topic型糖尿病合并nafld的臨床管理

1、2型糖尿病合并NAFLD的臨床管理,從糖尿病專家的角度，如何看待NAFLD？,Joseph M. Pappachan, et al. Endocrine (2014) 45:344–353,內(nèi)分泌疾病,NAFLD,新,主要內(nèi)容,1,,2,,3,,T2DM合并NAFLD的流行病學(xué),NAFLD與T2DM發(fā)病之間的關(guān)系,NAFLD與T2DM對(duì)疾病預(yù)后的相互影響,4,,NAFLD的治療措施,42.6%的T2DM患者有NAFLD,患者比例,n=9

2、39,RACHEL M. WILLIAMSON, et al. Diabetes Care 34:1139–1144, 2011,愛丁堡2型糖尿病研究（ET2DS）中939例年齡61-76歲的T2DM患者，通過(guò)肝臟超聲評(píng)估脂肪肝的情況,,grade 0, normal appearance of liver on ultrasound and initially graded as a “normal ultrasound”;grad

3、e 1, possible slight increase in echogenicity or slightly impaired visualization of the diaphragm or intrahepatic vessels, or difficulty in grading as a result of a diseased or absent right kidney—initially termed an “in

4、determinate ultrasound”;grade 2, definite increase in echogenicity and/or definite impaired visualization of the intrahepatic vessels and diaphragm, no or little evidence of focal fatty sparing, initially graded as “evi

5、dence 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, initially graded as “evide

6、nce of severe steatosis on ultrasound.” Evidence of hepatic cirrhosis was also sought systematically.,NAFLD患者中前驅(qū)糖尿病和T2DM患病率高于非NAFLD人群,We studied the prevalence and the metabolic impact of prediabetes and T2DM in 118 pat

7、ients with NAFLD. The control group comprised 20 subjects withoutNAFLD matched for age, sex, and adiposity.,NAFLD患者和非NAFLD人群前驅(qū)糖尿病和T2DM患病率,**P <0.001 vs. without NAFLD,CAROLINA ORTIZ-LOPEZ, et al. Diabetes Care 35:873

8、–878, 2012,發(fā)生率,NAFLD及其嚴(yán)重性與糖尿病發(fā)生率有獨(dú)立的強(qiáng)相關(guān)性,NFS：NAFLD纖維化評(píng)分,A cross-sectional study was performed in 43,166 apparently healthy Koreans aged 30-59 years, who underwent a health checkup in 2005 and 2006. Of these, 38,291 subj

9、ects without diabetes were followed annually or biennially until December 2011 for the cohort study.,Yoosoo Chang , et al. Am J Gastroenterol 2013; 108:1861–1868,NAFLD及其嚴(yán)重性與T2DM的累積發(fā)生率,P -trend < 0.001,主要內(nèi)容,1,,2,,3,,T2

10、DM合并NAFLD的流行病學(xué),NAFLD與T2DM發(fā)病之間的關(guān)系,NAFLD與T2DM對(duì)疾病預(yù)后的相互影響,4,,NAFLD的治療措施,脂質(zhì)沉積與肝胰島素敏感度降低有關(guān),IHTG：肝甘油三酯；VF：腹部脂肪,Melania Gaggini, et al. Nutrients 2013, 5, 1544-1560;,肝胰島素敏感性,肝胰島素抵抗指數(shù),14例正常糖耐量患者和43例T2DM患者，使用核磁共振光譜和核磁共振成像評(píng)估內(nèi)源性糖生成

11、的情況。,新,肝脂質(zhì)沉積與胰島素抵抗的線性關(guān)系,肝胰島素抵抗,肝胰島素清除率,14例正常糖耐量患者和43例T2DM患者，使用核磁共振光譜和核磁共振成像評(píng)估內(nèi)源性糖生成的情況。,Melania Gaggini, et al. Nutrients 2013, 5, 1544-1560;,新,發(fā)生胰島素抵抗時(shí)，肝臟能量代謝改變,在肥胖和脂肪變性階段，肝臟提高氧化活性以獲得暫時(shí)性適應(yīng)。,,發(fā)生NASH和DM時(shí)(胰島素抵抗)，肝線粒體功能進(jìn)行性

12、下降。,,Chrysi Koliaki , Michael Roden. Molecular and Cellular Endocrinology 379 (2013) 35–42,新,從某種意義上說(shuō)，脂質(zhì)沉積的肝細(xì)胞也是脂肪細(xì)胞，參與胰島素抵抗的發(fā)生,Toshinari Takamura, et al. Endocrine Journal 2012, 59 (9), 745-763,新,ALT是新發(fā)T2DM的獨(dú)立預(yù)測(cè)因素,We ex

13、amined the association of serum alanine aminotransferase (ALT) with features of the metabolic syndrome and whether it predicted incident diabetes independently of routinely measured factors in 5,974 men,血ALT水平與新發(fā)糖尿病發(fā)生率的關(guān)

14、系,Naveed Sattar, et al. Diabetes 53:2855–2860, 2004,新,肝酶升高與糖尿病前期和T2DM發(fā)生有關(guān),The Bogalusa Heart Study：In this retrospective cohort study, normoglycemic(n=874), prediabetic (n= 101), and diabetic (n= 80) adults aged 26–50 y

15、ears (average age 41.3 years) were followed over an average period of 16 years since their young adulthood (aged 18–38 years, average age 25.1 years), with measurements of cardiometabolic risk factor variables including

16、ALT and GGT.,QUOC MANH NGUYEN, et al. Diabetes Care 34:2603–2607, 2011,ALT 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 an

17、d 15 to 22 UI/L for quartile 3; and from 29 to 126 UI/L and 23 to 476 UI/L for quartile 4,,新,NAFLD預(yù)測(cè)T2DM：中國(guó)的臨床研究數(shù)據(jù),The population-based cohort study held in Xi’an, Northwestern China, was basedon China National Diabetes

18、 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-diabetes were diagnosed based on oral gl

19、ucose tolerance test.,Jie Ming, et al. Liver Int 2015 Apr,新,為什么NAFLD可預(yù)測(cè)T2DM？,研究指出：脂肪肝與進(jìn)展為2型糖尿病的風(fēng)險(xiǎn)強(qiáng)關(guān)聯(lián)NAFLD是代謝綜合征患者的典型肝臟表現(xiàn)；肝功能不全模型強(qiáng)烈支持：肝病可繼發(fā)胰島素抵抗、β細(xì)胞功能障礙、糖耐量異常、糖尿??；T2DM的發(fā)生可能與肝脂肪浸潤(rùn)具有強(qiáng)相關(guān)性,Guido Lattuada, et al. Curr Diab

20、Rep (2011) 11:167–172,主要內(nèi)容,1,,2,,3,,T2DM合并NAFLD的流行病學(xué),NAFLD與T2DM發(fā)病之間的關(guān)系,NAFLD與T2DM對(duì)疾病預(yù)后的相互影響,4,,NAFLD的治療措施,NAFLD可能與DM患者多種并發(fā)癥發(fā)生有關(guān),Nathalie C Leite, et al. World J Gastroenterol 2014 July 14; 20(26): 8377-8392,NAFLD 可能與糖尿病患

21、者微血管和大血管并發(fā)癥發(fā)生相關(guān)；在1,2型糖尿病患者中，NAFLD與微量白蛋白尿、腎小球?yàn)V過(guò)率降低、視網(wǎng)膜病的發(fā)生率高有關(guān)；T2DM合并NAFLD的患者，慢性腎病的發(fā)生率高，獨(dú)立于其他危險(xiǎn)因素之外；1,2型糖尿病合并NAFLD較無(wú)NAFLD患者，亞臨床動(dòng)脈粥樣硬化指標(biāo)如頸動(dòng)脈內(nèi)膜中層厚度、動(dòng)脈硬度增加，臨床心血管疾病發(fā)生率增加。,對(duì)于T2DM患者，伴NAFLD的CVD患病率增加,Targher G,et al. Diabetes

22、Med.2006;23(4):403-9,伴NAFLD的2型糖尿病病人心腦血管事件的患病率顯著高于不伴有NAFLD的病人,從門診2型糖尿病病人中選取400例伴NAFLD和400例不伴NAFLD的病人，年齡及性別隨機(jī)選擇配對(duì)，進(jìn)行心血管疾病評(píng)估。,伴嚴(yán)重脂肪肝的T2DM患者10年生存率低于不伴嚴(yán)重脂肪肝的患者,H. Perazzo, et al. Aliment Pharmacol Ther. Accepted 13 August 2

23、014,T2DM患者的10年生存率,NAFLD增加T2DM和CVD發(fā)病風(fēng)險(xiǎn)的可能機(jī)制,Quentin M. Anstee, et al. Rev. Gastroenterol. Hepatol. advance online publication 19 March 2013,反之，動(dòng)物實(shí)驗(yàn)提示T2DM促進(jìn)NAFLD向纖維化發(fā)展,膠原纖維Azan染色,α-SMA染色,蛋氨酸和膽堿缺乏（MCD）飲食造模的NAFLD大鼠：LETO鼠

24、和OLETF鼠（肥胖的T2DM鼠），α-SMA：α-平滑肌收縮蛋白，是肝星狀細(xì)胞激活的標(biāo)志。,Toshinari Takamura, et al. Endocrine Journal 2012, 59 (9), 745-763,胰島素抵抗和糖尿病加速NAFLD動(dòng)物模型的病理發(fā)展。代表性的顯微照片顯示了MCD飲食、MCD+高脂飲食和MCD飲食+吡格列酮治療8周時(shí)對(duì)OLETF和LETO大鼠的影響。插圖中可以看到肝細(xì)胞氣球樣變，箭頭顯示α-

25、SMA陽(yáng)性星狀細(xì)胞浸潤(rùn)。,肥胖的T2DM大鼠的脂肪性肝炎的進(jìn)展性更高，吡格列酮可減輕OLETF大鼠中MCD飲食誘導(dǎo)的脂肪性肝炎。,T2DM顯著提高NAFLD患者肝硬化和死亡風(fēng)險(xiǎn),ZOBAIR M. YOUNOSSI, et al. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2004;2:262–265,NAFLD患者中伴2型糖尿病病人肝硬化和死亡的發(fā)生率顯著高于不伴有2型糖尿病的病人,P=0.

26、04,P=0.001,A cohort of patients with NAFLD was identified(n=132), Clinical, pathological, and mortality data were available for this cohort. Patients were categorized and compared according to the presence or absence of

27、T2DM.,糖尿病可能是HCC的獨(dú)立危險(xiǎn)因素,Olivier Rosmorduc. Annales d’Endocrinologie 74 (2013) 115–120,病例對(duì)照研究中，糖尿病相關(guān)的肝癌相對(duì)風(fēng)險(xiǎn),主要內(nèi)容,1,,2,,3,,T2DM合并NAFLD的流行病學(xué),NAFLD與T2DM發(fā)病之間的關(guān)系,NAFLD與T2DM對(duì)疾病預(yù)后的相互影響,4,,NAFLD的治療措施,以改善脂肪肝為目的的T2DM治療策略,糖尿病的治療應(yīng)前移至

28、肝臟脂肪沉積階段：降低肝臟脂肪含量降低T2DM的發(fā)生率降低T2DM的并發(fā)癥發(fā)生率,NAFLD治療應(yīng)是一個(gè)綜合防治的過(guò)程,中華醫(yī)學(xué)會(huì)肝病學(xué)分會(huì)脂肪肝和酒精性肝病學(xué)組.胃腸病學(xué)和肝病學(xué)雜志，2010; 19(6):483-487,積極處理肝硬化的并發(fā)癥,健康宣傳教育，改變生活方式,控制體質(zhì)量，減少腰圍,改善IR，糾正代謝紊亂,減少附加打擊以免加重肝臟損害,保肝抗炎藥物防治肝炎和纖維化,1,2,3,4,5,6,調(diào)整飲食和生活方式,中等

29、程度的熱量限制,肥胖成人每日熱量攝入需減少2092～4184 kJ (500～1000千卡) ；,改變飲食組分，低糖低脂的平衡膳食，減少含蔗糖飲料以及飽和脂肪和反式脂肪的攝入并增加膳食纖維含量；,中華醫(yī)學(xué)會(huì)肝病學(xué)分會(huì)脂肪肝和酒精性肝病學(xué)組.胃腸病學(xué)和肝病學(xué)雜志，2010; 19(6):483-487,體育鍛煉,中等量有氧運(yùn)動(dòng)，每周4次以上，累計(jì)鍛煉時(shí)間至少150 min；1每個(gè)患者都應(yīng)計(jì)算每天的體育鍛煉量，每個(gè)患者都應(yīng)有一個(gè)標(biāo)準(zhǔn)；2

30、無(wú)論鍛煉是否可以減重，但都可以提高心肺健康，改善胰島素抵抗及肝酶異常。2,中華醫(yī)學(xué)會(huì)肝病學(xué)分會(huì)脂肪肝和酒精性肝病學(xué)組.胃腸病學(xué)和肝病學(xué)雜志，2010; 19(6):483-487意大利肝病學(xué)會(huì)非酒精性脂肪性肝病診療指南（2010）,減輕體重的方法和速度,減輕體重的速度：早期研究顯示，每周體重下降>1.6kg會(huì)導(dǎo)致肝臟炎癥改變或肝門脈區(qū)纖維化風(fēng)險(xiǎn)。,Nila Rafiq, et al. SEMINARS IN LIVER DIS

31、EASE, 2008;28(4):427-434,改善IR/糾正代謝紊亂藥物的專業(yè)意見,根據(jù)臨床需要,可采用相關(guān)藥物治療代謝危險(xiǎn)因素及其合并癥；這些藥物對(duì)NAFLD患者血清酶譜異常和肝組織學(xué)病變的改善作用,尚有待進(jìn)一步臨床試驗(yàn)證實(shí)。,均為小樣本研究，對(duì)二甲雙胍報(bào)道的療效不一；目前暫不建議對(duì)無(wú)糖尿病異常的NAFLD患者常規(guī)應(yīng)用TZD藥物治療。,中華醫(yī)學(xué)會(huì)肝病學(xué)分會(huì)脂肪肝和酒精性肝病學(xué)組.胃腸病學(xué)和肝病學(xué)雜志，2010; 19(6):4

32、83-487中華醫(yī)學(xué)會(huì)內(nèi)分泌學(xué)分會(huì)肝病與代謝學(xué)組. 中華內(nèi)分泌代謝雜志, 2010;26(7): 531-534,2,1,抗炎保肝藥物治療的應(yīng)用地位,合理選用多烯磷脂酰膽堿、維生素E、水飛薊素(賓)、S-腺苷蛋氨酸和還原型谷胱甘肽等1～2種藥物作為輔助治療。,中華醫(yī)學(xué)會(huì)內(nèi)分泌學(xué)分會(huì)肝病與代謝學(xué)組. 中華內(nèi)分泌代謝雜志, 2010;26(7): 531-534,NAFLD經(jīng)基礎(chǔ)治療3-6個(gè)月仍無(wú)效，且伴肝酶增高、MS、2型糖尿病伴NAF

33、LD患者以及肝活體組織檢查證實(shí)為NASH和病程呈慢性進(jìn)展性經(jīng)過(guò)者。,T2DM合并NAFLD的綜合治療：PPC+Met vs Met,孫存序,等.臨床薈萃.2008.23(17):1272-3.,研究病例選擇：邯鄲市中心醫(yī)院2007年3月-12月門診及住院治療初診為T2DM合并NAFLD的患者，n=74，28-60歲治療組在飲食控制和運(yùn)動(dòng)治療基礎(chǔ)上口服二甲雙胍500mg，每日3次，多烯磷脂酰膽堿膠囊2粒(456 mg)口服；對(duì)照組

34、只在飲食控制和運(yùn)動(dòng)治療的基礎(chǔ)上口服二甲雙胍500mg，每日3次，總療程12周,p<0.05,臨床控制：臨床癥狀消失，血脂正常，超聲復(fù)查脂肪肝樣變消失。顯效：癥狀、體征基本消失，肝臟超聲示脂肪肝消失或下降2個(gè)級(jí)別(如重度轉(zhuǎn)為輕度)，血脂恢復(fù)正常或基本正常。有效：癥狀、體征明顯改善，肝臟超聲示脂肪肝表現(xiàn)明顯好轉(zhuǎn)或下降1個(gè)級(jí)別(如重度轉(zhuǎn)為中度)，血脂指標(biāo)改變率30％。無(wú)效：癥狀、體征無(wú)改善，肝臟超聲示脂肪肝表現(xiàn)無(wú)明顯變化，血脂指標(biāo)無(wú)明顯

35、改善。,,T2DM合并NAFLD的綜合治療：PPC+Met vs Met,甘油三酯,孫存序,等.臨床薈萃.2008.23(17):1272-3.,研究病例選擇：邯鄲市中心醫(yī)院2007年3月-12月門診及住院治療初診為T2DM合并NAFLD的患者，n=74，28-60歲治療組在飲食控制和運(yùn)動(dòng)治療基礎(chǔ)上口服二甲雙胍500mg，每日3次，多烯磷脂酰膽堿膠囊2粒(456 mg)口服；對(duì)照組只在飲食控制和運(yùn)動(dòng)治療的基礎(chǔ)上口服二甲雙胍500

36、mg，每日3次，總療程12周,*,*,* p<0.01,6.18,6.19,5.12,5.72,總膽固醇,孫存序,等.臨床薈萃.2008.23(17):1272-3.,T2DM合并NAFLD的綜合治療：PPC+Met vs Met,研究病例選擇：邯鄲市中心醫(yī)院2007年3月-12月門診及住院治療初診為T2DM合并NAFLD的患者，n=74，28-60歲治療組在飲食控制和運(yùn)動(dòng)治療基礎(chǔ)上口服二甲雙胍500mg，每日3次，多烯磷

37、脂酰膽堿膠囊2粒(456 mg)口服；對(duì)照組只在飲食控制和運(yùn)動(dòng)治療的基礎(chǔ)上口服二甲雙胍500mg，每日3次，總療程12周,,,*,*,* p<0.01,針對(duì)NAFLD的治療藥物主要隨機(jī)臨床研究,Natalia Mazzella, et al. Clin Liver Dis 18 (2014) 73–89,小 結(jié)：NAFLD的治療,NAFLD的治療包括調(diào)整生活方式、糾正代謝紊亂、合理抗炎保肝等；糾正代謝紊亂方面：目前沒(méi)有確切的一

38、致性證據(jù)證明相關(guān)藥物的有效性和安全性；臨床研究證明，對(duì)T2DM合并NAFLD的患者，綜合治療能有效地糾正代謝異常、改善NAFLD病情。針對(duì)NAFLD治療的藥物還在進(jìn)一步研發(fā)中。,糖尿病合并NAFLD：未來(lái)仍需解決的問(wèn)題,藥物治療是否獨(dú)立于生活方式改變而啟動(dòng)？根據(jù)年齡、并發(fā)癥、疾病嚴(yán)重程度的個(gè)體化因素，應(yīng)如何選擇治療藥物？對(duì)于合并糖尿病的NAFLD患者，應(yīng)選擇哪種調(diào)節(jié)代謝的藥物？在生活方式改變不明顯時(shí)，是否要終身持續(xù)藥物治療？,