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Increased risk of cardiovascular disease and chronic kidney disease in NAFLD

Abstract

NAFLD is very common in the general population and its prevalence is increasing worldwide in parallel with the increasing incidences of obesity and metabolic diseases, mainly type 2 diabetes. In some cases, however, the diagnosis of NAFLD remains uncertain because other causes of liver disease are not easy to exclude in patients who are diagnosed with NAFLD after a biochemical or ultrasonographic analysis. Several studies have documented a strong association between NAFLD and traditional and nontraditional risk factors for cardiovascular disease (CVD) and chronic kidney disease (CKD). Accordingly, patients with NAFLD have an increased prevalence and incidence of both CVD and CKD. It is reasonable to believe that NAFLD, CVD and CKD share common risk factors (such as visceral obesity, insulin resistance, dysglycaemia, dyslipidaemia and hypertension) and therefore that NAFLD might simply be a marker rather than a causal risk factor of CVD and CKD. In this context, the identification of NAFLD might be an additional clinical feature to improve the stratification of patients for their risk of CVD and CKD. Growing evidence suggests that in patients with NAFLD, especially if NASH is present, several molecules released from the steatotic and inflamed liver might have pathogenic roles in the development of atherosclerosis and kidney damage. If these findings are confirmed by further studies, NAFLD could become a target for the prevention and treatment of CVD and CKD. NAFLD, whatever its role (marker or causal risk factor), is therefore a clinical condition that deserves greater attention from gastroenterologists, endocrinologists, cardiologists and nephrologists, as well as internists and general practitioners.

Key Points

  • NAFLD is very frequent in the general population and its prevalence is increasing in parallel with the increases in the incidences of obesity and metabolic diseases

  • Risk factors for cardiovascular disease (CVD) and chronic kidney disease (CKD) are common in patients with NAFLD, who are more likely to have these diseases than the general population

  • Visceral obesity, insulin resistance and the metabolic syndrome are certainly common to NAFLD, CVD and CKD, but NAFLD might be a pathogenic factor of both CVD and CKD

  • Various molecules released by the steatotic and inflamed liver might contribute to the development and progression of both CVD and CKD

  • Clinicians who manage patients with NAFLD (particularly NASH) should be aware of the increased risk of CVD and CKD, and should target individual risk factors and underlying disorders

  • Targeting NAFLD with specific tools, when available, might also result in a reduction of the risk of both CVD and CKD

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Figure 1: The metabolic syndrome is a constellation of inter-related metabolic abnormalities that includes glucose intolerance, insulin resistance, visceral obesity, atherogenic dyslipidaemia, thrombophilia, hyperuricaemia and hypertension, all risk factors for CVD and CKD.
Figure 2: NAFLD, CVD and CKD: an intriguing pathophysiological network.
Figure 3: Potential molecules and factors linking NAFLD to the development and progression of atherosclerosis and kidney disease.

References

  1. Targher, G., Day, C. P. & Bonora, E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N. Engl. J. Med. 363, 1341–1350 (2010).

    CAS  PubMed  Article  Google Scholar 

  2. Loria, P., Lonardo, A. & Targher, G. Is liver fat detrimental to vessels?: intersections in the pathogenesis of NAFLD and atherosclerosis. Clin. Sci. (Lond.) 115, 1–12 (2008).

    CAS  Article  Google Scholar 

  3. Targher, G., Marra, F. & Marchesini, G. Increased risk of cardiovascular disease in nonalcoholic fatty liver disease: causal effect or epiphenomenon? Diabetologia 51, 1947–1953 (2008).

    CAS  PubMed  Article  Google Scholar 

  4. Ghouri, N., Preiss, D. & Sattar, N. Liver enzymes, nonalcoholic fatty liver disease, and incident cardiovascular disease: a narrative review and clinical perspective of prospective data. Hepatology 52, 1156–1161 (2010).

    PubMed  Article  Google Scholar 

  5. Treeprasertsuk, S., Lopez-Jimenez, F. & Lindor, K. D. Nonalcoholic fatty liver disease and the coronary artery disease. Dig. Dis. Sci. 56, 35–45 (2011).

    PubMed  Article  Google Scholar 

  6. Targher, G., Chonchol, M., Zoppini, G., Abaterusso, C. & Bonora, E. Risk of chronic kidney disease in patients with non-alcoholic fatty liver disease: is there a link? J. Hepatol. 54, 1020–1029 (2011).

    CAS  PubMed  Article  Google Scholar 

  7. Ix, J. H. & Sharma, K. Mechanisms linking obesity, chronic kidney disease, and fatty liver disease: the roles of fetuin-A, adiponectin, and AMPK. J. Am. Soc. Nephrol. 21, 406–412 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. Angulo, P. Nonalcoholic fatty liver disease. N. Engl. J. Med. 346, 1221–1231 (2002).

    CAS  PubMed  Article  Google Scholar 

  9. Vuppalanchi, R. & Chalasani, N. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: selected practical issues in their evaluation and management. Hepatology 49, 306–317 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  10. Ratziu, V., Bellentani, S., Cortez-Pinto, H., Day, C. & Marchesini, G. A position statement on NAFLD/NASH based on the EASL 2009 special conference. J. Hepatol. 53, 372–384 (2010).

    PubMed  Article  Google Scholar 

  11. Torres, D. M. & Harrison, S. A. Diagnosis and therapy of nonalcoholic steatohepatitis. Gastroenterology 134, 1682–1698 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. Mehta, S. R., Thomas, E. L., Bell, J. D., Johnston, D. G. & Taylor-Robinson, S. D. Non-invasive means of measuring hepatic fat content. World J. Gastroenterol. 14, 3476–3483 (2008).

    PubMed  PubMed Central  Article  Google Scholar 

  13. Schwenzer, N. F. et al. Non-invasive assessment and quantification of liver steatosis by ultrasound, computed tomography and magnetic resonance. J. Hepatol. 51, 433–445 (2009).

    PubMed  Article  Google Scholar 

  14. Browning, J. D. Statins and hepatic steatosis: perspectives from the Dallas Heart Study. Hepatology 44, 466–471 (2006).

    CAS  PubMed  Article  Google Scholar 

  15. Jimba, S. et al. Prevalence of non-alcoholic fatty liver disease and its association with impaired glucose metabolism in Japanese adults. Diabet. Med. 22, 1141–1145 (2005).

    CAS  PubMed  Article  Google Scholar 

  16. Targher, G. et al. Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care 30, 1212–1218 (2007).

    PubMed  Article  Google Scholar 

  17. Williams, C. D. et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 140, 124–131 (2011).

    Article  PubMed  Google Scholar 

  18. Marceau, P. et al. Liver pathology and the metabolic syndrome X in severe obesity. J. Clin. Endocrinol. Metab. 84, 1513–1517 (1999).

    CAS  PubMed  Article  Google Scholar 

  19. Gholam, P. M., Flancbaum, L., Machan, J. T., Charney, D. A. & Kotler, D. P. Nonalcoholic fatty liver disease in severely obese subjects. Am. J. Gastroenterol. 102, 399–408 (2007).

    CAS  PubMed  Article  Google Scholar 

  20. Machado, M., Mrquez-Vidal, P. A. & Cortez-Pinto, H. Hepatic histology in obese patients undergoing bariatric surgery. J. Hepatol. 45, 600–606 (2006).

    PubMed  Article  Google Scholar 

  21. De Ridder, R. J. et al. Review article: non-alcoholic fatty liver disease in morbidly obese patients and the effect of bariatric surgery. Aliment. Pharmacol. Ther. 26 (Suppl. 2), 195–201 (2007).

    PubMed  Article  Google Scholar 

  22. Fox, C. S. et al. Predictors of new-onset kidney disease in a community-based population. JAMA 291, 844–850 (2004).

    CAS  PubMed  Article  Google Scholar 

  23. Vlagopoulos, P. T. & Sarnak, M. J. Traditional and non-traditional cardiovascular risk factors in chronic kidney disease. Med. Clin. North Am. 89, 587–611 (2005).

    PubMed  Article  Google Scholar 

  24. Speliotes, E. K. et al. Fatty liver is associated with dyslipidemia and dysglycemia independent of visceral fat: the Framingham Heart Study. Hepatology 51, 1979–1987 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. Bonora, E. Relationship between regional fat distribution and insulin resistance. Int. J. Obes. Relat. Metab. Disord. 24 (Suppl. 2), S32–S35 (2000).

    CAS  PubMed  Article  Google Scholar 

  26. Bonora, E. The metabolic syndrome and cardiovascular disease. Ann. Med. 38, 64–80 (2006).

    CAS  PubMed  Article  Google Scholar 

  27. Grundy, S. M. Metabolic syndrome pandemic. Arterioscler. Thromb. Vasc. Biol. 28, 629–636 (2008).

    CAS  PubMed  Article  Google Scholar 

  28. Hwang, J. H. et al. Increased intrahepatic triglyceride is associated with peripheral insulin resistance: in vivo MR imaging and spectroscopy studies. Am. J. Physiol. Endocrinol. Metab. 293, E1663–E1669 (2007).

    CAS  PubMed  Article  Google Scholar 

  29. Koska, J. et al. Increased fat accumulation in liver may link insulin resistance with subcutaneous abdominal adipocyte enlargement, visceral adiposity, and hypoadiponectinemia in obese individuals. Am. J. Clin. Nutr. 87, 295–302 (2008).

    CAS  PubMed  Article  Google Scholar 

  30. Bonora, E. et al. Insulin resistance as estimated by homeostasis model assessment predicts incident symptomatic cardiovascular disease in Caucasian subjects from the general population: the Bruneck study. Diabetes Care 30, 318–324 (2007).

    PubMed  Article  Google Scholar 

  31. Kurella, M., Lo, J. C. & Chertow, G. M. Metabolic syndrome and the risk for chronic kidney disease among nondiabetic adults. J. Am. Soc. Nephrol. 16, 2134–2140 (2005).

    PubMed  Article  Google Scholar 

  32. Kronenberg, F. Emerging risk factors and markers of chronic kidney disease progression. Nat. Rev. Nephrol. 5, 677–689 (2009).

    CAS  PubMed  Article  Google Scholar 

  33. Targher, G. et al. Nonalcoholic fatty liver disease as a contributor to hypercoagulation and thrombophilia in the metabolic syndrome. Semin. Thromb. Hemost. 35, 277–287 (2009).

    CAS  PubMed  Article  Google Scholar 

  34. Targher, G. et al. NASH predicts plasma inflammatory biomarkers independently of visceral fat in men. Obesity (Silver Spring) 16, 1394–1399 (2008).

    CAS  Article  Google Scholar 

  35. Edens, M. A., Kuipers, F. & Stolk, R. P. Non-alcoholic fatty liver disease is associated with cardiovascular disease risk markers. Obes. Rev. 10, 412–419 (2009).

    CAS  PubMed  Article  Google Scholar 

  36. Westerbacka, J. et al. Genes involved in fatty acid partitioning and binding, lipolysis, monocyte/macrophage recruitment, and inflammation are overexpressed in the human fatty liver of insulin resistant subjects. Diabetes 56, 2759–2765 (2007).

    CAS  PubMed  Article  Google Scholar 

  37. Sookoian, S. et al. Liver transcriptional profile of atherosclerosis-related genes in human nonalcoholic fatty liver disease. Atherosclerosis 218, 378–385 (2011).

    CAS  PubMed  Article  Google Scholar 

  38. Yoneda, M. et al. High-sensitivity C-reactive protein is an independent clinical feature of nonalcoholic steatohepatitis (NASH) and also of the severity of fibrosis in NASH. J. Gastroenterol. 42, 573–582 (2007).

    CAS  PubMed  Article  Google Scholar 

  39. Wieckowska, A. et al. Increased hepatic and circulating interleukin-6 levels in human nonalcoholic steatohepatitis. Am. J. Gastroenterol. 103, 1372–1379 (2008).

    CAS  PubMed  Article  Google Scholar 

  40. Thuy, S. et al. Nonalcoholic fatty liver disease in humans is associated with increased plasma endotoxin and plasminogen activator inhibitor 1 concentrations and with fructose intake. J. Nutr. 138, 1452–1455 (2008).

    CAS  PubMed  Article  Google Scholar 

  41. Villanova, N. et al. Endothelial dysfunction and cardiovascular risk profile in nonalcoholic fatty liver disease. Hepatology 42, 473–480 (2005).

    PubMed  Article  Google Scholar 

  42. Targher, G. et al. Relation of nonalcoholic hepatic steatosis to early carotid atherosclerosis in healthy men: role of visceral fat accumulation. Diabetes Care 27, 2498–2500 (2004).

    PubMed  Article  Google Scholar 

  43. Brea, A. et al. Nonalcoholic fatty liver disease is associated with carotid atherosclerosis. A case-control study. Arterioscler. Thromb. Vasc. Biol. 25, 1045–1050 (2005).

    CAS  PubMed  Article  Google Scholar 

  44. Volzke, H. et al. Hepatic steatosis is associated with an increased risk of carotid atherosclerosis. World J. Gastroenterol. 11, 1848–1853 (2005).

    PubMed  PubMed Central  Article  Google Scholar 

  45. Fracanzani, A. L. et al. Carotid artery intima-media thickness in nonalcoholic fatty liver disease. Am. J. Med. 121, 72–78 (2008).

    PubMed  Article  Google Scholar 

  46. Sookoian, S. & Pirola, C. J. Non-alcoholic fatty liver disease is strongly associated with carotid atherosclerosis: a systematic review. J. Hepatol. 49, 600–607 (2008).

    PubMed  PubMed Central  Article  Google Scholar 

  47. Petit, J. M. et al. Nonalcoholic fatty liver is not associated with carotid intima-media thickness in type 2 diabetic patients. J. Clin. Endocrinol. Metab. 94, 4103–4106 (2009).

    CAS  PubMed  Article  Google Scholar 

  48. McKimmie, R. L. et al. Hepatic steatosis and subclinical cardiovascular disease in a cohort enriched for type 2 diabetes: the Diabetes Heart Study. Am. J. Gastroenterol. 103, 3029–3035 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. Targher, G. et al. Relations between carotid artery wall thickness and liver histology in subjects with nonalcoholic fatty liver disease. Diabetes Care 29, 1325–1330 (2006).

    PubMed  Article  Google Scholar 

  50. Bonapace, S. et al. Nonalcoholic fatty liver disease is associated with left ventricular diastolic dysfunction in patients with type 2 diabetes. Diabetes Care 35, 389–395 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. Perseghin, G. et al. Increased mediastinal fat and impaired left ventricular energy metabolism in young men with newly found fatty liver. Hepatology 47, 51–58 (2008).

    CAS  PubMed  Article  Google Scholar 

  52. Mirbagheri, S. A., Rashidi, A., Abdi, S., Saedi, D. & Abouzari, M. Liver: an alarm for the heart? Liver Int. 27, 891–894 (2007).

    PubMed  Article  Google Scholar 

  53. Wong, V. W. et al. Coronary artery disease and cardiovascular outcomes in patients with non-alcoholic fatty liver disease. Gut 60, 1721–1727 (2011).

    CAS  PubMed  Article  Google Scholar 

  54. Lautamäki, R. et al. Liver steatosis coexists with myocardial insulin resistance and coronary dysfunction in patients with type 2 diabetes. Am. J. Physiol. Endocrinol. Metab. 291, E282–E290 (2006).

    PubMed  Article  CAS  Google Scholar 

  55. Ruttmann, E. et al. γ-glutamyltransferase as a risk factor for cardiovascular disease mortality: an epidemiological investigation in a cohort of 163,944 Austrian adults. Circulation 112, 2130–2137 (2005).

    CAS  PubMed  Article  Google Scholar 

  56. Lee, D. H. et al. Serum γ-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28,838 middle-aged men and women. Eur. Heart J. 27, 2170–2176 (2006).

    CAS  PubMed  Article  Google Scholar 

  57. Schindhelm, R. K. et al. Alanine aminotransferase predicts coronary heart disease events: a 10-year follow-up of the Hoorn Study. Atherosclerosis 191, 391–396 (2007).

    CAS  PubMed  Article  Google Scholar 

  58. Lee, D. S. et al. γ-glutamyltransferase and metabolic syndrome, cardiovascular disease, and mortality risk: the Framingham Heart Study. Arterioscler. Thromb. Vasc. Biol. 27, 127–133 (2007).

    CAS  PubMed  Article  Google Scholar 

  59. Wannamethee, S. G., Lennon, L. & Shaper, A. G. The value of γ-glutamyltransferase in cardiovascular risk prediction in men without diagnosed cardiovascular disease or diabetes. Atherosclerosis 201, 168–175 (2008).

    CAS  PubMed  Article  Google Scholar 

  60. Fraser, A. et al. γ-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. 27, 2729–2735 (2007).

    CAS  PubMed  Article  Google Scholar 

  61. Goessling, W. et al. Aminotransferase levels and 20-year risk of metabolic syndrome, diabetes, and cardiovascular disease. Gastroenterology 135, 1935–1944 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. Ruhl, C. E. & Everhart, J. E. Elevated serum alanine aminotransferase and γ-glutamyltransferase and mortality in the United States population. Gastroenterology 136, 477–485 (2009).

    CAS  PubMed  Article  Google Scholar 

  63. Strasak, A. M. et al. Longitudinal change in serum γ-glutamyltransferase and cardiovascular disease mortality: a prospective population-based study in 76,113 Austrian adults. Arterioscler. Thromb. Vasc. Biol. 28, 1857–1865 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. Targher, G. Elevated serum γ-glutamyltransferase activity is associated with increased risk of mortality, incident type 2 diabetes, cardiovascular events, chronic kidney disease and cancer—a narrative review. Clin. Chem. Lab. Med. 48, 147–157 (2010).

    CAS  PubMed  Article  Google Scholar 

  65. Pompella, A., Emdin, M., Passino, C. & Paolicchi, A. The significance of serum γ-glutamyltransferase in cardiovascular diseases. Clin. Chem. Lab. Med. 42, 1085–1091 (2004).

    CAS  PubMed  Article  Google Scholar 

  66. Franzini, M. et al. Cardiovascular risk factors and γ-glutamyltransferase fractions in healthy individuals. Clin. Chem. Lab. Med. 48, 713–717 (2010).

    CAS  PubMed  Article  Google Scholar 

  67. Jepsen, P. et al. Prognosis of patients with a diagnosis of fatty liver—a registry-based cohort study. Hepatogastroenterology 50, 2101–2104 (2003).

    PubMed  Google Scholar 

  68. Hamaguchi, M. et al. Nonalcoholic fatty liver disease is a novel predictor of cardiovascular disease. World J. Gastroenterol. 13, 1579–1584 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. Haring, R. et al. Ultrasonographic hepatic steatosis increases prediction of mortality risk from elevated serum γ-glutamyl-transpeptidase levels. Hepatology 50, 1403–1411 (2009).

    PubMed  Article  Google Scholar 

  70. Targher, G. et al. Nonalcoholic fatty liver disease and risk of future cardiovascular events among type 2 diabetic patients. Diabetes 54, 3541–3546 (2005).

    CAS  PubMed  Article  Google Scholar 

  71. Targher, G. et al. Nonalcoholic fatty liver disease is independently associated with an increased incidence of cardiovascular events in type 2 diabetic patients. Diabetes Care 30, 2119–2221 (2007).

    CAS  PubMed  Article  Google Scholar 

  72. Lazo, M. et al. Nonalcoholic fatty liver disease and mortality among US adults: prospective cohort study. BMJ 343, d6891 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  73. Matteoni, C. A. et al. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 116, 1413–1419 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  74. Dam-Larsen, S. et al. Long-term prognosis of fatty liver: risk of chronic liver disease and death. Gut 53, 750–755 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. Adams, L. A. et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 129, 113–121 (2005).

    PubMed  Article  Google Scholar 

  76. Rafiq, N. et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin. Gastroenterol. Hepatol. 7, 234–238 (2009).

    PubMed  Article  Google Scholar 

  77. Ekstedt, M. et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 44, 865–873 (2006).

    CAS  Article  PubMed  Google Scholar 

  78. Söderberg, C. et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology 51, 595–602 (2010).

    PubMed  Article  Google Scholar 

  79. Targher, G., Kendrick, J., Smits, G. & Chonchol, M. Relationship between serum γ-glutamyltransferase concentrations and chronic kidney disease in the United States population. Findings from the National Health and Nutrition Examination Survey 2001–2006. Nutr. Metab. Cardiovasc. Dis. 20, 583–590 (2010).

    CAS  PubMed  Article  Google Scholar 

  80. Yun, K. E., Shin, C. Y., Yoon, Y. S. & Park, H. S. Elevated alanine aminotransferase levels predict mortality from cardiovascular disease and diabetes in Koreans. Atherosclerosis 205, 533–537 (2009).

    CAS  PubMed  Article  Google Scholar 

  81. Targher, G. 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 51, 444–450 (2008).

    CAS  PubMed  Article  Google Scholar 

  82. Targher, G. et al. Nonalcoholic fatty liver disease is independently associated with an increased prevalence of chronic kidney disease and retinopathy in type 1 diabetic patients. Diabetologia 53, 1341–1348 (2010).

    CAS  PubMed  Article  Google Scholar 

  83. Targher, G., Pichiri, I., Zoppini, G., Trombetta, M. & Bonora, E. Increased prevalence of chronic kidney disease in patients with type 1 diabetes and non-alcoholic fatty liver. Diabet. Med. 29, 220–226 (2012).

    CAS  PubMed  Article  Google Scholar 

  84. Hwang, S. T. et al. Impact of nonalcoholic fatty liver disease on microalbuminuria in patients with prediabetes and diabetes. Intern. Med. J. 40, 437–442 (2010).

    CAS  PubMed  Article  Google Scholar 

  85. Yilmaz, Y. et al. Microalbuminuria in nondiabetic patients with nonalcoholic fatty liver disease: association with liver fibrosis. Metabolism 59, 1327–1330 (2010).

    CAS  PubMed  Article  Google Scholar 

  86. Yasui, K. et al. Nonalcoholic steatohepatitis and increased risk of chronic kidney disease. Metabolism 60, 735–739 (2011).

    CAS  PubMed  Article  Google Scholar 

  87. Targher, G. et al. Relationship between kidney function and liver histology in subjects with nonalcoholic steatohepatitis. Clin. J. Am. Soc. Nephrol. 5, 2166–2171 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. Machado, M. V. et al. Impaired renal function in morbid obese patients with nonalcoholic fatty liver disease. Liver Int. 32, 241–248 (2012).

    CAS  PubMed  Article  Google Scholar 

  89. Lee, D. H., Jacobs, D. R. Jr, Gross, M. & Steffes, M. Serum γ-glutamyltransferase was differently associated with microalbuminuria by status of hypertension and diabetes: the Coronary Artery Risk Development in Young Adults (CARDIA) study. Clin. Chem. 51, 1185–1191 (2005).

    CAS  PubMed  Article  Google Scholar 

  90. Ryu, S., Chang, Y., Kim, D. I., Kim, W. S. & Suh, B. S. γ-glutamyltransferase as a predictor of chronic kidney disease in nonhypertensive and nondiabetic Korean men. Clin. Chem. 53, 71–77 (2007).

    CAS  PubMed  Article  Google Scholar 

  91. Arase, Y. et al. The development of chronic kidney disease in Japanese patients with non-alcoholic fatty liver disease. Intern. Med. 50, 1081–1087 (2011).

    CAS  PubMed  Article  Google Scholar 

  92. Targher, G. et al. Increased risk of CKD among type 2 diabetics with nonalcoholic fatty liver disease. J. Am. Soc. Nephrol. 19, 1564–1570 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. Chang, Y. et al. Nonalcoholic fatty liver disease predicts chronic kidney disease in nonhypertensive and nondiabetic Korean men. Metabolism 57, 569–576 (2008).

    CAS  PubMed  Article  Google Scholar 

  94. Badman, M. K. & Flier, J. S. The adipocyte as an active participant in the energy balance and metabolism. Gastroenterology 132, 2103–2115 (2007).

    CAS  PubMed  Article  Google Scholar 

  95. Shoelson, S. E., Herrero, L. & Naaz, A. Obesity, inflammation, and insulin resistance. Gastroenterology 132, 2169–2180 (2007).

    CAS  PubMed  Article  Google Scholar 

  96. Yki-Järvinen, H. Liver fat in the pathogenesis of insulin resistance and type 2 diabetes. Dig. Dis. 28, 203–209 (2010).

    PubMed  Article  CAS  Google Scholar 

  97. Cohen, J. C., Horton, J. D. & Hobbs, H. H. Human fatty liver disease: old questions and new insights. Science 332, 1519–1523 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. Stefan, N., Kantartzis, K. & Häring, H. U. Causes and metabolic consequences of fatty liver. Endocr. Rev. 29, 939–960 (2008).

    CAS  PubMed  Article  Google Scholar 

  99. Gastaldelli, A. et al. Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects. Gastroenterology 133, 496–506 (2007).

    CAS  PubMed  Article  Google Scholar 

  100. Fabbrini, E., Sullivan, S. & Klein, S. Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology 51, 679–689 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. Kumashiro, N. et al. Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease. Proc. Natl Acad. Sci. USA 108, 16381–16385 (2011).

    CAS  PubMed  Article  Google Scholar 

  102. Smith, B. W. & Adams, L. A. Nonalcoholic fatty liver disease and diabetes mellitus: pathogenesis and treatment. Nat. Rev. Endocrinol. 7, 456–465 (2011).

    CAS  PubMed  Article  Google Scholar 

  103. Tilg, H. & Moschen, A. R. Insulin resistance, inflammation, and non-alcoholic fatty liver disease. Trends Endocrinol. Metab. 19, 371–379 (2008).

    CAS  PubMed  Article  Google Scholar 

  104. Targher, G., Zoppini, G., Moghetti, P. & Day, C. P. Disorders of coagulation and hemostasis in abdominal obesity: emerging role of fatty liver. Semin. Thromb. Hemost. 36, 41–48 (2010).

    CAS  PubMed  Article  Google Scholar 

  105. Luchtefeld, M. et al. Signal transducer of inflammation gp130 modulates atherosclerosis in mice and man. J. Exp. Med. 204, 1935–1944 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  106. Fabbrini, E. et al. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc. Natl Acad. Sci. USA 106, 15430–15435 (2009).

    CAS  PubMed  Article  Google Scholar 

  107. Assy N., Djibren, A., Farah, R., Grosovski, M. & Marmor, A. Presence of coronary plaques in patients with nonalcoholic fatty liver disease. Radiology 254, 393–400 (2010).

    PubMed  Article  Google Scholar 

  108. Targher, G. et al. Prevalence of non-alcoholic fatty liver disease and its association with cardiovascular disease in patients with type 1 diabetes. J. Hepatol. 53, 713–718 (2010).

    CAS  PubMed  Article  Google Scholar 

  109. Targher, G., Pichiri, I., Zoppini, G., Trombetta, M. & Bonora, E. Increased prevalence of cardiovascular disease in type 1 diabetic patients with non-alcoholic fatty liver disease. J. Endocrinol. Invest. http://dx.doi.org/10.3275/7875.

  110. Calori, G. et al. Fatty liver index and mortality: the Cremona study in the 15th year of follow-up. Hepatology 54, 145–152 (2011).

    CAS  PubMed  Article  Google Scholar 

  111. Bonora, E. et al. Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: studies in subjects with various degrees of glucose tolerance and insulin sensitivity. Diabetes Care 23, 57–63 (2000).

    CAS  PubMed  Article  Google Scholar 

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Bonora, E., Targher, G. Increased risk of cardiovascular disease and chronic kidney disease in NAFLD. Nat Rev Gastroenterol Hepatol 9, 372–381 (2012). https://doi.org/10.1038/nrgastro.2012.79

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  • DOI: https://doi.org/10.1038/nrgastro.2012.79

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