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Nonalcoholic Fatty Liver Disease

  • Melissa PalmerEmail author
Chapter
Part of the Nutrition and Health book series (NH)

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. With the current obesity epidemic, its prevalence is increasing among both adults and children at an alarming rate. NAFLD occurs in individuals who do not drink excessive alcohol, yet have hepatic histology that mimics alcoholic liver disease. NAFLD is often associated with type 2 diabetes mellitus, central obesity, dyslipemia, and/or hypertension—conditions which comprise the metabolic syndrome. The spectrum of NAFLD ranges from simple steatosis, which is typically nonprogressive, to nonalcoholic steatohepatitis (NASH), which may progress to cirrhosis and its complications. Patients are usually asymptomatic, and histologic evaluation via liver biopsy is the gold standard for both diagnosing NAFLD and differentiating between simple steatosis and NASH. Patients with simple steatosis typically have a benign, nonprogressive disease course, while people with NASH have a progressive disease course, with an estimated 20 % advancing to cirrhosis. While clinical trials of numerous medications have been performed, there are currently no pharmacological agents approved for treatment. Management includes lifestyle modification comprising weight reduction, nutritional alterations, and exercise, in addition to aggressive treatment of other components of the metabolic syndrome.

Keywords

Nonalcoholic fatty liver disease NAFLD Steatosis Nonalcoholic steatohepatitis NASH Obesity Insulin resistance Cirrhosis Metabolic syndrome NAFLD Activity Score (NAS) 

Abbreviations

AASLD

American Association for the Study of Liver Disease

ALT

Alanine aminotransferase

AST

Aspartate aminotransferase

BMI

Body mass index

CK

Cytokeratin

DM

Diabetes mellitus

GGT

Gamma-glutamyl transferase

GI

Glycemic index

HCC

Hepatocellular carcinoma

HDL

High-density lipoproteins

HDL-C

High-density lipoprotein cholesterol

HFCS

High-fructose corn syrup

HTN

Hypertension

IHTG

Intrahepatic triglyceride content

MOA

Mechanism of action

MRI

Magnetic resonance imaging

MUFAs

Monounsaturated fatty acids

NAFLD

Nonalcoholic fatty liver disease

NAS

NAFLD Activity Score

NASH

Nonalcoholic steatohepatitis

NHANES III

Third National Health and Nutrition Examination Survey

PNPLA3

Patatin-like phospholipase 3 gene

SFAs

Saturated fatty acids

SNP

Single-nucleotide polymorphism

US

United States

VLDL

Very-low-density lipoproteins

References

  1. 1.
    Abdelmalek MF, Angulo P, Jorgensen RA, et al. Betaine, a promising new agent for patients with nonalcoholic steatohepatitis: results of a pilot study. Am J Gastroenterol. 2001;96:2711–7.PubMedGoogle Scholar
  2. 2.
    Abdelmalek MF, Liu C, Shuster J, Nelson DR, Asal NR. Familial aggregation of insulin resistance in first-degree relatives of patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2006;4:1162–9.PubMedGoogle Scholar
  3. 3.
    Abdelmalek MF, Sanderson SO, Angulo P, et al. Betaine for nonalcoholic fatty liver disease: results of a randomized placebo-controlled trial. Hepatology. 2009;50(6):1818–26.PubMedGoogle Scholar
  4. 4.
    Abdelmalek MF, Suzuki A, Guy C, et al.; Nonalcoholic Steatohepatitis Clinical Research Network. Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease. Hepatology. 2010;51(6):1961–71.Google Scholar
  5. 5.
    Abid A, Taha O, Nseir W. Soft drink consumption is associated with fatty liver disease independent of metabolic syndrome. J Hepatol. 2009;51(5):918–24.PubMedGoogle Scholar
  6. 6.
    Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology. 2005;129:113–21.PubMedGoogle Scholar
  7. 7.
    Adams LA. Biomakers of liver fibrosis. J Gastroenterol Hepatol. 2011;26:802–9.PubMedGoogle Scholar
  8. 8.
    Adibi A, Janghorbani M, Shayganfar S, Amini M. First-degree relatives of patients with type 2 diabetes mellitus and risk of non-alcoholic fatty liver disease. Rev Diabet Stud. 2007;4:236–41.PubMedCentralPubMedGoogle Scholar
  9. 9.
    Aigner E, Theurl I, Theurl M. Pathways underlying iron accumulation in human nonalcoholic fatty liver disease. Am J Clin Nutr. 2008;87(5):1374–83.PubMedGoogle Scholar
  10. 10.
    Aithal GP, Thomas JA, Kaye PV, Lawson A, Ryder SD, Spendlove I, et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology. 2008;135:1176–84.PubMedGoogle Scholar
  11. 11.
    Alwayn IP, Gura K, Nosé V. Omega-3 fatty acid supplementation prevents hepatic steatosis in a murine model of nonalcoholic fatty liver disease. Pediatr Res. 2005;57(3):445–52.PubMedGoogle Scholar
  12. 12.
    Amarapurkar D, Kamani P, Patel N, Gupte P, Kumar P, Agal S, et al. Prevalence of non-alcoholic fatty liver disease: population based study. Ann Hepatol. 2007;6(3):161–3.PubMedGoogle Scholar
  13. 13.
    Angelico F, Del Ben M, Conti R, Francioso S, Feole K, Fiorello S, et al. Nonalcoholic fatty liver syndrome: a hepatic consequence of common metabolic diseases. J Gastroenterol Hepatol. 2003;18:588–94.PubMedGoogle Scholar
  14. 14.
    Angulo P, Hui JM, Marchesini G. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45:846–54.PubMedGoogle Scholar
  15. 15.
    Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002;346:1221–31.PubMedGoogle Scholar
  16. 16.
    Anty R, Marjoux S, Iannelli A, Patouraux S, Schneck AS, Bonnafous S, et al. Regular coffee but not espresso drinking is protective against fibrosis in a cohort mainly composed of morbidly obese European women with NAFLD undergoing bariatric surgery. J Hepatol. 2012;57(5):1090–6.PubMedGoogle Scholar
  17. 17.
    Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology. 2010;51:1972–8.PubMedGoogle Scholar
  18. 18.
    Assy N, Kaita K, Mymin D, Levy C, Rosser B, Minuk G. Fatty infiltration of liver in hyperlipidemic patients. Dig Dis Sci. 2000;45:1929–34.PubMedGoogle Scholar
  19. 19.
    Bambha K, Belt P, Abraham M, Wilson LA, Pabst M, Ferrell L, et al.; Nonalcoholic Steatohepatitis Clinical Research Network Research Group. Ethnicity and nonalcoholic fatty liver disease. Hepatology. 2012;55(3):769–80.Google Scholar
  20. 20.
    Barchetta I, Angelico F, Del Ben M. Strong association between nonalcoholic fatty liver disease (NAFLD) and low 25(OH) vitamin D levels in an adult population with normal liver enzymes. BMC Med. 2011;9:85.PubMedCentralPubMedGoogle Scholar
  21. 21.
    Barclay AW, Petocz P, McMillan-Price J, Flood VM, et al. Glycemic index, glycemic load, and chronic disease risk–a meta-analysis of observational studies. Am J Clin Nutr. 2008;87(3):627–37.PubMedGoogle Scholar
  22. 22.
    Barker KB, Palekar NA, Bowers SP, Goldberg JE, Pulcini JP, Harrison SA. Non-alcoholic steatohepatitis: effect of Roux-en-Y gastric bypass surgery. Am J Gastroenterol. 2006;101(2):368–73.PubMedGoogle Scholar
  23. 23.
    Baur JA, Pearson KJ, Price NL, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006;444(7117):337–42.PubMedGoogle Scholar
  24. 24.
    Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006;355:2297–307.PubMedGoogle Scholar
  25. 25.
    Bertelli AA, Das DK. Grapes, wines, resveratrol, and heart health. J Cardiovasc Pharmacol. 2009;54(6):468–76.PubMedGoogle Scholar
  26. 26.
    Birerdinc A, Stepanova M, Pawloski L, Younossi ZM. Caffeine is protective in patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2012;35(1):76–82.PubMedGoogle Scholar
  27. 27.
    Bonekamp S, Barone BB, Clark J, Stewart KJ. The effects of an exercise training intervention on hepatic steatosis [abstract]. Hepatology. 2008;48:806A.Google Scholar
  28. 28.
    Brand-Miller JC, Holt SH, Pawlak DB, McMillan J. Glycemic index and obesity. Am J Clin Nutr. 2002;76(1):281S–5.PubMedGoogle Scholar
  29. 29.
    Bray G, Nielsen S, Popkin M. Consumption of HFCS in beverages may play a role in the epidemic of obesity. Am J Clin Nutr. 2004;79:537–43.PubMedGoogle Scholar
  30. 30.
    Brochu M, Tchernof A, Dionne IJ, Sites CK, Eltabbakh GH, Sims EA, et al. What are the physical characteristics associated with a normal metabolic profile despite a high level of obesity in postmenopausal women? J Clin Endocrinol Metab. 2001;86:1020–5.PubMedGoogle Scholar
  31. 31.
    Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004;40:1387–95.PubMedGoogle Scholar
  32. 32.
    Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol. 1999;94(9):2467–74.PubMedGoogle Scholar
  33. 33.
    Bugianesi E, Gentilcore E, Manini R, Natale S, Vanni E, Villanova N, et al. A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol. 2005;100:1082–90.PubMedGoogle Scholar
  34. 34.
    Bugianesi E, Leone N, Vanni E. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology. 2002;123:134–40.PubMedGoogle Scholar
  35. 35.
    Caballeria L, Pera G, Auladell MA, Torán P, Muñoz L, Miranda D, et al. Prevalence and factors associated with the presence of nonalcoholic fatty liver disease in an adult population in Spain. Eur J Gastroenterol Hepatol. 2010;21:24–32.Google Scholar
  36. 36.
    Capanni M, Calella F, Biagini MR. Prolonged n-3 polyunsaturated fatty acid supplementation ameliorates hepatic steatosis in patients with non-alcoholic fatty liver disease: a pilot study. Aliment Pharmacol Ther. 2006;23(8):1143–51.PubMedGoogle Scholar
  37. 37.
    Capristo E, Miele L, Forgione A. Nutritional aspects in patients with non-alcoholic steatohepatitis (NASH). Eur Rev Med Pharmacol Sci. 2005;9(5):265–8.PubMedGoogle Scholar
  38. 38.
    Catalano D, Martines GF, Tonzuso A. Protective role of coffee in non-alcoholic fatty liver disease (NAFLD). Dig Dis Sci. 2010;55(11):3200–6.PubMedGoogle Scholar
  39. 39.
    Cave M, Deaciuc I, Mendez C, Song Z, Joshi-Barve S, Barve S, McClain C. Nonalcoholic fatty liver disease: predisposing factors and the role of nutrition. J Nutr Biochem. 2007;18(3):184–95. Review.PubMedGoogle Scholar
  40. 40.
    Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, 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. Hepatology. 2012;55:2005–23.PubMedGoogle Scholar
  41. 41.
    Chen CH, Huang MH, Yang JC, Nien CK, Yang CC, Yeh YH, et al. Prevalence and etiology of elevated serum alanine aminotransferase level in an adult population in Taiwan. J Gastroenterol Hepatol. 2007;22:1482–9.PubMedGoogle Scholar
  42. 42.
    Chen ZW, Chen LY, Dai HL, Chen JH, Fang LZ. Relationship between alanine aminotransferase levels and metabolic syndrome in nonalcoholic fatty liver disease. J Zhejiang Univ Sci B. 2008;9(8):616–22.PubMedCentralPubMedGoogle Scholar
  43. 43.
    Clark JM, Alkhuraishi AR, Solga SF, Alli P, Diehl AM, Magnuson TH. Roux-en-Y gastric bypass improves liver histology in patients with non-alcoholic fatty liver disease. Obes Res. 2005;13(7):1180–6.PubMedGoogle Scholar
  44. 44.
    Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol. 2003;98:960–7.PubMedGoogle Scholar
  45. 45.
    Csendes A, Smok G, Burgos AM. Histological findings in the liver before and after gastric bypass. Obes Surg. 2006;16(5):607–11.PubMedGoogle Scholar
  46. 46.
    Cussons AJ, Watts GF, Mori TA, Stuckey BG. Omega-3 fatty acid supplementation decreases liver fat content in polycystic ovary syndrome: a randomized controlled trial employing proton magnetic resonance spectroscopy. J Clin Endocrinol Metab. 2009;94(10):3842–8.PubMedGoogle Scholar
  47. 47.
    Dâmaso AR, do Prado WL, De Piano A, et al. Relationship between nonalcoholic fatty liver disease prevalence and visceral fat in obese adolescents. Dig Liver Dis. 2008;40(2):132–9.PubMedGoogle Scholar
  48. 48.
    Dam-Larsen S, Becker U, Franzmann MB. Final results of a long-term, clinical follow-up in fatty liver patients. Scand J Gastroenterol. 2009;44:1236–43.PubMedGoogle Scholar
  49. 49.
    Dam-Larsen S, Franzmann M, Andersen IB. Long term prognosis of fatty liver: risk of chronic liver disease and death. Gut. 2004;53:750–5.PubMedCentralPubMedGoogle Scholar
  50. 50.
    de Almeida SR, Rocha PR, Sanches MD. Roux-en-Y gastric bypass improves the nonalcoholic steatohepatitis (NASH) of morbid obesity. Obes Surg. 2006;16(3):270–8.PubMedGoogle Scholar
  51. 51.
    de Alwis NM, Day CP. Non-alcoholic fatty liver disease: the mist gradually clears. J Hepatol. 2008;48 Suppl 1:S104–12.PubMedGoogle Scholar
  52. 52.
    Dixon JB, Bhathal PS, Hughes NR. Nonalcoholic fatty liver disease: improvement in liver histological analysis with weight loss. Hepatology. 2004;39:1647–54.PubMedGoogle Scholar
  53. 53.
    Dixon JB, Bhathal PS, O’Brien PE. Weight loss and non-alcoholic fatty liver disease: falls in gamma-glutamyl transferase concentrations are associated with histologic improvement. Obes Surg. 2006;16(10):1278–86.PubMedGoogle Scholar
  54. 54.
    Donati G, Stagni B, Piscaglia F, Venturoli N, Morselli-Labate AM, Rasciti L, et al. Increased prevalence of fatty liver in arterial hypertensive patients with normal liver enzymes: role of insulin resistance. Gut. 2004;53:1020–3.PubMedCentralPubMedGoogle Scholar
  55. 55.
    Dunn W, Sanyal AJ, Brunt EM, Unalp-Arida A, Donohue M, McCullough AJ, et al. Modest alcohol consumption is associated with decreased prevalence of steatohepatitis in patients with non-alcoholic fatty liver disease (NAFLD). J Hepatol. 2012;57(2):384–91.PubMedCentralPubMedGoogle Scholar
  56. 56.
    Dunn W, Xu R, Schwimmer JB. Modest wine drinking and decreased prevalence of suspected nonalcoholic fatty liver disease. Hepatology. 2008;47(6):1947–54.PubMedGoogle Scholar
  57. 57.
    Duseja A, Das A, Dhiman RK, Chawla YK, Thumburu KT, Bhadada S, et al. Metformin is effective in achieving biochemical response in patients with nonalcoholic fatty liver disease (NAFLD) not responding to lifestyle interventions. Ann Hepatol. 2007;6:222–6.PubMedGoogle Scholar
  58. 58.
    Duseja A, Nanda M, Das A, Das R, Bhansali A, Chawla Y. Prevalence of obesity, diabetes mellitus and hyperlipidaemia in patients with cryptogenic liver cirrhosis. Trop Gastroenterol. 2004;25:15–7.PubMedGoogle Scholar
  59. 59.
    Ekstedt M, Franzen LE, Mathiesen UL. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology. 2006;44:865–73.PubMedGoogle Scholar
  60. 60.
    Ekstedt M, Franzén LE, Holmqvist M. Alcohol consumption is associated with progression of hepatic fibrosis in non-alcoholic fatty liver disease. Scand J Gastroenterol. 2009;44:366–74.PubMedGoogle Scholar
  61. 61.
    El-Serag HB, Davila JA, Petersen NJ, McGlynn KA. The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med. 2003;139(10):817–23. Erratum in: Ann Intern Med. 2004 Jan 20;140(2):151.PubMedGoogle Scholar
  62. 62.
    Ersöz G, Günşar F, Karasu Z, et al. Management of fatty liver disease with vitamin E and C compared to ursodeoxycholic acid treatment. Turk J Gastroenterol. 2005;16(3):124–8.PubMedGoogle Scholar
  63. 63.
    Facchini FS, Hua NW, Stoohs RA. Effect of iron depletion in carbohydrate-intolerant patients with clinical evidence of nonalcoholic fatty liver disease. Gastroenterology. 2002;122(4):931–9.PubMedGoogle Scholar
  64. 64.
    Fan JG, Farrell GC. VAT fat is bad for the liver, SAT fat is not! J Gastroenterol Hepatol. 2008;23(6):829–32.PubMedGoogle Scholar
  65. 65.
    Fan JG, Farrell G. Epidemiology of non-alcoholic fatty liver disease in China. J Hepatol. 2009;50:204–10.PubMedGoogle Scholar
  66. 66.
    Fargion S, Dongiovanni P, Guzzo A. Iron and insulin resistance. Aliment Pharmacol Ther. 2005;22 Suppl 2:61–3.PubMedGoogle Scholar
  67. 67.
    Fassio E, Alvarez E, Domínguez N, Landeira G, Longo C. Natural history of nonalcoholic steatohepatitis: a longitudinal study of repeat liver biopsies. Hepatology. 2004;40:820–6.PubMedGoogle Scholar
  68. 68.
    Fealy CE, Haus JM, Solomon TP, Pagadala M, Flask CA, McCullough AJ, et al. Short-term exercise reduces markers of hepatocyte apoptosis in nonalcoholic fatty liver disease. J Appl Physiol. 2012;113(1):1–6.PubMedCentralPubMedGoogle Scholar
  69. 69.
    Feldstein AE, Charatcharoenwitthaya P, Treeprasertsuk S. The natural history of non-alcoholic fatty liver disease in children: a follow-up study for up to 20 years. Gut. 2009;58:1538–44.PubMedCentralPubMedGoogle Scholar
  70. 70.
    Feldstein AE, Wieckowska A, Lopez AR, Liu YC, Zein NN, McCullough AJ. Cytokeratin-18 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis: a multicenter validation study. Hepatology. 2009;50(4):1072–8.PubMedCentralPubMedGoogle Scholar
  71. 71.
    Fracanzani AL, Valenti L, Bugianesi E, et al. Risk of severe liver disease in nonalcoholic fatty liver disease with normal aminotransferase levels: a role for insulin resistance and diabetes. Hepatology. 2008;48:792–8.PubMedGoogle Scholar
  72. 72.
    Frantzides CT, Carlson MA, Moore RE. Effect of body mass index on non-alcoholic fatty liver disease in patients undergoing minimally invasive bariatric surgery. J Gastrointest Surg. 2004;8:849–55.PubMedGoogle Scholar
  73. 73.
    Frith J, Day CP, Henderson E, Burt AD, Newton JL. Non-alcoholic fatty liver disease in older people. Gerontology. 2009;55:607–13.PubMedGoogle Scholar
  74. 74.
    Furuya Jr CK, de Oliveira CP, de Mello ES. Effects of bariatric surgery on nonalcoholic fatty liver disease: preliminary findings after 2 years. J Gastroenterol Hepatol. 2007;22(4):510–4.PubMedGoogle Scholar
  75. 75.
    George DK, Goldwurm S, MacDonald GA. Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis. Gastroenterology. 1998;114:311–8.PubMedGoogle Scholar
  76. 76.
    German JB, Dillard CJ. Saturated fats: what dietary intake? Am J Clin Nutr. 2004;80:550–9.PubMedGoogle Scholar
  77. 77.
    Gholam PM, Flancbaum L, Machan JT, Charney DA, Kotler DP. Nonalcoholic fatty liver disease in severely obese subjects. Am J Gastroenterol. 2007;102(2):399–408.PubMedGoogle Scholar
  78. 78.
    Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C; American Heart Association; National Heart, Lung, and Blood Institute. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation. 2004;109:433–8.Google Scholar
  79. 79.
    Grundy SM, Cleeman JI, Daniels SR, et al.; American Heart Association; National Heart, Lung, and Blood Institute. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005;112(17):2735–52.Google Scholar
  80. 80.
    Guerrero RF, García-Parrilla MC, Puertas B. Wine, resveratrol and health: a review. Nat Prod Commun. 2009;4(5):635–58.PubMedGoogle Scholar
  81. 81.
    Hamaguchi M, Kojima T, Takeda N, Nakagawa T, Taniguchi H, Fujii K, Omatsu T, Nakajima T, Sarui H, Shimazaki M, Kato T, Okuda J, Ida K. The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med. 2005;143:722–8.PubMedGoogle Scholar
  82. 82.
    Haring R, Wallaschofski H, Nauck H. Ultrasonographic hepatic steatosis increases prediction of mortality risk from elevated serum gamma-glutamyl transpeptidase levels. Hepatology. 2009;50:1403–11.PubMedGoogle Scholar
  83. 83.
    Harrison SA, Brunt EM, Fecht WJ, Neuschwander-Tetri BA. Orlistat for overweight subjects with nonalcoholic steatohepatitis (NASH): a randomized prospective trial. Hepatology. 2009;49:80–6.PubMedGoogle Scholar
  84. 84.
    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(10):1441–7.PubMedGoogle Scholar
  85. 85.
    Harrison SA, Torgerson S, Hayashi PH. The natural history of nonalcoholic fatty liver disease: a clinical histopathological study. Am J Gastroenterol. 2003;98:2042–7.PubMedGoogle Scholar
  86. 86.
    Hashimoto E, Yatsuji S, Kaneda H, Yoshioka Y, Taniai M, Tokushige K, et al. The characteristics and natural history of Japanese patients with nonalcoholic fatty liver disease. Hepatol Res. 2005;33(2):72–6.PubMedGoogle Scholar
  87. 87.
    Hatzitolios A, Savopoulos C, Lazaraki G. Efficacy of omega-3 fatty acids, atorvastatin and orlistat in non-alcoholic fatty liver disease with dyslipidemia. Indian J Gastroenterol. 2004;23(4):131–4.PubMedGoogle Scholar
  88. 88.
    Haukeland JW, Konopski Z, Eggesbø HB. Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial. Scand J Gastroenterol. 2009;44:853–60.PubMedGoogle Scholar
  89. 89.
    Hjelkrem M, Morales A, Williams CD, Harrison SA. Unconjugated hyperbilirubinemia is inversely associated with non-alcoholic steatohepatitis (NASH). Aliment Pharmacol Ther. 2012;35(12):1416–23.PubMedGoogle Scholar
  90. 90.
    Hotta K, Yoneda M, Hyogo H, Ochi H, Mizusawa S, Ueno T, Chayama K, et al. Association of the rs738409 polymorphism in PNPLA3 with liver damage and the development of nonalcoholic fatty liver disease. BMC Med Genet. 2010;11:172. doi: 10.1186/1471-2350-11-172.PubMedCentralPubMedGoogle Scholar
  91. 91.
    Huang MA, Greenson JK, Chao C, Anderson L, Peterman D, Jacobson J, et al. One-year intense nutritional counseling results in histological improvement in patients with non-alcoholic steatohepatitis: a pilot study. Am J Gastroenterol. 2005;100:1072–81.PubMedGoogle Scholar
  92. 92.
    Hui AY, Wong VW, Chan HL. Histological progression of non-alcoholic fatty liver disease in Chinese patients. Aliment Pharmacol Ther. 2005;21(4):407–13.PubMedGoogle Scholar
  93. 93.
    Idilman R, Mizrak D, Corapcioglu D, Bektas M, Doganay B, Sayki M, et al. Clinical trial: insulin-sensitizing agents may reduce consequences of insulin resistance in individuals with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2008;28:200–8.PubMedGoogle Scholar
  94. 94.
    Jaskiewicz K, Raczynska S, Rzepko R, Sledziński Z. Nonalcoholic fatty liver disease treated by gastroplasty. Dig Dis Sci. 2006;51(1):21–6.PubMedGoogle Scholar
  95. 95.
    Jin R, Le NA, Liu S, Farkas Epperson M, Zieglbrrer TR, Welsh JA, et al. Children with NAFLD are more sensitive to the adverse metabolic effects of fructose beverages than children without NAFLD. J Clin Endocrinol Metab. 2012;97(7):E1088–98.PubMedCentralPubMedGoogle Scholar
  96. 96.
    Johnson NA, George J. Fitness versus fatness: moving beyond weight loss in nonalcoholic fatty liver disease. Hepatology. 2010;52(1):370–81.PubMedGoogle Scholar
  97. 97.
    Johnson NA, Sachinwalla T, Walton DW. Aerobic exercise training reduces hepatic and visceral lipids in obese individuals without weight loss. Hepatology. 2009;50(4):1105–12.PubMedGoogle Scholar
  98. 98.
    Kallwitz ER, Kumar M, Aggarwal R, Berger R, Layden-Almer J, et al. Ethnicity and nonalcoholic fatty liver disease in an obesity clinic: the impact of triglycerides. Dig Dis Sci. 2008;53:1358–63.PubMedGoogle Scholar
  99. 99.
    Kantartzis K, Thamer C, Peter A, Machann J, Schick F, Schraml C, et al. High cardiorespiratory fitness is an independent predictor of the reduction in liver fat during a lifestyle intervention in non-alcoholic fatty liver disease. Gut. 2009;58:1281–8.PubMedGoogle Scholar
  100. 100.
    Keshishian A, Zahriya K, Willes EB. Duodenal switch has no detrimental effects on hepatic function and improves hepatic steatohepatitis after 6 months. Obes Surg. 2005;15(10):1418–23.PubMedGoogle Scholar
  101. 101.
    Klein S, Mittendorfer B, Eagon JC. Gastric bypass surgery improves metabolic and hepatic abnormalities associated with nonalcoholic fatty liver disease. Gastroenterology. 2006;130(6):1564–72.PubMedGoogle Scholar
  102. 102.
    Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al.; Nonalcoholic Steatohepatitis Clinical Research Network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41(6):1313–21.Google Scholar
  103. 103.
    Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393–403.PubMedGoogle Scholar
  104. 104.
    Kowdley KV, Belt P, Wilson LA. Serum ferritin is an independent predictor of histologic severity and advanced fibrosis in patients with nonalcoholic fatty liver disease. Hepatology. 2012;55:77–85.PubMedCentralPubMedGoogle Scholar
  105. 105.
    Kral JG, Thung SN, Biron S. Effects of surgical treatment of the metabolic syndrome on liver fibrosis and cirrhosis. Surgery. 2004;135(1):48–58.PubMedGoogle Scholar
  106. 106.
    Kris-Etherton PM, Pearson TA, Wan Y, et al. High-monounsaturated fatty acid diets lower both plasma cholesterol and triacylglycerol concentrations. Am J Clin Nutr. 1999;70(6):1009–15.PubMedGoogle Scholar
  107. 107.
    Laaksonen DE, Lindstrom J, Lakka TA, Eriksson JG, Niskanen L, Wikstrom K, et al. Physical activity in the prevention of type 2 diabetes: the Finnish diabetes prevention study. Diabetes. 2005;54:158–65.PubMedGoogle Scholar
  108. 108.
    Lê KA, Tappy L, D’Alessio DA. Mitochondrial dysfunction and insulin resistance: a matter of lifestyle? Curr Opin Clin Nutr Metab Care. 2007;10(4):494–7. Review.PubMedGoogle Scholar
  109. 109.
    Lee SP. Non-alcoholic fatty liver disease, a marker of subclinical atherosclerosis applicable only to metabolic syndrome?: Time to organize the connection between metabolism and atherosclerosis. J Cardiovasc Ultrasound. 2012;20(3):124–5. doi: 10.4250/jcu.2012.20.3.124.PubMedCentralPubMedGoogle Scholar
  110. 110.
    Leite NC, Salles GF, Araujo AL, Villela-Nogueira CA, Cardoso CR. Prevalence and associated factors of non-alcoholic fatty liver disease in patients with type-2 diabetes mellitus. Liver Int. 2009;29:113–9.PubMedGoogle Scholar
  111. 111.
    Li Y, Xu C, Yu C. Association of serum uric acid level with non-alcoholic fatty liver disease: a cross-sectional study. J Hepatol. 2009;50:1029–34.PubMedGoogle Scholar
  112. 112.
    Liangpunsakul S, Chalasani NP. Metabolic syndrome following liver transplantation is associated with major vascular events. Liver Transpl. 2007;13(8):1078–9.PubMedGoogle Scholar
  113. 113.
    Lichtenstein AH. Thematic review series: patient-oriented research. Dietary fat, carbohydrate, and protein: effects on plasma lipoprotein patterns. J Lipid Res. 2006;47(8):1661–7.PubMedGoogle Scholar
  114. 114.
    Lin YC, Chang PF, Hu FC, Yang WS, Chang MH, Ni YH. A common variant in the PNPLA3 gene is a risk factor for non-alcoholic fatty liver disease in obese Taiwanese children. J Pediatr. 2011;158(5):740–4.PubMedGoogle Scholar
  115. 115.
    Liu KH, Chan YL, Chan JC. Mesenteric fat thickness as an independent determinant of fatty liver. Int J Obes (Lond). 2006;30(5):787–93.Google Scholar
  116. 116.
    Liu X, Lazenby AJ, Clements RH, Jhala N, Abrams GA. Resolution of nonalcoholic steatohepatitis after gastric bypass surgery. Obes Surg. 2007;17(4):486–92.PubMedGoogle Scholar
  117. 117.
    Loomba R, Abraham M, Unalp A, Wilson L, Lavine J, Doo E, Bass NM; Nonalcoholic Steatohepatitis Clinical Research Network. Association between diabetes, family history of diabetes and risk of nonalcoholic steatohepatitis and fibrosis. Hepatology. 2012;56(3):943–51.Google Scholar
  118. 118.
    Loomba R, Hwang SJ, O’Donnell CJ, Ellison RC, Vasan RS, D’Agostino RB, et al. Parental obesity and offspring serum alanine and aspartate aminotransferase levels: the Framingham heart study. Gastroenterology. 2008;134:953–9.PubMedCentralPubMedGoogle Scholar
  119. 119.
    Loomba R, Lutchman G, Kleiner DE, Ricks M, Feld JJ, et al. Clinical trial: pilot study of metformin for the treatment of non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2009;29:172–82.PubMedCentralPubMedGoogle Scholar
  120. 120.
    Lutchman G, Modi A, Kleiner DE, Promrat K, Heller T, Ghany M, et al. The effects of discontinuing pioglitazone in patients with nonalcoholic steatohepatitis. Hepatology. 2007;46(2):424–9.PubMedGoogle Scholar
  121. 121.
    Luyckx FH, Desaive C, Thiry A. Liver abnormalities in severely obese subjects: effect of drastic weight loss after gastroplasty. Int J Obes Relat Metab Disord. 1998;22(3):222–6.PubMedGoogle Scholar
  122. 122.
    Machado M, Marques-Vidal P, Cortez-Pinto H. Hepatic histology in obese patients undergoing bariatric surgery. J Hepatol. 2006;45(4):600–6.PubMedGoogle Scholar
  123. 123.
    Manco M, Ciampalini P, Nobili V. Low levels of 25-hydroxyvitamin D(3) in children with biopsy-proven nonalcoholic fatty liver disease. Hepatology. 2010;51:2229. author reply 2230.PubMedGoogle Scholar
  124. 124.
    Marchesini G, Brizi M, Bianchi G, Tomassetti S, Zoli M, Melchionda N. Metformin in non-alcoholic steatohepatitis. Lancet. 2001;358:893–4.PubMedGoogle Scholar
  125. 125.
    Marchesini G, Marzocchi R, Agostini F, Bugianesi E. Nonalcoholic fatty liver disease and the metabolic syndrome. Curr Opin Lipidol. 2005;16:421–7.PubMedGoogle Scholar
  126. 126.
    Mathurin P, Hollebecque A, Arnalsteen L. Prospective study of the long-term effects of bariatric surgery on liver injury in patients without advanced disease. Gastroenterology. 2009;137(2):532–40.PubMedGoogle Scholar
  127. 127.
    Mattar SG, Velcu LM, Rabinovitz M. Surgically-induced weight loss significantly improves nonalcoholic fatty liver disease and the metabolic syndrome. Ann Surg. 2005;242:610–20.PubMedCentralPubMedGoogle Scholar
  128. 128.
    McNear S, Harrison S. Review: current status of therapy in nonalcoholic fatty liver disease. Ther Adv Gastroenterol. 2009;2(1):29–43.Google Scholar
  129. 129.
    Mendler MH, Turlin B, Moirand R, Jouanolle AM, Sapey T, Guyader D, Le Gall JY, Brissot P, David V, Deugnier Y. Insulin resistance-associated hepatic iron overload. Gastroenterology. 1999;117(5):1155–63.PubMedGoogle Scholar
  130. 130.
    Miglio F, Rovati LC, Santoro A. Efficacy and safety of oral betaine glucuronate in non-alcoholic steatohepatitis. A double-blind, randomized, parallel-group, placebo-controlled prospective clinical study. Arzneimittelforschung. 2000;50(8):722–7.PubMedGoogle Scholar
  131. 131.
    Mofrad P, Contos MJ, Haque M. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology. 2003;37:1286–92.PubMedGoogle Scholar
  132. 132.
    Moirand R, Mortaji AM, Loréal O, Paillard F, Brissot P, Deugnier Y. A new syndrome of liver iron overload with normal transferrin saturation. Lancet. 1997;349(9045):95–7.PubMedGoogle Scholar
  133. 133.
    Monthly Prescribing Reference. FDA warns of hepatotoxicity risk with Xenical and Alli (orlistat). 2009. http://www.empr.com/fda-warns-of-hepatotoxicity-risk-with-xenical-and-alli-orlistat/article/147229/#. Accessed 17 Mar 2013.Google Scholar
  134. 134.
    Moretto M, Kupski C, da Silva VD, Padoin AV, Mottin CC. Effect of bariatric surgery on liver fibrosis. Obes Surg. 2012;22(7):1044–9.PubMedGoogle Scholar
  135. 135.
    Mottin CC, Moretto M, Padoin AV. Histological behavior of hepatic steatosis in morbidly obese patients after weight loss induced by bariatric surgery. Obes Surg. 2005;15:788–93.PubMedGoogle Scholar
  136. 136.
    Mottin CC, Moretto M, Padoin AV. The role of ultrasound in the diagnosis of hepatic steatosis in morbidly obese patients. Obes Surg. 2004;14(5):635–7.PubMedGoogle Scholar
  137. 137.
    Mukherjee S, Schafer D, Barak A, et al. Impact of betaine on hepatic fibrosis and homocysteine in nonalcoholic steatohepatitis—a prospective cohort study. Hepatology. 2005;42:610A [Abstract #1052].Google Scholar
  138. 138.
    Murphy CE, Rodgers PT. Effects of thiazolidinediones on bone loss and fracture. Ann Pharmacother. 2007;41(12):2014–8.PubMedGoogle Scholar
  139. 139.
    Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med. 2011;43(8):617–49.PubMedGoogle Scholar
  140. 140.
    Nair S, Diehl AM, Wiseman M, Farr Jr GH, Perrillo RP. Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial. Aliment Pharmacol Ther. 2004;20:23–8.PubMedGoogle Scholar
  141. 141.
    Nar A, Gedik O. The effect of metformin on leptin in obese patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease. Acta Diabetol. 2009;46:113–8.PubMedGoogle Scholar
  142. 142.
    Neuschwander-Tetri BA, Clark JM, Bass NM, Van Natta ML, Unalp-Arida A, Tonascia J, et al. Clinical, laboratory, and histological associations in adults with nonalcoholic fatty liver disease. Hepatology. 2010;52:913–24.PubMedCentralPubMedGoogle Scholar
  143. 143.
    Neuschwander-Tetri BA. Nonalcoholic steatohepatitis and the metabolic syndrome. Am J Med Sci. 2005;330:326–35.PubMedGoogle Scholar
  144. 144.
    Nseir W, Taha H, Khateeb J. Fatty liver is associated with recurrent bacterial infections independent of metabolic syndrome. Dig Dis Sci. 2011;56(11):3328–34.PubMedGoogle Scholar
  145. 145.
    Odegaard AO, Choh AC, Czerwinski SA, Towne B, Demerath EW. Sugar-sweetened and diet beverages in relation to visceral adipose tissue. Obesity (Silver Spring). 2012;20(3):689–91.Google Scholar
  146. 146.
    Omer Z, Cetinkalp S, Akyildiz M, Yilmaz F, Batur Y, Yimaz C, et al. Efficacy of insulin-sensitizing agents in nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol. 2010;22:18–23.PubMedGoogle Scholar
  147. 147.
    Ong JP, Elariny H, Collantes R. Predictors of nonalcoholic steatohepatitis and advanced fibrosis in morbidly obese patients. Obes Surg. 2005;15:310–5.PubMedGoogle Scholar
  148. 148.
    Ong JP, Pitts A, Younossi ZM. Increased overall mortality and liver-related mortality in non-alcoholic fatty liver disease. J Hepatol. 2008;49:608–12.PubMedGoogle Scholar
  149. 149.
    Pais R, Pascale A, Fedchuck L, Charlotte F, Poynard T, Ratziu V. Progression from isolated steatosis to steatohepatitis and fibrosis in nonalcoholic fatty liver disease. Clin Res Hepatol Gastroenterol. 2011;35(1):23–8.PubMedGoogle Scholar
  150. 150.
    Palmentieri B, de Sio I, La Mura V. The role of bright liver echo pattern on ultrasound B-mode examination in the diagnosis of liver steatosis. Dig Liver Dis. 2006;38(7):485–9.PubMedGoogle Scholar
  151. 151.
    Palmer M, Schaffner F. Effect of weight reduction on hepatic abnormalities in overweight patients. Gastroenterology. 1990;99(5):1408–13.PubMedGoogle Scholar
  152. 152.
    Palmer M. Practice guidelines on NAFLD. Hepatology. 2013;57(2):853.PubMedCentralPubMedGoogle Scholar
  153. 153.
    Park SH, Jeon WK, Kim SH, Kim HJ, Park DI, Cho YK, et al. Prevalence and risk factors of non-alcoholic fatty liver disease among Korean adults. J Gastroenterol Hepatol. 2006;21(1 Pt 1):138–43.PubMedGoogle Scholar
  154. 154.
    Park SH, Kim PN, Kim KW. Macrovesicular hepatic steatosis in living liver donors: use of CT for quantitative and qualitative assessment. Radiology. 2006;239(1):105–12.PubMedGoogle Scholar
  155. 155.
    Perseghin G, Lattuada G, De Cobelli F, Ragogna F, Ntali G, Esposito A, et al. Habitual physical activity is associated with intrahepatic fat content in humans. Diabetes Care. 2007;30:683–8.PubMedGoogle Scholar
  156. 156.
    Petta S, Camma C, Cabibi D. Hyperuricemia is associated with histological liver damage in patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2011;34:757–66.PubMedGoogle Scholar
  157. 157.
    Prashanth M, Ganesh HK, Vima MV, John M, Bandgar T, Joshi SR, et al. Prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus. J Assoc Physicians India. 2009;57:205–10.PubMedGoogle Scholar
  158. 158.
    Promrat K, Kleiner DE, Niemeier HM, Jackvony E, Kearns M, Wands JR, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology. 2010;51:121–9.PubMedCentralPubMedGoogle Scholar
  159. 159.
    Purnak T, Beyazit Y, Ozaslan E, Efe C, Hayretci M. The evaluation of bone mineral density in patients with nonalcoholic fatty liver disease. Wien Klin Wochenschr. 2012;124(15–16):526–31.PubMedGoogle Scholar
  160. 160.
    Rabl C, Campos GM. The impact of bariatric surgery on nonalcoholic steatohepatitis. Semin Liver Dis. 2012;32(1):80–91. Review.PubMedGoogle Scholar
  161. 161.
    Rafiq N, Bai C, Fang Y. Long-term follow-up of patients with nonalcoholic fatty liver. Clin Gastroenterol Hepatol. 2009;7:234–8.PubMedGoogle Scholar
  162. 162.
    Ranheim T, Halvorsen B. Coffee consumption and human health—beneficial or detrimental?—Mechanisms for effects of coffee consumption on different risk factors for cardiovascular disease and type 2 diabetes mellitus. Mol Nutr Food Res. 2005;49(3):274–84.PubMedGoogle Scholar
  163. 163.
    Ranløv I, Hardt F. Regression of liver steatosis following gastroplasty or gastric bypass for morbid obesity. Digestion. 1990;47(4):208–14.PubMedGoogle Scholar
  164. 164.
    Riley MR, Bass NM, Rosenthal P. Under diagnosis of pediatric obesity and under screening for fatty liver disease and metabolic syndrome by pediatricians and pediatric subspecialists. J Pediatr. 2005;147:839–42.PubMedGoogle Scholar
  165. 165.
    Rodríguez-Villar C, Pérez-Heras A, Mercadé I, Casals E, Ros E. Comparison of a high-carbohydrate and a high-monounsaturated fat, olive oil-rich diet on the susceptibility of LDL to oxidative modification in subjects with type 2 diabetes mellitus. Diabet Med. 2004;21(2):142–9.PubMedGoogle Scholar
  166. 166.
    Roth CL, Elfers CT, Figlewicz DP, Melhorn SJ, Morton GJ, Hoofnagle A, et al. Vitamin D deficiency in obese rats exacerbates nonalcoholic fatty liver disease and increases hepatic resistin and toll-like receptor activation. Hepatology. 2012;55(4):1103–11.PubMedGoogle Scholar
  167. 167.
    Ruhl CE, Everhart JE. Joint effects of body weight and alcohol on elevated serum alanine aminotransferase in the United States population. Clin Gastroenterol Hepatol. 2005;3:1260–8.PubMedGoogle Scholar
  168. 168.
    Ruhl CE, Everhart JE. Elevated serum alanine aminotransferase and gamma glutamyltransferase and mortality in the United States population. Gastroenterology. 2009;136:477–85.PubMedGoogle Scholar
  169. 169.
    Ryan MC, Abbasi F, Lamendola C, Carter S, McLaughlin TL. Serum alanine aminotransferase levels decrease further with carbohydrate than fat restriction in insulin-resistant adults. Diabetes Care. 2007;30(5):1075–80.PubMedGoogle Scholar
  170. 170.
    Saeian K, Curro K, Binion DG, et al. Plasma total homocysteine levels are higher in nonalcoholic steatohepatitis. Hepatology. 1999;30:436A.Google Scholar
  171. 171.
    Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362:1675–85.PubMedCentralPubMedGoogle Scholar
  172. 172.
    Sato F, Tamura Y, Watada H, et al. Effects of diet-induced moderate weight reduction on intrahepatic and intramyocellular triglycerides and glucose metabolism in obese subjects. J Clin Endocrinol Metab. 2007;92(8):3326–9.PubMedGoogle Scholar
  173. 173.
    Schafer S, Kantartzis K, Machann J. Lifestyle intervention in individuals with normal versus impaired glucose tolerance. Eur J Clin Invest. 2007;37:535–43.PubMedGoogle Scholar
  174. 174.
    Schwimmer JB, Celedon MA, Lavine JE, Salem R, Campbell N, Schork NJ, et al. Heritability of nonalcoholic fatty liver disease. Gastroenterology. 2009;136:1585–92.PubMedCentralPubMedGoogle Scholar
  175. 175.
    Schwimmer JB, Deutsch R, Kahen T. Prevalence of fatty liver in children and adolescents. Pediatrics. 2006;118:1388–93.PubMedGoogle Scholar
  176. 176.
    Shields WW, Thompson KE, Grice GA, Harrison SA, Coyle WJ. The effect of metformin and standard therapy versus standard therapy alone in nondiabetic patients with insulin resistance and nonalcoholic steatohepatitis (NASH): a pilot study. Therap Adv Gastroenterol. 2009;2:157–63.PubMedCentralPubMedGoogle Scholar
  177. 177.
    Shojaee-Moradie F, Baynes KC, Pentecost C, Bell JD, Thomas EL, Jackson NC, et al. Exercise training reduces fatty acid availability and improves the insulin sensitivity of glucose metabolism. Diabetologia. 2007;50:404–13.PubMedGoogle Scholar
  178. 178.
    Silverman EM, Sapala JA, Appelman HD. Regression of hepatic steatosis in morbidly obese persons after gastric bypass. Am J Clin Pathol. 1995;104:23–31.PubMedGoogle Scholar
  179. 179.
    Sorrentino P, Tarantino G, Conca P. Silent non-alcoholic fatty liver disease—a clinical-histological study. J Hepatol. 2004;41:751–7.PubMedGoogle Scholar
  180. 180.
    Souza MR, Diniz Mde F, Medeiros-Filho JE, Araújo MS. Metabolic syndrome and risk factors for non-alcoholic fatty liver disease. Arq Gastroenterol. 2012;49(1):89–96.PubMedGoogle Scholar
  181. 181.
    Spadaro L, Magliocco O, Spampinato D. Effects of n-3 polyunsaturated fatty acids in subjects with nonalcoholic fatty liver disease. Dig Liver Dis. 2008;40(3):194–9.PubMedGoogle Scholar
  182. 182.
    St George A, Bauman A, Johnston A. Independent effects of physical activity in patients with nonalcoholic fatty liver disease. Hepatology. 2009;50(1):68–76.PubMedGoogle Scholar
  183. 183.
    Stratopoulos C, Papakonstantinou A, Terzis I. Changes in liver histology accompanying massive weight loss after gastroplasty for morbid obesity. Obes Surg. 2005;15(8):1154–60.PubMedGoogle Scholar
  184. 184.
    Struben VM, Hespenheide EE, Caldwell SH. Nonalcoholic steatohepatitis and cryptogenic cirrhosis within kindreds. Am J Med. 2000;108:9–13.PubMedGoogle Scholar
  185. 185.
    Sullivan S, Kirk EP, Mittendorfer B, Patterson BW, Klein S. Randomized trial of exercise effect on intrahepatic triglyceride content and lipid kinetics in nonalcoholic fatty liver disease. Hepatology. 2012;55(6):1738–45.PubMedCentralPubMedGoogle Scholar
  186. 186.
    Suzuki A, Lindor K, St Saver J, Lymp J, Mendes F, Muto A, Okada T, Angulo P. Effect of changes on body weight and lifestyle in nonalcoholic fatty liver disease. J Hepatol. 2005;43(6):1060–6.PubMedGoogle Scholar
  187. 187.
    Tahan V, Canbakan B, Balci H. Serum gamma-glutamyltranspeptidase distinguishes non-alcoholic fatty liver disease at high risk. Hepatogastroenterology. 2008;55:1433–8.PubMedGoogle Scholar
  188. 188.
    Tamura Y, Tanaka Y, Sato Y. Effects of diet and exercise on muscle and liver intracellular lipid contents and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab. 2005;90:3191–6.PubMedGoogle Scholar
  189. 189.
    Targher G, Bertolini L, Padovani R. Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease in type 2 diabetic patients. Diabetes Care. 2007;30:1212–8.PubMedGoogle Scholar
  190. 190.
    Teli MR, James OF, Burt AD, Bennett MK, Day CP. The natural history of nonalcoholic fatty liver: a follow-up study. Hepatology. 1995;22:1714–9.PubMedGoogle Scholar
  191. 191.
    Tellez-Avila FI, Sanchez-Avila F, Garcıa-Saenz-de-Sicilia M, et al. Prevalence of metabolic syndrome, obesity and diabetes type 2 in cryptogenic cirrhosis. World J Gastroenterol. 2008;14:4771–5.PubMedCentralPubMedGoogle Scholar
  192. 192.
    Tendler D, Lin S, Yancy Jr WS, et al. The effect of a low-carbohydrate, ketogenic diet on nonalcoholic fatty liver disease: a pilot study. Dig Dis Sci. 2007;52(2):589–93.PubMedGoogle Scholar
  193. 193.
    National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III) final report. Circulation. 2002;106:3143–421.Google Scholar
  194. 194.
    Tilg H, Diehl AM. Cytokines in alcoholic and nonalcoholic steatohepatitis. N Engl J Med. 2000;343(20):1467–76.PubMedGoogle Scholar
  195. 195.
    Utzschneider KM, Bayer-Carter JL, Arbuckle MD, Tidwell JM, Richards TL, Craft S. Beneficial effect of a weight-stable, low-fat/low-saturated fat/low-glycaemic index diet to reduce liver fat in older subjects. Br J Nutr. 2012;31:1–9.Google Scholar
  196. 196.
    Uygun A, Kadayifci A, Isik AT, Ozgurtas T, Deveci S, Tuzun A, et al. Metformin in the treatment of patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2004;19:537–44.PubMedGoogle Scholar
  197. 197.
    Valenti L, Fracanzani AL, Dongiovanni P. Iron depletion by phlebotomy improves insulin resistance in patients with nonalcoholic fatty liver disease and hyperferritinemia: evidence from a case-control study. Am J Gastroenterol. 2007;102(6):1251–8.PubMedGoogle Scholar
  198. 198.
    Valtueña S, Pellegrini N, Ardigò D. Dietary glycemic index and liver steatosis. Am J Clin Nutr. 2006;84:136–42.PubMedGoogle Scholar
  199. 199.
    Van der Heijden GJ, Wang ZJ, Chu ZD, Sauer PJ, Haymond MW, Rodriguez LM, et al. A 12-week aerobic exercise program reduces hepatic fat accumulation and insulin resistance in obese Hispanic adolescents. Obesity (Silver Spring). 2010;18(2):384–90.Google Scholar
  200. 200.
    Verna EC, Berk PD. Role of fatty acids in the pathogenesis of obesity and fatty liver: impact of bariatric surgery. Semin Liver Dis. 2008;28(4):407–26. doi: 10.1055/s-0028-1091985.PubMedGoogle Scholar
  201. 201.
    Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011;34(3):274–85.PubMedGoogle Scholar
  202. 202.
    Vuppalanchi R, Chalasani N. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: selected practical issues in their evaluation and management. Hepatology. 2009;49:306–17.PubMedCentralPubMedGoogle Scholar
  203. 203.
    Wagenknecht LE, Scherzinger AL, Stamm ER, Hanley AJ, Norris JM, Chen YD, Bryer-Ash M, Haffner SM, Rotter JI. Correlates and heritability of nonalcoholic fatty liver disease in a minority cohort. Obesity (Silver Spring). 2009;17(6):1240–6. doi: 10.1038/oby.2009.4.Google Scholar
  204. 204.
    Wanless IR, Lentz JS. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology. 1990;12:1106–10.PubMedGoogle Scholar
  205. 205.
    Weingarten TN, Swain JM, Kendrick ML, Charlton MR, Schroeder BJ, Lee RE, et al. Nonalcoholic steatohepatitis (NASH) does not increase complications after laparoscopic bariatric surgery. Obes Surg. 2011;21(11):1714–20.PubMedGoogle Scholar
  206. 206.
    Wieckowska A, McCullough AJ, Feldstein AE. Noninvasive diagnosis and monitoring of nonalcoholic steatohepatitis: present and future. Hepatology. 2007;46:582–9.PubMedGoogle Scholar
  207. 207.
    Wieckowska A, Zein NN, Yerian LM. In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease. Hepatology. 2006;44:27–33.PubMedGoogle Scholar
  208. 208.
    Weiner RA. Surgical treatment of non-alcoholic steatohepatitis and non-alcoholic fatty liver disease. Dig Dis. 2010;28(1):274–9.PubMedGoogle Scholar
  209. 209.
    Wildman RP, Muntner P, Reynolds K, McGinn AP, Rajpathak S, Wylie-Rosett J, et al. The obese without cardiometabolic risk factor clustering and the normal weight with cardiometabolic risk factor clustering: prevalence and correlates of 2 phenotypes among the US population (NHANES 1999–2004). Arch Intern Med. 2008;168:1617–24.PubMedGoogle Scholar
  210. 210.
    Williams CD, Stengel J, Asike MI, 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. 2011;140:124–31.PubMedGoogle Scholar
  211. 211.
    Willner IR, Walters B, Patil SR, Reuben A, Morelli J, Riely CA. Ninety patients with nonalcoholic steatohepatitis: insulin resistance, familial tendency, and severity of disease. Am J Gastroenterol. 2001;96:2957–61.PubMedGoogle Scholar
  212. 212.
    Wong VW, Won GL, Chim AM, Chu WC, Yeung DK, Li KC, et al. Treatment of nonalcoholic steatohepatitis with probiotics. A proof-of-concept study. Ann Hepatol. 2013;12(2):256–62.PubMedGoogle Scholar
  213. 213.
    Wong VW, Wong GL, Choi PC. Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years. Gut. 2010;59:969–74.PubMedGoogle Scholar
  214. 214.
    Yamauchi R, Kobayashi M, Matsuda Y, Ojika M, Shigeoka S, Yamamoto Y, et al. Coffee and caffeine ameliorate hyperglycemia, fatty liver, and inflammatory adipocytokine expression in spontaneously diabetic KK-Ay mice. J Agric Food Chem. 2010;58(9):5597–603.PubMedGoogle Scholar
  215. 215.
    Younossi ZM, Gramlich T, Matteoni CA, et al. Nonalcoholic fatty liver disease in patients with type 2 diabetes. Clin Gastroenterol Hepatol. 2004;2:262–5.PubMedGoogle Scholar
  216. 216.
    Younossi ZM. Review article: current management of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2008;28(1):2–12. Review.PubMedGoogle Scholar
  217. 217.
    Zelber-Sagi S, Kessler A, Brazowsky E, Webb M, Lurie Y, Santo M, et al. A double-blind randomized placebo-controlled trial of orlistat for the treatment of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2006;4:639–44.PubMedGoogle Scholar
  218. 218.
    Zhu FS, Liu S, Chen XM, Huang ZG, Zhang DW. Effects of n-3 polyunsaturated fatty acids from seal oils on nonalcoholic fatty liver disease associated with hyperlipidemia. World J Gastroenterol. 2008;14(41):6395–400.PubMedCentralPubMedGoogle Scholar

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© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.NYU Langone Medical CenterNew YorkUSA

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