Non-alcoholic fatty liver disease and risk of cardiovascular disease

Metabolism: Clinical and Experimental

Volumn 65, Issue 8, 2016, Pages 1136-1150

  Lonardo, Amedeo ^a   Sookoian, Silvia ^b   Pirola, Carlos J ^b   Targher, Giovanni ^c  

^a UNIVERSITY OF MODENA AND REGGIO EMILIA   (Italy)

^b Facultad de Ciencias Naturales e Instituto M Lillo   (Argentina)

^c UNIVERSITY HOSPITAL OF VERONA   (Italy)

Author keywords

Cardiovascular risk; CVD; NAFLD

Indexed keywords

PROTEIN; PROTEIN PNPLA 3; PROTEIN TM6SF2; UNCLASSIFIED DRUG;

ARTICLE; CALCIFICATION; CARDIOVASCULAR DISEASE; CARDIOVASCULAR RISK; CLINICAL STUDY; DISEASE ASSOCIATION; GENETIC POLYMORPHISM; GENETIC VARIABILITY; HEART ARRHYTHMIA; HUMAN; HYPOBETALIPOPROTEINEMIA; NONALCOHOLIC FATTY LIVER; PRIORITY JOURNAL; CARDIOVASCULAR DISEASES; COMPLICATION; GENETICS; LIVER; PATHOPHYSIOLOGY; RISK FACTOR;

CARDIOVASCULAR DISEASES; HUMANS; LIVER; NON-ALCOHOLIC FATTY LIVER DISEASE; POLYMORPHISM, GENETIC; RISK FACTORS;

EID: 84951818844     PISSN: 00260495     EISSN: 15328600     Source Type: Journal    
DOI: 10.1016/j.metabol.2015.09.017     Document Type: Article

References (149)

1. [1] Chalasani, N., Younossi, Z., Lavine, J.E., Diehl, A.M., Brunt, E.M., Cusi, K., et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Am J Gastroenterol 107 (2012), 811–826.
2. [2] Anstee, Q.M., Targher, G., Day, C.P., Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol 10 (2013), 330–344.
3. [3] Targher, G., Day, C.P., Bonora, E., Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 363 (2010), 1341–1350.
4. [4] Ballestri, S., Lonardo, A., Bonapace, S., Byrne, C.D., Loria, P., Targher, G., Risk of cardiovascular, cardiac and arrhythmic complications in patients with non-alcoholic fatty liver disease. World J Gastroenterol 20 (2014), 1724–1745.
5. [5] Byrne, C.D., Targher, G., NAFLD: a multisystem disease. J Hepatol 62 (2015), S47–S64.
6. [6] Lonardo, A., Ballestri, S., Marchesini, G., Angulo, P., Loria, P., Nonalcoholic fatty liver disease: a precursor of the metabolic syndrome. Dig Liver Dis 47 (2015), 181–190.
7. [7] Armstrong, M.J., Adams, L.A., Canbay, A., Syn, W.K., Extra-hepatic complications of nonalcoholic fatty liver disease. Hepatology 59 (2014), 1174–1197.
8. [8] Targher, G., Chonchol, M.B., Byrne, C.D., CKD and nonalcoholic fatty liver disease. Am J Kidney Dis 64 (2014), 638–652.
9. [9] Targher, G., Rossini, M., Lonardo, A., Evidence that non-alcoholic fatty liver disease and polycystic ovary syndrome are associated by necessity rather than chance: a novel hepato-ovarian axis?. Endocrine, 2015 [Epub ahead of print].
10. [10] Targher, G., Lonardo, A., Rossini, M., Nonalcoholic fatty liver disease and decreased bone mineral density: is there a link?. J Endocrinol Invest 38 (2015), 817–825.
11. [11] Targher, G., Byrne, C.D., Diagnosis and management of nonalcoholic fatty liver disease and its hemostatic/thrombotic and vascular complications. Semin Thromb Hemost 39 (2013), 214–228.
12. [12] Sookoian, S., Pirola, C.J., Non-alcoholic fatty liver disease is strongly associated with carotid atherosclerosis: a systematic review. J Hepatol 49 (2008), 600–607.
13. [13] Oni, E.T., Agatston, A.S., Blaha, M.J., Fialkow, J., Cury, R., Sposito, A., et al. A systematic review: burden and severity of subclinical cardiovascular disease among those with nonalcoholic fatty liver; should we care?. Atherosclerosis 230 (2013), 258–267.
14. [14] Mellinger, J.L., Pencina, K.M., Massaro, J.M., Hoffmann, U., Seshadri, S., Fox, C.S., et al. Hepatic steatosis and cardiovascular disease outcomes: an analysis of the Framingham Heart Study. J Hepatol 63 (2015), 470–476.
15. [15] Mirbagheri, S.A., Rashidi, A., Abdi, S., Saedi, D., Abouzari, M., Liver: an alarm for the heart?. Liver Int 27 (2007), 891–894.
16. [16] Assy, N., Djibre, A., Farah, R., Grosovski, M., Marmor, A., Presence of coronary plaques in patients with nonalcoholic fatty liver disease. Radiology 254 (2010), 393–400.
17. [17] Wong, V.W., Wong, G.L., Yip, G.W., Lo, A.O., Limquiaco, J., Chu, W.C., et al. Coronary artery disease and cardiovascular outcomes in patients with non-alcoholic fatty liver disease. Gut 60 (2011), 1721–1727.
18. [18] Puchner, S.B., Lu, M.T., Mayrhofer, T., Liu, T., Pursnani, A., Ghoshhajra, B.B., et al. High-risk coronary plaque at coronary CT angiography is associated with nonalcoholic fatty liver disease, independent of coronary plaque and stenosis burden: results from the ROMICAT II trial. Radiology 274 (2015), 693–701.
19. [19] Moon, S.H., Noh, T.S., Cho, Y.S., Hong, S.P., Hyun, S.H., Choi, J.Y., et al. Association between nonalcoholic fatty liver disease and carotid artery inflammation evaluated by 18F-fluoro-deoxyglucose positron emission tomography. Angiology 66 (2015), 472–480.
20. [20] Matteoni, C.A., Younossi, Z.M., Gramlich, T., Boparai, N., Liu, Y.C., McCullough, A.J., Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 116 (1999), 1413–1419.
21. [21] Dam-Larsen, S., Franzmann, M., Andersen, I.B., Christoffersen, P., Jensen, L.B., Sørensen, T.I., et al. Long term prognosis of fatty liver: risk of chronic liver disease and death. Gut 53 (2004), 750–755.
22. [22] Ekstedt, M., Franzén, L.E., Mathiesen, U.L., Thorelius, L., Holmqvist, M., Bodemar, G., et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 44 (2006), 865–873.
23. [23] Rafiq, N., Bai, C., Fang, Y., Srishord, M., McCullough, A., Gramlich, T., et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin Gastroenterol Hepatol 7 (2009), 234–238.
24. [24] Soderberg, C., Stål, P., Askling, J., Glaumann, H., Lindberg, G., Marmur, J., et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology 51 (2010), 595–602.
25. [25] Ekstedt, M., Hagström, H., Nasr, P., Fredrikson, M., Stål, P., Kechagias, S., et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology 61 (2015), 1547–1554.
26. [26] Jepsen, P., Vilstrup, H., Mellemkjaer, L., Thulstrup, A.M., Olsen, J.H., Baron, J.A., et al. Prognosis of patients with a diagnosis of fatty liver—a registry-based cohort study. Hepatogastroenterology 50 (2003), 2101–2104.
27. [27] Adams, L.A., Lymp, J.F., St, S.J., Sanderson, S.O., Lindor, K.D., Feldstein, A., et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 129 (2005), 113–121.
28. [28] Targher, G., Bertolini, L., Rodella, S., Tessari, R., Zenari, L., Lippi, G., et al. Non-alcoholic fatty liver disease is independently associated with an increased incidence of cardiovascular events in type 2 diabetic patients. Diabetes Care 30 (2007), 2119–2121.
29. [29] Hamaguchi, M., Kojima, T., Takeda, N., Nagata, C., Takeda, J., Sarui, H., et al. Nonalcoholic fatty liver disease is a novel predictor of cardiovascular disease. World J Gastroenterol 13 (2007), 1579–1584.
30. [30] Haring, R., Wallaschofski, H., Nauck, M., Dorr, M., Baumeister, S.E., Volzke, H., Ultrasonographic hepatic steatosis increases prediction of mortality risk from elevated serum gamma-glutamyltranspeptidase levels. Hepatology 50 (2009), 1403–1411.
31. [31] Lazo, M., Hernaez, R., Bonekamp, S., Kamel, I.R., Brancati, F.L., Guallar, E., et al. Non-alcoholic fatty liver disease and mortality among US adults: prospective cohort study. BMJ, 343, 2011, d6891.
32. [32] Stepanova, M., Younossi, Z.M., Independent association between nonalcoholic fatty liver disease and cardiovascular disease in the US population. Clin Gastroenterol Hepatol 10 (2012), 646–650.
33. [33] Treeprasertsuk, S., Leverage, S., Adams, L.A., Lindor, K.D., St, S.J., Angulo, P., The Framingham risk score and heart disease in nonalcoholic fatty liver disease. Liver Int 32 (2012), 945–950.
34. [34] Zhou, Y.J., Li, Y.Y., Nie, Y.Q., Huang, C.M., Cao, C.Y., Natural course of nonalcoholic fatty liver disease in southern China: a prospective cohort study. J Dig Dis 13 (2012), 153–160.
35. [35] Dunn, M.A., Behari, J., Rogal, S.S., O'Connell, M.R., Furlan, A., Aghayev, A., et al. Hepatic steatosis in diabetic patients does not predict adverse liver-related or cardiovascular outcomes. Liver Int 33 (2013), 1575–1582.
36. [36] Kim, D., Kim, W.R., Kim, H.J., Therneau, T.M., Association between non-invasive fibrosis markers and mortality among adults with nonalcoholic fatty liver disease in the United States. Hepatology 57 (2013), 1357–1365.
37. [37] Targher, G., Byrne, C.D., Circulating markers of liver function and cardiovascular disease risk. Arterioscler Thromb Vasc Biol, 2015 [pii: ATVBAHA.115.305235. [Epub ahead of print]].
38. [38] 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 43 (2011), 617–649.
39. [39] Kim, N.H., Park, J., Kim, S.H., Kim, Y.H., Kim, D.H., Cho, G.Y., et al. Non-alcoholic fatty liver disease, metabolic syndrome and subclinical cardiovascular changes in the general population. Heart 100 (2014), 938–943.
40. [40] Granér, M., Nyman, K., Siren, R., Pentikäinen, M.O., Lundbom, J., Hakkarainen, A., et al. Ectopic fat depots and left ventricular function in nondiabetic men with nonalcoholic fatty liver disease. Circ Cardiovasc Imaging, 2014.
41. [41] Pacifico, L., Di Martino, M., De Merulis, A., Bezzi, M., Osborn, J.F., Catalano, C., et al. Left ventricular dysfunction in obese children and adolescents with nonalcoholic fatty liver disease. Hepatology 59 (2014), 461–470.
42. [42] Petta, S., Argano, C., Colomba, D., Cammà, C., Di Marco, V., Cabibi, D., et al. Epicardial fat, cardiac geometry and cardiac function in patients with non-alcoholic fatty liver disease: association with the severity of liver disease. J Hepatol 62 (2015), 928–933.
43. [43] VanWagner, L.B., Wilcox, J.E., Colangelo, L.A., Lloyd-Jones, D.M., Carr, J.J., Lima, J.A., et al. Association of nonalcoholic fatty liver disease with subclinical myocardial remodeling and dysfunction: a population-based study. Hepatology 62 (2015), 773–783.
44. [44] Dhingra, R., Gona, P., Wang, T.J., Fox, C.S., D'Agostino, R.B., Vasan, R.S., Serum gamma-glutamyltransferase and risk of heart failure in the community. Arterioscler Thromb Vasc Biol 30 (2010), 1855–1860.
45. [45] Wannamethee, S.G., Whincup, P.H., Shaper, A.G., Lennon, L., Sattar, N., Gamma-glutamyltransferase, hepatic enzymes, and risk of incident heart failure in older men. Arterioscler Thromb Vasc Biol 32 (2012), 830–835.
46. [46] Sinner, M.F., Wang, N., Fox, C.S., Fontes, J.D., Rienstra, M., Magnani, J.W., et al. Relation of circulating liver transaminase concentrations to risk of new-onset atrial fibrillation. Am J Cardiol 111 (2013), 219–224.
47. [47] Alonso, A., Misialek, J.R., Amiin, M.A., Hoogeveen, R.C., Chen, L.Y., Agarwal, S.K., et al. Circulating levels of liver enzymes and incidence of atrial fibrillation: the Atherosclerosis Risk in Communities cohort. Heart 100 (2014), 1511–1516.
48. [48] Targher, G., Mantovani, A., Pichiri, I., Rigolon, R., Dauriz, M., Zoppini, G., et al. Non-alcoholic fatty liver disease is associated with an increased prevalence of atrial fibrillation in hospitalized patients with type 2 diabetes. Clin Sci (Lond) 125 (2013), 301–309.
49. [49] Targher, G., Valbusa, F., Bonapace, S., Bertolini, L., Zenari, L., Rodella, S., et al. Non-alcoholic fatty liver disease is associated with an increased incidence of atrial fibrillation in patients with type 2 diabetes. PLoS One, 8(2), 2013, e57183.
50. [50] Targher, G., Valbusa, F., Bonapace, S., Bertolini, L., Zenari, L., Pichiri, I., et al. Association of nonalcoholic fatty liver disease with QTc interval in patients with type 2 diabetes. Nutr Metab Cardiovasc Dis 24 (2014), 663–669.
51. [51] Otto, C.M., Prendergast, B., Aortic-valve stenosis—from patients at risk to severe valve obstruction. N Engl J Med 371 (2014), 744–756.
52. [52] Markus, M.R., Baumeister, S.E., Stritzke, J., Dörr, M., Wallaschofski, H., Völzke, H., et al. Hepatic steatosis is associated with aortic valve sclerosis in the general population: the Study of Health in Pomerania (SHIP). Arterioscler Thromb Vasc Biol 33 (2013), 1690–1695.
53. [53] Bonapace, S., Valbusa, F., Bertolini, L., Pichiri, I., Mantovani, A., Rossi, A., et al. Nonalcoholic fatty liver disease is associated with aortic valve sclerosis in patients with type 2 diabetes mellitus. PLoS One, 9, 2014, e88371.
54. [54] Mantovani, A., Pernigo, M., Bergamini, C., Bonapace, S., Lipari, P., Valbusa, F., et al. Heart valve calcification in patients with type 2 diabetes and nonalcoholic fatty liver disease. Metabolism 64 (2015), 879–887.
55. [55] Romeo, S., Kozlitina, J., Xing, C., Pertsemlidis, A., Cox, D., Pennacchio, L.A., et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 40 (2008), 1461–1465.
56. [56] Sookoian, S., Pirola, C.J., Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology 53 (2011), 1883–1894.
57. [57] Sookoian, S., Castaño, G.O., Burgueño, A.L., Gianotti, T.F., Rosselli, M.S., Pirola, C.J., A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity. J Lipid Res 50 (2009), 2111–2116.
58. [58] Kozlitina, J., Smagris, E., Stender, S., Nordestgaard, B.G., Zhou, H.H., Tybjærg-Hansen, A., et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 46 (2014), 352–356.
59. [59] Holmen, O.L., Zhang, H., Fan, Y., Hovelson, D.H., Schmidt, E.M., Zhou, W., et al. Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk. Nat Genet 46 (2014), 345–351.
60. [60] Global Lipids Genetics Consortium, Willer, C.J., Schmidt, E.M., Sengupta, S., Peloso, G.M., Gustafsson, S., et al. Discovery and refinement of loci associated with lipid levels. Nat Genet 45 (2013), 1274–1283.
61. [61] Dongiovanni, P., Petta, S., Maglio, C., Fracanzani, A.L., Pipitone, R., Mozzi, E., et al. Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology 61 (2015), 506–514.
62. [62] Sookoian, S., Castaño, G.O., Scian, R., Mallardi, P., Fernández Gianotti, T., Burgueño, A.L., et al. Genetic variation in transmembrane 6 superfamily member 2 and the risk of nonalcoholic fatty liver disease and histological disease severity. Hepatology 61 (2015), 515–525.
63. [63] Wang, X., Liu, Z., Peng, Z., Liu, W., The TM6SF2 rs58542926 T allele is significantly associated with non-alcoholic fatty liver disease in Chinese. J Hepatol 62 (2015), 1438–1439.
64. [64] Zhou, Y., Llauradó, G., Orešič, M., Hyötyläinen, T., Orho-Melander, M., Yki-Järvinen, H., Circulating triacylglycerol signatures and insulin sensitivity in NAFLD associated with the E167K variant in TM6SF2. J Hepatol 62 (2015), 657–663.
65. [65] Liu, Y.L., Reeves, H.L., Burt, A.D., Tiniakos, D., McPherson, S., Leathart, J.B., et al. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nat Commun, 5, 2014, 4309.
66. [66] Dongiovanni, P., Petta, S., Mannisto, V., Margherita Mancina, R., Pipitone, R., Karja, V., et al. Statin use and nonalcoholic steatohepatitis in at risk individuals. J Hepatol 63 (2015), 705–712 [pii: S0168-8278(15)00328-1].
67. [67] Huang, Y., Cohen, J.C., Hobbs, H.H., Expression and characterization of a PNPLA3 protein isoform (I148M) associated with nonalcoholic fatty liver disease. J Biol Chem 286 (2011), 37085–37093.
68. [68] Mahdessian, H., Taxiarchis, A., Popov, S., Silveira, A., Franco-Cereceda, A., Hamsten, A., et al. TM6SF2 is a regulator of liver fat metabolism influencing triglyceride secretion and hepatic lipid droplet content. Proc Natl Acad Sci U S A 111 (2014), 8913–8918.
69. [69] Smagris, E., BasuRay, S., Li, J., Huang, Y., Lai, K.M., Gromada, J., et al. Pnpla3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis. Hepatology 61 (2015), 108–118.
70. [70] Morris, A.P., Fine mapping of type 2 diabetes susceptibility loci. Curr Diab Rep, 14, 2014, 549.
71. [71] He, S., McPhaul, C., Li, J.Z., Garuti, R., Kinch, L., Grishin, N.V., et al. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis. J Biol Chem 285 (2010), 6706–6715.
72. [72] Perttilä, J., Huaman-Samanez, C., Caron, S., Tanhuanpää, K., Staels, B., Yki-Järvinen, H., et al. PNPLA3 is regulated by glucose in human hepatocytes, and its I148M mutant slows down triglyceride hydrolysis. Am J Physiol Endocrinol Metab 302 (2012), E1063–E1069.
73. [73] Huang, Y., He, S., Li, J.Z., Seo, Y.K., Osborne, T.F., Cohen, J.C., et al. A feed-forward loop amplifies nutritional regulation of PNPLA3. Proc Natl Acad Sci U S A 107 (2010), 7892–7897.
74. [74] Rae-Whitcombe, S.M., Kennedy, D., Voyles, M., Thompson, M.P., Regulation of the promoter region of the human adiponutrin/PNPLA3 gene by glucose and insulin. Biochem Biophys Res Commun 402 (2010), 767–772.
75. [75] Sookoian, S., Pirola, C.J., The genetic epidemiology of nonalcoholic fatty liver disease: toward a personalized medicine. Clin Liver Dis 16 (2012), 467–485.
76. [76] Sookoian, S., Pirola, C.J., PNPLA3, the history of an orphan gene of the potato tuber protein family that found an organ: the liver. Hepatology 59 (2014), 2068–2071.
77. [77] Petta, S., Valenti, L., Marchesini, G., Di Marco, V., Licata, A., Cammà, C., et al. PNPLA3 GG genotype and carotid atherosclerosis in patients with non-alcoholic fatty liver disease. PLoS One, 8, 2013, e74089.
78. [78] Palmer, C.N., Maglio, C., Pirazzi, C., Burza, M.A., Adiels, M., Burch, L., et al. Paradoxical lower serum triglyceride levels and higher type 2 diabetes mellitus susceptibility in obese individuals with the PNPLA3 148M variant. PLoS One, 7, 2012, e39362.
79. [79] Pirazzi, C., Adiels, M., Burza, M.A., Mancina, R.M., Levin, M., Ståhlman, M., et al. Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitro. J Hepatol 57 (2012), 1276–1282.
80. [80] Paré, G., Ridker, P.M., Rose, L., Barbalic, M., Dupuis, J., Dehghan, A., et al. Genome-wide association analysis of soluble ICAM-1 concentration reveals novel associations at the NFKBIK, PNPLA3, RELA, and SH2B3 loci. PLoS Genet, 7, 2011, e1001374.
81. [81] Sookoian, S., Castaño, G.O., Burgueño, A.L., Rosselli, M.S., Gianotti, T.F., Mallardi, P., et al. Circulating levels and hepatic expression of molecular mediators of atherosclerosis in nonalcoholic fatty liver disease. Atherosclerosis 209 (2010), 585–591.
82. [82] Tarugi, P., Averna, M., Hypobetalipoproteinemia: genetics, biochemistry, and clinical spectrum. Adv Clin Chem 54 (2011), 81–107.
83. [83] Gutiérrez-Cirlos, C., Ordóñez-Sánchez, M.L., Tusié-Luna, M.T., Patterson, B.W., Schonfeld, G., Aguilar-Salinas, C.A., Familial hypobetalipoproteinemia in a hospital survey: genetics, metabolism and non-alcoholic fatty liver disease. Ann Hepatol 10 (2011), 155–164.
84. [84] Tarugi, P., Lonardo, A., Ballarini, G., Grisendi, A., Pulvirenti, M., Bagni, A., et al. Fatty liver in heterozygous hypobetalipoproteinemia caused by a novel truncated form of apolipoprotein B. Gastroenterology 111 (1996), 1125–1133.
85. [85] Lonardo, A., Lombardini, S., Scaglioni, F., Carulli, L., Ricchi, M., Ganazzi, D., et al. Hepatic steatosis and insulin resistance does etiology make a difference?. J Hepatol 44 (2006), 190–196.
86. [86] Amaro, A., Fabbrini, E., Kars, M., Yue, P., Schechtman, K., Schonfeld, G., et al. Dissociation between intrahepatic triglyceride content and insulin resistance in familial hypobetalipoproteinemia. Gastroenterology 139 (2010), 149–153.
87. [87] Della Corte, C., Fintini, D., Giordano, U., Cappa, M., Brufani, C., Majo, F., et al. Fatty liver and insulin resistance in children with hypobetalipoproteinemia: the importance of aetiology. Clin Endocrinol (Oxf) 79 (2013), 49–54.
88. [88] Sankatsing, R.R., Fouchier, S.W., de Haan, S., Hutten, B.A., de Groot, E., Kastelein, J.J., et al. Hepatic and cardiovascular consequences of familial hypobetalipoproteinemia. Arterioscler Thromb Vasc Biol 25 (2005), 1979–1984.
89. [89] Eichler, K., Puhan, M.A., Steurer, J., Bachmann, L.M., Prediction of first coronary events with the Framingham score: a systematic review. Am Heart J 153 (2007), 722–731.
90. [90] Rabar, S., Harker, M., O'Flynn, N., Wierzbicki, A.S., Guideline Development Group. Lipid modification and cardiovascular risk assessment for the primary and secondary prevention of cardiovascular disease: summary of updated NICE guidance. BMJ, 349, 2014, g4356.
91. [91] Lonardo, A., Ballestri, S., Targher, G., Loria, P., Diagnosis and management of cardiovascular risk in nonalcoholic fatty liver disease. Expert Rev Gastroenterol Hepatol 9 (2015), 629–650.
92. [92] Alkhouri, N., Tamimi, T.A., Yerian, L., Lopez, R., Zein, N.N., Feldstein, A.E., The inflamed liver and atherosclerosis: a link between histologic severity of nonalcoholic fatty liver disease and increased cardiovascular risk. Dig Dis Sci 55 (2010), 2644–2650.
93. [93] Sunbul, M., Agirbasli, M., Durmus, E., Kivrak, T., Akin, H., Aydin, Y., et al. Arterial stiffness in patients with non-alcoholic fatty liver disease is related to fibrosis stage and epicardial adipose tissue thickness. Atherosclerosis 237 (2014), 490–493.
94. [94] You, S.C., Kim, K.J., Kim, S.U., Kim, B.K., Park, J.Y., Kim, D.Y., et al. Hepatic fibrosis assessed using transient elastography is independently associated with coronary artery calcification. J Gastroenterol Hepatol, 2015, 10.1111/jgh.12992 [Epub ahead of print].
95. [95] Jin, R., Le, N.A., Cleeton, R., Sun, X., Cruz Muños, J., Otvos, J., et al. Amount of hepatic fat predicts cardiovascular risk independent of insulin resistance among Hispanic-American adolescents. Lipids Health Dis, 14, 2015, 39.
96. [96] Arulanandan, A., Ang, B., Bettencourt, R., Hooker, J., Behling, C., Lin, G.Y., et al. Association between quantity of liver fat and cardiovascular risk in patients with nonalcoholic fatty liver disease independent of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 13 (2015), 1513–1520.
97. [97] Pisto, P., Santaniemi, M., Bloigu, R., Ukkola, O., Kesäniemi, Y.A., Fatty liver predicts the risk for cardiovascular events in middle-aged population: a population-based cohort study. BMJ Open, 4, 2014, e004973.
98. [98] Adams, L.A., Accurate quantification of hepatic fat—is it important?. Nat Rev Gastroenterol 12 (2015), 126–127.
99. [99] Morling, J.R., Fallowfield, J.A., Williamson, R.M., Robertson, C.M., Glancy, S., Guha, I.N., et al. γ-Glutamyltransferase, but not markers of hepatic fibrosis, is associated with cardiovascular disease in older people with type 2 diabetes mellitus: the Edinburgh Type 2 Diabetes Study. Diabetologia 58 (2015), 1484–1493.
100. [100] Pirola, C.J., Fernández Gianotti, T., Castaño, G.O., Mallardi, P., San Martino, J., Mora Gonzalez Lopez Ledesma, M., et al. Circulating microRNA signature in non-alcoholic fatty liver disease: from serum non-coding RNAs to liver histology and disease pathogenesis. Gut 64 (2015), 800–812.
101. [101] Ballestri, S., Lonardo, A., Romagnoli, D., Carulli, L., Losi, L., Day, C.P., et al. Ultrasonographic fatty liver indicator, a novel score which rules out NASH and is correlated with metabolic parameters in NAFLD. Liver Int 32 (2012), 1242–1252.
102. [102] Lonardo, A., Romagnoli, D., GGT: a novel cardiovascular outfit for an old liver test?. Indian J Med Res, 2015 [in press].
103. [103] Lin, J.S., O'Connor, E., Evans, C.V., Senger, C.A., Rowland, M.G., Groom, H.C., Behavioral counseling to promote a healthy lifestyle in persons with cardiovascular risk factors: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 161 (2014), 568–578.
104. [104] Long, M.T., Pedley, A., Massaro, J.M., Hoffmann, U., Esliger, D.W., Vasan, R.S., et al. Hepatic steatosis is associated with lower levels of physical activity measured via accelerometry. Obesity (Silver Spring) 23 (2015), 1259–1266.
105. [105] Oh, S., Shida, T., Yamagishi, K., Tanaka, K., So, R., Tsujimoto, T., et al. Moderate to vigorous physical activity volume is an important factor for managing nonalcoholic fatty liver disease: a retrospective study. Hepatology 61 (2015), 1205–1215.
106. [106] Oni, E.T., Kalathiya, R., Aneni, E.C., Martin, S.S., Blaha, M.J., Feldman, T., et al. Relation of physical activity to prevalence of nonalcoholic Fatty liver disease independent of cardiometabolic risk. Am J Cardiol 115 (2015), 34–39.
107. [107] Pugh, C.J., Cuthbertson, D.J., Sprung, V.S., Kemp, G.J., Richardson, P., Umpleby, A.M., et al. Exercise training improves cutaneous microvascular function in nonalcoholic fatty liver disease. Am J Physiol Endocrinol Metab 305 (2013), E50–E58.
108. [108] Pugh, C.J., Spring, V.S., Kemp, G.J., Richardson, P., Shojaee-Moradie, F., Umpleby, A.M., et al. Exercise training reverses endothelial dysfunction in nonalcoholic fatty liver disease. Am J Physiol Heart Circ Physiol 307 (2014), H1298–H1306.
109. [109] Keating, S.E., Hackett, D.A., George, J., Johnson, N.A., Exercise and non-alcoholic fatty liver disease: a systematic review and meta-analysis. J Hepatol 57 (2012), 157–166.
110. [110] Bacchi, E., Negri, C., Targher, G., Faccioli, N., Lanza, M., Zoppini, G., et al. Both resistance training and aerobic training reduce hepatic fat content in type 2 diabetic subjects with nonalcoholic fatty liver disease (the RAED2 Randomized Trial). Hepatology 58 (2013), 1287–1295.
111. [111] Lee, S., Bacha, F., Hannon, T., Kuk, J.L., Boesch, C., Arslanian, S., Effects of aerobic versus resistance exercise without caloric restriction on abdominal fat, intrahepatic lipid, and insulin sensitivity in obese adolescent boys: a randomized, controlled trial. Diabetes 61 (2012), 2787–2795.
112. [112] Whitsett, M., VanWagner, L.B., Physical activity as a treatment of non-alcoholic fatty liver disease: a systematic review. World J Hepatol 7 (2015), 2041–2052.
113. [113] Hallsworth, K., Thoma, C., Hollingsworth, K.G., Cassidy, S., Anstee, Q.M., Day, C.P., et al. Modified high-intensity interval training reduces liver fat and improves cardiac function in non-alcoholic fatty liver disease: a randomised controlled trial. Clin Sci (Lond), 2015 [pii: CS20150308 [Epub ahead of print]].
114. [114] Montesi, L., Caselli, C., Centis, E., Nuccitelli, C., Moscatiello, S., Suppini, A., et al. Physical activity support or weight loss counseling for nonalcoholic fatty liver disease?. World J Gastroenterol 20 (2014), 10128–10136.
115. [115] Piguet, A.C., Saran, U., Simillion, C., Keller, I., Terracciano, L., Reeves, H.L., et al. Regular exercise decreases liver tumors development in hepatocyte-specific PTEN-deficient mice independently of steatosis. J Hepatol 62 (2015), 1296–1303.
116. [116] Pirola, C.J., Gianotti, T.F., Burgueño, A.L., Rey-Funes, M., Loidl, C.F., Mallardi, P., et al. Epigenetic modification of liver mitochondrial DNA is associated with histological severity of nonalcoholic fatty liver disease. Gut 62 (2013), 1356–1363.
117. [117] Arab, J.P., Candia, R., Zapata, R., Muñoz, C., Arancibia, J.P., Poniachik, J., et al. Management of nonalcoholic fatty liver disease: an evidence-based clinical practice review. World J Gastroenterol 20 (2014), 12182–12201.
118. [118] Ratziu, V., Goodman, Z., Sanyal, A., Current efforts and trends in the treatment of NASH. J Hepatol 62 (2015), S65–S75.
119. [119] Taylor, F., Huffman, M.D., Macedo, A.F., Moore, T.H., Burke, M., Davey Smith, G., et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev, 1, 2013, CD004816.
120. [120] Keene, D., Price, C., Shun-Shin, M.J., Francis, D.P., Effect on cardiovascular risk of high-density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117,411 patients. BMJ, 349, 2014, g4379.
121. [121] Gudzune, K.A., Monroe, A.K., Sharma, R., Ranasinghe, P.D., Chelladurai, Y., Robinson, K.A., Effectiveness of combination therapy with statin and another lipid-modifying agent compared with intensified statin monotherapy: a systematic review. Ann Intern Med 160 (2014), 468–476.
122. [122] Argo, C.K., Loria, P., Caldwell, S.H., Lonardo, A., Statins in liver disease: a molehill, an iceberg, or neither?. Hepatology 48 (2008), 662–669.
123. [123] Desai, C.S., Martin, S.S., Blumenthal, R.S., Non-cardiovascular effects associated with statins. BMJ, 349, 2014, g3743.
124. [124] Leise, M.D., Poterucha, J.J., Talwalkar, J.A., Drug-induced liver injury. Mayo Clin Proc 89 (2014), 95–106.
125. [125] Lewis, J.H., Clinical perspective: statins and the liver—harmful or helpful?. Dig Dis Sci 57 (2012), 1754–1763.
126. [126] Bader, T., Liver tests are irrelevant when prescribing statins. Lancet 376 (2010), 1882–1883.
127. [127] Rzouq, F.S., Volk, M.L., Hatoum, H.H., Talluri, S.K., Mummadi, R.R., Sood, G.K., Hepatotoxicity fears contribute to underutilization of statin medications by primary care physicians. Am J Med Sci 340 (2010), 89–93.
128. [128] Hippisley-Cox, J., Coupland, C., Individualising the risks of statins in men and women in England and Wales: population-based cohort study. Heart 96 (2010), 939–947.
129. [129] Athyros, V.G., Tziomalos, K., Gossios, T.D., Griva, T., Anagnostis, P., Kargiotis, K., et al. 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 376 (2010), 1916–1922.
130. [130] Tikkanen, M.J., Fayyad, R., Faergeman, O., Olsson, A.G., Wun, C.C., Laskey, R., et al. Effect of intensive lipid lowering with atorvastatin on cardiovascular outcomes in coronary heart disease patients with mild-to-moderate baseline elevations in alanine aminotransferase levels. Int J Cardiol 168 (2013), 3846–3852.
131. [131] Musso, G., Cassader, M., Rosina, F., Gambino, R., Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials. Diabetologia 55 (2012), 885–904.
132. [132] Lonardo, A., Loria, P., Potential for statins in the chemoprevention and management of hepatocellular carcinoma. J Gastroenterol Hepatol 27 (2012), 1654–1664.
133. [133] Tousoulis, D., Papageorgiou, N., Androulakis, E., Siasos, G., Latsios, G., Tentolouris, K., et al. Diabetes mellitus-associated vascular impairment: novel circulating biomarkers and therapeutic approaches. J Am Coll Cardiol 62 (2013), 667–676.
134. [134] Bennett, W.L., Maruthur, N.M., Singh, S., Segal, J.B., Wilson, L.M., Chatterjee, R., et al. Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations. Ann Intern Med 154 (2011), 602–613.
135. [135] Rouabhia, S., Milic, N., Abenavoli, L., Metformin in the treatment of non-alcoholic fatty liver disease: safety, efficacy and mechanism. Expert Rev Gastroenterol Hepatol 8 (2014), 343–349.
136. [136] Lonardo, A., Bellentani, S., Ratziu, V., Loria, P., Insulin resistance in nonalcoholic steatohepatitis: necessary but not sufficient — death of a dogma from analysis of therapeutic studies?. Expert Rev Gastroenterol Hepatol 5 (2011), 279–289.
137. [137] Rosselli, M.S., Burgueño, A.L., Carabelli, J., Schuman, M., Pirola, C.J., Sookoian, S., Losartan reduces liver expression of plasminogen activator inhibitor-1 (PAI-1) in a high fat-induced rat nonalcoholic fatty liver disease model. Atherosclerosis 206 (2009), 119–126.
138. [138] Yokohama, S., Yoneda, M., Haneda, M., Okamoto, S., Okada, M., Aso, K., et al. Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis. Hepatology 40 (2004), 1222–1225.
139. [139] Neuschwander-Tetri, B.A., Loomba, R., Sanyal, A.J., Lavine, J.E., Van Natta, M.L., Abdelmalek, M.F., et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385 (2015), 956–965.
140. [140] Stefan, N., Ramsauer, M., Jordan, P., Nowotny, B., Kantartzis, K., Machann, J., et al. Inhibition of 11β-HSD1 with RO5093151 for non-alcoholic fatty liver disease: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2 (2014), 406–416.
141. [141] Buss, C., Valle-Tovo, C., Miozzo, S., Alves de Mattos, A., Probiotics and synbiotics may improve liver aminotransferases levels in non-alcoholic fatty liver disease patients. Ann Hepatol 13 (2014), 482–488.
142. [142] Rerksuppaphol, S., Rerksuppaphol, L., A randomized double-blind controlled trial of lactobacillus acidophilus plus bifidobacterium bifidum versus placebo in patients with hypercholesterolemia. J Clin Diagn Res 9 (2015), KC01–KC04.
143. [143] Ivey, K.L., Hodgson, J.M., Kerr, D.A., Thompson, P.L., Stojceski, B., Prince, R.L., The effect of yoghurt and its probiotics on blood pressure and serum lipid profile; a randomised controlled trial. Nutr Metab Cardiovasc Dis 25 (2015), 46–51.
144. [144] Maurantonio, M., Ballestri, S., Odoardi, M.R., Lonardo, A., Loria, P., Treatment of atherogenic liver based on the pathogenesis of nonalcoholic fatty liver disease: a novel approach to reduce cardiovascular risk?. Arch Med Res 42 (2011), 337–353.
145. [145] de Wit, N.J., Afman, L.A., Mensink, M., Müller, M., Phenotyping the effect of diet on non-alcoholic fatty liver disease. J Hepatol 57 (2012), 1370–1373.
146. [146] Rinella, M.E., The “dose” of exercise and its effects beyond weight loss. Hepatology 61 (2015), 1115–1117.
147. [147] Lonardo, A., Loria, P., If steatosis is the atherosclerosis of the liver, are statins the “aspirin” for steatosis?. Dig Liver Dis 44 (2012), 451–452.
148. [148] Rinella, M.E., Nonalcoholic fatty liver disease: a systematic review. JAMA 313 (2015), 2263–2273.
149. [149] Tziomalos, K., Athyros, V.G., Paschos, P., Karagiannis, A., Nonalcoholic fatty liver disease and statins. Metabolism 64 (2015), 1215–1223, 10.1016/j.metabol.2015.07.003.