topic型糖尿病合并nafld的临床管理

1、2型糖尿病合并型糖尿病合并NAFLD的临床管理的临床管理.从从糖尿病糖尿病专家的角度，如何看待专家的角度，如何看待NAFLD？Joseph M. Pappachan, et al. Endocrine (2014) 45:344353内分泌内分泌疾病疾病NAFLD.主要主要内容内容123T2DM合并合并NAFLD的流行病学的流行病学NAFLD与与T2DM发病之间的关系发病之间的关系NAFLD与与T2DM对疾病预后的相互影响对疾病预后的相互影响4NAFLD的治疗措施的治疗措施.42.6%的的T2DM患者有患者有NAFLD23.5%2.3%16.9%56.9%0.4%42.6%0%10%20%30

2、%40%50%60%正常Grade 1Grade 2Grade 3超声检查肝硬化NAFLD患者比例n=939RACHEL M. WILLIAMSON, et al. Diabetes Care 34:11391144, 2011爱丁堡2型糖尿病研究（ET2DS）中939例年龄61-76岁的T2DM患者，通过肝脏超声评估脂肪肝的情况grade 0, normal appearance of liver on ultrasound and initially graded as a “normal ultrasound”;grade 1, possible slight increase in e

3、chogenicity or slightly impaired visualization of the diaphragm or intrahepatic vessels, or difficulty in grading as a result of a diseased or absent right kidneyinitially termed an “indeterminate ultrasound”;grade 2, definite increase in echogenicity and/or definite impaired visualization of the in

4、trahepatic vessels and diaphragm, no or little evidence of focal fatty sparing, initially graded as “evidence of mild steatosis on ultrasound”; grade 3, marked increase in echogenicity and/or poor or no visualization of the diaphragm and intrahepatic vessels, with or without focal fatty sparing, ini

5、tially graded as “evidence of severe steatosis on ultrasound.” Evidence of hepatic cirrhosis was also sought systematically.NAFLD患者中前驱糖尿病和患者中前驱糖尿病和T2DM患病患病率高于非率高于非NAFLD人群人群We studied the prevalence and the metabolic impact of prediabetes and T2DM in 118 patients with NAFLD. The control group compris

6、ed 20 subjects withoutNAFLD matched for age, sex, and adiposity.NAFLD患者和非NAFLD人群前驱糖尿病和T2DM患病率*P 0.001 vs. without NAFLDCAROLINA ORTIZ-LOPEZ, et al. Diabetes Care 35:873878, 2012发生率.NAFLD及其严重性与糖尿病发生率及其严重性与糖尿病发生率有独立的强相关性有独立的强相关性NFS：NAFLD纤维化评分A cross-sectional study was performed in 43,166 apparently h

7、ealthy Koreans aged 30-59 years, who underwent a health checkup in 2005 and 2006. Of these, 38,291 subjects without diabetes were followed annually or biennially until December 2011 for the cohort study.Yoosoo Chang , et al. Am J Gastroenterol 2013; 108:18611868NAFLD及其严重性与及其严重性与T2DM的累积发生率的累积发生率P -tr

8、end .主要主要内容内容123T2DM合并合并NAFLD的流行病学的流行病学NAFLD与与T2DM发病之间的关系发病之间的关系NAFLD与与T2DM对疾病预后的相互影响对疾病预后的相互影响4NAFLD的治疗措施的治疗措施.脂质脂质沉积与肝胰岛素敏感度降低有关沉积与肝胰岛素敏感度降低有关IHTG：肝甘油三酯；VF：腹部脂肪Melania Gaggini, et al. Nutrients 2013, 5, 1544-1560;肝胰岛素敏感性肝胰岛素敏感性肝胰岛素抵抗指数肝胰岛素抵抗指数14例正常糖耐量患者和43例T2DM患者，使用核磁共振光谱和核磁共振成像评估内源性糖生成的情况。.肝肝脂质脂质

9、沉积与胰岛素抵抗的线性关系沉积与胰岛素抵抗的线性关系肝胰岛素抵抗肝胰岛素抵抗肝胰岛素清除率肝胰岛素清除率14例正常糖耐量患者和43例T2DM患者，使用核磁共振光谱和核磁共振成像评估内源性糖生成的情况。Melania Gaggini, et al. Nutrients 2013, 5, 1544-1560;.发生胰岛素抵抗时，肝脏能量代谢改变发生胰岛素抵抗时，肝脏能量代谢改变在肥胖和脂肪变性阶段，肝脏提高氧化活性以获得暂时性适应。发生NASH和DM时(胰岛素抵抗)，肝线粒体功能进行性下降。Chrysi Koliaki , Michael Roden. Molecular and Cellular

10、 Endocrinology 379 (2013) 3542.从某种意义上说，脂质沉积的肝细胞从某种意义上说，脂质沉积的肝细胞也是脂肪细胞，参与胰岛素抵抗的发生也是脂肪细胞，参与胰岛素抵抗的发生Toshinari Takamura, et al. Endocrine Journal 2012, 59 (9), 745-763.ALT是新发是新发T2DM的独立预测因素的独立预测因素We examined the association of serum alanine aminotransferase (ALT) with features of the metabolic syndrome a

11、nd whether it predicted incident diabetes independently of routinely measured factors in 5,974 men血血ALT水平与新发糖尿病发生率的关系水平与新发糖尿病发生率的关系Naveed Sattar, et al. Diabetes 53:28552860, 2004.肝酶升高肝酶升高与与糖尿病前期和糖尿病前期和T2DM发生有关发生有关The Bogalusa Heart Study：In this retrospective cohort study, normoglycemic(n=874), pre

12、diabetic (n= 101), and diabetic (n= 80) adults aged 2650 years (average age 41.3 years) were followed over an average period of 16 years since their young adulthood (aged 1838 years, average age 25.1 years), with measurements of cardiometabolic risk factor variables including ALT and GGT.QUOC MANH N

13、GUYEN, et al. Diabetes Care 34:26032607, 2011ALT and GGT values by quartiles were ,13.0 UI/L and,10 UI/L for quartile 1; from 13 to 18 UI/L and 10 to 14 UI/L for quartile 2; from19 to 28 UI/L and 15 to 22 UI/L for quartile 3; and from 29 to 126 UI/L and 23 to 476 UI/L for quartile 4,.NAFLD预测预测T2DM：中

14、国的临床研究数据：中国的临床研究数据The population-based cohort study held in Xian, Northwestern China, was basedon China National Diabetes and Metabolic Disorders Survey. During a follow-up of 5 years, 508 healthy subjects were included as study sample. NAFLD was determined by abdominal ultrasonography. T2DM and pre

15、-diabetes were diagnosed based on oral glucose tolerance test.Jie Ming, et al. Liver Int 2015 Apr.为什么为什么NAFLD可预测可预测T2DM？ 研究指出：脂肪肝与进展为研究指出：脂肪肝与进展为2型糖尿病的风险强关联型糖尿病的风险强关联1. NAFLD是代谢综合征患者的典型肝脏表现；是代谢综合征患者的典型肝脏表现；2. 肝功能不全模型强烈支持：肝病可继发胰岛素抵抗、肝功能不全模型强烈支持：肝病可继发胰岛素抵抗、细细胞功能障碍、糖耐量异常、糖尿病；胞功能障碍、糖耐量异常、糖尿病；3. T2DM的发生可

16、能与肝脂肪浸润具有强相关性的发生可能与肝脂肪浸润具有强相关性Guido Lattuada, et al. Curr Diab Rep (2011) 11:167172.主要主要内容内容123T2DM合并合并NAFLD的流行病学的流行病学NAFLD与与T2DM发病之间的关系发病之间的关系NAFLD与与T2DM对疾病预后的相互影响对疾病预后的相互影响4NAFLD的治疗措施的治疗措施.NAFLD可能可能与与DM患者患者多种多种并发症并发症发生发生有关有关Nathalie C Leite, et al. World J Gastroenterol 2014 July 14; 20(26): 8377-

17、8392 NAFLD 可能与糖尿病患者微血管和大血管并发症发生相关；可能与糖尿病患者微血管和大血管并发症发生相关； 在在1,2型糖尿病患者中，型糖尿病患者中，NAFLD与微量白蛋白尿、肾小球滤过率降低、与微量白蛋白尿、肾小球滤过率降低、视网膜病的发生率高有关；视网膜病的发生率高有关； T2DM合并合并NAFLD的患者，慢性肾病的发生率高，独立于其他危险因素的患者，慢性肾病的发生率高，独立于其他危险因素之外；之外； 1,2型糖尿病合并型糖尿病合并NAFLD较无较无NAFLD患者，亚临床动脉粥样硬化指标如患者，亚临床动脉粥样硬化指标如颈动脉内膜中层厚度、动脉硬度增加，临床心血管疾病发生率增加。颈动

18、脉内膜中层厚度、动脉硬度增加，临床心血管疾病发生率增加。.对于对于T2DM患者，伴患者，伴NAFLD的的CVD患病率患病率增加增加Targher G,et al. Diabetes Med.2006;23(4):403-9伴伴NAFLD的的2型糖尿病病人型糖尿病病人心脑血管心脑血管事件事件的的患病患病率率显著高于不伴有显著高于不伴有NAFLD的病人的病人*两组比较，两组比较，p会导致肝脏炎症改变或肝门脉区纤维化风险。Nila Rafiq, et al. SEMINARS IN LIVER DISEASE, 2008;28(4):427-434.改善改善IR/纠正纠正代谢代谢紊乱药物的专业意见紊

19、乱药物的专业意见 根据临床需要根据临床需要, ,可可采用相关采用相关药物治疗代谢危险因素及其药物治疗代谢危险因素及其合并症合并症； 这些这些药物对药物对NAFLDNAFLD患者患者血清酶谱血清酶谱异常和肝组织学病变的改善作异常和肝组织学病变的改善作用用, ,尚有待尚有待进一步临床试验证实。进一步临床试验证实。 均为小样本研究，对二甲双胍报道的疗效不一；均为小样本研究，对二甲双胍报道的疗效不一； 目前暂不建议对无糖尿病异常的目前暂不建议对无糖尿病异常的NAFLDNAFLD患者常规应用患者常规应用TZDTZD药物药物治疗。治疗。1.中华医学会肝病学分会脂肪肝和酒精性肝病学组.胃肠病学和肝病学杂志，

20、2010; 19(6):483-4872.中华医学会内分泌学分会肝病与代谢学组. 中华内分泌代谢杂志, 2010;26(7): 531-53421.抗炎保肝药物治疗的应用地位抗炎保肝药物治疗的应用地位合理选用多合理选用多烯磷脂酰胆碱烯磷脂酰胆碱、维生素、维生素E、水飞蓟素、水飞蓟素(宾宾)、S-腺苷腺苷蛋氨蛋氨酸和酸和还原型谷胱甘肽等还原型谷胱甘肽等12种种药物作为药物作为辅助治疗。辅助治疗。中华医学会内分泌学分会肝病与代谢学组. 中华内分泌代谢杂志, 2010;26(7): 531-534NAFLD经基础治疗3-6个月仍无效，且伴肝酶增高、MS、2型糖尿病伴NAFLD患者以及肝活体组织检查证

21、实为NASH和病程呈慢性进展性经过者。.T2DM合并合并NAFLD的综合治疗：的综合治疗：PPC+Met vs Met孙存序,等.临床荟萃.2008.23(17):1272-3.研究病例选择：邯郸市中心医院2007年3月-12月门诊及住院治疗初诊为T2DM合并NAFLD的患者，n=74，28-60岁治疗组在饮食控制和运动治疗基础上口服二甲双胍500mg，每日3次，多烯磷脂酰胆碱胶囊2粒(456 mg)口服；对照组只在饮食控制和运动治疗的基础上口服二甲双胍500mg，每日3次，总疗程12周24.316.232.424.321.713.521.6460%20%40%60%80%100%二甲双胍+易

22、善复二甲双胍比例比例临床控制显效有效无效临床控制：临床症状消失，血脂正常，超声复查脂肪肝样变消失。显效：症状、体征基本消失，肝脏超声示脂肪肝消失或下降2个级别(如重度转为轻度)，血脂恢复正常或基本正常。有效：症状、体征明显改善，肝脏超声示脂肪肝表现明显好转或下降1个级别(如重度转为中度)，血脂指标改变率30。无效：症状、体征无改善，肝脏超声示脂肪肝表现无明显变化，血脂指标无明显改善。.T2DM合并合并NAFLD的综合的综合治疗：治疗：PPC+Met vs Met甘油三酯甘油三酯孙存序,等.临床荟萃.2008.23(17):1272-3.研究病例选择：邯郸市中心医院2007年3月-12月门诊及住院治疗初诊为T2DM合并NAFLD的患者，n=74，28-60岁治疗组在饮食控制和运动治疗基础上口服二甲双胍500mg，每日3次，多烯磷脂酰胆碱胶囊2粒(456 mg)口