修回日期: 2014-09-19
接受日期: 2014-09-30
在线出版日期: 2014-11-08
谷氨酰转肽酶(gamma-glutamyltransferase, γ-GT/GGT)是临床常见的肝损指标, 常用于病毒性肝炎及酒精性肝病的诊断, 但是近年来有一系列临床研究显示其对非酒精性脂肪肝、胰岛素抵抗、代谢综合征及心血管疾病均有一定的指示作用, 并参与到氧化应激及血管损伤的过程中. 本文就GGT现有研究进展进行综述.
核心提示: 本文针对非酒精性脂肪性肝病(non-alcoholic fatty liver disease)及其相关的代谢疾病与谷氨酰转肽酶(gamma-glutamyltransferase)之间的关系进行综述, 详细阐述了近年相关研究进展, 并对其机制进行了一定的探讨.
引文著录: 孙晓琦, 方南元, 薛博瑜. GGT与非酒精性脂肪肝及相关疾病的研究进展. 世界华人消化杂志 2014; 22(31): 4745-4749
Revised: September 19, 2014
Accepted: September 30, 2014
Published online: November 8, 2014
Gamma-glutamyltransferase (GGT) activity is a sensitive marker of liver dysfunction. It is commonly used to evaluate liver diseases such as viral hepatitis or alcoholic hepatitis. Several studies have shown the association between GGT levels and risk of non-alcoholic fatty liver disease, insulin resistance, metabolic syndrome and cardiovascular disease. This paper will review recent advances in understanding the association of GGT with these diseases.
- Citation: Sun XQ, Fang NY, Xue BY. Association of gamma-glutamyltransferase with non-alcoholic fatty liver disease and other related diseases. Shijie Huaren Xiaohua Zazhi 2014; 22(31): 4745-4749
- URL: https://www.wjgnet.com/1009-3079/full/v22/i31/4745.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v22.i31.4745
谷氨酰转肽酶(gamma-glutamyltransferase, γ-GT/GGT)是含有巯基的线粒体酶[1,2], 负责细胞外谷胱甘肽代谢的关键酶之一, 在谷氨酰循环中催化谷氨酰基从谷胱甘肽或其他含谷氨酰基的物质中转移到氨基酸上, 形成γ-谷氨酰氨基酸, 为细胞内谷胱甘肽的再合成提供原料. GGT广泛存在于人体内肝、胆、肾、胰、肠、心、脑、前列腺等组织细胞中, 人体血清中GGT主要来自肝胆组织, 由肝内胆管上皮细胞线粒体产生, 局限于肝细胞浆和肝内胆管上皮中, 经胆道排泌, 与酒精摄入有关[3].
近年来, 不断有临床及基础研究指向GGT不止是简单的肝酶标志物, 还对非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD)、代谢综合征(metabolicsyndrome, MS)及相关心血管疾病(cardiovascular disease, CVD)具有指标作用[4], 现综述如下.
NAFLD是指除酒精外和其他明确的损肝因素所致的, 病变主体在肝小叶的, 以弥漫性肝细胞大泡性脂肪变性和脂肪贮积为病理特征的临床病理综合征, 包括非酒精性单纯性脂肪肝(non-alcoholic fatty liver, NAFL)、非酒精性脂肪性肝炎(non-alcoholic steatohepatitis, NASH)和非酒精性脂肪性肝硬化(nonalcoholic cirrhosis)3种主要类型[5-7]. GGT一直以来都是作为肝损及滥用酒精的指症被临床广泛认可[8], 早期曾有个例报道发现GGT与死亡率存在一定联系[9], 而随着人群的研究发现GGT还与MS、肥胖及代谢相关的CVD密切相关[10,11]. 由于NAFLD临床上主要依赖超声、谷丙转氨酶(alanine transaminase, ALT)、谷草转氨酶(aspartate transaminase, AST)、血脂等诊断, 但是本病为慢性温和性病变, 目前还没有特异性的生物学指标, 尤其在其不同的发病阶段, 因此研究者开始将目光转向GGT与NAFLD之间的联系[12]. 学术界普遍认为胰岛素抵抗促进了脂质在肝内的沉积, 在NAFLD的发生发展中起到了关键作用[13,14], 因此胰岛素抵抗、糖尿病及MS与NAFLD密切相关[15-17]. 澳洲学者在1999-2001年间对北昆士兰791名当地人进行的研究中显示, GGT与中心性肥胖呈显著性相关并且不依赖于生活习惯, MS也与GGT的升高显著相关, 习惯性的体力劳动可对这一指标具有保护作用[18]. 北京大学10076个个体组成的动态队列中, 平均随访2.54年后共1181例发生MS, MS的发生风险随GGT水平升高而上升, 显示GGT可能是MS的风险因子及预测因子[19]. Liu等[20]对GGT和MS相关的前瞻性研究进行了荟萃分析, 其中九个前瞻性研究列队5009个病例, 结果显示GGT的水平与MS密切相关, 并且独立于酒精摄入. 类似的临床研究显示GGT的水平与肝胰岛素抵抗、胰岛素分泌及高胰岛素血症之间存在了相关性[21].
在针对NAFLD的研究中, 三星医疗中心健康促进中心2001-2003年, 对29959人(中位年龄48岁的16706位男性和13253位女性)进行了调查. 不同性别的受试者被分成5组, 根据他们的血清GGT浓度, 血清GGT正常范围的分为4个梯度组(组1、2、3和4)和GGT升高组(第5组). 结果显示, 即使血清GGT在正常范围, 其浓度都与糖尿病和心血管危险因素存在相关性[22].
韩国圆光大学的课题组收录了1069例观察对象, 根据血清ALT及GGT水平分为4个组别, 检测了肝功能、血脂及B超, 通过统计分析关联NAFLD或是MS与指标间的关系, 结果显示, NAFLD和MS与GGT的水平呈现数量依赖性, 有代谢异常的人群出现GGT升高的更多, 由此认为肝脏过多的脂质沉积与血清高GGT及胰岛素抵抗相关[23].
Kozakova等[24]两年内对欧洲14个国家19个中心, 收纳了排除相关干扰疾病的30-60岁受试者1012人, 为观察脂肪肝和CVD的相关性生物学指标, 采用动脉分叉早期斑块及脂肪肝指数(fat liver index, FLI), FLI>60时动脉斑块发生风险大, 而GGT作为FLI中的重要变量与动脉斑块及脂肪肝有关联. 来自波兰的研究者对42例已诊断NASH的患者进行治疗, 其中30例采用褪黑素治疗, 经治后AST和GGT都显著下降, 其中GGT在治疗和回访期间均低于基线值[25], 显示出了GGT在病情预测中的作用. Robin采用GGT结合超声对肝脂肪变的人群进行长期随访, 无HBV、HCV感染及肝硬化的2044例男性和2116例女性, 其中>80%的人群可通过GGT结合超声来确诊肝脏脂肪变. 在每例平均7.3年的观察周期中, 有307例(7.5%)死亡, 其中GGT的升高与男性的死亡率风险增加有关, 而女性则无; 认为GGT与肝脏脂肪病变的关系与男性更为密切[26]. Banderas等[27]观察了193例无糖尿病的MS患者, 其中160例(82.9%)罹患NAFLD, 结果显示在对NAFLD的预测中起到重要作用的是血清甘油三酯、GGT及肥胖程度, 此外肝脏的氧化及氧化应激水平也对肝脏病变风险有一定的提示作用.
Rakha等[28]对160例酒精性肝病(alcoholic fatty liver disease, AFLD)和214例NAFLD患者进行研究, 通过病理数据和肝酶的比较, 发现在AFLD和NAFLD中分别有47%和30%的患者存在门静脉的轻微炎症病变, 无论是AFLD或是NAFLD中出现的门静脉炎症均与GGT和铁蛋白的水平相关, 显示出了GGT与肝脏炎症及血管炎症中存在的关联.
GGT在人体内分别存在4个活性组分, 即大GGT(big, b-GGT)、中型GGT(media, m-GGT)、小GGT(small, s-GGT)和游离GTT(free, f-GGT), 可通过分子排阻色谱法获得[29,30]. Franzini等[31]在对NAFLD患者(90例)对比健康人的GGT(70例)的研究中发现, GGT与NAFLD的发病具有密切关系, 并采用上法比较4种活性组分, 其中b-GGT对NAFLD发病最具有敏感性和特异性, 提示GGT可以作为NAFLD的诊断标志物.
土耳其的Arinc等[32]观察50例NASH患者及30例正常人, 所有患者除进行常规肝酶及糖脂检测外还进行经胸超声心动图和肱动脉和颈动脉多普勒超声评价血流介导的扩张(flowmediated vasodilation, FMD)和颈动脉内膜中层厚度(carotid intima-media thickness, CIMT). NASH的患者较正常人具有更高的FMD和CIMT, 而线性回归分析显示, 血清GGT及ALT的浓度与FMD和CIMT密切相关. 显示出了NASH与血流扩张的损伤和动脉内膜厚度存在的联系, 及GGT和ALT水平对NASH患者血管病变具有预测作用.
在大规模的前瞻性研究及荟萃分析中均显示GGT与死亡终点事件的相关性, 且与急性冠脉综合征密切相关[33-35]. 在对MS及NAFLD的研究中也提示了GGT与血管损伤的关联, 近年来GGT与冠脉综合症及动脉粥样硬化的研究也日益增多[36].
在对7613位中年英国男人平均11.5年的随访中发现, GGT水平升高是独立的与CVD的死亡率相关, 尤其是缺血性心脏病[37]. 2005年在奥地利对163944人的前瞻性研究也显示GGT与CVD的死亡率密切相关, 男性与女性均显示出了GGT与CVD的关系, 并与病情的轻重呈现对应关系, 其中在男性中, 高GGT均与冠状动脉心脏疾病(P = 0.009)、充血性心脏衰竭(P<0.001)、出血性(P = 0.01)和缺血性中风的慢性形式致命事故事件相关(P<0.001), 但与急性心肌梗死(P = 0.16)无显著关联. 在女性中则高GGT与上述的CVD疾病均有关[33]. 同一课题组在2008年扩大了观察面积对76113人的前瞻性研究, 显示GGT的基线值与CVD的风险因素有关, 并与CVD导致的死亡率密切相关, 与之前的研究一致在女性中风险的增加更为显著[38], 这样的结果也得到了其他课题研究的证实[39].
Franzini等[40]对18例患者的颈动脉粥样斑块进行取样分析, 结果显示beta-脂蛋白可以削弱GGT的活性, 而斑块中的GGT酶产物半胱酰胺-甘氨酸呈游离或与蛋白结合形式的, 提示在斑块中出现了GGT依赖的促氧化反应. 有研究[41]显示在动脉粥样硬化斑块中发现活化的GGT和CD68+的泡沫细胞. 由此可见GGT参与到心血管病变中可能与其氧化反应及相应的炎症反应有关.
GGT是负责抗氧化剂谷胱甘肽的细胞外分解代谢的酶, 血清GGT的主要作用是启动细胞外还原型谷胱甘肽的降解, 允许其前体氨基酸被吸收, 并用其来合成细胞内谷胱甘肽. 除了对谷胱甘肽的切割作用, GGT还能对内源性的如白介素或前列腺素进行代谢, 并能依赖于细胞的氧化还原反应来对环境中的化合物和毒物进行解毒[42-44]. 在体外研究中显示, 活化的GGT暴露于微量铁及谷胱甘肽下, 作为生理性底物他可以催化自由基和活性氧的产生, 促进LDL的氧化[45]. 此外, 还原性辅酶Ⅱ氧化酶产生活性氧和活性氮能够诱导GGT的表达, 参与到代谢疾病中[46,47]. 临床研究中对机制的探讨并不深入, 但总体认为其与氧化应激相关[48], 因而参与到相关的铁代谢及脂蛋白表达中[49,50], 此外也有研究显示GGT与血管内皮损伤有关. 虽然有较多的前瞻性研究及荟萃分析均显示GGT的水平与NAFLD的病程密切相关, 但是数据主要来自于欧洲或亚洲其他国家, 在我国人群中的研究还鲜有报道, 且相关的基础研究也较少, 还需要更深入的研究与探讨.
非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD)及相关的代谢性疾病在临床中为常见病多发病, 但临床中对其诊断方法还在不断发展, 虽然有较多的前瞻性研究及荟萃分析均显示谷氨酰转肽酶(gamma-glutamyltransferase, γ-GT/GGT)的水平与NAFLD的病程密切相关, 但是数据主要来自于欧洲或亚洲其他国家, 在我国人群中的研究还鲜有报道, 且相关的基础研究也较少, 还需要更深入的研究与探讨.
杜雅菊, 教授, 哈尔滨医科大学附属第二医院消化内科
GGT在人体内分别存在4个活性组分, 即大GGT(big, b-GGT)、中型GGT(media, m-GGT)、小GGT(small, s-GGT)和游离GTT(free, f-GGT), 可通过分子排阻色谱法获得.
国内外均有报道GGT与非酒精性脂肪肝及代谢相关的心血管疾病密切相关.
本文不仅对NA-FLD与GGT的相关性进行阐述, 还对GGT与代谢疾病及心血管疾病的关系进行分述.
本文就GGT对脂肪肝及相关代谢性疾病的关系进行综述, 具有一定的临床指导意义.
本文具有一定临床指导意义.
编辑:郭鹏 电编:都珍珍
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