Digestive Diseases and Sciences

, Volume 61, Issue 5, pp 1234–1245 | Cite as

Hepatocellular Carcinoma in Obesity, Type 2 Diabetes, and NAFLD

  • Helen L. Reeves
  • Marco Y. W. Zaki
  • Christopher P. Day


Hepatocellular carcinoma (HCC) is the second commonest cause of cancer death worldwide. Rather than falling as a result of prevention and treatments for viral hepatitis, an increase is evident in developed nations consequent to the rising prevalence of obesity and type 2 diabetes mellitus (T2DM)—the two major risk factors for nonalcoholic fatty liver disease (NAFLD). The majority of patients with HCC complicating these conditions present with advanced disease as the tools for surveillance are inadequate, and the “at-risk” population is not well characterized. This review will summarize the epidemiological evidence linking obesity, T2DM, and NAFLD with HCC, what is known about the pathogenic mechanisms involved, as well as their relevance for clinicians managing patients at risk. There will also be an overview of the “unmet needs” surrounding this topic, with suggestions for the direction translational research should take in order to prevent progression of NAFLD to HCC, to improve early detection of HCC in those with NAFLD, as well as to improve outcomes for those affected.


Hepatocellular carcinoma Obesity Type 2 diabetes Nonalcoholic fatty liver disease PNPLA3 Macrophage Inflammation Autophagy 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer. 2010;46:765–781.PubMedCrossRefGoogle Scholar
  2. 2.
    Tanaka H, et al. Declining incidence of hepatocellular carcinoma in Osaka, Japan, from 1990 to 2003. Ann Intern Med. 2008;148:820–826.PubMedCrossRefGoogle Scholar
  3. 3.
    Armstrong GL, et al. The past incidence of hepatitis C virus infection: implications for the future burden of chronic liver disease in the United States. Hepatology. 2000;31:777–782.PubMedCrossRefGoogle Scholar
  4. 4.
    Cancer, I.A.f.R.o. GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012; 2012.Google Scholar
  5. 5.
    Moller H, et al. Obesity and cancer risk: a Danish record-linkage study. Eur J Cancer. 1994;30A:344–350.PubMedCrossRefGoogle Scholar
  6. 6.
    Wolk A, et al. A prospective study of obesity and cancer risk (Sweden). Cancer Causes Control. 2001;12:13–21.PubMedCrossRefGoogle Scholar
  7. 7.
    Calle EE, et al. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348:1625–1638.PubMedCrossRefGoogle Scholar
  8. 8.
    Marrero JA, et al. NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States. Hepatology. 2002;36:1349–1354.PubMedCrossRefGoogle Scholar
  9. 9.
    Dyson J, et al. Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team. J Hepatol. 2014;60:110–117.PubMedCrossRefGoogle Scholar
  10. 10.
    Friedman SL. Focus. J Hepatol. 2014;60:1–2.PubMedCrossRefGoogle Scholar
  11. 11.
    Marengo A, Rosso C, Bugianesi E. Liver cancer: connections with obesity, fatty liver, and cirrhosis. Annu Rev Med. 2016;67:103–117.PubMedCrossRefGoogle Scholar
  12. 12.
    Margini C, Dufour JF. The story of HCC in NAFLD: from epidemiology, across pathogenesis, to prevention and treatment. Liver Int. 2016;36:317–324.PubMedCrossRefGoogle Scholar
  13. 13.
    Giovannucci E, et al. Diabetes and cancer: a consensus report. Diabetes Care. 2010;33:1674–1685.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Tsilidis KK, et al. Type 2 diabetes and cancer: umbrella review of meta-analyses of observational studies. BMJ. 2015;350:g7607.PubMedCrossRefGoogle Scholar
  15. 15.
    El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology. 2004;126:460–468.PubMedCrossRefGoogle Scholar
  16. 16.
    Nordenstedt H, White DL, El-Serag HB. The changing pattern of epidemiology in hepatocellular carcinoma. Dig Liver Dis. 2010;42 Suppl 3:S206–S214.PubMedCrossRefGoogle Scholar
  17. 17.
    Ascha MS, et al. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology. 2010;51:1972–1978.PubMedCrossRefGoogle Scholar
  18. 18.
    Sanyal A, et al. Population-based risk factors and resource utilization for HCC: US perspective. Curr Med Res Opin. 2010;26:2183–2191.PubMedCrossRefGoogle Scholar
  19. 19.
    International Working P. Terminology of nodular hepatocellular lesions. Hepatology. 1995;22:983–993.CrossRefGoogle Scholar
  20. 20.
    Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology. 2003;37:1202–1219.PubMedCrossRefGoogle Scholar
  21. 21.
    Farrell GC. The liver and the waistline: fifty years of growth. J Gastroenterol Hepatol. 2009;24 Suppl 3:S105–S118.PubMedCrossRefGoogle Scholar
  22. 22.
    Younossi ZM, et al. Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009. Hepatology. 2015;62:1723–1730.PubMedCrossRefGoogle Scholar
  23. 23.
    Struben VM, Hespenheide EE, Caldwell SH. Nonalcoholic steatohepatitis and cryptogenic cirrhosis within kindreds. Am J Med. 2000;108:9–13.PubMedCrossRefGoogle Scholar
  24. 24.
    Willner IR, et al. Ninety patients with nonalcoholic steatohepatitis: insulin resistance, familial tendency, and severity of disease. Am J Gastroenterol. 2001;96:2957–2961.PubMedCrossRefGoogle Scholar
  25. 25.
    Anstee QM, Daly AK, Day CP. Genetic modifiers of non-alcoholic fatty liver disease progression. Biochim Biophys Acta. 2011;1812:1557–1566.PubMedCrossRefGoogle Scholar
  26. 26.
    Grarup N, et al. Genetic susceptibility to type 2 diabetes and obesity: from genome-wide association studies to rare variants and beyond. Diabetologia. 2014;57:1528–1541.PubMedCrossRefGoogle Scholar
  27. 27.
    Larter CZ, et al. A fresh look at NASH pathogenesis. Part 1: the metabolic movers. J Gastroenterol Hepatol. 2010;25:672–690.PubMedCrossRefGoogle Scholar
  28. 28.
    Anstee QM, Daly A, Day CP. Genetics of alcoholic and non-alcoholic fatty liver disease. Semin Liver Dis. 2011;31:128–146.PubMedCrossRefGoogle Scholar
  29. 29.
    Romeo S, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2008;40:1461–1465.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Kotronen A, et al. A common variant in PNPLA3, which encodes adiponutrin, is associated with liver fat content in humans. Diabetologia. 2009;52:1056–1060.PubMedCrossRefGoogle Scholar
  31. 31.
    Burza MA, et al. PNPLA3 I148M (rs738409) genetic variant is associated with hepatocellular carcinoma in obese individuals. Dig Liver Dis. 2012;44:1037–1041.PubMedCrossRefGoogle Scholar
  32. 32.
    Liu YL, 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;61:75–81.PubMedCrossRefGoogle Scholar
  33. 33.
    Pirazzi C, et al. PNPLA3 has retinyl-palmitate lipase activity in human hepatic stellate cells. Hum Mol Genet. 2014;23:4077–4085.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Ballestri S, et al. Risk of cardiovascular, cardiac and arrhythmic complications in patients with non-alcoholic fatty liver disease. World J Gastroenterol. 2014;20:1724–1745.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Zimmermann R, et al. Fate of fat: the role of adipose triglyceride lipase in lipolysis. Biochim Biophys Acta. 2009;1791:494–500.PubMedCrossRefGoogle Scholar
  36. 36.
    Musso G, Gambino R, Cassader M. Non-alcoholic fatty liver disease from pathogenesis to management: an update. Obes Rev. 2010;11:430–445.PubMedCrossRefGoogle Scholar
  37. 37.
    Cheung O, Sanyal AJ. Abnormalities of lipid metabolism in nonalcoholic fatty liver disease. Semin Liver Dis. 2008;28:351–359.PubMedCrossRefGoogle Scholar
  38. 38.
    Joost HG. Diabetes and cancer: epidemiology and potential mechanisms. Diab Vasc Dis Res. 2014;11:390–394.PubMedCrossRefGoogle Scholar
  39. 39.
    Xu Y, Qian SY. Anti-cancer activities of omega-6 polyunsaturated fatty acids. Biomed J. 2014;37:112–119.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Roberts DL, Dive C, Renehan AG. Biological mechanisms linking obesity and cancer risk: new perspectives. Annu Rev Med. 2010;61:301–316.PubMedCrossRefGoogle Scholar
  41. 41.
    Ruan K, Song G, Ouyang G. Role of hypoxia in the hallmarks of human cancer. J Cell Biochem. 2009;107:1053–1062.PubMedCrossRefGoogle Scholar
  42. 42.
    Bedogni B, et al. The hypoxic microenvironment of the skin contributes to Akt-mediated melanocyte transformation. Cancer Cell. 2005;8:443–454.PubMedCrossRefGoogle Scholar
  43. 43.
    Trayhurn P, Wang B, Wood IS. Hypoxia in adipose tissue: a basis for the dysregulation of tissue function in obesity? Br J Nutr. 2008;100:227–235.PubMedCrossRefGoogle Scholar
  44. 44.
    Ahmed MH, Byrne CD. Obstructive sleep apnea syndrome and fatty liver: association or causal link? World J Gastroenterol. 2010;16:4243–4252.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Weisberg SP, et al. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112:1796–1808.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Sun K, et al. Fibrosis and adipose tissue dysfunction. Cell Metab. 2013;18:470–477.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Keophiphath M, et al. Macrophage-secreted factors promote a profibrotic phenotype in human preadipocytes. Mol Endocrinol. 2009;23:11–24.PubMedCrossRefGoogle Scholar
  48. 48.
    McNelis JC, Olefsky JM. Macrophages, immunity, and metabolic disease. Immunity. 2014;41:36–48.PubMedCrossRefGoogle Scholar
  49. 49.
    Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol. 2010;72:219–246.PubMedCrossRefGoogle Scholar
  50. 50.
    Solinas G, Karin M. JNK1 and IKKbeta: molecular links between obesity and metabolic dysfunction. FASEB J. 2010;24:2596–2611.PubMedCrossRefGoogle Scholar
  51. 51.
    Fischer-Posovszky P, Wabitsch M, Hochberg Z. Endocrinology of adipose tissue—an update. Horm Metab Res. 2007;39:314–321.PubMedCrossRefGoogle Scholar
  52. 52.
    Anstee QM, Goldin RD. Mouse models in non-alcoholic fatty liver disease and steatohepatitis research. Int J Exp Pathol. 2006;87:1–16.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Zhang Y, et al. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372:425–432.PubMedCrossRefGoogle Scholar
  54. 54.
    Zimmet P, et al. Serum leptin concentration, obesity, and insulin resistance in Western Samoans: cross sectional study. BMJ. 1996;313:965–969.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    de Courten M, et al. Hyperleptinaemia: the missing link in the, metabolic syndrome? Diabet Med. 1997;14:200–208.PubMedCrossRefGoogle Scholar
  56. 56.
    Wauters M, et al. Leptin levels in type 2 diabetes: associations with measures of insulin resistance and insulin secretion. Horm Metab Res. 2003;35:92–96.PubMedCrossRefGoogle Scholar
  57. 57.
    Wang SN, Lee KT, Ker CG. Leptin in hepatocellular carcinoma. World J Gastroenterol. 2010;16:5801–5809.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Uddin S, et al. Role of leptin and its receptors in the pathogenesis of thyroid cancer. Int J Clin Exp Pathol. 2011;4:637–643.PubMedPubMedCentralGoogle Scholar
  59. 59.
    Berg AH, et al. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med. 2001;7:947–953.PubMedCrossRefGoogle Scholar
  60. 60.
    Saxena NK, et al. Adiponectin modulates C-jun N-terminal kinase and mammalian target of rapamycin and inhibits hepatocellular carcinoma. Gastroenterology. 2010;139:1762–1773. (1773 e1–1773 e5).PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Sharma D, et al. Adiponectin antagonizes the oncogenic actions of leptin in hepatocellular carcinogenesis. Hepatology. 2010;52:1713–1722.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Dalamaga M, Diakopoulos KN, Mantzoros CS. The role of adiponectin in cancer: a review of current evidence. Endocr Rev. 2012;33:547–594.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Fasshauer M, Bluher M. Adipokines in health and disease. Trends Pharmacol Sci. 2015;36:461–470.PubMedCrossRefGoogle Scholar
  64. 64.
    Ganeshan K, Chawla A. Metabolic regulation of immune responses. Annu Rev Immunol. 2014;32:609–634.PubMedCrossRefGoogle Scholar
  65. 65.
    Tanaka S, et al. T lymphopenia in genetically obese-diabetic Wistar fatty rats: effects of body weight reduction on T cells. Metabolism. 2000;49:1261–1266.PubMedCrossRefGoogle Scholar
  66. 66.
    Macia L, et al. Impairment of dendritic cell functionality and steady-state number in obese mice. J Immunol. 2006;177:5997–6006.PubMedCrossRefGoogle Scholar
  67. 67.
    Lamas O, Marti A, Martinez JA. Obesity and immunocompetence. Eur J Clin Nutr. 2002;56:S42–S45.PubMedCrossRefGoogle Scholar
  68. 68.
    Sheridan PA, et al. Obesity is associated with impaired immune response to influenza vaccination in humans. Int J Obes (Lond). 2012;36:1072–1077.CrossRefGoogle Scholar
  69. 69.
    Schwabe RF, Jobin C. The microbiome and cancer. Nat Rev Cancer. 2013;13:800–812.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Louis P, Hold GL, Flint HJ. The gut microbiota, bacterial metabolites and colorectal cancer. Nat Rev Microbiol. 2014;12:661–672.PubMedCrossRefGoogle Scholar
  71. 71.
    McCullough AJ. The clinical features, diagnosis and natural history of nonalcoholic fatty liver disease. Clin Liver Dis. 2004;8:521–533. (viii).PubMedCrossRefGoogle Scholar
  72. 72.
    Jou J, Choi SS, Diehl AM. Mechanisms of disease progression in nonalcoholic fatty liver disease. Semin Liver Dis. 2008;28:370–379.PubMedCrossRefGoogle Scholar
  73. 73.
    Maeda S, et al. IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell. 2005;121:977–990.PubMedCrossRefGoogle Scholar
  74. 74.
    He G, et al. Identification of liver cancer progenitors whose malignant progression depends on autocrine IL-6 signaling. Cell. 2013;155:384–396.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Nakagawa H, et al. ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development. Cancer Cell. 2014;26:331–343.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Tal-Kremer S, Day CP, Reeves HL. The genetic basis of hepatocellular cancer. In: Ali S, Mann DA, Friedman SL, eds. Liver Diseases: Biochemical Mechanisms and New Therapeutic Insights. Enfield, New Hampshire: Science Publishers; 2006. pp. 273–308.Google Scholar
  77. 77.
    Guy CD, et al. Hedgehog pathway activation parallels histologic severity of injury and fibrosis in human nonalcoholic fatty liver disease. Hepatology. 2012;55:1711–1721.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Kubes P, Mehal WZ. Sterile inflammation in the liver. Gastroenterology. 2012;143:1158–1172.PubMedCrossRefGoogle Scholar
  79. 79.
    McDonald B, Kubes P. Neutrophils and intravascular immunity in the liver during infection and sterile inflammation. Toxicol Pathol. 2012;40:157–165.PubMedCrossRefGoogle Scholar
  80. 80.
    Wilson CL, et al. NFkappaB1 is a suppressor of neutrophil-driven hepatocellular carcinoma. Nat Commun. 2015;6:6818.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Wolf MJ, et al. Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes. Cancer Cell. 2014;26:549–564.PubMedCrossRefGoogle Scholar
  82. 82.
    Wolf MJ, et al. The unexpected role of lymphotoxin beta receptor signaling in carcinogenesis: from lymphoid tissue formation to liver and prostate cancer development. Oncogene. 2010;29:5006–5018.PubMedCrossRefGoogle Scholar
  83. 83.
    Bajaj JS, et al. Altered profile of human gut microbiome is associated with cirrhosis and its complications. J Hepatol. 2014;60:940–947.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Aron-Wisnewsky J, et al. Gut microbiota and non-alcoholic fatty liver disease: new insights. Clin Microbiol Infect. 2013;19:338–348.PubMedCrossRefGoogle Scholar
  85. 85.
    Dumas ME, et al. Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice. Proc Natl Acad Sci USA. 2006;103:12511–12516.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Wang X, et al. Bile acid receptors and liver cancer. Curr Pathobiol Rep. 2013;1:29–35.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Lade A, Noon LA, Friedman SL. Contributions of metabolic dysregulation and inflammation to nonalcoholic steatohepatitis, hepatic fibrosis, and cancer. Curr Opin Oncol. 2014;26:100–107.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Neuschwander-Tetri BA, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015;385:956–965.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Wu AL, et al. FGF19 regulates cell proliferation, glucose and bile acid metabolism via FGFR4-dependent and independent pathways. PLoS One. 2011;6:e17868.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Ravikumar B, et al. Regulation of mammalian autophagy in physiology and pathophysiology. Physiol Rev. 2010;90:1383–1435.PubMedCrossRefGoogle Scholar
  91. 91.
    Singh R, et al. Autophagy regulates lipid metabolism. Nature. 2009;458:1131–1135.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Kim J, et al. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol. 2011;13:132–141.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Aghajan M, Li N, Karin M. Obesity, autophagy and the pathogenesis of liver and pancreatic cancers. J Gastroenterol Hepatol. 2012;27 Suppl 2:10–14.PubMedCrossRefGoogle Scholar
  94. 94.
    Komatsu M, et al. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol. 2010;12:213–223.PubMedGoogle Scholar
  95. 95.
    Inami Y, et al. Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells. J Cell Biol. 2011;193:275–284.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Lee YJ, Jang BK. The role of autophagy in hepatocellular carcinoma. Int J Mol Sci. 2015;16:26629–26643.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Czaja MJ, et al. Functions of autophagy in normal and diseased liver. Autophagy. 2013;9:1131–1158.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Jain D, et al. Steatohepatitic hepatocellular carcinoma, a morphologic indicator of associated metabolic risk factors: a study from India. Arch Pathol Lab Med. 2013;137:961–966.PubMedCrossRefGoogle Scholar
  99. 99.
    Salomao M, et al. Steatohepatitic hepatocellular carcinoma (SH-HCC): a distinctive histological variant of HCC in hepatitis C virus-related cirrhosis with associated NAFLD/NASH. Am J Surg Pathol. 2010;34:1630–1636.PubMedGoogle Scholar
  100. 100.
    Brenner C, et al. Decoding cell death signals in liver inflammation. J Hepatol. 2013;59:583–594.PubMedCrossRefGoogle Scholar
  101. 101.
    McKee C, et al. Amphiregulin activates human hepatic stellate cells and is upregulated in non alcoholic steatohepatitis. Sci Rep. 2015;5:8812.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Gori M, Arciello M, Balsano C. MicroRNAs in nonalcoholic fatty liver disease: novel biomarkers and prognostic tools during the transition from steatosis to hepatocarcinoma. Biomed Res Int. 2014;2014:741465.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Shah N, Nelson JE, Kowdley KV. MicroRNAs in liver disease: bench to bedside. J Clin Exp Hepatol. 2013;3:231–242.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Morishita A, Masaki T. miRNA in hepatocellular carcinoma. Hepatol Res. 2015;45:128–141.PubMedCrossRefGoogle Scholar
  105. 105.
    Reddy SK, et al. Outcomes of curative treatment for hepatocellular cancer in nonalcoholic steatohepatitis versus hepatitis C and alcoholic liver disease. Hepatology. 2012;55:1809–1819.PubMedCrossRefGoogle Scholar
  106. 106.
    European Association For The Study Of The Liver, European Organisation For Research And Treatment Of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56:908–943.Google Scholar
  107. 107.
    Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020–1022.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Saran U, et al. Hepatocellular carcinoma and lifestyles. J Hepatol. 2016;64:203–214.PubMedCrossRefGoogle Scholar
  109. 109.
    Turati F, et al. Mediterranean diet and hepatocellular carcinoma. J Hepatol. 2014;60:606–611.PubMedCrossRefGoogle Scholar
  110. 110.
    Piguet AC, et al. Regular exercise decreases liver tumors development in hepatocyte-specific PTEN-deficient mice independently of steatosis. J Hepatol. 2015;62:1296–1303.PubMedCrossRefGoogle Scholar
  111. 111.
    El-Serag HB, et al. Statins are associated with a reduced risk of hepatocellular carcinoma in a large cohort of patients with diabetes. Gastroenterology. 2009;136:1601–1608.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Dongiovanni P, et al. Statin use and non-alcoholic steatohepatitis in at risk individuals. J Hepatol. 2015;63:705–712.PubMedCrossRefGoogle Scholar
  113. 113.
    Hoki T, et al. Increased duodenal iron absorption through up-regulation of divalent metal transporter 1 from enhancement of iron regulatory protein 1 activity in patients with nonalcoholic steatohepatitis. Hepatology. 2015;62:751–761.PubMedCrossRefGoogle Scholar
  114. 114.
    Sorrentino P, et al. Liver iron excess in patients with hepatocellular carcinoma developed on non-alcoholic steato-hepatitis. J Hepatol. 2009;50:351–357.PubMedCrossRefGoogle Scholar
  115. 115.
    Williamson RM, et al. Prevalence and markers of advanced liver disease in type 2 diabetes. QJM. 2012;105:425–432.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Helen L. Reeves
    • 1
  • Marco Y. W. Zaki
    • 1
  • Christopher P. Day
    • 2
  1. 1.Northern Institute for Cancer ResearchNewcastle upon TyneUK
  2. 2.Institute of Cellular MedicineNewcastle UniversityNewcastle upon TyneUK

Personalised recommendations