Semin Liver Dis 2015; 35(03): 236-249
DOI: 10.1055/s-0035-1562944
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Systemic Complications of Nonalcoholic Fatty Liver Disease: When the Liver Is Not an Innocent Bystander

Ester Vanni
1   Department of Medical Sciences, Division of Gastro-Hepatology, A.O. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
,
Andrea Marengo
1   Department of Medical Sciences, Division of Gastro-Hepatology, A.O. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
,
Lavinia Mezzabotta
1   Department of Medical Sciences, Division of Gastro-Hepatology, A.O. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
,
Elisabetta Bugianesi
1   Department of Medical Sciences, Division of Gastro-Hepatology, A.O. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
› Author Affiliations
Further Information

Publication History

Publication Date:
17 September 2015 (online)

Abstract

The top three leading causes of death in patients with nonalcoholic fatty liver disease (NAFLD) in descending order are cardiovascular disease, cancer, and liver disease. It is clear now that the increased risk of metabolic and macro- and microvascular complications in NAFLD stems from the associated features of metabolic syndrome. However, NAFLD itself may contribute to the spectrum of risk factors associated with insulin resistance. The primary focus of this review is to summarize the main systemic associations of NAFLD, as well as to discuss the mechanisms that link them to NAFLD. Hepatic lipid accumulation in NAFLD impairs hepatic glucose and lipid metabolism further increasing the risk of type 2 diabetes mellitus and of cardiovascular disease, independently of established risk factors. The incidence, prevalence, and severity of these complications are proportional to the histological severity of liver damage suggesting that NAFLD, but particularly nonalcoholic steatohepatitis, can also contribute to the low-grade inflammatory state through the systemic release of several markers of inflammation, oxidative stress, and of procoagulant factors. The clinical implication of these findings is that patients with NAFLD require a multidisciplinary evaluation, with a major focus on type 2 diabetes mellitus and cardiovascular disease complications and may benefit from more intensive surveillance and early treatment interventions to decrease the risk for cardiovascular and kidney complications.

 
  • References

  • 1 Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002; 346 (16) 1221-1231
  • 2 Bugianesi E, McCullough AJ, Marchesini G. Insulin resistance: a metabolic pathway to chronic liver disease. Hepatology 2005; 42 (5) 987-1000
  • 3 Perseghin G. Viewpoints on the way to a consensus session: where does insulin resistance start? The liver. Diabetes Care 2009; 32 (Suppl. 02) S164-S167
  • 4 Reaven GM. The metabolic syndrome: requiescat in pace. Clin Chem 2005; 51 (6) 931-938
  • 5 Simmons RK, Alberti KG, Gale EA , et al. The metabolic syndrome: useful concept or clinical tool? Report of a WHO Expert Consultation. Diabetologia 2010; 53 (4) 600-605
  • 6 Shulman GI. Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease. N Engl J Med 2014; 371 (12) 1131-1141
  • 7 Seppälä-Lindroos A, Vehkavaara S, Häkkinen AM , et al. Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. J Clin Endocrinol Metab 2002; 87 (7) 3023-3028
  • 8 Browning JD, Szczepaniak LS, Dobbins R , et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004; 40 (6) 1387-1395
  • 9 Ricci C, Longo R, Gioulis E , et al. Noninvasive in vivo quantitative assessment of fat content in human liver. J Hepatol 1997; 27 (1) 108-113
  • 10 Fraser A, Harris R, Sattar N, Ebrahim S, Davey Smith G, Lawlor DA. Alanine aminotransferase, gamma-glutamyltransferase, and incident diabetes: the British Women's Heart and Health Study and meta-analysis. Diabetes Care 2009; 32 (4) 741-750
  • 11 Park SK, Seo MH, Shin HC, Ryoo JH. Clinical availability of nonalcoholic fatty liver disease as an early predictor of type 2 diabetes mellitus in Korean men: 5-year prospective cohort study. Hepatology 2013; 57 (4) 1378-1383
  • 12 Balkau B, Lange C, Vol S, Fumeron F, Bonnet F ; Group Study D.E.S.I.R. Nine-year incident diabetes is predicted by fatty liver indices: the French D.E.S.I.R. study. BMC Gastroenterol 2010; 10: 56
  • 13 Ryysy L, Häkkinen A-M, Goto T , et al. Hepatic fat content and insulin action on free fatty acids and glucose metabolism rather than insulin absorption are associated with insulin requirements during insulin therapy in type 2 diabetic patients. Diabetes 2000; 49 (5) 749-758
  • 14 de Marco R, Locatelli F, Zoppini G, Verlato G, Bonora E, Muggeo M. Cause-specific mortality in type 2 diabetes. The Verona Diabetes Study. Diabetes Care 1999; 22 (5) 756-761
  • 15 Ekstedt M, Franzén LE, Mathiesen UL , et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006; 44 (4) 865-873
  • 16 Okamoto M, Takeda Y, Yoda Y, Kobayashi K, Fujino MA, Yamagata Z. The association of fatty liver and diabetes risk. J Epidemiol 2003; 13 (1) 15-21
  • 17 Fan JG, Li F, Cai XB, Peng YD, Ao QH, Gao Y. Effects of nonalcoholic fatty liver disease on the development of metabolic disorders. J Gastroenterol Hepatol 2007; 22 (7) 1086-1091
  • 18 Shibata M, Kihara Y, Taguchi M, Tashiro M, Otsuki M. Nonalcoholic fatty liver disease is a risk factor for type 2 diabetes in middle-aged Japanese men. Diabetes Care 2007; 30 (11) 2940-2944
  • 19 Kim CH, Park JY, Lee KU, Kim JH, Kim HK. Fatty liver is an independent risk factor for the development of Type 2 diabetes in Korean adults. Diabet Med 2008; 25 (4) 476-481
  • 20 Yamada T, Fukatsu M, Suzuki S, Wada T, Yoshida T, Joh T. Fatty liver predicts impaired fasting glucose and type 2 diabetes mellitus in Japanese undergoing a health checkup. J Gastroenterol Hepatol 2010; 25 (2) 352-356
  • 21 Sung KC, Jeong WS, Wild SH, Byrne CD. Combined influence of insulin resistance, overweight/obesity, and fatty liver as risk factors for type 2 diabetes. Diabetes Care 2012; 35 (4) 717-722
  • 22 Bae JC, Rhee EJ, Lee WY , et al. Combined effect of nonalcoholic fatty liver disease and impaired fasting glucose on the development of type 2 diabetes: a 4-year retrospective longitudinal study. Diabetes Care 2011; 34 (3) 727-729
  • 23 Sung KC, Wild SH, Byrne CD. Resolution of fatty liver and risk of incident diabetes. J Clin Endocrinol Metab 2013; 98 (9) 3637-3643
  • 24 Chang Y, Jung HS, Yun KE, Cho J, Cho YK, Ryu S. Cohort study of non-alcoholic fatty liver disease, NAFLD fibrosis score, and the risk of incident diabetes in a Korean population. Am J Gastroenterol 2013; 108 (12) 1861-1868
  • 25 Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 2010; 363 (14) 1341-1350
  • 26 Fabbrini E, Mohammed BS, Magkos F, Korenblat KM, Patterson BW, Klein S. Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease. Gastroenterology 2008; 134 (2) 424-431
  • 27 Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest 2005; 115 (5) 1343-1351
  • 28 Lorenzo C, Hanley AJ, Rewers MJ, Haffner SM. The association of alanine aminotransferase within the normal and mildly elevated range with lipoproteins and apolipoproteins: the Insulin Resistance Atherosclerosis Study. Diabetologia 2013; 56 (4) 746-757
  • 29 Bugianesi E, Gastaldelli A, Vanni E , et al. Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms. Diabetologia 2005; 48 (4) 634-642
  • 30 Siddiqui MS, Sterling RK, Luketic VA , et al. Association between high-normal levels of alanine aminotransferase and risk factors for atherogenesis. Gastroenterology 2013; 145 (6) 1271-9.e1 , 3
  • 31 Oni ET, Agatston AS, Blaha MJ , et al. A systematic review: burden and severity of subclinical cardiovascular disease among those with nonalcoholic fatty liver; should we care?. Atherosclerosis 2013; 230 (2) 258-267
  • 32 Gastaldelli A, Kozakova M, Højlund K , et al; RISC Investigators. Fatty liver is associated with insulin resistance, risk of coronary heart disease, and early atherosclerosis in a large European population. Hepatology 2009; 49 (5) 1537-1544
  • 33 Moon SH, Noh TS, Cho YS , et al. Association between nonalcoholic fatty liver disease and carotid artery inflammation evaluated by 18F-fluorodeoxyglucose positron emission tomography. Angiology 2015; 66 (5) 472-480
  • 34 Targher G, Bertolini L, Padovani R , et al. Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care 2007; 30 (5) 1212-1218
  • 35 Wong VW, Wong GL, Yip GW , et al. Coronary artery disease and cardiovascular outcomes in patients with non-alcoholic fatty liver disease. Gut 2011; 60 (12) 1721-1727
  • 36 Anstee QM, Targher G, Day CP. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol 2013; 10 (6) 330-344
  • 37 Schindhelm RK, Dekker JM, Nijpels G , et al. Alanine aminotransferase predicts coronary heart disease events: a 10-year follow-up of the Hoorn Study. Atherosclerosis 2007; 191 (2) 391-396
  • 38 Fraser A, Harris R, Sattar N, Ebrahim S, Smith GD, Lawlor DA. Gamma-glutamyltransferase is associated with incident vascular events independently of alcohol intake: analysis of the British Women's Heart and Health Study and Meta-Analysis. Arterioscler Thromb Vasc Biol 2007; 27 (12) 2729-2735
  • 39 Stepanova M, Younossi ZM. Independent association between nonalcoholic fatty liver disease and cardiovascular disease in the US population. Clin Gastroenterol Hepatol 2012; 10 (6) 646-650
  • 40 Lazo M, Hernaez R, Bonekamp S , et al. Non-alcoholic fatty liver disease and mortality among US adults: prospective cohort study. BMJ 2011; 343: d6891
  • 41 Kim D, Kim WR, Kim HJ, Therneau TM. Association between noninvasive fibrosis markers and mortality among adults with nonalcoholic fatty liver disease in the United States. Hepatology 2013; 57 (4) 1357-1365
  • 42 Söderberg C, Stål P, Askling J , et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology 2010; 51 (2) 595-602
  • 43 Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999; 116 (6) 1413-1419
  • 44 Dam-Larsen S, Franzmann M, Andersen IB , et al. Long term prognosis of fatty liver: risk of chronic liver disease and death. Gut 2004; 53 (5) 750-755
  • 45 Adams LA, Lymp JF, St Sauver J , et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 2005; 129 (1) 113-121
  • 46 Rafiq N, Bai C, Fang Y , et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin Gastroenterol Hepatol 2009; 7 (2) 234-238
  • 47 Hamaguchi M, Kojima T, Takeda N , et al. Nonalcoholic fatty liver disease is a novel predictor of cardiovascular disease. World J Gastroenterol 2007; 13 (10) 1579-1584
  • 48 Haring R, Wallaschofski H, Nauck M, Dörr M, Baumeister SE, Völzke H. Ultrasonographic hepatic steatosis increases prediction of mortality risk from elevated serum γ-glutamyl transpeptidase levels. Hepatology 2009; 50 (5) 1403-1411
  • 49 Zhou YJ, Li YY, Nie YQ, Huang CM, Cao CY. Natural course of nonalcoholic fatty liver disease in southern China: a prospective cohort study. J Dig Dis 2012; 13 (3) 153-160
  • 50 Bugianesi E, Gastaldelli A. Hepatic and cardiac steatosis: are they coupled?. Heart Fail Clin 2012; 8 (4) 663-670
  • 51 Lautamäki R, Borra R, Iozzo P , et al. Liver steatosis coexists with myocardial insulin resistance and coronary dysfunction in patients with type 2 diabetes. Am J Physiol Endocrinol Metab 2006; 291 (2) E282-E290
  • 52 Rijzewijk LJ, Jonker JT, van der Meer RW , et al. Effects of hepatic triglyceride content on myocardial metabolism in type 2 diabetes. J Am Coll Cardiol 2010; 56 (3) 225-233
  • 53 Kim NH, Park J, Kim SH , et al. Non-alcoholic fatty liver disease, metabolic syndrome and subclinical cardiovascular changes in the general population. Heart 2014; 100 (12) 938-943
  • 54 Perseghin G, Lattuada G, De Cobelli F , et al. Increased mediastinal fat and impaired left ventricular energy metabolism in young men with newly found fatty liver. Hepatology 2008; 47 (1) 51-58
  • 55 Singh GK, Vitola BE, Holland MR , et al. Alterations in ventricular structure and function in obese adolescents with nonalcoholic fatty liver disease. J Pediatr 2013; 162 (6) 1160-1168 , 1168.e1
  • 56 Sert A, Aypar E, Pirgon O, Yilmaz H, Odabas D, Tolu I. Left ventricular function by echocardiography, tissue Doppler imaging, and carotid intima-media thickness in obese adolescents with nonalcoholic fatty liver disease. Am J Cardiol 2013; 112 (3) 436-443
  • 57 Fintini D, Chinali M, Cafiero G , et al. Early left ventricular abnormality/dysfunction in obese children affected by NAFLD. Nutr Metab Cardiovasc Dis 2014; 24 (1) 72-74
  • 58 Pacifico L, Di Martino M, De Merulis A , et al. Left ventricular dysfunction in obese children and adolescents with nonalcoholic fatty liver disease. Hepatology 2014; 59 (2) 461-470
  • 59 Dhingra R, Gona P, Wang TJ, Fox CS, D'Agostino Sr RB, Vasan RS. Serum gamma-glutamyl transferase and risk of heart failure in the community. Arterioscler Thromb Vasc Biol 2010; 30 (9) 1855-1860
  • 60 Wannamethee SG, Whincup PH, Shaper AG, Lennon L, Sattar N. Γ-glutamyltransferase, hepatic enzymes, and risk of incident heart failure in older men. Arterioscler Thromb Vasc Biol 2012; 32 (3) 830-835
  • 61 Fragasso G, Perseghin G, De Cobelli F , et al. Effects of metabolic modulation by trimetazidine on left ventricular function and phosphocreatine/adenosine triphosphate ratio in patients with heart failure. Eur Heart J 2006; 27 (8) 942-948
  • 62 Matthew Morris E, Fletcher JA, Thyfault JP, Rector RS. The role of angiotensin II in nonalcoholic steatohepatitis. Mol Cell Endocrinol 2013; 378 (1-2) 29-40
  • 63 Targher G, Kendrick J, Smits G, Chonchol M. Relationship between serum gamma-glutamyltransferase and chronic kidney disease in the United States adult population. Findings from the National Health and Nutrition Examination Survey 2001-2006. Nutr Metab Cardiovasc Dis 2010; 20 (8) 583-590
  • 64 Targher G, Bertolini L, Rodella S , et al. Non-alcoholic fatty liver disease is independently associated with an increased prevalence of chronic kidney disease and proliferative/laser-treated retinopathy in type 2 diabetic patients. Diabetologia 2008; 51 (3) 444-450
  • 65 Hwang ST, Cho YK, Yun JW , et al. Impact of non-alcoholic fatty liver disease on microalbuminuria in patients with prediabetes and diabetes. Intern Med J 2010; 40 (6) 437-442
  • 66 Li G, Shi W, Hug H, Chen Y, Liu L, Yin D. Nonalcoholic fatty liver disease associated with impairment of kidney function in nondiabetes population. Biochem Med (Zagreb) 2012; 22 (1) 92-99
  • 67 Sirota JC, McFann K, Targher G, Chonchol M, Jalal DI. Association between nonalcoholic liver disease and chronic kidney disease: an ultrasound analysis from NHANES 1988-1994. Am J Nephrol 2012; 36 (5) 466-471
  • 68 Ahn AL, Choi JK, Kim MN , et al. Non-alcoholic fatty liver disease and chronic kidney disease in Koreans aged 50 years or older. Korean J Fam Med 2013; 34 (3) 199-205
  • 69 Li Y, Zhu S, Li B , et al. Association between non-alcoholic fatty liver disease and chronic kidney disease in population with prediabetes or diabetes. Int Urol Nephrol 2014; 46 (9) 1785-1791
  • 70 Targher G, Bertolini L, Rodella S, Lippi G, Zoppini G, Chonchol M. Relationship between kidney function and liver histology in subjects with nonalcoholic steatohepatitis. Clin J Am Soc Nephrol 2010; 5 (12) 2166-2171
  • 71 Yilmaz Y, Alahdab YO, Yonal O , et al. Microalbuminuria in nondiabetic patients with nonalcoholic fatty liver disease: association with liver fibrosis. Metabolism 2010; 59 (9) 1327-1330
  • 72 Yasui K, Sumida Y, Mori Y , et al. Nonalcoholic steatohepatitis and increased risk of chronic kidney disease. Metabolism 2011; 60 (5) 735-739
  • 73 Machado MV, Gonçalves S, Carepa F , et al. Impaired renal function in morbid obese patients with nonalcoholic fatty liver disease. Liver Int 2012; 32 (2) 241-248
  • 74 Chang Y, Ryu S, Sung E , et al. Nonalcoholic fatty liver disease predicts chronic kidney disease in nonhypertensive and nondiabetic Korean men. Metabolism 2008; 57 (4) 569-576
  • 75 Arase Y, Suzuki F, Kobayashi M , et al. The development of chronic kidney disease in Japanese patients with non-alcoholic fatty liver disease. Intern Med 2011; 50 (10) 1081-1087
  • 76 Targher G, Chonchol M, Bertolini L , et al. Increased risk of CKD among type 2 diabetics with nonalcoholic fatty liver disease. J Am Soc Nephrol 2008; 19 (8) 1564-1570
  • 77 Targher G, Mantovani A, Pichiri I , et al. Nonalcoholic fatty liver disease is independently associated with an increased incidence of chronic kidney disease in patients with type 1 diabetes. Diabetes Care 2014; 37 (6) 1729-1736
  • 78 Musso G, Gambino R, Tabibian JH , et al. Association of non-alcoholic fatty liver disease with chronic kidney disease: a systematic review and meta-analysis. PLoS Med 2014; 11 (7) e1001680
  • 79 Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med 2011; 43 (8) 617-649
  • 80 Tilg H, Diehl AM. NAFLD and extrahepatic cancers: have a look at the colon. Gut 2011; 60 (6) 745-746
  • 81 Angulo P. Long-term mortality in nonalcoholic fatty liver disease: is liver histology of any prognostic significance?. Hepatology 2010; 51 (2) 373-375
  • 82 Lee YI, Lim YS, Park HS. Colorectal neoplasms in relation to non-alcoholic fatty liver disease in Korean women: a retrospective cohort study. J Gastroenterol Hepatol 2012; 27 (1) 91-95
  • 83 Wong VWS, Wong GLH, Tsang SWC , et al. High prevalence of colorectal neoplasm in patients with non-alcoholic steatohepatitis. Gut 2011; 60 (6) 829-836
  • 84 Huang KW, Leu HB, Wang YJ , et al. Patients with nonalcoholic fatty liver disease have higher risk of colorectal adenoma after negative baseline colonoscopy. Colorectal Dis 2013; 15 (7) 830-835
  • 85 Stadlmayr A, Aigner E, Steger B , et al. Nonalcoholic fatty liver disease: an independent risk factor for colorectal neoplasia. J Intern Med 2011; 270 (1) 41-49
  • 86 Touzin NT, Bush KNV, Williams CD, Harrison SA. Prevalence of colonic adenomas in patients with nonalcoholic fatty liver disease. Therap Adv Gastroenterol 2011; 4 (3) 169-176
  • 87 Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, George J. Beyond insulin resistance in NASH: TNF-α or adiponectin?. Hepatology 2004; 40 (1) 46-54
  • 88 Kim AY, Lee YS, Kim KH , et al. Adiponectin represses colon cancer cell proliferation via AdipoR1- and -R2-mediated AMPK activation. Mol Endocrinol 2010; 24 (7) 1441-1452
  • 89 Bråkenhielm E, Veitonmäki N, Cao R , et al. Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis. Proc Natl Acad Sci U S A 2004; 101 (8) 2476-2481
  • 90 Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest 2006; 116 (7) 1793-1801
  • 91 Pittas AG, Joseph NA, Greenberg AS. Adipocytokines and insulin resistance. J Clin Endocrinol Metab 2004; 89 (2) 447-452
  • 92 Mehal WZ. The Gordian Knot of dysbiosis, obesity and NAFLD. Nat Rev Gastroenterol Hepatol 2013; 10 (11) 637-644
  • 93 Henao-Mejia J, Elinav E, Jin C , et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 2012; 482 (7384) 179-185
  • 94 Louis P, Hold GL, Flint HJ. The gut microbiota, bacterial metabolites and colorectal cancer. Nat Rev Microbiol 2014; 12 (10) 661-672
  • 95 Amar J, Burcelin R, Ruidavets JB , et al. Energy intake is associated with endotoxemia in apparently healthy men. Am J Clin Nutr 2008; 87 (5) 1219-1223
  • 96 Armstrong MJ, Adams LA, Canbay A, Syn WK. Extrahepatic complications of nonalcoholic fatty liver disease. Hepatology 2014; 59 (3) 1174-1197
  • 97 Vassilatou E. Nonalcoholic fatty liver disease and polycystic ovary syndrome. World J Gastroenterol 2014; 20 (26) 8351-8363
  • 98 Hossain N, Stepanova M, Afendy A , et al. Non-alcoholic steatohepatitis (NASH) in patients with polycystic ovarian syndrome (PCOS). Scand J Gastroenterol 2011; 46 (4) 479-484
  • 99 Chen LY, Qiao QH, Zhang SC, Chen YH, Chao GQ, Fang LZ. Metabolic syndrome and gallstone disease. World J Gastroenterol 2012; 18 (31) 4215-4220
  • 100 Chiu HM, Lin JT, Shun CT , et al. Association of metabolic syndrome with proximal and synchronous colorectal neoplasm. Clin Gastroenterol Hepatol 2007; 5 (2) 221-229 , quiz 141
  • 101 Athyros VG, Tziomalos K, Gossios TD , et al; GREACE Study Collaborative Group. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis. Lancet 2010; 376 (9756) 1916-1922