Gastroenterology
Volume 137, Issue 3 , Pages 865-872 , September 2009

Prediction of Non-Alcoholic Fatty Liver Disease and Liver Fat Using Metabolic and Genetic Factors

  • Anna Kotronen

      Affiliations

    • Department of Medicine, Division of Diabetes, University of Helsinki, Helsinki, Finland
    • Minerva Medical Research Institute, Helsinki, Finland
    • Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland
    • Corresponding Author InformationReprint requests Address requests for reprints to: Anna Kotronen, MB, PhD, Department of Medicine, Division of Diabetes, University of Helsinki, Finland, P.O. Box 700, room C425B, FIN-00029 HUCH, Helsinki, Finland. fax: (358)-9-471-71896
  • ,
  • Markku Peltonen

      Affiliations

    • Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland
  • ,
  • Antti Hakkarainen

      Affiliations

    • Department of Medicine, Division of Diabetes, University of Helsinki, Helsinki, Finland
    • Helsinki Medical Imaging Center, University of Helsinki, Helsinki, Finland
  • ,
  • Ksenia Sevastianova

      Affiliations

    • Department of Medicine, Division of Diabetes, University of Helsinki, Helsinki, Finland
    • Minerva Medical Research Institute, Helsinki, Finland
  • ,
  • Robert Bergholm

      Affiliations

    • Department of Medicine, Division of Diabetes, University of Helsinki, Helsinki, Finland
    • Minerva Medical Research Institute, Helsinki, Finland
  • ,
  • Lina M. Johansson

      Affiliations

    • Department of Clinical Sciences, Clinical Obesity, University Hospital Malmö, Lund University, Malmö, Sweden
  • ,
  • Nina Lundbom

      Affiliations

    • Helsinki Medical Imaging Center, University of Helsinki, Helsinki, Finland
  • ,
  • Aila Rissanen

      Affiliations

    • Obesity Research Unit, Department of Psychiatry, University of Helsinki, Helsinki, Finland
  • ,
  • Martin Ridderstråle

      Affiliations

    • Department of Clinical Sciences, Clinical Obesity, University Hospital Malmö, Lund University, Malmö, Sweden
  • ,
  • Leif Groop

      Affiliations

    • Department of Clinical Sciences, Diabetes and Endocrinology, University Hospital Malmö, Lund University, Malmö, Sweden
  • ,
  • Marju Orho–Melander

      Affiliations

    • Department of Clinical Sciences, Diabetes and Endocrinology, University Hospital Malmö, Lund University, Malmö, Sweden
  • ,
  • Hannele Yki–Järvinen

      Affiliations

    • Department of Medicine, Division of Diabetes, University of Helsinki, Helsinki, Finland

Received 13 February 2009 ,Accepted 2 June 2009.

References 

  1. Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology. 2003;37:1202–1219
  2. 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;40:1387–1395
  3. Cortez-Pinto H, Camilo ME. Non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH): diagnosis and clinical course. Best Pract Res Clin Gastroenterol. 2004;18:1089–1104
  4. 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
  5. Kopelman PG. Obesity as a medical problem. Nature. 2000;404:635–643
  6. Schreuder TC, Verwer BJ, van Nieuwkerk CM, et al. Nonalcoholic fatty liver disease: an overview of current insights in pathogenesis, diagnosis and treatment. World J Gastroenterol. 2008;14:2474–2486
  7. Siegelman ES, Rosen MA. Imaging of hepatic steatosis. Semin Liver Dis. 2001;21:71–80
  8. 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
  9. Kotronen A, Westerbacka J, Bergholm R, et al. Liver fat in the metabolic syndrome. J Clin Endocrinol Metab. 2007;92:3490–3497
  10. Kotronen A, Juurinen L, Hakkarainen A, et al. Liver fat is increased in type 2 diabetic patients and underestimated by serum alanine aminotransferase compared with equally obese nondiabetic subjects. Diabetes Care. 2008;31:165–169
  11. Romeo S, Kozlitina J, Xing C, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2008;40:1461–1465
  12. Seppala-Lindroos A, Vehkavaara S, Hakkinen 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;87:3023–3028
  13. Tiikkainen M, Tamminen M, Hakkinen AM, et al. Liver-fat accumulation and insulin resistance in obese women with previous gestational diabetes. Obes Res. 2002;10:859–867
  14. 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
  15. Westerbacka J, Lammi K, Hakkinen AM, et al. Dietary fat content modifies liver fat in overweight nondiabetic subjects. J Clin Endocrinol Metab. 2005;90:2804–2809
  16. Pietilainen KH, Rissanen A, Kaprio J, et al. Acquired obesity is associated with increased liver fat, intra-abdominal fat, and insulin resistance in young adult monozygotic twins. Am J Physiol Endocrinol Metab. 2005;288:E768–E774
  17. Makkonen J, Westerbacka J, Kolak M, et al. Increased expression of the macrophage markers and of 11β-HSD-1 in subcutaneous adipose tissue, but not in cultured monocyte-derived macrophages, is associated with liver fat in human obesity. Int J Obes (Lond). 2007;31:1617–1625
  18. Ryysy L, Hakkinen AM, 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;49:749–758
  19. 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
  20. Juurinen L, Kotronen A, Graner M, et al. Rosiglitazone reduces liver fat and insulin requirements and improves hepatic insulin sensitivity and glycemic control in patients with type 2 diabetes requiring high insulin doses. J Clin Endocrinol Metab. 2008;93:118–124
  21. Juurinen L, Tiikkainen M, Hakkinen AM, et al. Effects of insulin therapy on liver fat content and hepatic insulin sensitivity in patients with type 2 diabetes. Am J Physiol Endocrinol Metab. 2007;292:E829–E835
  22. WHO Consultation. Definition, diagnosis and classification of diabetes mellitus and its complications (Part 1: diagnosis and classification of diabetes mellitus). Geneva: World Health Organization; 1999;Report No. 99.2
  23. Kotronen A, Juurinen L, Tiikkainen M, et al. Increased liver fat, impaired insulin clearance, and hepatic and adipose tissue insulin resistance in type 2 diabetes. Gastroenterology. 2008;135:122–130
  24. Stanisz GJ, Odrobina EE, Pun J, et al. T1, T2 relaxation and magnetization transfer in tissue at 3T. Magn Reson Med. 2005;54:507–512
  25. Graham SJ, Stanisz GJ, Kecojevic A, et al. Analysis of changes in MR properties of tissues after heat treatment. Magn Reson Med. 1999;42:1061–1071
  26. van der Boogaart A, van Hecke A, van Huffel P, et al. MRUI: a graphical user interface for accurate routine MRS data analysis. Proceedings of the ESMRMB, 13th Annual Meeting 1996;318.
  27. Vanhamme L, van den Boogaart A, Van Huffel S. Improved method for accurate and efficient quantification of MRS data with use of prior knowledge. J Magn Reson. 1997;129:35–43
  28. Longo R, Pollesello P, Ricci C, et al. Proton MR spectroscopy in quantitative in vivo determination of fat content in human liver steatosis. J Magn Reson Imaging. 1995;5:281–285
  29. Szczepaniak LS, Nurenberg P, Leonard D, et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab. 2005;288:E462–E468
  30. Szczepaniak LS, Babcock EE, Schick F, et al. Measurement of intracellular triglyceride stores by H spectroscopy: validation in vivo. Am J Physiol. 1999;276:E977–E989
  31. Skogsberg J, Kannisto K, Cassel TN, et al. Evidence that peroxisome proliferator-activated receptor δ influences cholesterol metabolism in men. Arterioscler Thromb Vasc Biol. 2003;23:637–643
  32. Alberti KG, Zimmet P, Shaw J IDF Epidemiology Task Force Consensus Group. The metabolic syndrome—a new worldwide definition. Lancet. 2005;366:1059–1062
  33. Marti B, Tuomilehto J, Salomaa V, et al. Body fat distribution in the Finnish population: environmental determinants and predictive power for cardiovascular risk factor levels. J Epidemiol Community Health. 1991;45:131–137
  34. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002;346:1221–1231
  35. 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;30:1212–1218
  36. Marchesini G, Brizi M, Bianchi G, et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes. 2001;50:1844–1850
  37. Kotronen A, Vehkavaara S, Seppala-Lindroos A, et al. Effect of liver fat on insulin clearance. Am J Physiol Endocrinol Metab. 2007;293:E1709–E1715
  38. Mofrad P, Contos MJ, Haque M, et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology. 2003;37:1286–1292
  39. Matteoni CA, Younossi ZM, Gramlich T, et al. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116:1413–1419
  40. Bugianesi E, Pagotto U, Manini R, et al. Plasma adiponectin in nonalcoholic fatty liver is related to hepatic insulin resistance and hepatic fat content, not to liver disease severity. J Clin Endocrinol Metab. 2005;90:3498–3504
  41. Yesilova Z, Yaman H, Oktenli C, et al. Systemic markers of lipid peroxidation and antioxidants in patients with nonalcoholic fatty liver disease. Am J Gastroenterol. 2005;100:850–855
  42. Sorbi D, Boynton J, Lindor KD. The ratio of aspartate aminotransferase to alanine aminotransferase: potential value in differentiating nonalcoholic steatohepatitis from alcoholic liver disease. Am J Gastroenterol. 1999;94:1018–1022
  43. Harrison SA, Oliver D, Arnold HL, et al. Development and validation of a simple NAFLD clinical scoring system for identifying patients without advanced disease. Gut. 2008;57:1441–1447
  44. Angulo P, Hui JM, Marchesini G, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45:846–854
  45. Poynard T, Ratziu V, Naveau S, et al. The diagnostic value of biomarkers (SteatoTest) for the prediction of liver steatosis. Comp Hepatol. 2005;4:10
  46. Bedogni G, Bellentani S, Miglioli L, et al. The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol. 2006;6:33
  47. Kantartzis K, Rittig K, Balletshofer B, et al. The relationships of plasma adiponectin with a favorable lipid profile, decreased inflammation, and less ectopic fat accumulation depend on adiposity. Clin Chem. 2006;52:1934–1942
  48. Targher G. Relationship between high-sensitivity C-reactive protein levels and liver histology in subjects with non-alcoholic fatty liver disease. J Hepatol. 2006;45:879–881
  49. Stefan N, Hennige AM, Staiger H, et al. High circulating retinol-binding protein 4 is associated with elevated liver fat, but not with total-, subcutaneous-, visceral-, or intramyocellular fat in humans. Diabetes Care. 2007;30:1173–1178
  50. Kotronen A, Yki-Jarvinen H. Fatty liver: a novel component of the metabolic syndrome. Arterioscler Thromb Vasc Biol. 2008;28:27–38
  51. Bathum L, Petersen HC, Rosholm JU, et al. Evidence for a substantial genetic influence on biochemical liver function tests: results from a population-based Danish twin study. Clin Chem. 2001;47:81–87
  52. Makkonen J, Pietilainen KH, Rissanen A, et al. Genetic factors contribute to variation in serum alanine aminotransferase activity independent of obesity and alcohol: a study in monozygotic and dizygotic twins. J Hepatol. 2009;50:1035–1042
  53. Lyssenko V, Jonsson A, Almgren P, et al. Clinical risk factors, DNA variants, and the development of type 2 diabetes. N Engl J Med. 2008;359:2220–2232
  54. Carey DG, Cowin GJ, Galloway GJ, et al. Effect of rosiglitazone on insulin sensitivity and body composition in type 2 diabetic patients (corrected). Obes Res. 2002;10:1008–1015
  55. 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
  56. Hamaguchi M, Kojima T, Takeda N, et al. Nonalcoholic fatty liver disease is a novel predictor of cardiovascular disease. World J Gastroenterol. 2007;13:1579–1584
  57. Targher G, Bertolini L, Poli F, et al. Nonalcoholic fatty liver disease and risk of future cardiovascular events among type 2 diabetic patients. Diabetes. 2005;54:3541–3546
  58. 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
  59. 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

 Conflicts of interest The authors disclose no conflicts.

 Funding Supported by research grants from the Academy of Finland (to H.Y.-J.); the Sigrid Juselius Foundation (to H.Y.-J.); the Novo Nordisk Foundation (to H.Y.-J., M.R.); the Biomedicum Helsinki Foundation (to A.K.); the Paulo Foundation (to A.K.); the Wallenberg Foundation (to L.G.); a Nordic Centre of Excellence in Disease Genetics grant by the Nordic Research Councils (to L.G.); the Swedish Research Council, Region Skåne (to M.R.); Påhlsson Foundation (to M.R.); the UMAS Foundation (to M.R.); the Swedish Diabetes Foundation (to M.R.); the Crafoord Foundation (to M.R.); the Lundgren Foundation (to M.R.); the Bergvall Foundation (to M.R.); and the European Commission as an Integrated Project under the 6th Framework Programme (contract LSHM-CT-2005-018734) (to H.Y.-J.) as part of the project “Hepatic and adipose tissue and functions in the metabolic syndrome (www.hepadip.org).

PII: S0016-5085(09)00913-5

doi: 10.1053/j.gastro.2009.06.005

Gastroenterology
Volume 137, Issue 3 , Pages 865-872 , September 2009