Abstract: Background and objective: non-alcoholic fatty liver disease (NAFLD) is associated with arterial stiffness in the general population. Age, obesity, hypertension, and diabetics are risk factors for arterial stiffness. In this study, we aimed to investigate the association between NAFLD and arterial stiffness as measured by brachial-ankle pulse wave velocity (baPWV) in the non-obese, non-hypertensive, and non-diabetic young and middle-aged Chinese population. Methods: A cross-sectional study with 1296 non-obese, non-hypertensive, and non-diabetic young and middle-aged (20–65 years) subjects undergoing routine medical check-ups in the International Health Care Center of the Second Affiliated Hospital of School of Medicine of Zhejiang University was carried out. Fatty liver was diagnosed by ultrasonography, and baPWV was measured using an automatic waveform analyzer. The subjects were classified into two groups according to the presence of NAFLD, and divided into a further two groups according to their baPWV. Results: The overall incidence of NAFLD was 19.0%, and NAFLD patients had a significantly higher level of baPWV than the controls ((1321±158) cm/s vs. (1244±154) cm/s; P<0.001). The incidence of NAFLD was clearly higher in the increased baPWV group than in the normal baPWV group (29.3% vs. 16.9%; P<0.001), and the incidence increased in line with the increase of baPWV quartiles in the normal range as well as with the severity of arterial stiffness (both P for trend <0.001). Multiple linear logistic regression analysis showed that the presence of NAFLD was positively and independently associated with baPWV. Conclusions: Our results suggest that the presence of NAFLD is associated with arterial stiffness as measured by baPWV in the non-obese, non-hypertensive, and non-diabetic young and middle-aged Chinese population.

非肥胖、高血压和糖尿病的中国中青年人群中非酒精性脂肪性肝病和动脉硬度的关系研究

研究目的：探讨在非肥胖、高血压和糖尿病的中国中青年群人中非酒精性脂肪性肝病（NAFLD）和动脉硬度的关系。
创新要点：在非肥胖、高血压和糖尿病的中青年人群中，阐明NAFLD和动脉硬度的关系，对预防和诊断早期动脉硬度有重要临床意义。
研究方法：在非肥胖、高血压和糖尿病的中青年体检人群中进行一项大型横断面研究。用B超诊断脂肪肝，用臂踝脉搏波指数（baPWV）测量动脉硬度，根据是否有NAFLD和baPWV水平分组。
重要结论：NAFLD组患者的baPWV水平明显高于对照组（(1321±158)cm/svs.(1244±154)cm/s；P<0.001），NAFLD患病率在baPWV升高组明显高于baPWV正常组（29.3%vs.16.9%；P<0.001），且NAFLD患病率随baPWV水平和动脉硬度程度的升高而升高（两者趋势P值<0.001）。多因素线性回归分析表明，NAFLD发生与baPWV独立相关。因此，在非肥胖、高血压和糖尿病的中国中青年群人中，NAFLD发生与动脉硬度密切相关。
非酒精性脂肪性肝病；动脉硬度；臂踝脉搏波指数；危险因素

[1] Adams,L.A, Lymp,J.F, St. Sauver,J, 2005, The natural history of nonalcoholic fatty liver disease: a population-based cohort study  Gastroenterology, 129(1):113-121.

[2] Angulo,P, 2007, GI epidemiology: nonalcoholic fatty liver disease  Aliment Pharmacol Ther, 25(8):883-889.

[3] Angulo,P, Alba,L.M, Petrovic,L.M, 2004, Leptin, insulin resistance, and liver fibrosis in human nonalcoholic fatty liver disease  J Hepatol, 41(6):943-949.

[4] Asmar,R, Benetos,A, Topouchian,J, 1995, Assessment of arterial distensibility by automatic pulse wave velocity measurement. Validation and clinical application studies  Hypertension, 26(3):485-490.

[5] Bahcecioglu,I.H, Yalniz,M, Ataseven,H, 2005, Levels of serum hyaluronic acid, TNF- and IL-8 in patients with nonalcoholic steatohepatitis  Hepatogastroenterology, 52(65):1549-1553.

[6] Bedogni,G, Miglioli,L, Masutti,F, 2005, Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and liver study  Hepatology, 42(1):44-52.

[7] Bellentani,S, Saccoccio,G, Masutti,F, 2000, Prevalence of and risk factors for hepatic steatosis in Northern Italy  Ann Intern Med, 132(2):112-117.

[8] Cerda,C, Prez-Ayuso,R.M, Riquelme,A, 2007, Nonalcoholic fatty liver disease in women with polycystic ovary syndrome  J Hepatol, 47(3):412-417.

[9] Chen,J.Y, Chou,C.H, Tsai,W.C, 2012, Effects of increased systemic inflammation and central obesity on arterial stiffness in patients with nonalcoholic fatty liver disease  J Am Soc Hypertens, 6(4):253-260.

[10] Choi,S.Y, Oh,B.H, Bae Park,J, 2013, Age-associated increase in arterial stiffness measured according to the cardio-ankle vascular index without blood pressure changes in healthy adults  J Atheroscler Thromb, 20(12):911-923.

[11] Dogru,T, Ercin,C.N, Erdem,G, 2008, Increased hepatic and circulating interleukin-6 levels in human nonalcoholic steatohepatitis  Am J Gastroenterol, 103(12):3217-3218.

[12] Dunn,W, Xu,R, Wingard,D.L, 2008, Suspected nonalcoholic fatty liver disease and mortality risk in a population-based cohort study  Am J Gastroenterol, 103(9):2263-2271.

[13] Ekstedt,M, Franzn,L.E, Mathiesen,U.L, 2006, Long-term follow-up of patients with NAFLD and elevated liver enzymes  Hepatology, 44(4):865-873.

[14] Fan,J.G, Saibara,T, Chitturi,S, 2007, What are the risk factors and settings for non-alcoholic fatty liver disease in Asia-Pacific?  J Gastroenterol Hepatol, 22(6):794-800.

[15] Henry,R.M, Kostense,P.J, Spijkerman,A.M, 2003, Arterial stiffness increases with deteriorating glucose tolerance status: the Hoorn Study  Circulation, 107(16):2089-2095.

[16] Kim,B.J, Kim,N.H, Kim,B.S, 2012, The association between nonalcoholic fatty liver disease, metabolic syndrome and arterial stiffness in nondiabetic, nonhypertensive individuals  Cardiology, 123(1):54-61.

[17] Kogiso,T, Moriyoshi,Y, Shimizu,S, 2009, High-sensitivity C-reactive protein as a serum predictor of nonalcoholic fatty liver disease based on the Akaike Information Criterion scoring system in the general Japanese population  J Gastroenterol, 44(4):313-321.

[18] Lee,Y.J, Lee,H.R, Shim,J.Y, 2010, Relationship between white blood cell count and nonalcoholic fatty liver disease  Dig Liver Dis, 42(12):888-894.

[19] Lee,Y.J, Shim,J.Y, Moon,B.S, 2012, The relationship between arterial stiffness and nonalcoholic fatty liver disease  Dig Dis Sci, 57(1):196-203.

[20] Lin,W.Y, Lai,M.M, Li,C.I, 2009, In addition to insulin resistance and obesity, brachial-ankle pulse wave velocity is strongly associated with metabolic syndrome in Chinesea population-based study (Taichung Community Health Study, TCHS)  J Atheroscler Thromb, 16(2):105-112.

[21] Lonardo,A, Lombardini,S, Scaglioni,F, 2006, Fatty liver, carotid disease and gallstones: a study of age-related associations  World J Gastroenterol, 12(36):5826-5833.

[22] Machado,M, Cortez-Pinto,H, 2005, Non-alcoholic fatty liver disease and insulin resistance  Eur J Gastroenterol Hepatol, 17(8):823-826.

[23] Mahmud,A, Feely,J, 2005, Adiponectin and arterial stiffness  Am J Hypertens, 18(12):1543-1548.

[24] Matthews,D.R, Hosker,J.P, Rudenski,A.S, 1985, Homeostasis model assessment: insulin resistance and -cell function from fasting plasma glucose and insulin concentrations in man  Diabetologia, 28(7):412-419.

[25] Pal,S, Radavelli-Bagatini,S, 2013, Association of arterial stiffness with obesity in Australian women: a pilot study  J Clin Hypertens, 15(2):118-123.

[26] Park,S.H, Kim,B.I, Yun,J.W, 2004, Insulin resistance and C-reactive protein as independent risk factors for non-alcoholic fatty liver disease in non-obese Asian men  J Gastroenterol Hepatol, 19(6):694-698.

[27] Saverymuttu,S.H, Joseph,A.E, Maxwell,J.D, 1986, Ultrasound scanning in the detection of hepatic fibrosis and steatosis  BMJ, 292(6512):13-15.

[28] Singhal,A, Farooqi,I.S, Cole,T.J, 2002, Influence of leptin on arterial distensibility: a novel link between obesity and cardiovascular disease  Circulation, 106(15):1919-1924.

[29] Stopeck,A.T, Nicholson,A.C, Mancini,F.P, 1993, Cytokine regulation of low density lipoprotein receptor gene transcription in hepG2 cells  J Biol Chem, 268(23):17489-17494.

[30] Strong,J.P, Malcom,G.T, McMahan,C.A, 1999, Prevalence and extent of atherosclerosis in adolescents and young adults: implications for prevention from the Pathobiological Determinants of Atherosclerosis in Youth Study  JAMA, 281(8):727-735.

[31] Targher,G, Arcaro,G, 2007, Non-alcoholic fatty liver disease and increased risk of cardiovascular disease  Atherosclerosis, 191(2):235-240.

[32] Targher,G, Bertolini,L, Rodella,S, 2006, Associations between plasma adiponectin concentrations and liver histology in patients with nonalcoholic fatty liver disease  Clin Endocrinol, 64(6):679-683.

[33] Targher,G, Bertolini,L, Padovani,R, 2006, Relations between carotid artery wall thickness and liver histology in subjects with nonalcoholic fatty liver disease  Diabetes Care, 29(6):1325-1330.

[34] Targher,G, Bertolini,L, Rodella,S, 2007, Nonalcoholic fatty liver disease is independently associated with an increased incidence of cardiovascular events in type 2 diabetic patients  Diabetes Care, 30(8):2119-2121.

[35] Targher,G, Day,C.P, Bonora,E, 2010, Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease  N Engl J Med, 363(14):1341-1350.

[36] Tolman,K.G, Fonseca,V, Dalpiaz,A, 2007, Spectrum of liver disease in type 2 diabetes and management of patients with diabetes and liver disease  Diabetes Care, 30(3):734-743.

[37] Tomiyama,H, Koji,Y, Yambe,M, 2005, Brachial-ankle pulse wave velocity is a simple and independent predictor of prognosis in patients with acute coronary syndrome  Circ J, 69(7):815-822.

[38] Vaitkevicius,P.V, Fleg,J.L, Engel,J.H, 1993, Effects of age and aerobic capacity on arterial stiffness in healthy adults  Circulation, 88(4):1456-1462.

[39] van Popele,N.M, Mattace-Raso,F.U, Vliegenthart,R, 2006, Aortic stiffness is associated with atherosclerosis of the coronary arteries in older adults: the Rotterdam Study  J Hypertens, 24(12):2371-2376.

[40] Vernon,G, Baranova,A, Younossi,Z.M, 2011, Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults  Aliment Pharmacol Ther, 34(3):274-285.

[41] Villanova,N, Moscatiello,S, Ramilli,S, 2005, Endothelial dysfunction and cardiovascular risk profile in nonalcoholic fatty liver disease  Hepatology, 42(2):473-480.

[42] Weng,C.M, Chou,C.H, Huang,Y.Y, 2010, Increased C-reactive protein is associated with future development of diabetes mellitus in essential hypertensive patients  Heart Vessels, 25(5):386-391.

[43] Yamashina,A, Tomiyama,H, Takeda,K, 2002, Validity, reproducibility, and clinical significance of noninvasive brachial-ankle pulse wave velocity measurement  Hypertens Res, 25(3):359-364.

[44] Yamashina,A, Tomiyama,H, Arai,T, 2003, Brachial-ankle pulse wave velocity as a marker of atherosclerotic vascular damage and cardiovascular risk  Hypertens Res, 26(8):615-622.

[45] Zebekakis,P.E, Nawrot,T, Thijs,L, 2005, Obesity is associated with increased arterial stiffness from adolescence until old age  J Hypertens, 23(10):1839-1846.