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Current Hepatology Reports

, Volume 15, Issue 2, pp 103–112 | Cite as

NAFLD-Associated Hepatocellular Carcinoma: a Threat to Patients with Metabolic Disorders

  • Anna Simona Sasdelli
  • Lucia Brodosi
  • Giulio Marchesini
Fatty Liver Disease (SA Harrison and J George, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Fatty Liver Disease

Abstract

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and its prevalence is increasing in relation to the epidemics of obesity and type 2 diabetes mellitus, via non-alcoholic fatty liver disease (NAFLD). Unhealthy lifestyles associated with metabolic disorders are per se risk conditions for NAFLD progression, and specific gene polymorphisms may also favor oncogenesis, particularly in the presence of advanced fibrosis or cryptogenic cirrhosis. However, NAFLD-associated HCC may also develop in non-cirrhotic NAFLD and is frequently diagnosed at a more advanced tumor stage, compared with virus/alcohol-related HCC. This highlights the need for screening programs and long-term surveillance for earlier HCC detection in patients with metabolic risk factors, a policy hindered by the large number of cases at risk, with costs unaffordable by National health systems. New screening tools and cost-utility studies are eagerly awaited to develop more appropriate programs for early detection and treatment of NAFLD-associated HCC.

Keywords

Hepatocellular carcinoma (HCC) Non-alcoholic steatohepatitis (NAFLD) Surveillance Treatment 

Notes

Compliance with Ethical Standards

Conflicts of Interest

AS, LB, and GM declare that they have no conflicts of interest.

Human and Animal Rights and Informed Consent

With regard to the authors’ research cited in this paper, all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any animal studies performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132(7):2557–76.CrossRefPubMedGoogle Scholar
  2. 2.
    Charlton MR, Burns JM, Pedersen RA, Watt KD, Heimbach JK, Dierkhising RA. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology. 2011;141(4):1249–53.CrossRefPubMedGoogle Scholar
  3. 3.
    Yopp AC, Choti MA. Non-alcoholic steatohepatitis-related hepatocellular carcinoma: a growing epidemic? Dig Dis. 2015;33(5):642–7.CrossRefPubMedGoogle Scholar
  4. 4.
    Bugianesi E, Leone N, Vanni E, Marchesini G, Brunello F, Carucci P, et al. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology. 2002;123(1):134–40.CrossRefPubMedGoogle Scholar
  5. 5.
    Adami HO, Chow WH, Nyren O, Berne C, Linet MS, Ekbom A, et al. Excess risk of primary liver cancer in patients with diabetes mellitus. J Natl Cancer Inst. 1996;88(20):1472–7.CrossRefPubMedGoogle Scholar
  6. 6.
    El-Serag HB, Richardson PA, Everhart JE. The role of diabetes in hepatocellular carcinoma: a case-control study among United States Veterans. Am J Gastroenterol. 2001;96(8):2462–7.CrossRefPubMedGoogle Scholar
  7. 7.
    Schlesinger S, Aleksandrova K, Pischon T, Jenab M, Fedirko V, Trepo E, et al. Diabetes mellitus, insulin treatment, diabetes duration, and risk of biliary tract cancer and hepatocellular carcinoma in a European cohort. Ann Oncol. 2013;24(9):2449–55.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.••
    Shetty K, Chen J, Shin JH, Jogunoori W, Mishra L. Pathogenesis of hepatocellular carcinoma development in non alcoholic fatty liver disease. Curr Hepatol Rep. 2015;14(2):119–27. Comprehensive review on the pathogenesis of hepatocellular carcinoma.CrossRefPubMedGoogle Scholar
  9. 9.•
    Weinmann A, Alt Y, Koch S, Nelles C, Duber C, Lang H, et al. Treatment and survival of non-alcoholic steatohepatitis associated hepatocellular carcinoma. BMC Cancer. 2015;15:210. The most recent such study.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Marrero JA, Fontana RJ, Fu S, Conjeevaram HS, Su GL, Lok AS. Alcohol, tobacco and obesity are synergistic risk factors for hepatocellular carcinoma. J Hepatol. 2005;42(2):218–24.CrossRefPubMedGoogle Scholar
  11. 11.
    White DL, Kanwal F, El-Serag HB. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol. 2012;10(12):1342–59. e1342.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    European Association for the Study of the Liver, European Organisation for Research Treatment of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56(4):908–43.CrossRefGoogle Scholar
  13. 13.
    Ertle J, Dechene A, Sowa JP, Penndorf V, Herzer K, Kaiser G, et al. Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis. Int J Cancer. 2011;128(10):2436–43.CrossRefPubMedGoogle Scholar
  14. 14.
    Sanyal A, Poklepovic A, Moyneur E, Barghout V. Population-based risk factors and resource utilization for HCC: US perspective. Curr Med Res Opin. 2010;26(9):2183–91.CrossRefPubMedGoogle Scholar
  15. 15.••
    Wong RJ, Cheung R, Ahmed A. Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U.S. Hepatology. 2014;59(6):2188–95. In a large U.S. series, the study identifies NASH as the most rapidly growing indication for liver transplantation, accounting for the present and future burden of disease.CrossRefPubMedGoogle Scholar
  16. 16.
    Wong RJ, Aguilar M, Cheung R, Perumpail RB, Harrison SA, Younossi ZM, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology. 2015;148(3):547–55.CrossRefPubMedGoogle 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(6):1972–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Browning JD, Kumar KS, Saboorian MH, Thiele DL. Ethnic differences in the prevalence of cryptogenic cirrhosis. Am J Gastroenterol. 2004;99(2):292–8.CrossRefPubMedGoogle Scholar
  19. 19.
    Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348(17):1625–38.CrossRefPubMedGoogle Scholar
  20. 20.
    Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. 2008;371(9612):569–78.CrossRefPubMedGoogle Scholar
  21. 21.
    La Vecchia C, Negri E, Decarli A, Franceschi S. Diabetes mellitus and the risk of primary liver cancer. Int J Cancer. 1997;73(2):204–7.CrossRefPubMedGoogle Scholar
  22. 22.
    Lai MS, Hsieh MS, Chiu YH, Chen TH. Type 2 diabetes and hepatocellular carcinoma: a cohort study in high prevalence area of hepatitis virus infection. Hepatology. 2006;43(6):1295–302.CrossRefPubMedGoogle Scholar
  23. 23.
    El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology. 2004;126(2):460–8.CrossRefPubMedGoogle Scholar
  24. 24.
    Marchesini G, Forlani G. Diabetes and hepatocellular cancer risk: not only a matter of hyperglycemia. Hepatology. 2012;55(4):1298–300.CrossRefPubMedGoogle Scholar
  25. 25.
    Wang C, Wang X, Gong G, Ben Q, Qiu W, Chen Y, et al. Increased risk of hepatocellular carcinoma in patients with diabetes mellitus: a systematic review and meta-analysis of cohort studies. Int J Cancer. 2012;130(7):1639–48.CrossRefPubMedGoogle Scholar
  26. 26.
    Marrero JA, Fontana RJ, Su GL, Conjeevaram HS, Emick DM, Lok AS. NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States. Hepatology. 2002;36(6):1349–54.CrossRefPubMedGoogle Scholar
  27. 27.
    Regimbeau JM, Colombat M, Mognol P, Durand F, Abdalla E, Degott C, et al. Obesity and diabetes as a risk factor for hepatocellular carcinoma. Liver Transpl. 2004;10(2 Suppl 1):S69–73.CrossRefPubMedGoogle Scholar
  28. 28.
    Paradis V, Zalinski S, Chelbi E, Guedj N, Degos F, Vilgrain V, et al. Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis. Hepatology. 2009;49(3):851–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Reddy SK, Steel JL, Chen HW, DeMateo DJ, Cardinal J, Behari J, et al. Outcomes of curative treatment for hepatocellular cancer in nonalcoholic steatohepatitis versus hepatitis C and alcoholic liver disease. Hepatology. 2012;55(6):1809–19.CrossRefPubMedGoogle Scholar
  30. 30.••
    Valenti L, Motta BM, Soardo G, Iavarone M, Donati B, Sangiovanni A, et al. PNPLA3 I148M polymorphism, clinical presentation, and survival in patients with hepatocellular carcinoma. PLoS One. 2013;8(10):e75982. The study identifies PNPLA3 as a genetic factor associated with an increased risk of HCC development.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Tateishi R, Okanoue T, Fujiwara N, Okita K, Kiyosawa K, Omata M, et al. Clinical characteristics, treatment, and prognosis of non-B, non-C hepatocellular carcinoma: a large retrospective multicenter cohort study. J Gastroenterol. 2015;50(3):350–60.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.••
    Mittal S, Sada YH, El-Serag HB, Kanwal F, Duan Z, Temple S, et al. Temporal trends of nonalcoholic fatty liver disease-related hepatocellular carcinoma in the veteran affairs population. Clin Gastroenterol Hepatol. 2015;13(3):594–601 e591. An analysis of HCC patients survival following transplantation.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Mittal S, El-Serag HB, Sada YH, Kanwal F, Duan Z, Temple S, et al. Hepatocellular carcinoma in the absence of cirrhosis in United States veterans is associated with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2016;14(1):124–31.CrossRefPubMedGoogle Scholar
  34. 34.•
    Piscaglia F, Svegliati-Baroni G, Barchetti A, Pecorelli A, Marinelli S, Tiribelli C, et al. Clinical patterns of hepatocellular carcinoma (HCC) in non alcoholic fatty liver disease (NAFLD): a multicenter prospective study. Hepatology. 2016;63:827–38. Italian experience, including personal data, on HCC presentation in relation to etiology and cirrhosis at diagnosis Google Scholar
  35. 35.
    Hashimoto E, Yatsuji S, Tobari M, Taniai M, Torii N, Tokushige K, et al. Hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. J Gastroenterol. 2009;44 Suppl 19:89–95.CrossRefPubMedGoogle Scholar
  36. 36.
    Yasui K, Hashimoto E, Komorizono Y, Koike K, Arii S, Imai Y, et al. Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2011;9(5):428–33. quiz e450.CrossRefPubMedGoogle Scholar
  37. 37.
    Kawamura Y, Arase Y, Ikeda K, Seko Y, Imai N, Hosaka T, et al. Large-scale long-term follow-up study of Japanese patients with non-alcoholic fatty liver disease for the onset of hepatocellular carcinoma. Am J Gastroenterol. 2012;107(2):253–61.CrossRefPubMedGoogle Scholar
  38. 38.•
    Liu YL, Patman GL, Leathart JB, Piguet AC, Burt AD, Dufour JF, et al. Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma. J Hepatol. 2014;61(1):75–81. Confirmatory data on the significance of PNPLA3 as a risk factor for HCC development.CrossRefPubMedGoogle Scholar
  39. 39.
    Mohamad B, Shah V, Onyshchenko M, Elshamy M, Aucejo F, Lopez R, et al. Characterization of hepatocellular carcinoma (HCC) in non-alcoholic fatty liver disease (NAFLD) patients without cirrhosis. Hepatol Int 2015 (ePub Nov 11).Google Scholar
  40. 40.
    Wong RJ, Chou C, Bonham CA, Concepcion W, Esquivel CO, Ahmed A. Improved survival outcomes in patients with non-alcoholic steatohepatitis and alcoholic liver disease following liver transplantation: an analysis of 2002-2012 United Network for Organ Sharing data. Clin Transplant. 2014;28(6):713–21.CrossRefPubMedGoogle Scholar
  41. 41.
    Wang X, Li J, Riaz DR, Shi G, Liu C, Dai Y. Outcomes of liver transplantation for nonalcoholic steatohepatitis: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2014;12(3):394–402. e391.CrossRefPubMedGoogle Scholar
  42. 42.
    Yasui K, Hashimoto E, Komorizono Y, Koike K, Arii S, Imai Y, et al. Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2011;9(5):428–33. quiz e450.CrossRefPubMedGoogle Scholar
  43. 43.
    Chang CY, Hernandez-Prera JC, Roayaie S, Schwartz M, Thung SN. Changing epidemiology of hepatocellular adenoma in the United States: review of the literature. Int J Hepatol. 2013;2013604860.Google Scholar
  44. 44.
    Baffy G, Brunt EM, Caldwell SH. Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace. J Hepatol. 2012;56(6):1384–91.CrossRefPubMedGoogle Scholar
  45. 45.
    Stickel F, Hellerbrand C. Non-alcoholic fatty liver disease as a risk factor for hepatocellular carcinoma: mechanisms and implications. Gut. 2010;59(10):1303–7.CrossRefPubMedGoogle Scholar
  46. 46.
    Fukushima J, Kamada Y, Matsumoto H, Yoshida Y, Ezaki H, Takemura T, et al. Adiponectin prevents progression of steatohepatitis in mice by regulating oxidative stress and Kupffer cell phenotype polarization. Hepatol Res. 2009;39(7):724–38.CrossRefPubMedGoogle Scholar
  47. 47.
    Saxena NK, Sharma D, Ding X, Lin S, Marra F, Merlin D, et al. Concomitant activation of the JAK/STAT, PI3K/AKT, and ERK signaling is involved in leptin-mediated promotion of invasion and migration of hepatocellular carcinoma cells. Cancer Res. 2007;67(6):2497–507.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Dalamaga M, Diakopoulos KN, Mantzoros CS. The role of adiponectin in cancer: a review of current evidence. Endocr Rev. 2012;33(4):547–94.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Vinciguerra M, Carrozzino F, Peyrou M, Carlone S, Montesano R, Benelli R, et al. Unsaturated fatty acids promote hepatoma proliferation and progression through downregulation of the tumor suppressor PTEN. J Hepatol. 2009;50(6):1132–41.CrossRefPubMedGoogle Scholar
  50. 50.
    Malhi H, Bronk SF, Werneburg NW, Gores GJ. Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis. J Biol Chem. 2006;281(17):12093–101.CrossRefPubMedGoogle Scholar
  51. 51.
    Chettouh H, Lequoy M, Fartoux L, Vigouroux C, Desbois-Mouthon C. Hyperinsulinaemia and insulin signalling in the pathogenesis and the clinical course of hepatocellular carcinoma. Liver Int. 2015;35(10):2203–17.CrossRefPubMedGoogle Scholar
  52. 52.
    Alexander J, Torbenson M, Wu TT, Yeh MM. Non-alcoholic fatty liver disease contributes to hepatocarcinogenesis in non-cirrhotic liver: a clinical and pathological study. J Gastroenterol Hepatol. 2013;28(5):848–54.CrossRefPubMedGoogle Scholar
  53. 53.
    Chun YS, Huang M, Rink L, Von Mehren M. Expression levels of insulin-like growth factors and receptors in hepatocellular carcinoma: a retrospective study. World J Surg Oncol. 2014;12231.Google Scholar
  54. 54.
    Aron-Wisnewsky J, Gaborit B, Dutour A, Clement K. Gut microbiota and non-alcoholic fatty liver disease: new insights. Clin Microbiol Infect. 2013;19(4):338–48.CrossRefPubMedGoogle Scholar
  55. 55.
    De Minicis S, Rychlicki C, Agostinelli L, Saccomanno S, Candelaresi C, Trozzi L, et al. Dysbiosis contributes to fibrogenesis in the course of chronic liver injury in mice. Hepatology. 2014;59(5):1738–49.CrossRefPubMedGoogle Scholar
  56. 56.
    Fedirko V, Duarte-Salles T, Bamia C, Trichopoulou A, Aleksandrova K, Trichopoulos D, et al. Prediagnostic circulating vitamin D levels and risk of hepatocellular carcinoma in European populations: a nested case-control study. Hepatology. 2014;60(4):1222–30.CrossRefPubMedGoogle Scholar
  57. 57.
    Wang JB, Abnet CC, Chen W, Dawsey SM, Fan JH, Yin LY, et al. Association between serum 25(OH) vitamin D, incident liver cancer and chronic liver disease mortality in the Linxian Nutrition Intervention Trials: a nested case-control study. Br J Cancer. 2013;109(7):1997–2004.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Pirazzi C, Valenti L, Motta BM, Pingitore P, Hedfalk K, Mancina RM, et al. PNPLA3 has retinyl-palmitate lipase activity in human hepatic stellate cells. Hum Mol Genet. 2014;23(15):4077–85.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    El-Serag HB. Hepatocellular carcinoma. N Engl J Med. 2011;365(12):1118–27.CrossRefPubMedGoogle Scholar
  60. 60.
    Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis. 1999;19(3):329–38.CrossRefPubMedGoogle Scholar
  61. 61.
    Iavarone M, Cabibbo G, Piscaglia F, Zavaglia C, Grieco A, Villa E, et al. Field-practice study of sorafenib therapy for hepatocellular carcinoma: a prospective multicenter study in Italy. Hepatology. 2011;54(6):2055–63.CrossRefPubMedGoogle Scholar
  62. 62.
    Buzzai M, Jones RG, Amaravadi RK, Lum JJ, DeBerardinis RJ, Zhao F, et al. Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res. 2007;67(14):6745–52.CrossRefPubMedGoogle Scholar
  63. 63.
    Kohjima M, Higuchi N, Kato M, Kotoh K, Yoshimoto T, Fujino T, et al. SREBP-1c, regulated by the insulin and AMPK signaling pathways, plays a role in nonalcoholic fatty liver disease. Int J Mol Med. 2008;21(4):507–11.PubMedGoogle Scholar
  64. 64.
    Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005;330(7503):1304–5.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.•
    Bhat A, Sebastiani G, Bhat M. Systematic review: preventive and therapeutic applications of metformin in liver disease. World J Hepatol. 2015;7(12):1652–9. Comprehensive review on metfoirmin use in hepatic malignancies.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.•
    Zhang X, Harmsen WS, Mettler TA, Kim WR, Roberts RO, Therneau TM, et al. Continuation of metformin use after a diagnosis of cirrhosis significantly improves survival of patients with diabetes. Hepatology. 2014;60(6):2008–16. Examines beneficial effects of metformin in subjects with liver disease.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Singh S, Singh PP, Singh AG, Murad MH, Sanchez W. Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis. Gastroenterology. 2013;144(2):323–32.CrossRefPubMedGoogle Scholar
  68. 68.
    Teratani T, Tomita K, Suzuki T, Oshikawa T, Yokoyama H, Shimamura K, et al. A high-cholesterol diet exacerbates liver fibrosis in mice via accumulation of free cholesterol in hepatic stellate cells. Gastroenterology. 2012;142(1):152–64. e110.CrossRefPubMedGoogle Scholar
  69. 69.
    Musso G, Gambino R, Cassader M. Cholesterol metabolism and the pathogenesis of non-alcoholic steatohepatitis. Prog Lipid Res. 2013;52(1):175–91.CrossRefPubMedGoogle Scholar
  70. 70.
    Mazzella N, Ricciardi LM, Mazzotti A, Marchesini G. The role of medications for the management of patients with NAFLD. Clin Liver Dis. 2014;18(1):73–89.CrossRefPubMedGoogle Scholar
  71. 71.
    Calder PC. Polyunsaturated fatty acids and inflammation. Prostaglandins Leukot Essent Fatty Acids. 2006;75(3):197–202.CrossRefPubMedGoogle Scholar
  72. 72.
    Monteiro J, Leslie M, Moghadasian MH, Arendt BM, Allard JP, Ma DW. The role of n-6 and n-3 polyunsaturated fatty acids in the manifestation of the metabolic syndrome in cardiovascular disease and non-alcoholic fatty liver disease. Food Funct. 2014;5(3):426–35.CrossRefPubMedGoogle Scholar
  73. 73.
    Koh WP. Dan YY. Jin A, Wang R, Yuan JM. Dietary fatty acids and risk of hepatocellular carcinoma in the Singapore Chinese health study. Liver Int. 2015. doi: 10.1111/liv.12978.
  74. 74.••
    Duarte-Salles T, Fedirko V, Stepien M, Aleksandrova K, Bamia C, Lagiou P, et al. Dietary fat, fat subtypes and hepatocellular carcinoma in a large European cohort. Int J Cancer. 2015;137(11):2715–28. An analysis on the relationship between fat intake and HCC development in the large EPIC cohort.CrossRefPubMedGoogle Scholar
  75. 75.
    Li WQ, Park Y, McGlynn KA, Hollenbeck AR, Taylor PR, Goldstein AM, et al. Index-based dietary patterns and risk of incident hepatocellular carcinoma and mortality from chronic liver disease in a prospective study. Hepatology. 2014;60(2):588–97.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    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 Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology. 2012;142(7):1592–609.CrossRefPubMedGoogle Scholar
  77. 77.
    Dyson J, Jaques B, Chattopadyhay D, Lochan R, Graham J, Das D, et al. Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team. J Hepatol. 2014;60(1):110–7.CrossRefPubMedGoogle Scholar
  78. 78.
    Zoppini G, Fedeli U, Gennaro N, Saugo M, Targher G, Bonora E. Mortality from chronic liver diseases in diabetes. Am J Gastroenterol. 2014;109(7):1020–5.CrossRefPubMedGoogle Scholar
  79. 79.
    Prati D, Taioli E, Zanella A, Della Torre E, Butelli S, Del Vecchio E, et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med. 2002;137(1):1–10.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Anna Simona Sasdelli
    • 1
  • Lucia Brodosi
    • 1
  • Giulio Marchesini
    • 1
  1. 1.Unit of Metabolic Diseases and Clinical Dietetics, “Alma Mater Studiorum” UniversityS. Orsola-Malpighi HospitalBolognaItaly

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