Advertisement

Obesity and Liver Cancer

  • Krasimira Aleksandrova
  • Marta Stelmach-Mardas
  • Sabrina Schlesinger
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 208)

Abstract

Obesity and related metabolic disorders have become globally prevalent posing a challenge for the chronically damaged liver and predisposing the development and progression of cancer. The rising phenomenon of “obesity epidemic” may provide means for understanding why liver cancer is one of the few malignancies with rising incidence in developed countries over the last decades. Non-alcoholic fatty liver disease associated with obesity, insulin resistance, and type 2 diabetes is an increasingly recognized trigger for liver cancer in Western populations characterized by low prevalence of established risk factors for liver cancer such as viral hepatitis and hepatotoxin exposure. Accumulating evidence has established an association between higher body mass index as an indicator of general obesity and higher risk of primary liver cancer. The associations are stronger in men, in patients with underlying liver disease and in white ethnic groups. Abdominal obesity, weight gain in adult life and metabolic factors related to visceral fat accumulation were also suggested as important risk factors for liver cancer; however, more studies are needed to evaluate these associations. The association of obesity and metabolic parameters with liver cancer survival remains controversial. It is unclear which exact mechanisms could provide links between obesity and liver cancer risk. Recent evidence has implicated several molecular pathways in obesity-associated liver cancer. These include insulin resistance leading to increased levels of insulin and insulin-like growth factors, chronic inflammation, adipose tissue remodeling, pro-inflammatory cytokine and adipokine secretion, and altered gut microbiota. These mechanisms coincide with inflammatory and metabolic processes occurring in non-alcoholic fatty liver disease predisposing cancer development and progression. In the context of the current evidence, better understanding of the role of obesity and related metabolic factors may help in improving current strategies for liver cancer prevention.

Keywords

Obesity Metabolic factors Inflammation Non-alcoholic fatty liver disease Liver cancer Prevention 

Abbreviations

HCC

Hepatocellular carcinoma

IBDC

Intrahepatic bile duct cancer

ICC

Intrahepatic cholangiocarcinoma

HCV

Hepatitis C virus

HBV

Hepatitis B virus

NAFLD

Non-alcoholic fatty liver disease

NASH

Non-alcoholic steatohepatitis

WCRF

World Cancer Research Fund

BMI

Body mass index

EPIC

The European Prospective Investigation into Cancer and Nutrition

WHO

World Health Organization

WC

Waist circumference

JNK-c

Jun N-terminal kinase

NF-kβ

Nuclear factor-kappaB

TLR

Toll-like receptors

IGF-I

The insulin-like growth factors I

IGF-II

The insulin-like growth factors II

IGFBP4

The insulin-like growth factors binding protein-4

HOMA

Homeostasis model assessment

ROS

Reactive oxygen species

TNF

Tumor necrosis factor

IL-6

Interleukin 6

CRP

C reactive protein

DCA

Deoxycholic acid

HSCs

Hepatic stellate cells

References

  1. 1.
    Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J (2012) Jemal A (2015) Global cancer statistics. CA Cancer J Clin 65(2):87–108. doi: 10.3322/caac.21262 CrossRefGoogle Scholar
  2. 2.
    World Health Organization, Fact sheet: Cancer. Available online: http://www.who.int/mediacentre/factsheets/fs297/en/. Accessed on 30 Aug 2015
  3. 3.
    Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin D, Forman D, Bray F (2014) v1.1 G cancer incidence and mortality worldwide: IARC CancerBase No. 11 [Internet]. International Agency for Research on Cancer, Lyon. Available from: http://globocan.iarc.fr. Accessed on 30 Aug 2015
  4. 4.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90. doi: 10.3322/caac.20107 (caac.20107 [pii])
  5. 5.
    El-Serag HB, Rudolph KL (2007) Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132(7):2557–2576. doi: 10.1053/j.gastro.2007.04.061 (S0016-5085(07)00799-8 [pii])
  6. 6.
    El-Serag HB (2011) Hepatocellular carcinoma. N Engl J Med 365(12):1118–1127. doi: 10.1056/NEJMra1001683 CrossRefPubMedGoogle Scholar
  7. 7.
    Center MM, Jemal A (2011) International trends in liver cancer incidence rates. Cancer Epidemiol Biomark Prev 20(11):2362–2368. doi: 10.1158/1055-9965.EPI-11-0643 (1055-9965.EPI-11-0643 [pii])
  8. 8.
    Cabibbo G, Craxi A (2010) Epidemiology, risk factors and surveillance of hepatocellular carcinoma. Eur Rev Med Pharmacol Sci 14(4):352–355PubMedGoogle Scholar
  9. 9.
    Welzel TM, Graubard BI, Zeuzem S, El-Serag HB, Davila JA, McGlynn KA (2011) Metabolic syndrome increases the risk of primary liver cancer in the United States: a study in the SEER-Medicare database. Hepatology 54(2):463–471. doi: 10.1002/hep.24397
  10. 10.
    Caldwell SH, Crespo DM, Kang HS, Al-Osaimi AM (2004) Obesity and hepatocellular carcinoma. Gastroenterology 127(5 Suppl 1):S97–S103. doi:S0016508504016002 [pii]Google Scholar
  11. 11.
    Vanni E, Bugianesi E, Kotronen A, De Minicis S, Yki-Jarvinen H, Svegliati-Baroni G (2010) From the metabolic syndrome to NAFLD or vice versa? Dig Liver Dis 42(5):320–330. doi: 10.1016/j.dld.2010.01.016 (S1590-8658(10)00020-4 [pii])
  12. 12.
    Alzahrani B, Iseli TJ, Hebbard LW (2014) Non-viral causes of liver cancer: does obesity led inflammation play a role? Cancer Lett 345(2):223–229. doi: 10.1016/j.canlet.2013.08.036
  13. 13.
    Bellentani S, Marino M (2009) Epidemiology and natural history of non-alcoholic fatty liver disease (NAFLD). Ann Hepatol 8(Suppl 1):S4–S8. doi:880345 [pii]Google Scholar
  14. 14.
    World Cancer Research Fund International/American Institute for Cancer Research (2015) Continuous update project report: diet, nutrition, physical activity and liver cancer. Available at: www.wcrf.org/sites/default/files/Liver-Cancer-2015-Report.pdf. Accessed on 30 Aug 2015
  15. 15.
    Larsson SC, Wolk A (2007) Overweight, obesity and risk of liver cancer: a meta-analysis of cohort studies. Br J Cancer 97(7):1005–1008. doi: 10.1038/sj.bjc.6603932 PubMedPubMedCentralGoogle Scholar
  16. 16.
    Rui R, Lou J, Zou L, Zhong R, Wang J, Xia D, Wang Q, Li H, Wu J, Lu X, Li C, Liu L, Xia J, Xu H (2012) Excess body mass index and risk of liver cancer: a nonlinear dose-response meta-analysis of prospective studies. PLoS ONE 7(9):e44522. doi: 10.1371/journal.pone.0044522 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Wang Y, Wang B, Shen F, Fan J, Cao H (2012) Body mass index and risk of primary liver cancer: a meta-analysis of prospective studies. Oncologist 17(11):1461–1468. doi: 10.1634/theoncologist.2012-0066 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Saunders D, Seidel D, Allison M, Lyratzopoulos G (2010) Systematic review: the association between obesity and hepatocellular carcinoma—epidemiological evidence. Aliment Pharmacol Ther 31(10):1051–1063. doi: 10.1111/j.1365-2036.2010.04271.x PubMedGoogle Scholar
  19. 19.
    Chen Y, Wang X, Wang J, Yan Z, Luo J (2012) Excess body weight and the risk of primary liver cancer: an updated meta-analysis of prospective studies. Eur J Cancer 48(14):2137–2145. doi: 10.1016/j.ejca.2012.02.063 CrossRefPubMedGoogle Scholar
  20. 20.
    World Health Organization (2000) Obesity: preventing and managing the global epidemic. Report of a WHO consultation. World Health Organ Tech Rep Ser 894:i–xii, 1–253Google Scholar
  21. 21.
    Setiawan VW, Lim U, Lipworth L, Lu SC, Shepherd J, Ernst T, Wilkens LR, Henderson BE, Le Marchand L (2016) Sex and ethnic differences in the association of obesity with risk of hepatocellular carcinoma. Clin Gastroenterol Hepatol 14(2):309–316. doi: 10.1016/j.cgh.2015.09.015 CrossRefPubMedGoogle Scholar
  22. 22.
    Garrow JS, Webster J (1985) Quetelet’s index (W/H2) as a measure of fatness. Int J Obes 9(2):147–153PubMedGoogle Scholar
  23. 23.
    Molarius A, Seidell JC (1998) Selection of anthropometric indicators for classification of abdominal fatness-a critical review. Int J Obes Relat Metab Disord 22(8):719–727CrossRefPubMedGoogle Scholar
  24. 24.
    Ashwell M (2009) Obesity risk: importance of the waist-to-height ratio. Nurs Stand 23(41):49–54CrossRefPubMedGoogle Scholar
  25. 25.
    Schlesinger S, Aleksandrova K, Pischon T, Fedirko V, Jenab M, Trepo E, Boffetta P, Dahm CC, Overvad K, Tjonneland A, Halkjaer J, Fagherazzi G, Boutron-Ruault MC, Carbonnel F, Kaaks R, Lukanova A, Boeing H, Trichopoulou A, Bamia C, Lagiou P, Palli D, Grioni S, Panico S, Tumino R, Vineis P, Hb BD, van den Berg S, Peeters PH, Braaten T, Weiderpass E, Quiros JR, Travier N, Sanchez MJ, Navarro C, Barricarte A, Dorronsoro M, Lindkvist B, Regner S, Werner M, Sund M, Khaw KT, Wareham N, Travis RC, Norat T, Wark PA, Riboli E, Nothlings U (2013) Abdominal obesity, weight gain during adulthood and risk of liver and biliary tract cancer in a European cohort. Int J Cancer 132(3):645–657. doi: 10.1002/ijc.27645 CrossRefPubMedGoogle Scholar
  26. 26.
    Pang Q, Zhang JY, Qu K, Song SD, Liu SS, Liu C (2015) Central obesity induces a greater risk of hepatocellular carcinoma than general obesity. Hepatology 62(3):979–980. doi: 10.1002/hep.27668 CrossRefPubMedGoogle Scholar
  27. 27.
    Hassan MM, Abdel-Wahab R, Kaseb A, Shalaby A, Phan AT, El-Serag HB, Hawk E, Morris J, Singh Raghav KP, Lee JS, Vauthey JN, Bortus G, Torres HA, Amos CI, Wolff RA, Li D (2015) Obesity early in adulthood increases risk but does not affect outcomes of hepatocellular carcinoma. Gastroenterology 149(1):119–129. doi: 10.1053/j.gastro.2015.03.044 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Li Y, Yatsuya H, Yamagishi K, Wakai K, Tamakoshi A, Iso H, Mori M, Sakauchi F, Motohashi Y, Tsuji I, Nakamura Y, Mikami H, Kurosawa M, Hoshiyama Y, Tanabe N, Tamakoshi K, Tokudome S, Suzuki K, Hashimoto S, Kikuchi S, Wada Y, Kawamura T, Watanabe Y, Ozasa K, Miki T, Date C, Sakata K, Kurozawa Y, Yoshimura T, Fujino Y, Shibata A, Okamoto N, Shio H (2013) Body mass index and weight change during adulthood are associated with increased mortality from liver cancer: the JACC Study. J Epidemiol/Jpn Epidemiol Assoc 23(3):219–226CrossRefGoogle Scholar
  29. 29.
    Duan XY, Zhang L, Fan JG, Qiao L (2014) NAFLD leads to liver cancer: do we have sufficient evidence? Cancer Lett 345(2):230–234. doi: 10.1016/j.canlet.2013.07.033
  30. 30.
    Michelotti GA, Machado MV, Diehl AM (2013) NAFLD, NASH and liver cancer. Nat Rev Gastroenterol Hepatol 10(11):656–665. doi: 10.1038/nrgastro.2013.183 CrossRefPubMedGoogle Scholar
  31. 31.
    Dongiovanni P, Romeo S, Valenti L (2014) Hepatocellular carcinoma in nonalcoholic fatty liver: role of environmental and genetic factors. World J Gastroenterol 20(36):12945–12955. doi: 10.3748/wjg.v20.i36.12945 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Clark JM (2006) The epidemiology of nonalcoholic fatty liver disease in adults. J Clin Gastroenterol 40(Suppl 1):S5–S10. doi: 10.1097/01.mcg.0000168638.84840.ff PubMedGoogle Scholar
  33. 33.
    Marrero JA, Fontana RJ, Su GL, Conjeevaram HS, Emick DM, Lok AS (2002) NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States. Hepatology 36(6):1349–1354. doi: 10.1053/jhep.2002.36939 CrossRefPubMedGoogle Scholar
  34. 34.
    Colicchio P, Tarantino G, del Genio F, Sorrentino P, Saldalamacchia G, Finelli C, Conca P, Contaldo F, Pasanisi F (2005) Non-alcoholic fatty liver disease in young adult severely obese non-diabetic patients in South Italy. Ann Nutr Metab 49(5):289–295. doi: 10.1159/000087295 CrossRefPubMedGoogle Scholar
  35. 35.
    Yu J, Shen J, Sun TT, Zhang X, Wong N (2013) Obesity, insulin resistance, NASH and hepatocellular carcinoma. Semin Cancer Biol 23(6 Pt B):483–491. doi: 10.1016/j.semcancer.2013.07.003
  36. 36.
    Kashyap SR, Diab DL, Baker AR, Yerian L, Bajaj H, Gray-McGuire C, Schauer PR, Gupta M, Feldstein AE, Hazen SL, Stein CM (2009) Triglyceride levels and not adipokine concentrations are closely related to severity of nonalcoholic fatty liver disease in an obesity surgery cohort. Obesity 17(9):1696–1701. doi: 10.1038/oby.2009.89
  37. 37.
    Park EJ, Lee JH, Yu GY, He G, Ali SR, Holzer RG, Osterreicher CH, Takahashi H, Karin M (2010) Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140(2):197–208. doi: 10.1016/j.cell.2009.12.052 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Guzman G, Brunt EM, Petrovic LM, Chejfec G, Layden TJ, Cotler SJ (2008) Does nonalcoholic fatty liver disease predispose patients to hepatocellular carcinoma in the absence of cirrhosis? Arch Pathol Lab Med 132(11):1761–1766. doi: 10.1043/1543-2165-132.11.1761
  39. 39.
    Rahman R, Hammoud GM, Almashhrawi AA, Ahmed KT, Ibdah JA (2013) Primary hepatocellular carcinoma and metabolic syndrome: an update. World J Gastrointest Oncol 5(9):186–194. doi: 10.4251/wjgo.v5.i9.186 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Grundy SM (2015) Metabolic syndrome update. Trends Cardiovasc Med. doi: 10.1016/j.tcm.2015.10.004 PubMedGoogle Scholar
  41. 41.
    Aleksandrova K, Boeing H, Jenab M, Bas Bueno-de-Mesquita H, Jansen E, van Duijnhoven FJ, Fedirko V, Rinaldi S, Romieu I, Riboli E, Romaguera D, Overvad K, Ostergaard JN, Olsen A, Tjonneland A, Boutron-Ruault MC, Clavel-Chapelon F, Morois S, Masala G, Agnoli C, Panico S, Tumino R, Vineis P, Kaaks R, Lukanova A, Trichopoulou A, Naska A, Bamia C, Peeters PH, Rodriguez L, Buckland G, Sanchez MJ, Dorronsoro M, Huerta JM, Barricarte A, Hallmans G, Palmqvist R, Khaw KT, Wareham N, Allen NE, Tsilidis KK, Pischon T (2011) Metabolic syndrome and risks of colon and rectal cancer: the European prospective investigation into cancer and nutrition study. Cancer Prev Res 4(11):1873–1883. doi: 10.1158/1940-6207.CAPR-11-0218 CrossRefGoogle Scholar
  42. 42.
    Siegel AB, Zhu AX (2009) Metabolic syndrome and hepatocellular carcinoma: two growing epidemics with a potential link. Cancer 115(24):5651–5661. doi: 10.1002/cncr.24687 CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Ertle J, Dechene A, Sowa JP, Penndorf V, Herzer K, Kaiser G, Schlaak JF, Gerken G, Syn WK, Canbay A (2011) Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis. Int J Cancer J Int Cancer 128(10):2436–2443. doi: 10.1002/ijc.25797 CrossRefGoogle Scholar
  44. 44.
    Paradis V, Zalinski S, Chelbi E, Guedj N, Degos F, Vilgrain V, Bedossa P, Belghiti J (2009) Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis. Hepatology 49(3):851–859. doi: 10.1002/hep.22734 CrossRefPubMedGoogle Scholar
  45. 45.
    Borena W, Strohmaier S, Lukanova A, Bjorge T, Lindkvist B, Hallmans G, Edlinger M, Stocks T, Nagel G, Manjer J, Engeland A, Selmer R, Haggstrom C, Tretli S, Concin H, Jonsson H, Stattin P, Ulmer H (2012) Metabolic risk factors and primary liver cancer in a prospective study of 578,700 adults. Int J Cancer J Int Cancer 131(1):193–200. doi: 10.1002/ijc.26338 CrossRefGoogle Scholar
  46. 46.
    Yasui K, Hashimoto E, Komorizono Y, Koike K, Arii S, Imai Y, Shima T, Kanbara Y, Saibara T, Mori T, Kawata S, Uto H, Takami S, Sumida Y, Takamura T, Kawanaka M, Okanoue T (2011) Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma. Clin Gastroenterol Hepatol (The Official Clinical Practice Journal of the American Gastroenterological Association) 9(5):428–433; quiz e450. doi: 10.1016/j.cgh.2011.01.023
  47. 47.
    Duan XY, Qiao L, Fan JG (2012) Clinical features of nonalcoholic fatty liver disease-associated hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int (HBPD INT) 11(1):18–27CrossRefGoogle Scholar
  48. 48.
    Nagaoki Y, Hyogo H, Aikata H, Tanaka M, Naeshiro N, Nakahara T, Honda Y, Miyaki D, Kawaoka T, Takaki S, Hiramatsu A, Waki K, Imamura M, Kawakami Y, Takahashi S, Chayama K (2012) Recent trend of clinical features in patients with hepatocellular carcinoma. Hepatol Res (The Official Journal of the Japan Society of Hepatology) 42(4):368–375. doi: 10.1111/j.1872-034X.2011.00929.x CrossRefGoogle Scholar
  49. 49.
    Wang C, Wang X, Gong G, Ben Q, Qiu W, Chen Y, Li G, Wang L (2012) Increased risk of hepatocellular carcinoma in patients with diabetes mellitus: a systematic review and meta-analysis of cohort studies. Int J Cancer 130(7):1639–1648. doi: 10.1002/ijc.26165 CrossRefPubMedGoogle Scholar
  50. 50.
    Kawaguchi T, Kohjima M, Ichikawa T, Seike M, Ide Y, Mizuta T, Honda K, Nakao K, Nakamuta M, Sata M (2015) The morbidity and associated risk factors of cancer in chronic liver disease patients with diabetes mellitus: a multicenter field survey. J Gastroenterol 50(3):333–341. doi: 10.1007/s00535-014-0968-5 CrossRefPubMedGoogle Scholar
  51. 51.
    Turati F, Talamini R, Pelucchi C, Polesel J, Franceschi S, Crispo A, Izzo F, La Vecchia C, Boffetta P, Montella M (2012) Metabolic syndrome and hepatocellular carcinoma risk. Br J Cancer. doi: 10.1038/bjc.2012.492 (bjc2012492 [pii])
  52. 52.
    Polesel J, Zucchetto A, Montella M, Dal Maso L, Crispo A, La Vecchia C, Serraino D, Franceschi S, Talamini R (2009) The impact of obesity and diabetes mellitus on the risk of hepatocellular carcinoma. Ann Oncol 20(2):353–357. doi: 10.1093/annonc/mdn565 (mdn565 [pii])
  53. 53.
    Schlesinger S, Aleksandrova K, Pischon T, Jenab M, Fedirko V, Trepo E, Overvad K, Roswall N, Tjonneland A, Boutron-Ruault MC, Fagherazzi G, Racine A, Kaaks R, Grote VA, Boeing H, Trichopoulou A, Pantzalis M, Kritikou M, Mattiello A, Sieri S, Sacerdote C, Palli D, Tumino R, Peeters PH, Bueno-de-Mesquita HB, Weiderpass E, Quiros JR, Zamora-Ros R, Sanchez MJ, Arriola L, Ardanaz E, Tormo MJ, Nilsson P, Lindkvist B, Sund M, Rolandsson O, Khaw KT, Wareham N, Travis RC, Riboli E, Nothlings U (2013) Diabetes mellitus, insulin treatment, diabetes duration, and risk of biliary tract cancer and hepatocellular carcinoma in a European cohort. Ann Oncol. doi: 10.1093/annonc/mdt204 (mdt204 [pii])
  54. 54.
    Karagozian R, Derdak Z, Baffy G (2014) Obesity-associated mechanisms of hepatocarcinogenesis. Metab Clin Exp 63(5):607–617. doi: 10.1016/j.metabol.2014.01.011 CrossRefPubMedGoogle Scholar
  55. 55.
    Marchesini G, Moscatiello S, Di Domizio S, Forlani G (2008) Obesity-associated liver disease. J Clin Endocrinol Metab 93(11 Suppl 1):S74–S80. doi: 10.1210/jc.2008-1399 (93/11_Supplement_1/s74 [pii])
  56. 56.
    Xu L, Kitade H, Ni Y, Ota T (2015) Roles of chemokines and chemokine receptors in obesity-associated insulin resistance and nonalcoholic fatty liver disease. Biomolecules 5(3):1563–1579. doi: 10.3390/biom5031563 CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Wree A, Kahraman A, Gerken G, Canbay A (2011) Obesity affects the liver—the link between adipocytes and hepatocytes. Digestion 83(1–2):124–133. doi: 10.1159/000318741 (000318741 [pii])
  58. 58.
    Eguchi Y, Eguchi T, Mizuta T, Ide Y, Yasutake T, Iwakiri R, Hisatomi A, Ozaki I, Yamamoto K, Kitajima Y, Kawaguchi Y, Kuroki S, Ono N (2006) Visceral fat accumulation and insulin resistance are important factors in nonalcoholic fatty liver disease. J Gastroenterol 41(5):462–469. doi: 10.1007/s00535-006-1790-5 CrossRefPubMedGoogle Scholar
  59. 59.
    Eguchi Y, Mizuta T, Sumida Y, Ishibashi E, Kitajima Y, Isoda H, Horie H, Tashiro T, Iwamoto E, Takahashi H, Kuwashiro T, Soejima S, Kawaguchi Y, Oda Y, Emura S, Iwakiri R, Ozaki I, Eguchi T, Ono N, Anzai K, Fujimoto K, Koizumi S (2011) The pathological role of visceral fat accumulation in steatosis, inflammation, and progression of nonalcoholic fatty liver disease. J Gastroenterol 46(Suppl 1):70–78. doi: 10.1007/s00535-010-0340-3 CrossRefPubMedGoogle Scholar
  60. 60.
    Greenberg AS, Obin MS (2006) Obesity and the role of adipose tissue in inflammation and metabolism. Am J Clin Nutr 83(2):461S–465S. doi:83/2/461S [pii]Google Scholar
  61. 61.
    Calle EE, Kaaks R (2004) Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer 4(8):579–591. doi: 10.1038/nrc1408nrc1408
  62. 62.
    Aleksandrova K, Nimptsch K, Pischon T (2013) Influence of obesity and related metabolic alterations on colorectal cancer risk. Curr Nutr Rep 2(1):1–9. doi: 10.1007/s13668-012-0036-9 CrossRefPubMedGoogle Scholar
  63. 63.
    Balkau B, Kahn HS, Courbon D, Eschwege E, Ducimetiere P, Paris Prospective S (2001) Hyperinsulinemia predicts fatal liver cancer but is inversely associated with fatal cancer at some other sites: the Paris prospective study. Diabetes Care 24(5):843–849CrossRefPubMedGoogle Scholar
  64. 64.
    Tanaka S, Mohr L, Schmidt EV, Sugimachi K, Wands JR (1997) Biological effects of human insulin receptor substrate-1 overexpression in hepatocytes. Hepatology 26(3):598–604. doi: 10.1002/hep.510260310 CrossRefPubMedGoogle Scholar
  65. 65.
    LeRoith D, Baserga R, Helman L, Roberts CT Jr (1995) Insulin-like growth factors and cancer. Ann Intern Med 122(1):54–59CrossRefPubMedGoogle Scholar
  66. 66.
    Clemmons DR (1997) Insulin-like growth factor binding proteins and their role in controlling IGF actions. Cytokine Growth Factor Rev 8(1):45–62CrossRefPubMedGoogle Scholar
  67. 67.
    Scharf JG, Ramadori G, Dombrowski F (2000) Analysis of the IGF axis in preneoplastic hepatic foci and hepatocellular neoplasms developing after low-number pancreatic islet transplantation into the livers of streptozotocin diabetic rats. Lab Invest (A Journal of Technical Methods and Pathology) 80(9):1399–1411CrossRefGoogle Scholar
  68. 68.
    Mallea-Gil MS, Ballarino MC, Spiraquis A, Iriarte M, Kura M, Gimenez S, Oneto A, Guitelman M, Machado R, Miguel CM (2012) IGF-1 levels in different stages of liver steatosis and its association with metabolic syndrome. Acta Gastroenterol Latinoam 42(1):20–26PubMedGoogle Scholar
  69. 69.
    Runchey SS, Boyko EJ, Ioannou GN, Utzschneider KM (2014) Relationship between serum circulating insulin-like growth factor-1 and liver fat in the United States. J Gastroenterol Hepatol 29(3):589–596CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Qiao L, Li X (2014) Role of chronic inflammation in cancers of the gastrointestinal system and the liver: where we are now. Cancer Lett 345(2):150–152. doi: 10.1016/j.canlet.2013.10.013 CrossRefPubMedGoogle Scholar
  71. 71.
    Marra F, Tacke F (2014) Roles for chemokines in liver disease. Gastroenterology 147(3):577–594 e571. doi: 10.1053/j.gastro.2014.06.043
  72. 72.
    Stauffer JK, Scarzello AJ, Jiang Q, Wiltrout RH (2012) Chronic inflammation, immune escape, and oncogenesis in the liver: a unique neighborhood for novel intersections. Hepatology 56(4):1567–1574. doi: 10.1002/hep.25674 CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Aleksandrova K, Boeing H, Nothlings U, Jenab M, Fedirko V, Kaaks R, Lukanova A, Trichopoulou A, Trichopoulos D, Boffetta P, Trepo E, Westhpal S, Duarte-Salles T, Stepien M, Overvad K, Tjonneland A, Halkjaer J, Boutron-Ruault MC, Dossus L, Racine A, Lagiou P, Bamia C, Benetou V, Agnoli C, Palli D, Panico S, Tumino R, Vineis P, Bueno-de-Mesquita B, Peeters PH, Gram IT, Lund E, Weiderpass E, Quiros JR, Agudo A, Sanchez MJ, Gavrila D, Barricarte A, Dorronsoro M, Ohlsson B, Lindkvist B, Johansson A, Sund M, Khaw KT, Wareham N, Travis RC, Riboli E, Pischon T (2014) Inflammatory and metabolic biomarkers and risk of liver and biliary tract cancer. Hepatology 60(3):858–871. doi: 10.1002/hep.27016 CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Ohishi W, Cologne JB, Fujiwara S, Suzuki G, Hayashi T, Niwa Y, Akahoshi M, Ueda K, Tsuge M, Chayama K (2014) Serum interleukin-6 associated with hepatocellular carcinoma risk: a nested case-control study. Int J Cancer J Int Cancer 134(1):154–163. doi: 10.1002/ijc.28337 CrossRefGoogle Scholar
  75. 75.
    Abenavoli L, Peta V (2014) Role of adipokines and cytokines in non-alcoholic fatty liver disease. Rev Recent Clin Trials 9(3):134–140CrossRefPubMedGoogle Scholar
  76. 76.
    Bekaert M, Verhelst X, Geerts A, Lapauw B, Calders P (2016) Association of recently described adipokines with liver histology in biopsy-proven non-alcoholic fatty liver disease: a systematic review. Obes Rev (An Official Journal of the International Association for the Study of Obesity) 17(1):68–80. doi: 10.1111/obr.12333 CrossRefGoogle Scholar
  77. 77.
    Kalafateli M, Triantos C, Tsochatzis E, Michalaki M, Koutroumpakis E, Thomopoulos K, Kyriazopoulou V, Jelastopulu E, Burroughs A, Lambropoulou-Karatza C, Nikolopoulou V (2015) Adipokines levels are associated with the severity of liver disease in patients with alcoholic cirrhosis. World J Gastroenterol 21(10):3020–3029. doi: 10.3748/wjg.v21.i10.3020 CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Polyzos SA, Kountouras J, Mantzoros CS (2015) Adipokines in nonalcoholic fatty liver disease. Metab Clin Exp. doi: 10.1016/j.metabol.2015.11.006
  79. 79.
    Stojsavljevic S, Gomercic Palcic M, Virovic Jukic L, Smircic Duvnjak L, Duvnjak M (2014) Adipokines and proinflammatory cytokines, the key mediators in the pathogenesis of nonalcoholic fatty liver disease. World J Gastroenterol 20(48):18070–18091. doi: 10.3748/wjg.v20.i48.18070 CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Bertolani C, Marra F (2008) The role of adipokines in liver fibrosis. Pathophysiology (The Official Journal of the International Society for Pathophysiology/ISP) 15(2):91–101. doi: 10.1016/j.pathophys.2008.05.001 Google Scholar
  81. 81.
    Jung UJ, Choi MS (2014) Obesity and its metabolic complications: the role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease. Int J Mol Sci 15(4):6184–6223. doi: 10.3390/ijms15046184 CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Shah NR, Braverman ER (2012) Measuring adiposity in patients: the utility of body mass index (BMI), percent body fat, and leptin. PLoS ONE 7(4):e33308. doi: 10.1371/journal.pone.0033308 CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Polyzos SA, Kountouras J, Zavos C, Deretzi G (2011) The potential adverse role of leptin resistance in nonalcoholic fatty liver disease: a hypothesis based on critical review of the literature. J Clin Gastroenterol 45(1):50–54. doi: 10.1097/MCG.0b013e3181ec5c66 CrossRefPubMedGoogle Scholar
  84. 84.
    Dutta D, Ghosh S, Pandit K, Mukhopadhyay P, Chowdhury S (2012) Leptin and cancer: pathogenesis and modulation. Indian J Endocrinol Metab 16(Suppl 3):S596–S600. doi: 10.4103/2230-8210.105577 PubMedPubMedCentralGoogle Scholar
  85. 85.
    Polyzos SA, Aronis KN, Kountouras J, Raptis DD, Vasiloglou MF, Mantzoros CS (2016) Circulating leptin in non-alcoholic fatty liver disease: a systematic review and meta-analysis. Diabetologia 59(1):30–43. doi: 10.1007/s00125-015-3769-3 CrossRefPubMedGoogle Scholar
  86. 86.
    Ribatti D, Belloni AS, Nico B, Di Comite M, Crivellato E, Vacca A (2008) Leptin-leptin receptor are involved in angiogenesis in human hepatocellular carcinoma. Peptides 29(9):1596–1602. doi: 10.1016/j.peptides.2008.05.011 CrossRefPubMedGoogle Scholar
  87. 87.
    Elinav E, Abd-Elnabi A, Pappo O, Bernstein I, Klein A, Engelhardt D, Rabbani E, Ilan Y (2006) Suppression of hepatocellular carcinoma growth in mice via leptin, is associated with inhibition of tumor cell growth and natural killer cell activation. J Hepatol 44(3):529–536. doi: 10.1016/j.jhep.2005.08.013 CrossRefPubMedGoogle Scholar
  88. 88.
    Moschen AR, Wieser V, Tilg H (2012) Adiponectin: key player in the adipose tissue-liver crosstalk. Curr Med Chem 19(32):5467–5473CrossRefPubMedGoogle Scholar
  89. 89.
    Wieser V, Moschen AR, Tilg H (2012) Adipocytokines and hepatocellular carcinoma. Dig Dis 30(5):508–513. doi: 10.1159/000341702 CrossRefPubMedGoogle Scholar
  90. 90.
    Kamada Y, Takehara T, Hayashi N (2008) Adipocytokines and liver disease. J Gastroenterol 43(11):811–822. doi: 10.1007/s00535-008-2213-6 CrossRefPubMedGoogle Scholar
  91. 91.
    Nkontchou G, Bastard JP, Ziol M, Aout M, Cosson E, Ganne-Carrie N, Grando-Lemaire V, Roulot D, Capeau J, Trinchet JC, Vicaut E, Beaugrand M (2010) Insulin resistance, serum leptin, and adiponectin levels and outcomes of viral hepatitis C cirrhosis. J Hepatol 53(5):827–833. doi: 10.1016/j.jhep.2010.04.035 CrossRefPubMedGoogle Scholar
  92. 92.
    Arano T, Nakagawa H, Tateishi R, Ikeda H, Uchino K, Enooku K, Goto E, Masuzaki R, Asaoka Y, Kondo Y, Goto T, Shiina S, Omata M, Yoshida H, Koike K (2011) Serum level of adiponectin and the risk of liver cancer development in chronic hepatitis C patients. Int J Cancer J Int Cancer 129(9):2226–2235. doi: 10.1002/ijc.25861 CrossRefGoogle Scholar
  93. 93.
    Michikawa T, Inoue M, Sawada N, Sasazuki S, Tanaka Y, Iwasaki M, Shimazu T, Yamaji T, Mizokami M, Tsugane S, Japan Public Health Center-based Prospective Study G (2013) Plasma levels of adiponectin and primary liver cancer risk in middle-aged Japanese adults with hepatitis virus infection: a nested case-control study. Cancer Epidemiol Biomark Prev (A Publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology) 22(12):2250–2257. doi: 10.1158/1055-9965.EPI-13-0363
  94. 94.
    Hara E (2015) Relationship between obesity, gut microbiome and hepatocellular carcinoma development. Dig Dis 33(3):346–350. doi: 10.1159/000371679 CrossRefPubMedGoogle Scholar
  95. 95.
    Itoh S, Ikeda Y, Kawanaka H, Okuyama T, Kawasaki K, Eguchi D, Korenaga D, Takenaka K (2012) The effect of overweight status on the short-term and 20-y outcomes after hepatic resection in patients with hepatocellular carcinoma. J Surg Res 178(2):640–645. doi: 10.1016/j.jss.2012.05.063 CrossRefPubMedGoogle Scholar
  96. 96.
    Okamura Y, Maeda A, Matsunaga K, Kanemoto H, Uesaka K (2012) Negative impact of low body mass index on surgical outcomes after hepatectomy for hepatocellular carcinoma. J Hepato-Biliary-Pancreat Sci 19(4):449–457. doi: 10.1007/s00534-011-0461-y CrossRefGoogle Scholar
  97. 97.
    Mathur AK, Ghaferi AA, Sell K, Sonnenday CJ, Englesbe MJ, Welling TH (2010) Influence of body mass index on complications and oncologic outcomes following hepatectomy for malignancy. J Gastrointest Surg (Official Journal of the Society for Surgery of the Alimentary Tract) 14(5):849–857. doi: 10.1007/s11605-010-1163-5 CrossRefGoogle Scholar
  98. 98.
    Nishikawa H, Arimoto A, Wakasa T, Kita R, Kimura T, Osaki Y (2013) The relation between obesity and survival after surgical resection of hepatitis C virus-related hepatocellular carcinoma. Gastroenterol Res Pract 2013:430438. doi: 10.1155/2013/430438 CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Nishikawa H, Osaki Y, Takeda H, Sakamoto A, Saito S, Nishijima N, Nasu A, Arimoto A, Kita R, Kimura T (2013) Effect of body mass index on survival after curative therapy for non-B non-C hepatocellular carcinoma. J Gastrointest Liver Dis (JGLD) 22(2):173–181Google Scholar
  100. 100.
    Liu XY, Xu JF (2014) Liver resection for young patients with large hepatocellular carcinoma: a single center experience from China. World J Surg Oncol 12:175. doi: 10.1186/1477-7819-12-175 CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Guo Z, Zhang J, Jiang JH, Li LQ, Xiang BD (2015) Obesity does not influence outcomes in hepatocellular carcinoma patients following curative hepatectomy. PLoS ONE 10(5):e0125649. doi: 10.1371/journal.pone.0125649 CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Rong X, Wei F, Geng Q et al (2015) The Association Between Body Mass Index and the Prognosis and Postoperative Complications of Hepatocellular Carcinoma: A Meta-Analysis. In: Isabella R (ed) Medicine 94(31):e1269. doi: 10.1097/MD.0000000000001269

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Krasimira Aleksandrova
    • 1
  • Marta Stelmach-Mardas
    • 2
    • 3
  • Sabrina Schlesinger
    • 4
    • 5
  1. 1.Nutrition, Immunity and Metabolism Start-up Lab, Department of EpidemiologyGerman Institute of Human Nutrition Potsdam-RehbrückeNuthetalGermany
  2. 2.Department of EpidemiologyGerman Institute of Human Nutrition Potsdam-RehbrückeNuthetalGermany
  3. 3.Department of Pediatric Gastroenterology and Metabolic DiseasesPoznan University of Medical SciencesPoznanPoland
  4. 4.Institute of EpidemiologyChristian-Albrechts University of KielKielGermany
  5. 5.Department of Epidemiology and Biostatistics, School of Public HealthImperial College LondonLondonUK

Personalised recommendations