Skip to main content

Advertisement

SpringerLink
Log in

Hepatocellular Carcinoma in Obesity, Type 2 Diabetes, and NAFLD

  • Review
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  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.

    Article  CAS  PubMed  Google Scholar 

  2. Tanaka H, et al. Declining incidence of hepatocellular carcinoma in Osaka, Japan, from 1990 to 2003. Ann Intern Med. 2008;148:820–826.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  4. Cancer, I.A.f.R.o. GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012; 2012.

  5. Moller H, et al. Obesity and cancer risk: a Danish record-linkage study. Eur J Cancer. 1994;30A:344–350.

    Article  CAS  PubMed  Google Scholar 

  6. Wolk A, et al. A prospective study of obesity and cancer risk (Sweden). Cancer Causes Control. 2001;12:13–21.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  9. Dyson J, et al. Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team. J Hepatol. 2014;60:110–117.

    Article  PubMed  Google Scholar 

  10. Friedman SL. Focus. J Hepatol. 2014;60:1–2.

    Article  PubMed  Google Scholar 

  11. Marengo A, Rosso C, Bugianesi E. Liver cancer: connections with obesity, fatty liver, and cirrhosis. Annu Rev Med. 2016;67:103–117.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  13. Giovannucci E, et al. Diabetes and cancer: a consensus report. Diabetes Care. 2010;33:1674–1685.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Tsilidis KK, et al. Type 2 diabetes and cancer: umbrella review of meta-analyses of observational studies. BMJ. 2015;350:g7607.

    Article  PubMed  Google Scholar 

  15. El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology. 2004;126:460–468.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  17. Ascha MS, et al. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology. 2010;51:1972–1978.

    Article  PubMed  Google Scholar 

  18. Sanyal A, et al. Population-based risk factors and resource utilization for HCC: US perspective. Curr Med Res Opin. 2010;26:2183–2191.

    Article  CAS  PubMed  Google Scholar 

  19. International Working P. Terminology of nodular hepatocellular lesions. Hepatology. 1995;22:983–993.

    Article  Google Scholar 

  20. Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology. 2003;37:1202–1219.

    Article  PubMed  Google Scholar 

  21. Farrell GC. The liver and the waistline: fifty years of growth. J Gastroenterol Hepatol. 2009;24 Suppl 3:S105–S118.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  23. Struben VM, Hespenheide EE, Caldwell SH. Nonalcoholic steatohepatitis and cryptogenic cirrhosis within kindreds. Am J Med. 2000;108:9–13.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  25. Anstee QM, Daly AK, Day CP. Genetic modifiers of non-alcoholic fatty liver disease progression. Biochim Biophys Acta. 2011;1812:1557–1566.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  27. Larter CZ, et al. A fresh look at NASH pathogenesis. Part 1: the metabolic movers. J Gastroenterol Hepatol. 2010;25:672–690.

    Article  CAS  PubMed  Google Scholar 

  28. Anstee QM, Daly A, Day CP. Genetics of alcoholic and non-alcoholic fatty liver disease. Semin Liver Dis. 2011;31:128–146.

    Article  CAS  PubMed  Google Scholar 

  29. Romeo S, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2008;40:1461–1465.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  33. Pirazzi C, et al. PNPLA3 has retinyl-palmitate lipase activity in human hepatic stellate cells. Hum Mol Genet. 2014;23:4077–4085.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Zimmermann R, et al. Fate of fat: the role of adipose triglyceride lipase in lipolysis. Biochim Biophys Acta. 2009;1791:494–500.

    Article  CAS  PubMed  Google Scholar 

  36. Musso G, Gambino R, Cassader M. Non-alcoholic fatty liver disease from pathogenesis to management: an update. Obes Rev. 2010;11:430–445.

    Article  CAS  PubMed  Google Scholar 

  37. Cheung O, Sanyal AJ. Abnormalities of lipid metabolism in nonalcoholic fatty liver disease. Semin Liver Dis. 2008;28:351–359.

    Article  CAS  PubMed  Google Scholar 

  38. Joost HG. Diabetes and cancer: epidemiology and potential mechanisms. Diab Vasc Dis Res. 2014;11:390–394.

    Article  CAS  PubMed  Google Scholar 

  39. Xu Y, Qian SY. Anti-cancer activities of omega-6 polyunsaturated fatty acids. Biomed J. 2014;37:112–119.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Roberts DL, Dive C, Renehan AG. Biological mechanisms linking obesity and cancer risk: new perspectives. Annu Rev Med. 2010;61:301–316.

    Article  CAS  PubMed  Google Scholar 

  41. Ruan K, Song G, Ouyang G. Role of hypoxia in the hallmarks of human cancer. J Cell Biochem. 2009;107:1053–1062.

    Article  CAS  PubMed  Google Scholar 

  42. Bedogni B, et al. The hypoxic microenvironment of the skin contributes to Akt-mediated melanocyte transformation. Cancer Cell. 2005;8:443–454.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  44. Ahmed MH, Byrne CD. Obstructive sleep apnea syndrome and fatty liver: association or causal link? World J Gastroenterol. 2010;16:4243–4252.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Weisberg SP, et al. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112:1796–1808.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Sun K, et al. Fibrosis and adipose tissue dysfunction. Cell Metab. 2013;18:470–477.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Keophiphath M, et al. Macrophage-secreted factors promote a profibrotic phenotype in human preadipocytes. Mol Endocrinol. 2009;23:11–24.

    Article  CAS  PubMed  Google Scholar 

  48. McNelis JC, Olefsky JM. Macrophages, immunity, and metabolic disease. Immunity. 2014;41:36–48.

    Article  CAS  PubMed  Google Scholar 

  49. Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol. 2010;72:219–246.

    Article  CAS  PubMed  Google Scholar 

  50. Solinas G, Karin M. JNK1 and IKKbeta: molecular links between obesity and metabolic dysfunction. FASEB J. 2010;24:2596–2611.

    Article  CAS  PubMed  Google Scholar 

  51. Fischer-Posovszky P, Wabitsch M, Hochberg Z. Endocrinology of adipose tissue—an update. Horm Metab Res. 2007;39:314–321.

    Article  CAS  PubMed  Google Scholar 

  52. Anstee QM, Goldin RD. Mouse models in non-alcoholic fatty liver disease and steatohepatitis research. Int J Exp Pathol. 2006;87:1–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Zhang Y, et al. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372:425–432.

    Article  CAS  PubMed  Google Scholar 

  54. Zimmet P, et al. Serum leptin concentration, obesity, and insulin resistance in Western Samoans: cross sectional study. BMJ. 1996;313:965–969.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. de Courten M, et al. Hyperleptinaemia: the missing link in the, metabolic syndrome? Diabet Med. 1997;14:200–208.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  57. Wang SN, Lee KT, Ker CG. Leptin in hepatocellular carcinoma. World J Gastroenterol. 2010;16:5801–5809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Berg AH, et al. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med. 2001;7:947–953.

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Sharma D, et al. Adiponectin antagonizes the oncogenic actions of leptin in hepatocellular carcinogenesis. Hepatology. 2010;52:1713–1722.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Dalamaga M, Diakopoulos KN, Mantzoros CS. The role of adiponectin in cancer: a review of current evidence. Endocr Rev. 2012;33:547–594.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Fasshauer M, Bluher M. Adipokines in health and disease. Trends Pharmacol Sci. 2015;36:461–470.

    Article  CAS  PubMed  Google Scholar 

  64. Ganeshan K, Chawla A. Metabolic regulation of immune responses. Annu Rev Immunol. 2014;32:609–634.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  66. Macia L, et al. Impairment of dendritic cell functionality and steady-state number in obese mice. J Immunol. 2006;177:5997–6006.

    Article  CAS  PubMed  Google Scholar 

  67. Lamas O, Marti A, Martinez JA. Obesity and immunocompetence. Eur J Clin Nutr. 2002;56:S42–S45.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  69. Schwabe RF, Jobin C. The microbiome and cancer. Nat Rev Cancer. 2013;13:800–812.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Louis P, Hold GL, Flint HJ. The gut microbiota, bacterial metabolites and colorectal cancer. Nat Rev Microbiol. 2014;12:661–672.

    Article  CAS  PubMed  Google Scholar 

  71. McCullough AJ. The clinical features, diagnosis and natural history of nonalcoholic fatty liver disease. Clin Liver Dis. 2004;8:521–533. (viii).

    Article  PubMed  Google Scholar 

  72. Jou J, Choi SS, Diehl AM. Mechanisms of disease progression in nonalcoholic fatty liver disease. Semin Liver Dis. 2008;28:370–379.

    Article  CAS  PubMed  Google Scholar 

  73. Maeda S, et al. IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell. 2005;121:977–990.

    Article  CAS  PubMed  Google Scholar 

  74. He G, et al. Identification of liver cancer progenitors whose malignant progression depends on autocrine IL-6 signaling. Cell. 2013;155:384–396.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Nakagawa H, et al. ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development. Cancer Cell. 2014;26:331–343.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Kubes P, Mehal WZ. Sterile inflammation in the liver. Gastroenterology. 2012;143:1158–1172.

    Article  CAS  PubMed  Google Scholar 

  79. McDonald B, Kubes P. Neutrophils and intravascular immunity in the liver during infection and sterile inflammation. Toxicol Pathol. 2012;40:157–165.

    Article  CAS  PubMed  Google Scholar 

  80. Wilson CL, et al. NFkappaB1 is a suppressor of neutrophil-driven hepatocellular carcinoma. Nat Commun. 2015;6:6818.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  83. Bajaj JS, et al. Altered profile of human gut microbiome is associated with cirrhosis and its complications. J Hepatol. 2014;60:940–947.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Aron-Wisnewsky J, et al. Gut microbiota and non-alcoholic fatty liver disease: new insights. Clin Microbiol Infect. 2013;19:338–348.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Wang X, et al. Bile acid receptors and liver cancer. Curr Pathobiol Rep. 2013;1:29–35.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Ravikumar B, et al. Regulation of mammalian autophagy in physiology and pathophysiology. Physiol Rev. 2010;90:1383–1435.

    Article  CAS  PubMed  Google Scholar 

  91. Singh R, et al. Autophagy regulates lipid metabolism. Nature. 2009;458:1131–1135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Kim J, et al. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol. 2011;13:132–141.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  95. Inami Y, et al. Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells. J Cell Biol. 2011;193:275–284.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Lee YJ, Jang BK. The role of autophagy in hepatocellular carcinoma. Int J Mol Sci. 2015;16:26629–26643.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Czaja MJ, et al. Functions of autophagy in normal and diseased liver. Autophagy. 2013;9:1131–1158.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  100. Brenner C, et al. Decoding cell death signals in liver inflammation. J Hepatol. 2013;59:583–594.

    Article  CAS  PubMed  Google Scholar 

  101. McKee C, et al. Amphiregulin activates human hepatic stellate cells and is upregulated in non alcoholic steatohepatitis. Sci Rep. 2015;5:8812.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Shah N, Nelson JE, Kowdley KV. MicroRNAs in liver disease: bench to bedside. J Clin Exp Hepatol. 2013;3:231–242.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Morishita A, Masaki T. miRNA in hepatocellular carcinoma. Hepatol Res. 2015;45:128–141.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

  107. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020–1022.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Saran U, et al. Hepatocellular carcinoma and lifestyles. J Hepatol. 2016;64:203–214.

    Article  PubMed  Google Scholar 

  109. Turati F, et al. Mediterranean diet and hepatocellular carcinoma. J Hepatol. 2014;60:606–611.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Dongiovanni P, et al. Statin use and non-alcoholic steatohepatitis in at risk individuals. J Hepatol. 2015;63:705–712.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  115. Williamson RM, et al. Prevalence and markers of advanced liver disease in type 2 diabetes. QJM. 2012;105:425–432.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Northern Institute for Cancer Research, Newcastle upon Tyne, UK

    Helen L. Reeves & Marco Y. W. Zaki

  2. Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK

    Christopher P. Day

Authors
  1. Helen L. Reeves
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marco Y. W. Zaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christopher P. Day
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Helen L. Reeves.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Reeves, H.L., Zaki, M.Y.W. & Day, C.P. Hepatocellular Carcinoma in Obesity, Type 2 Diabetes, and NAFLD. Dig Dis Sci 61, 1234–1245 (2016). https://doi.org/10.1007/s10620-016-4085-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-016-4085-6

Keywords

Search

Navigation