),HbAlc下降0.54±0.74%(P<10.05)；4)三组间比较,FBG、2hBG、HbAlc下降绝对值差异均有统计学意义(P<0.05),校正性别、BMI与基线后,仅2hBG下降有统计学意义(P=0.014),两两比较吡格列酮与单纯生活方式干预组差异有统计学意义(P<0.05)；治疗后血脂变化：1)单纯生活方式干预组TC下降0.08±0.68 mmol/L P>0.05,TG升高0.01±0.92 mm01/(P>0.05),HDL-c升高0.02±0.13 mmol/L(P>0.05),LDL-c下降0.10±0.56 mmol/L(P>0.05):2)吡格列酮组TC下降0.13±0.85 mmol/L(P>0.05),TG下降0.17±0.88 mmol/L (P>0.05),HDL-c升高0.08±0.12mmol/L(P<0.05),LDL-c mmol/L下降0.09±0.85(P>0.05)：3)小檗碱组TC下降0.59±0.75 mmol/L(P<0.05),TG下降0.53±0.96 mmol/L (P<0.05),HDL-c升高0.02±0.18 mmol/L(P>0.05),LDL-c下降0.30±0.75 mmol/L(P<0.05);4)三组间比较,TC、TG下降绝对值差异有统计学意义(P均<0.05),校正性别、BMI、基线后,差异依然有统计学意义(P均<0.05),两两比较小檗碱组与毗格列酮组TC下降差异有统计学意义,与单纯生活方式相比TG下降差异有统计学意义;HDL-c、LDL-c变化的绝对值无统计学意义(P>0.05);治疗后肝酶变化：1)单纯生活方式干预组ALT下降12.52±21.50U/L(P<0.05),AST下降5.40±10.59 U/L(P<0.05),γ-GT下降4.94±33.93 U/L(P<.05);2)吡格列酮组ALT下降28.95±32.46U/L(P<0.05),AST下降12.55±16.46 U/L (P<0.05),γ-GT下降16.38±18.47 U/L(P<0.05)3)小檗碱组ALT下降16.60±21.07U/L(P<0.05),AST下降7.16±9.15 U/L (P<0.05),γ-GT下降12.48±22.73 U/L(P<0.05)4)三组间比较,ALT.AST下降绝对值差异有统计学意义(P均<0.05),校正性别、BMI、基线后,ALT下降绝对值差异依然有统计学意义(P<0.05),两两比较吡格列酮组与单纯生活方式干预组差异有统计学意义(P<0.05)；γ-GT下降绝对值差异无统计学意义(P>0.05)；三、次要终点：治疗后肝脏脂肪含量变化：1)单纯生活方式干预组肝脏脂肪含量绝对值下降11% (P<0.05)；2)吡格列酮组肝脏脂肪含量绝对值下降15%(P<0.05)；3)小檗碱组肝脏脂肪含量绝对值下降17%(P<0.05);4)三组间比较肝脏脂肪含量的下降差异无统计学意义(P=0.352)；其他指标变化：三组均可有效降低体重、腰围、WHR、血压(P均<0.05),吡格列酮组降低收缩压较明显,小檗碱降低体重、腰围、血压更明显(组间比较P均<0.05)；四、安全性评价：吡格列酮与小檗碱组总不良反应发生率分别为25%及41.38%,不良反应两组表现不同,吡格列酮组主要是肌肉酸痛(21.05%)、心悸(10.53%)、乏力(10.53%),小檗碱组主要是纳差(37.50%)、腹泻(21.88%)、严重便秘(12.50%)。两组均无严重不良事件。结论：对伴糖代谢异常的NAFLD患者,生活方式干预和生活方式加用吡格列酮或加用小檗碱治疗均可有效地改善糖代谢、降低肝脏脂肪含量及各项肝酶；小檗碱在改善血脂谱、降低体重、腰围和血压方面优于其他两组。吡格列酮和小檗碱治疗组均有良好的耐受性。第二部分血清成纤维细胞生长因子21与肝脏脂肪含量关系目的：成纤维细胞生长因子21(FGF21),是一个由肝脏分泌的具有调节糖脂质代谢功能的内分泌因子。近期研究表明非酒精性脂肪性肝病(NAFLD)患者中血清FGF21升高。本研究旨在检测血清FGF21水平和肝脏脂肪含量的量化关系。方法：伴糖代谢异常(IFG/IGT/新诊断糖尿病)经B超诊断为脂肪肝年龄18至65岁的受试者共138例(男／女：72／66)纳入研究。测量受试者隔夜空腹形体参数、血糖、血脂、肝酶等生化指标。血清FGF21水平采用内部化学发光免疫分析法测定,以质子核磁共振光谱方法(1H MRS)测定肝脏脂肪含量。结果：1.研究对象基线肝脏脂肪含量分布范围为：2.47%至81.95%,均数±标准差为32.30%±15.95%。2.以基线肝脏脂肪含量四分位分组29.76%(22.04%-44.58%),可见肝脏脂肪含量处于第一、二、三分位时,血清FGF21水平逐步增加,分别为194.12±126.96Pg/ml, 219.65±141.74Pg/ml和326.44±149.47Pg/ml,且第三分位组的血清FGF21水平与第一、第二分位组的相比,差异有统计学意义；当肝脏脂肪含量处于第四分位时,FGF21开始下降到258.75±124.69 Pg/ml(与第三分位相比,P值=0.059)。3.随着基线肝脏脂肪含量逐渐升高,各组血清ALT、AST水平逐渐升高(P值均<0.001),在肝脏脂肪含量第四分位时达到最高,分别为61.11±37.27 U/L及37.07±15.50 U/L。其他代谢参数各组间差异无统计学意义。4.单因素相关分析提示血清FGF21与基线肝脏脂肪含量正相关(r=0.198,P=0.047),把肝脏脂肪含量分为低于四分位组及第四分位组,可以发现在低于四分位组,血清FGF21与肝脏脂肪含量正相关(r=0.276,P=0.009),在第四分位组,两者相关性消失。5.多元逐步回归分析显示基线肝脏脂肪含量低于四分位时,FGF21是优于任何其他传统参数(包括A1T)反映肝脏脂肪含量的临床指标。当基线肝脏脂肪含量包括四分位时,血清FGF21和肝脏脂肪含量的定量关系被削弱。6.治疗后,随着肝脏脂肪含量下降,血清FGF21升高。结论：血清FGF21可反映未干预状态下轻/中度脂肪肝患者肝脏脂肪含量,在重度脂肪肝及治疗后患者中,FGF21与肝脏脂肪含量变化相反。以血清FGF21反映肝脏脂肪含量还缺少足够证据。更多还原

【Abstract】 PartⅠPioglitazone Versus Berberine for the Treatment of Non-Alcoholic Fatty Liver Disease Patients with Impaired Glucose Regulation or Type 2 Diabetes Mellitus- a randomized, open, controlled clinical trial.AIMSTo assess the effect and safety of Pioglitazone(PGZ) or Berberine(BBR) on treatment to Non-Alcoholic Fatty Liver Disease(NAFLD) patients with impaired glucose regulation(IGR) or Diabetes(DM).METHODSWe randomized 173 adults with NAFLD and with IGR or DM into 3 groups:Group A received lifestyle intervention(LI)without drugs(n=59); Group B received LI and PGZ (15 mg qd.) (n=56); Group C received LI and BBR(0.5g tid)(n=58); All of them were treated for 16 weeks. The primary outcome was an improvement in glucose(OGTT), HbAlc, lipid profile(TC, TG, HDL-c, LDL-c), liver enzymes (ALT, AST, GGT). The secondary outcome was a reduction in hepatic fat content(HFC) detected by proton magnetic resonance spectroscopy (1H MRS).RESULTS:1. There were no significant differences of baseline data in three group, including gender, age, BMI, waist circumference, WHR, blood Pressure;etc.2. Compared with pre-treatment, subjects after treatment have significant improvement in 2h glucose, HbAlc, liver enzyme, HFC, weight, waist, WHR, diastolic blood pressure(of the three group), in fasting glucose, systolic blood pressure of group B and C, in lipid profiles of group C(all paired t-test P<0.05).3. Although Group B(-15%)and Group C(-17%)have more obvious reduction in HFC than Group A(-11%), the differences of HFC after treatment are not significant among the three groups when baseline HFC, sex, BMI were adjusted(P=0.098). Other data changes such as fasting glucose, HbAlc, HDL-c, LDL-c, AST, GGT,WHR are similar (all ANOVA P>0.05).4. BBR therapy, as compared with LI, was associated with a significantly higher reduction in blood glucose, TC, TG, weight, waist, systolic and diastolic blood pressure(all P<0.05).5. Compared with PGZ, BBR therapy has a significantly higher reduction in TC,TG,, weight, waist, diastolic blood pressure(all P<0.05)while PGZ has a significantly higher reduction in ALT.6. PGZ therapy has a significantly higher reduction than LI in blood glucose, ALT, systolic blood pressure(all P<0.05).7.The major side effects related to the two drugs were different. Subjects who received PGZ felt muscular soreness(21.05%); palpitations(10.53%), fatigue(10.53%), subjects who received BBR appeared digestive symptoms such as anorexia(37.50%), diarrhea(21.88%), severe constipation(12.50%) etc. No severe adverse events were found about the two drugs.CONCLUSIONSFor NAFLD patients with IGR or DM, LI with or without PGZ or BBR are effective and safe methods to improve glucose and lipid and other metabolism, to lower HFC; BBR Showed stronger role for the treatment of serum glucose and lipid, weight, blood pressure. PartⅡCirculating Fibroblast Growth Factor 21 Levels and Hepatic Fat ContentBackground & Aims:Fibroblasts growth factor 21 (FGF21), a liver-secreted endocrine factor involved in regulating glucose and lipid metabolism, has been shown to be elevated in Patients with non-alcoholic fatty liver disease (NAFLD). This study aimed to evaluate the quantitative correlation between serum FGF21 level and hepatic fat content.Methods:Totally 138 subjects (72 male and 66 female) aged from 18 to 65 years with abnormal glucose metabolism and B-ultrasonograPhy diagnosed fatty liver were enrolled in the study. Serum FGF21 levels were determined by an in-house chemiluminescence immunoassay and hepatic fat contents were measured by proton magnetic resonance spectroscopy.Results:Serum FGF21 increased progressively with the increase of untreated hepatic fat content, but when hepatic fat content increased to the fourth quartile, FGF21 tended to decline. Serum FGF21 concentrations were positively correlated with untreated hepatic fat content especially in subjects with mild/moderate hepatic steatosis (r=0.276, P=0.009).Within the range of hepatic steatosis from the first to third quartile, FGF21 was superior to any other traditional clinical markers including ALT to reflect untreated hepatic fat content. When the patients with severe hepatic steatosis (the fourth quartile) were included, the quantitative correlation between FGF21 and untreated hepatic fat content was weakened. Unexpectedly, serum FGF21 increased while hepatic fat content decreased after treatment of lifestyle intervention and pioglitazone or berberine.Conclusions:Serum FGF21 can reflect the hepatic fat content only in untreated patients with mild or moderate NAFLD. In severe NAFLD or post-treatment patients, FGF21 concentration changes differently with hepatic fat content. The evidences are insufficient for taking serum FGF21 as a biomarker of hepatic fat content.更多还原