Current Diabetes Reports

, Volume 7, Issue 3, pp 181–187

Nonalcoholic fatty liver disease and cardiovascular disease risk

  • Roger K. Schindhelm
  • Michaela Diamant
  • Robert J. Heine
Open Access


Nonalcoholic fatty liver disease (NAFLD) is prevalent in people with the metabolic syndrome and type 2 diabetes. Evidence is now accumulating that NAFLD is associated with obesity and diabetes and may serve as a predictor of cardiovascular disease. Although at present, treatment of the individual risk factors pertinent to NAFLD is advocated, novel therapies are emerging that may target steatosis and/or inflammation, thus ameliorating the overall cardiovascular disease risk. Long-term outcome studies need to establish whether treatment of NAFLD (and in particular which therapy) will affect the long-term outcome.

References and Recommended Reading

  1. 1.
    Angulo P: Nonalcoholic fatty liver disease. N Engl J Med 2002, 346:1221–1231.PubMedCrossRefGoogle Scholar
  2. 2.
    Day CP: Genes or environment to determine alcoholic liver disease and non-alcoholic fatty liver disease. Liver Int 2006, 26:1021–1028.PubMedCrossRefGoogle Scholar
  3. 3.
    Ludwig J, Viggiano TR, McGill DB, Oh BJ: Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 1980, 55:434–438.PubMedGoogle Scholar
  4. 4.
    Cortez-Pinto H, Camilo ME, Baptista A, et al: Non-alcoholic fatty liver: another feature of the metabolic syndrome? Clin Nutr 1999, 18:353–358.PubMedCrossRefGoogle Scholar
  5. 5.
    Marchesini G, Brizi M, Bianchi G, et al.: Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 2001, 50:1844–1850.PubMedCrossRefGoogle Scholar
  6. 6.
    Bellentani S, Saccoccio G, Masutti F, et al.: Prevalence of and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med 2000, 132:112–117.PubMedGoogle Scholar
  7. 7.
    Nomura K, Yano E, Shinozaki T, Tagawa K: Efficacy and effectiveness of liver screening program to detect fatty liver in the periodic health check-ups. J Occup Health 2004, 46:423–428.PubMedCrossRefGoogle Scholar
  8. 8.
    Clark JM: The epidemiology of nonalcoholic fatty liver disease in adults. J Clin Gastroenterol 2006, 40:S5–S10.PubMedGoogle Scholar
  9. 9.
    Hultcrantz R, Gabrielsson N: Patients with persistent elevation of aminotransferases: investigation with ultrasonography, radionuclide imaging and liver biopsy. J Intern Med 1993, 233:7–12.PubMedCrossRefGoogle Scholar
  10. 10.
    Hubscher SG: Histological assessment of non-alcoholic fatty liver disease. Histopathology 2006, 49:450–465.PubMedCrossRefGoogle Scholar
  11. 11.
    Angulo P, Keach JC, Batts KP, Lindor KD: Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 1999, 30:1356–1362.PubMedCrossRefGoogle Scholar
  12. 12.
    Sanyal AJ: AGA technical review on nonalcoholic fatty liver disease. Gastroenterology 2002, 123:1705–1725.PubMedCrossRefGoogle Scholar
  13. 13.
    Kunde SS, Lazenby AJ, Clements RH, Abrams GA: Spectrum of NAFLD and diagnostic implications of the proposed new normal range for serum ALT in obese women. Hepatology 2005, 42:650–656.PubMedCrossRefGoogle Scholar
  14. 14.
    Zelber-Sagi S, Nitzan-Kaluski D, Halpern Z, Oren R: Prevalence of primary non-alcoholic fatty liver disease in a population-based study and its association with biochemical and anthropometric measures. Liver Int 2006, 26:856–863.PubMedCrossRefGoogle Scholar
  15. 15.
    Prati D, Taioli E, Zanella A, et al.: Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med 2002, 137:1–10.PubMedGoogle Scholar
  16. 16.
    Ratziu V, Imbert-Bismut F, Messous D, Poynard T: The elusiveness of “normal” ALT in fatty liver. Hepatology 2004, 39:1172.PubMedCrossRefGoogle Scholar
  17. 17.
    Westerbacka J, Corner A, Tiikkainen M, et al.: Women and men have similar amounts of liver and intra-abdominal fat, despite more subcutaneous fat in women: implications for sex differences in markers of cardiovascular risk. Diabetologia 2004, 47:1360–1369.PubMedCrossRefGoogle Scholar
  18. 18.
    Clark JM, Brancati FL, Diehl AM: The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol 2003, 98:960–967.PubMedCrossRefGoogle Scholar
  19. 19.
    Ruhl CE, Everhart JE: Determinants of the association of overweight with elevated serum alanine aminotransferase activity in the United States. Gastroenterology 2003, 124:71–79.PubMedCrossRefGoogle Scholar
  20. 20.
    Ioannou GN, Weiss NS, Boyko EJ, et al.: Contribution of metabolic factors to alanine aminotransferase activity in persons with other causes of liver disease. Gastroenterology 2005, 128:627–635.PubMedCrossRefGoogle Scholar
  21. 21.
    Nakanishi N, Suzuki K, Tatara K: Serum gamma-glutamyltransferase and risk of metabolic syndrome and type 2 diabetes in middle-aged Japanese men. Diabetes Care 2004, 27:1427–1432.PubMedCrossRefGoogle Scholar
  22. 22.
    Hanley AJ, Williams K, Festa A, et al.: Liver markers and development of the metabolic syndrome: the insulin resistance atherosclerosis study. Diabetes 2005, 54:3140–3147.PubMedCrossRefGoogle Scholar
  23. 23.
    Schindhelm RK, Dekker JM, Nijpels G, et al.: Alanine aminotransferase and the 6-year risk of the metabolic syndrome in Caucasian men and women: the Hoorn Study. Diabet Med 2007, in press.Google Scholar
  24. 24.
    Salmela PI, Sotaniemi EA, Niemi M, Maentausta O: Liver function tests in diabetic patients. Diabetes Care 1984, 7:248–254.PubMedCrossRefGoogle Scholar
  25. 25.
    Meltzer AA, Everhart JE: Association between diabetes and elevated serum alanine aminotransferase activity among Mexican Americans. Am J Epidemiol 1997, 146:565–571.PubMedGoogle Scholar
  26. 26.
    Ohlson LO, Larsson B, Bjorntorp P, et al.: Risk factors for type 2 (non-insulin-dependent) diabetes mellitus. Thirteen and one-half years of follow-up of the participants in a study of Swedish men born in 1913. Diabetologia 1988, 31:798–805.PubMedCrossRefGoogle Scholar
  27. 27.
    Vozarova B, Stefan N, Lindsay RS, et al.: High alanine aminotransferase is associated with decreased hepatic insulin sensitivity and predicts the development of type 2 diabetes. Diabetes 2002, 51:1889–1895.PubMedCrossRefGoogle Scholar
  28. 28.
    Sattar N, Scherbakova O, Ford I, et al.: Elevated alanine aminotransferase predicts new-onset type 2 diabetes independently of classical risk factors, metabolic syndrome, and C-reactive protein in the west of Scotland coronary prevention study. Diabetes 2004, 53:2855–2860.PubMedCrossRefGoogle Scholar
  29. 29.
    Hanley AJ, Williams K, Festa A, et al.: Elevations in markers of liver injury and risk of type 2 diabetes: the insulin resistance atherosclerosis study. Diabetes 2004, 53:2623–2632.PubMedCrossRefGoogle Scholar
  30. 30.
    Wannamethee SG, Shaper AG, Lennon L, Whincup PH: Hepatic enzymes, the metabolic syndrome, and the risk of type 2 diabetes in older men. Diabetes Care 2005, 28:2913–2918.PubMedCrossRefGoogle Scholar
  31. 31.
    Nannipieri M, Gonzales C, Baldi S, et al.: Liver enzymes, the metabolic syndrome, and incident diabetes: the Mexico City diabetes study. Diabetes Care 2005, 28:1757–1762.PubMedCrossRefGoogle Scholar
  32. 32.
    Schindhelm RK, Dekker JM, Nijpels G, et al.: No independent association of alanine aminotransferase with risk of future type 2 diabetes in the Hoorn study. Diabetes Care 2005, 28:2812.PubMedCrossRefGoogle Scholar
  33. 33.
    Andre P, Balkau B, Born C, et al.: Hepatic markers and development of type 2 diabetes in middle aged men and women: a three-year follow-up study. Diabetes Metab 2005, 31:542–550.PubMedCrossRefGoogle Scholar
  34. 34.
    Brea A, Mosquera D, Martin E, et al.: Nonalcoholic fatty liver disease is associated with carotid atherosclerosis: a case-control study. Arterioscler Thromb Vasc Biol 2005, 25:1045–1050.PubMedCrossRefGoogle Scholar
  35. 35.
    Targher G, Bertolini L, Padovani R, et al.: Non-alcoholic fatty liver disease is associated with carotid artery wall thickness in diet-controlled type 2 diabetic patients. J Endocrinol Invest 2006, 29:55–60.PubMedGoogle Scholar
  36. 36.
    Targher G, Bertolini L, Padovani R, et al.: Relation of nonalcoholic hepatic steatosis to early carotid atherosclerosis in healthy men: role of visceral fat accumulation. Diabetes Care 2004, 27:2498–2500.PubMedCrossRefGoogle Scholar
  37. 37.
    Targher G, Bertolini L, Padovani R, et al.: Relations between carotid artery wall thickness and liver histology in subjects with nonalcoholic fatty liver disease. Diabetes Care 2006, 29:1325–1330.PubMedCrossRefGoogle Scholar
  38. 38.
    Schindhelm RK, Diamant M, Bakker SJL, et al.: Liver alanine aminotransferase, insulin resistance and endothelial dysfunction in normotriglyceridaemic subjects with type 2 diabetes mellitus. Eur J Clin Invest 2005, 35:369–374.PubMedCrossRefGoogle Scholar
  39. 39.
    Villanova N, Moscatiello S, Ramilli S, et al.: Endothelial dysfunction and cardiovascular risk profile in nonalcoholic fatty liver disease. Hepatology 2005, 42:473–480.PubMedCrossRefGoogle Scholar
  40. 40.
    Ioannou GN, Weiss NS, Boyko EJ, et al.: Elevated serum alanine aminotransferase activity and calculated risk of coronary heart disease in the United States. Hepatology 2006, 43:1145–1151.PubMedCrossRefGoogle Scholar
  41. 41.
    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 2006, May 6; [Epub ahead of print].Google Scholar
  42. 42.
    Arndt V, Brenner H, Rothenbacher D, et al.: Elevated liver enzyme activity in construction workers: prevalence and impact on early retirement and all-cause mortality. Int Arch Occup Environ Health 1998, 71:405–412.PubMedCrossRefGoogle Scholar
  43. 43.
    Nakamura K, Okamura T, Kanda H, et al.: The value of combining serum alanine aminotransferase levels and body mass index to predict mortality and medical costs: a 10-year follow-up study of National Health Insurance in Shiga, Japan. J Epidemiol 2006, 16:15–20.PubMedCrossRefGoogle Scholar
  44. 44.
    Videla LA, Rodrigo R, Araya J, Poniachik J: Insulin resistance and oxidative stress interdependency in non-alcoholic fatty liver disease. Trends Mol Med 2006, 12:555–558.PubMedCrossRefGoogle Scholar
  45. 45.
    Kerner A, Avizohar O, Sella R, et al.: Association between elevated liver enzymes and C-reactive protein: possible hepatic contribution to systemic inflammation in the metabolic syndrome. Arterioscler Thromb Vasc Biol 2005, 25:193–197.PubMedGoogle Scholar
  46. 46.
    Haukeland JW, Damas JK, Konopski Z, et al.: Systemic inflammation in nonalcoholic fatty liver disease is characterized by elevated levels of CCL2. J Hepatol 2006, 44:1167–1174.PubMedCrossRefGoogle Scholar
  47. 47.
    Targher G, Bertolini L, Scala L, et al.: Non-alcoholic hepatic steatosis and its relation to increased plasma biomarkers of inflammation and endothelial dysfunction in non-diabetic men. Role of visceral adipose tissue. Diabet Med 2005, 22:1354–1358.PubMedCrossRefGoogle Scholar
  48. 48.
    Pagano C, Soardo G, Esposito W, et al.: Plasma adiponectin is decreased in nonalcoholic fatty liver disease. Eur J Endocrinol 2005, 152:113–118.PubMedCrossRefGoogle Scholar
  49. 49.
    Targher G, Bertolini L, Scala L, et al.: Decreased plasma adiponectin concentrations are closely associated with nonalcoholic hepatic steatosis in obese individuals. Clin Endocrinol (Oxf) 2004, 61:700–703.CrossRefGoogle Scholar
  50. 50.
    Pischon T, Girman CJ, Hotamisligil GS, et al.: Plasma adiponectin levels and risk of myocardial infarction in men. JAMA 2004, 291:1730–1737.PubMedCrossRefGoogle Scholar
  51. 51.
    Ikejima K, Okumura K, Lang T, et al.: The role of leptin in progression of non-alcoholic fatty liver disease. Hepatol Res 2005, 33:151–154.PubMedCrossRefGoogle Scholar
  52. 52.
    Pagano C, Soardo G, Pilon C, et al.: Increased serum resistin in nonalcoholic fatty liver disease is related to liver disease severity and not to insulin resistance. J Clin Endocrinol Metab 2006, 91:1081–1086.PubMedCrossRefGoogle Scholar
  53. 53.
    Muse ED, Obici S, Bhanot S, et al.: Role of resistin in diet-induced hepatic insulin resistance. J Clin Invest 2004, 114:232–239.PubMedCrossRefGoogle Scholar
  54. 54.
    Cassader M, Gambino R, Musso G, et al.: Postprandial triglyceride-rich lipoprotein metabolism and insulin sensitivity in nonalcoholic steatohepatitis patients. Lipids 2001, 36:1117–1124.PubMedCrossRefGoogle Scholar
  55. 55.
    Musso G, Gambino R, De Michieli F, et al.: Dietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis. Hepatology 2003, 37:909–916.PubMedCrossRefGoogle Scholar
  56. 56.
    Su CC, Wang K, Hsia TL, et al.: Association of nonalcoholic fatty liver disease with abnormal aminotransferase and postprandial hyperglycemia. J Clin Gastroenterol 2006, 40:551–554.PubMedCrossRefGoogle Scholar
  57. 57.
    Toledo FG, Sniderman AD, Kelley DE: Influence of hepatic steatosis (fatty liver) on severity and composition of dyslipidemia in type 2 diabetes. Diabetes Care 2006, 29:1845–1850.PubMedCrossRefGoogle Scholar
  58. 58.
    Ueno T, Sugawara H, Sujaku K, et al.: Therapeutic effects of restricted diet and exercise in obese patients with fatty liver. J Hepatol 1997, 27:103–107.PubMedCrossRefGoogle Scholar
  59. 59.
    Hickman IJ, Jonsson JR, Prins JB, et al.: Modest weight loss and physical activity in overweight patients with chronic liver disease results in sustained improvements in alanine aminotransferase, fasting insulin, and quality of life. Gut 2004, 53:413–419.PubMedCrossRefGoogle Scholar
  60. 60.
    Nair S, Diehl AM, Wiseman M, et al.: Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial. Aliment Pharmacol Ther 2004, 20:23–28.PubMedCrossRefGoogle Scholar
  61. 61.
    Tiikkainen M, Hakkinen AM, Korsheninnikova E, et al.: Effects of rosiglitazone and metformin on liver fat content, hepatic insulin resistance, insulin clearance, and gene expression in adipose tissue in patients with type 2 diabetes. Diabetes 2004, 53:2169–2176.PubMedCrossRefGoogle Scholar
  62. 62.
    Bugianesi E, Gentilcore E, Manini R, et al.: A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol 2005, 100:1082–1090.PubMedCrossRefGoogle Scholar
  63. 63.
    Belfort R, Harrison SA, Brown K, et al.: A Placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006, 355:2297–2307.PubMedCrossRefGoogle Scholar
  64. 64.
    Ding X, Saxena NK, Lin S, et al.: Exendin-4, a glucagonlike protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice. Hepatology 2006, 43:173–181.PubMedCrossRefGoogle Scholar
  65. 65.
    Tushuizen ME, Bunck MC, Pouwels PJ, et al.: Incretin mimetics as a novel therapeutic option for hepatic steatosis. Liver Int 2006, 26:1015–1017.PubMedCrossRefGoogle Scholar
  66. 66.
    Curioni C, Andre C: Rimonabant for overweight or obesity. Cochrane Database Syst Rev 2006, (4):CD006162.Google Scholar
  67. 67.
    Teixeira-Clerc F, Julien B, Grenard P, et al.: CB1 cannabinoid receptor antagonism: a new strategy for the treatment of liver fibrosis. Nat Med 2006, 12:671–676.PubMedCrossRefGoogle Scholar

Copyright information

© Current Medicine Group LLC 2007

Authors and Affiliations

  • Roger K. Schindhelm
  • Michaela Diamant
  • Robert J. Heine
    • 1
  1. 1.Department of Endocrinology/Diabetes CenterVU University Medical CenterAmsterdamThe Netherlands

Personalised recommendations