Obesity Early in Adulthood Increases Risk but Does Not Affect Outcomes of Hepatocellular Carcinoma

      Background & Aims

      Despite the significant association between obesity and several cancers, it has been difficult to establish an association between obesity and hepatocellular carcinoma (HCC). Patients with HCC often have ascites, making it a challenge to determine body mass index (BMI) accurately, and many factors contribute to the development of HCC. We performed a case–control study to investigate whether obesity early in adulthood affects risk, age of onset, or outcomes of patients with HCC.


      We interviewed 622 patients newly diagnosed with HCC from January 2004 through December 2013, along with 660 healthy controls (frequency-matched by age and sex) to determine weights, heights, and body sizes (self-reported) at various ages before HCC development or enrollment as controls. Multivariable logistic and Cox regression analyses were performed to determine the independent effects of early obesity on risk for HCC and patient outcomes, respectively. BMI was calculated, and patients with a BMI of 30 kg/m2 or greater were considered obese.


      Obesity in early adulthood (age, mid-20s to mid-40s) is a significant risk factor for HCC. The estimated odds ratios were 2.6 (95% confidence interval [CI], 1.4–4.4), 2.3 (95% CI, 1.2−4.4), and 3.6 (95% CI, 1.5–8.9) for the entire population, for men, and for women, respectively. Each unit increase in BMI at early adulthood was associated with a 3.89-month decrease in age at HCC diagnosis (P < .001). Moreover, there was a synergistic interaction between obesity and hepatitis virus infection. However, we found no effect of obesity on the overall survival of patients with HCC.


      Early adulthood obesity is associated with an increased risk of developing HCC at a young age in the absence of major HCC risk factors, with no effect on outcomes of patients with HCC.


      Abbreviations used in this paper:

      BMI (body mass index), CI (confidence interval), CLD (chronic liver disease), HBV (hepatitis B virus), HCC (hepatocellular carcinoma), HCV (hepatitis C virus), OR (odds ratio), S (synergetic index)
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        • Ng M.
        • Fleming T.
        • Robinson M.
        • et al.
        Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013.
        Lancet. 2014; 384: 766-781
        • Wild S.
        • Roglic G.
        • Green A.
        • et al.
        Global prevalence of diabetes: estimates for the year 2000 and projections for 2030.
        Diabetes Care. 2004; 27: 1047-1053
        • Venook A.P.
        • Papandreou C.
        • Furuse J.
        • et al.
        The incidence and epidemiology of hepatocellular carcinoma: a global and regional perspective.
        Oncologist. 2010; 15: 5-13
        • Altekruse S.F.
        • McGlynn K.A.
        • Reichman M.E.
        Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005.
        J Clin Oncol. 2009; 27: 1485-1491
        • Alhyas L.
        • McKay A.
        • Balasanthiran A.
        • et al.
        Prevalences of overweight, obesity, hyperglycaemia, hypertension and dyslipidaemia in the Gulf: systematic review.
        JRSM Short Rep. 2011; 2: 55
        • Ramirez A.G.
        • Munoz E.
        • Holden A.E.
        • et al.
        Incidence of hepatocellular carcinoma in Texas Latinos, 1995-2010: an update.
        PLoS One. 2014; 9: e99365
        • Renehan A.G.
        • Tyson M.
        • Egger M.
        • et al.
        Body mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies.
        Lancet. 2008; 371: 569-578
        • Saunders D.
        • Seidel D.
        • Allison M.
        • et al.
        Systematic review: the association between obesity and hepatocellular carcinoma–epidemiological evidence.
        Aliment Pharmacol Ther. 2010; 31: 1051-1063
        • Larsson S.C.
        • Wolk A.
        Overweight, obesity and risk of liver cancer: a meta-analysis of cohort studies.
        Br J Cancer. 2007; 97: 1005-1008
        • Donato F.
        • Tagger A.
        • Gelatti U.
        • et al.
        Alcohol and hepatocellular carcinoma: the effect of lifetime intake and hepatitis virus infections in men and women.
        Am J Epidemiol. 2002; 155: 323-331
        • Hassan M.M.
        • Kaseb A.
        • Etzel C.J.
        • et al.
        Genetic variation in the PNPLA3 gene and hepatocellular carcinoma in USA: risk and prognosis prediction.
        Mol Carcinog. 2013; 52: E139-E147
        • Kaseb A.O.
        • Morris J.S.
        • Hassan M.M.
        • et al.
        Clinical and prognostic implications of plasma insulin-like growth factor-1 and vascular endothelial growth factor in patients with hepatocellular carcinoma.
        J Clin Oncol. 2011; 29: 3892-3899
        • Kaseb A.O.
        • Xiao L.
        • Hassan M.M.
        • et al.
        Development and validation of insulin-like growth factor-1 score to assess hepatic reserve in hepatocellular carcinoma.
        J Natl Cancer Inst. 2014; 106: 5
        • Rothman K.J.
        • Greenland S.
        • Walker A.M.
        Concepts of interaction.
        Am J Epidemiol. 1980; 112: 467-470
        • Rothman K.J.
        The estimation of synergy or antagonism.
        Am J Epidemiol. 1976; 103: 506-511
        • Hassan M.M.
        • Spitz M.R.
        • Thomas M.B.
        • et al.
        Effect of different types of smoking and synergism with hepatitis C virus on risk of hepatocellular carcinoma in American men and women: case-control study.
        Int J Cancer. 2008; 123: 1883-1891
        • Hassan M.M.
        • Curley S.A.
        • Li D.
        • et al.
        Association of diabetes duration and diabetes treatment with the risk of hepatocellular carcinoma.
        Cancer. 2010; 116: 1938-1946
        • Hassan M.M.
        • Spitz M.R.
        • Thomas M.B.
        • et al.
        The association of family history of liver cancer with hepatocellular carcinoma: a case-control study in the United States.
        J Hepatol. 2009; 50: 334-341
        • Hassan M.M.
        • Hwang L.Y.
        • Hatten C.J.
        • et al.
        Risk factors for hepatocellular carcinoma: synergism of alcohol with viral hepatitis and diabetes mellitus.
        Hepatology. 2002; 36: 1206-1213
        • Marrero C.R.
        • Marrero J.A.
        Viral hepatitis and hepatocellular carcinoma.
        Arch Med Res. 2007; 38: 612-620
        • El-Serag H.B.
        • Hampel H.
        • Javadi F.
        The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence.
        Clin Gastroenterol Hepatol. 2006; 4: 369-380
        • Yu M.C.
        • Yuan J.M.
        • Lu S.C.
        Alcohol, cofactors and the genetics of hepatocellular carcinoma.
        J Gastroenterol Hepatol. 2008; 23: S92-S97
        • Persson E.C.
        • Schwartz L.M.
        • Park Y.
        • et al.
        Alcohol consumption, folate intake, hepatocellular carcinoma, and liver disease mortality.
        Cancer Epidemiol Biomarkers Prev. 2013; 22: 415-421
        • Bosetti C.
        • Turati F.
        • La V.C.
        Hepatocellular carcinoma epidemiology.
        Best Pract Res Clin Gastroenterol. 2014; 28: 753-770
        • Welzel T.M.
        • Graubard B.I.
        • Quraishi S.
        • et al.
        Population-attributable fractions of risk factors for hepatocellular carcinoma in the United States.
        Am J Gastroenterol. 2013; 108: 1314-1321
        • Ohki T.
        • Tateishi R.
        • Sato T.
        • et al.
        Obesity is an independent risk factor for hepatocellular carcinoma development in chronic hepatitis C patients.
        Clin Gastroenterol Hepatol. 2008; 6: 459-464
        • Chen C.L.
        • Yang H.I.
        • Yang W.S.
        • et al.
        Metabolic factors and risk of hepatocellular carcinoma by chronic hepatitis B/C infection: a follow-up study in Taiwan.
        Gastroenterology. 2008; 135: 111-121
        • Nair S.
        • Mason A.
        • Eason J.
        • et al.
        Is obesity an independent risk factor for hepatocellular carcinoma in cirrhosis?.
        Hepatology. 2002; 36: 150-155
        • Czaja A.J.
        • Carpenter H.A.
        • Santrach P.J.
        • et al.
        Host- and disease-specific factors affecting steatosis in chronic hepatitis C.
        J Hepatol. 1998; 29: 198-206
        • Khandekar M.J.
        • Cohen P.
        • Spiegelman B.M.
        Molecular mechanisms of cancer development in obesity.
        Nat Rev Cancer. 2011; 11: 886-895
        • Polonsky K.S.
        Dynamics of insulin secretion in obesity and diabetes.
        Int J Obes Relat Metab Disord. 2000; 24: S29-S31
        • Meyer M.R.
        • Clegg D.J.
        • Prossnitz E.R.
        • et al.
        Obesity, insulin resistance and diabetes: sex differences and role of oestrogen receptors.
        Acta Physiol (Oxf). 2011; 203: 259-269
        • Qian Y.
        • Fan J.G.
        Obesity, fatty liver and liver cancer.
        Hepatobiliary Pancreat Dis Int. 2005; 4: 173-177
        • Wood P.A.
        Connecting the dots: obesity, fatty acids and cancer.
        Lab Invest. 2009; 89: 1192-1194
        • Xu L.
        • Han C.
        • Lim K.
        • et al.
        Cross-talk between peroxisome proliferator-activated receptor delta and cytosolic phospholipase A(2)alpha/cyclooxygenase-2/prostaglandin E(2) signaling pathways in human hepatocellular carcinoma cells.
        Cancer Res. 2006; 66: 11859-11868
        • Frystyk J.
        • Skjaerbaek C.
        • Vestbo E.
        • et al.
        Circulating levels of free insulin-like growth factors in obese subjects: the impact of type 2 diabetes.
        Diabetes Metab Res Rev. 1999; 15: 314-322
        • Sohda T.
        • Kamimura S.
        • Iwata K.
        • et al.
        Immunohistochemical evidence of insulin-like growth factor II in human small hepatocellular carcinoma with hepatitis C virus infection: relationship to fatty change in carcinoma cells.
        J Gastroenterol Hepatol. 1997; 12: 224-228
        • Li D.
        • Morris J.S.
        • Liu J.
        • et al.
        Body mass index and risk, age of onset, and survival in patients with pancreatic cancer.
        JAMA. 2009; 301: 2553-2562
        • Utsunomiya T.
        • Okamoto M.
        • Kameyama T.
        • et al.
        Impact of obesity on the surgical outcome following repeat hepatic resection in Japanese patients with recurrent hepatocellular carcinoma.
        World J Gastroenterol. 2008; 14: 1553-1558
        • Mathur A.K.
        • Ghaferi A.A.
        • Osborne N.H.
        • et al.
        Body mass index and adverse perioperative outcomes following hepatic resection.
        J Gastrointest Surg. 2010; 14: 1285-1291
        • Tanaka S.
        • Iimuro Y.
        • Hirano T.
        • et al.
        Safety of hepatic resection for hepatocellular carcinoma in obese patients with cirrhosis.
        Surg Today. 2013; 43: 1290-1297
        • Balzan S.
        • Nagarajan G.
        • Farges O.
        • et al.
        Safety of liver resections in obese and overweight patients.
        World J Surg. 2010; 34: 2960-2968
        • Tateishi R.
        • Okanoue T.
        • Fujiwara N.
        • et al.
        Clinical characteristics, treatment, and prognosis of non-B, non-C hepatocellular carcinoma: a large retrospective multicenter cohort study.
        J Gastroenterol. 2015; 50: 350-360
        • Haluzik M.
        • Parizkova J.
        • Haluzik M.M.
        Adiponectin and its role in the obesity-induced insulin resistance and related complications.
        Physiol Res. 2004; 53: 123-129
        • Shin E.
        • Yu Y.D.
        • Kim D.S.
        • et al.
        Adiponectin receptor expression predicts favorable prognosis in cases of hepatocellular carcinoma.
        Pathol Oncol Res. 2014; 20: 667-675
        • Duan X.F.
        • Tang P.
        • Li Q.
        • et al.
        Obesity, adipokines and hepatocellular carcinoma.
        Int J Cancer. 2013; 133: 1776-1783
        • Wang S.N.
        • Lee K.T.
        • Ker C.G.
        Leptin in hepatocellular carcinoma.
        World J Gastroenterol. 2010; 16: 5801-5809
        • Siegel A.B.
        • Wang S.
        • Jacobson J.S.
        • et al.
        Obesity and microvascular invasion in hepatocellular carcinoma.
        Cancer Invest. 2010; 28: 1063-1069
        • Kawaguchi Y.
        • Mizuta T.
        Interaction between hepatitis C virus and metabolic factors.
        World J Gastroenterol. 2014; 20: 2888-2901
        • Loomba R.
        • Yang H.I.
        • Su J.
        • et al.
        Synergism between obesity and alcohol in increasing the risk of hepatocellular carcinoma: a prospective cohort study.
        Am J Epidemiol. 2013; 177: 333-342
        • Llovet J.M.
        • Burroughs A.
        • Bruix J.
        Hepatocellular carcinoma.
        Lancet. 2003; 362: 1907-1917
        • Bruix J.
        • Llovet J.M.
        Prognostic prediction and treatment strategy in hepatocellular carcinoma.
        Hepatology. 2002; 35: 519-524
        • Llovet J.M.
        • Ricci S.
        • Mazzaferro V.
        • et al.
        Sorafenib in advanced hepatocellular carcinoma.
        N Engl J Med. 2008; 359: 378-390
        • Thomas M.B.
        Systemic therapy for hepatocellular carcinoma.
        Cancer J. 2008; 14: 123-127
        • Simpson C.F.
        • Boyd C.M.
        • Carlson M.C.
        • et al.
        Agreement between self-report of disease diagnoses and medical record validation in disabled older women: factors that modify agreement.
        J Am Geriatr Soc. 2004; 52: 123-127
        • Bush T.L.
        • Miller S.R.
        • Golden A.L.
        • et al.
        Self-report and medical record report agreement of selected medical conditions in the elderly.
        Am J Public Health. 1989; 79: 1554-1556
        • Cavanaugh K.L.
        • Merkin S.S.
        • Plantinga L.C.
        • et al.
        Accuracy of patients' reports of comorbid disease and their association with mortality in ESRD.
        Am J Kidney Dis. 2008; 52: 118-127
        • Houston D.K.
        • Ding J.
        • Nicklas B.J.
        • et al.
        The association between weight history and physical performance in the Health, Aging and Body Composition study.
        Int J Obes (Lond). 2007; 31: 1680-1687
        • Casey V.A.
        • Dwyer J.T.
        • Berkey C.S.
        • et al.
        Long-term memory of body weight and past weight satisfaction: a longitudinal follow-up study.
        Am J Clin Nutr. 1991; 53: 1493-1498
        • Stevens J.
        • Keil J.E.
        • Waid L.R.
        • et al.
        Accuracy of current, 4-year, and 28-year self-reported body weight in an elderly population.
        Am J Epidemiol. 1990; 132: 1156-1163
        • Kuczmarski M.F.
        • Kuczmarski R.J.
        • Najjar M.
        Effects of age on validity of self-reported height, weight, and body mass index: findings from the Third National Health and Nutrition Examination Survey, 1988-1994.
        J Am Diet Assoc. 2001; 101: 28-34
        • Gunnell D.
        • Berney L.
        • Holland P.
        • et al.
        How accurately are height, weight and leg length reported by the elderly, and how closely are they related to measurements recorded in childhood?.
        Int J Epidemiol. 2000; 29: 456-464

      Linked Article

      • Central Obesity Early in Adulthood May Affect Outcomes of Hepatocellular Carcinoma
        GastroenterologyVol. 149Issue 6
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          The accepted case control study by Hassan et al1 suggested that general obesity (elevated body mass index, BMI) in early adulthood was significantly correlated with increased risk of developing hepatocellular carcinoma (HCC), but was not associated with prognosis of patients with HCC. Thus, they concluded that obesity had no effect on outcomes of HCC. Coincidentally, several other studies also showed the irrelevance between BMI and prognosis of HCC. This may be due to a high prevalence (ranged from 5.2% to 68%) of metabolically healthy obesity, which is lack of obesity-associated metabolic disorders, among populations with general obesity.
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