Advertisement

Excess body weight and the risk of primary liver cancer: An updated meta-analysis of prospective studies

Published:March 26, 2012DOI:https://doi.org/10.1016/j.ejca.2012.02.063

      Abstract

      Aims

      To provide a quantitative assessment of the association between excess body weight (EBW) and the risk of primary liver cancer (PLC), we performed an updated meta-analysis of prospective observational studies.

      Methods

      We searched PUBMED and EMBASE for studies of body mass index and the risk of PLC published through 15 th September 2011. Summary relative risks (SRRs) with their corresponding 95% confidence intervals (CIs) were calculated using a random-effects model. The meta-regression and stratified methods were used to examine heterogeneity across studies.

      Results

      A total of 26 prospective studies, including 25,337 PLC cases, were included in this analysis. Overall, excess body weight (EBW: body mass index (BMI) ⩾ 25 kg/m2) and obesity (BMI ⩾ 30 kg/m2) were associated with an increased risk of PLC, with significant heterogeneity (EBW: SRRs 1.48, 95%CIs 1.31–1.67, Ph < 0.001, I2 = 83.6%; Obesity: SRRs 1.83, 95% CIs 1.59–2.11, Ph < 0.001, I2 = 75.0%). Subgroup analyses revealed that the positive associations were independent of geographic locations, alcohol consumption, history of diabetes or infections with hepatitis B (HBV) and/or hepatitis C virus (HCV). Obese males had a higher risk of PLC than obese females did (P = 0.027). A stronger risk of PLC with EBW was observed for patients with HCV (but not HBV) infection or cirrhosis compared with the general population.

      Conclusions

      Findings from this meta-analysis strongly support that EBW or obesity is associated with an increased risk of PLC in both males and females.

      Keywords

      1. Introduction

      According to the definition from World Health Organization (WHO), there are an estimated 1.6 billion adults to be overweight, and at least 300 million of them to be obese worldwide in the year 2006.
      • Polesel J.
      • Zucchetto A.
      • Montella M.
      • et al.
      The impact of obesity and diabetes mellitus on the risk of hepatocellular carcinoma.
      Epidemiological evidence has linked excess body weight (EBW) with an increased risk for several cancers including cancers of the colon, breast (in premenopausal women), endometrium, pancreas, oesophagus and liver.
      • Kant P.
      • Hull M.A.
      Excess body weight and obesity–the link with gastrointestinal and hepatobiliary cancer.
      • Renehan A.G.
      • Soerjomataram I.
      • Leitzmann M.F.
      Interpreting the epidemiological evidence linking obesity and cancer: a framework for population-attributable risk estimations in Europe.
      It is estimated that 3.2% of all incident cancers in men and 8.6% of those in women in Europe are attributable to EBW.
      • Renehan A.G.
      • Soerjomataram I.
      • Tyson M.
      • et al.
      Incident cancer burden attributable to excess body mass index in 30 European countries.
      Primary liver cancer (PLC) is the sixth most common cancer worldwide, and the burden of PLC is increasing and will continue to increase until 2030.
      • Ohishi W.
      • Fujiwara S.
      • Cologne J.B.
      • et al.
      Impact of radiation and hepatitis virus infection on risk of hepatocellular carcinoma.
      Histologically, hepatocellular carcinoma (HCC) accounts for between 85% and 90% of all PLC. It has been established that chronic infection with hepatitis B (HBV) or hepatitis C virus (HCV) is the leading cause of HCC worldwide.
      • El-Serag H.B.
      • Mason A.C.
      Risk factors for the rising rates of primary liver cancer in the United States.
      Additionally, alcohol abuse, cigarette smoking, a history of diabetes mellitus (DM) and environmental exposure to aflatoxin B1 also increase the risk of HCC development.
      • Yu M.C.
      • Yuan J.M.
      Environmental factors and risk for hepatocellular carcinoma.
      • El-Serag H.B.
      • Tran T.
      • Everhart J.E.
      Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma.
      In addition to the increasing likelihood of developing cancer, EBW has also been associated with increased risk of cancer mortality.
      • Batty G.D.
      • Shipley M.J.
      • Kivimaki M.
      • et al.
      Obesity and overweight in relation to liver disease mortality in men: 38 year follow-up of the original Whitehall study.
      Changes in HCC incidence and prevalence of overweight and obesity, as measured by body mass index (BMI), have both followed a similar upwards pattern, suggesting that overweight and obesity may account for a significant proportion of HCC cases. A recent meta-analysis of 11 cohort studies showed increased PLC risks of 17% for overweight people and of 90% for obese ones compared to those in normal weight.
      • Larsson S.C.
      • Wolk A.
      Overweight, obesity and risk of liver cancer: a meta-analysis of cohort studies.
      However, this meta-analysis did not allow for potential confounders, in particular chronic HBV and HCV infections and alcohol abuse.
      • Larsson S.C.
      • Wolk A.
      Overweight, obesity and risk of liver cancer: a meta-analysis of cohort studies.
      Since then, lots of prospective studies, particularly from Asia (the endemic area for HBV/HCV), on the association between BMI and PLC risk have been published.
      • 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.
      • Jee S.H.
      • Yun J.E.
      • Park E.J.
      • et al.
      Body mass index and cancer risk in Korean men and women.
      • Joshi S.
      • Song Y.M.
      • Kim T.H.
      • Cho S.I.
      Socio-economic status and the risk of liver cancer mortality: a prospective study in Korean men.
      • Ohishi W.
      • Fujiwara S.
      • Cologne J.B.
      • et al.
      Risk factors for hepatocellular carcinoma in a Japanese population: a nested case-control study.
      • Ohki T.
      • Tateishi R.
      • Sato T.
      • et al.
      Obesity is an independent risk factor for hepatocellular carcinoma development in chronic hepatitis C patients.
      • Batty G.D.
      • Barzi F.
      • Huxley R.
      • et al.
      Obesity and liver cancer mortality in Asia: the Asia Pacific Cohort Studies Collaboration.
      • Inoue M.
      • Kurahashi N.
      • Iwasaki M.
      • et al.
      Metabolic factors and subsequent risk of hepatocellular carcinoma by hepatitis virus infection status: a large-scale population-based cohort study of Japanese men and women (JPHC Study Cohort II).
      • Hart C.L.
      • Batty G.D.
      • Morrison D.S.
      • Mitchell R.J.
      • Smith G.D.
      Obesity, overweight and liver disease in the Midspan prospective cohort studies.
      • Loomba R.
      • Yang H.I.
      • Su J.
      • et al.
      Obesity and alcohol synergize to increase the risk of incident hepatocellular carcinoma in men.
      • Nkontchou G.
      • Bastard J.P.
      • Ziol M.
      • et al.
      Insulin resistance, serum leptin, and adiponectin levels and outcomes of viral hepatitis C cirrhosis.
      • Arano T.
      • Nakagawa H.
      • Tateishi R.
      • et al.
      Serum level of adiponectin and the risk of liver cancer development in chronic hepatitis C patients.
      The aim of this meta-analysis was to update and expand the previous meta-analysis including all prospective studies on this issue published through 15th September 2011. Furthermore, we evaluated whether the risk of PLC varied between genders and sources of population.

      2. Materials and methods

      2.1 Search strategies

      Two of us (C.Y. and W.X.L.) identified eligible studies by a comprehensive search in PubMed and EMBASE (up to 15th September 2011). Research papers were selected using the following keywords or Medical Subject Heading (MeSH) terms: ‘body mass index’, ‘BMI’, or ‘obesity’ or ‘excess body weight’; ‘liver cancer’ or ‘hepatocellular carcinoma’ or ‘HCC’; ‘risk’ or ‘incidence’ or ‘mortality’. No language restrictions were imposed. Furthermore, the reference lists of the retrieved articles were examined for additional relevant studies.

      2.2 Inclusion and exclusion criteria

      Three authors (C.Y, W.X.L., and W.J.H.) independently evaluated all of the studies retrieved according to the pre-specified selection criteria. Discrepancies between the three reviewers were solved by discussion. To be included, the study had to meet the following criteria:(1) published as an original article; (2) with a prospective design and (3) reporting relative risk (RR) estimates with corresponding 95% confidence intervals (CIs) for BMI and PLC (or HCC); (4) the RR and corresponding 95% CIs were at least adjusted for age. If results based on the same study population were reported in more than one study, we included the one with the largest number of cases. We excluded studies that did not provide risk estimates, only provided an RR with corresponding 95% CIs per unit increase in BMI or duplicate publications.

      2.3 Data extraction

      The following information from each included study was extracted using a standardized data-collection protocol: the first author’s last name, country of origin, publication year, sample size, definition of the study population, ascertainment of exposure and outcome, duration of follow-up and variables adjusted for in the analysis. When several risk estimates were presented, we used the ones adjusted for the largest number of potential confounders. Data abstraction was performed independently by two investigators (C.Y. and W.X.L.) and then cross-checked.

      2.4 Statistical analysis

      We used body mass categories according to the definition from WHO: normal weight (BMI ⩾18.5 and <25 kg/m2), overweight (BMI ⩾25 and <30 kg/m2) and obese (BMI ⩾ 30 kg/m2). Combined overweight and obesity may be expressed as EBW (BMI ⩾ 25 kg/m2). For studies that reported RRs for several categories of BMI that fell into the category representing overweight, obesity or EBW, we pooled the relative risks and used the pooled estimates in the meta-analysis. If studies reported results separately for men and women, we combined the sex-specific estimates to generate an estimate for both genders combined. Summary RR (SRR) estimates with their corresponding 95% CIs were derived with the method of DerSimonian and Laird using the assumptions of a random-effects model, which incorporates between-study variability.
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      A two-tailed P < 0.05 was considered statistically significant.
      Heterogeneity among studies was assessed using Q and I2 statistics, which test total variation across studies that was attributable to heterogeneity rather than to chance.
      • Higgins J.P.
      • Thompson S.G.
      Quantifying heterogeneity in a meta-analysis.
      Potential sources of heterogeneity were investigated by using subgroup analyses and restricted maximum likelihood (REML)-based random-effects meta-regression analysis gender (males and females), geographic locations (Asia and non-Asia), ascertainment of exposure (self-reported and measured) ascertainment of outcome (cancer/death registry and histological finding or non-invasive diagnosis), the number of cases(<120 and ⩾120 cases of PLC), duration of follow-up (<10 ys and ⩾10 ys) for categories of EBW and obesity, respectively, because these two categories covered categories of overweight. We also performed subgroup meta-analyses by studies that did or did not adjust for the following confounders: alcohol use, infection with HBV and/or HCV and a history of diabetes.
      • Higgins J.P.
      • Thompson S.G.
      Controlling the risk of spurious findings from meta-regression.
      Univariate meta-regression analyses were performed first. Variables that were significant at the 0.1 level were entered into the multivariable model. Sensitivity analysis was also conducted to estimate the influence of each individual study on the summary results by repeating the random-effects meta-analysis after omitting one study at a time.
      To test evidence of publication bias, funnel plots and statistical test for funnel plot asymmetry were performed by using Begg’s adjusted rank correlation test.
      • Begg C.B.
      • Mazumdar M.
      Operating characteristics of a rank correlation test for publication bias.
      All statistical analyses were performed using STATA, version 11.0 (STATA, College Station, TX, United States of America (USA)) and R-package statistical software (Version 2.11.0 beta).

      3. Results

      3.1 Search results and study characteristics

      A total of 26 prospective studies, which included 9,053,369 of study population and 25,337 PLC (or HCC) cases, were found to match our inclusion criteria (11–19, 26–42). Of these 26 studies, 14 studies were conducted in Asia, four in the United States, six in Europe and two in Asia Pacific region. Characteristics of studies included in the meta-analysis are presented in Table 1.
      Table 1Characteristics of prospective studies of body mass index and risk of primary liver cancer.
      Author, year of publicationCountryNo. of caseStudy populationFollow-up, yearsAssessment of anthropometryCase ascertainmentAdjustments
      Møller et al. (1994)
      • Moller H.
      • Mellemgaard A.
      • Lindvig K.
      • Olsen J.H.
      Obesity and cancer risk: a Danish record-linkage study.
      Denmark58(HCC), total N = 43,968General population4.8Discharge diagnosisDeath certificates1
      Wolk et al. (2001)
      • Wolk A.
      • Gridley G.
      • Svensson M.
      • et al.
      A prospective study of obesity and cancer risk (Sweden).
      Sweden28(PLC), total N = 28,129Hospital patients10.3Discharge diagnosisCancer registry1, 18
      Yu et al. (2001)
      • Yu M.W.
      • Yang Y.C.
      • Yang S.Y.
      • et al.
      Hormonal markers and hepatitis B virus-related hepatocellular carcinoma risk: a nested case-control study among men.
      Taiwan119(HCC), total N = 4841(M)HBsAg carriers12Self-reportedHistologic finding or AFP ⩾ 400 ng/Ml + positive image1, 4, 5, 8, 9, 13, 31
      Nair et al. (2002)
      • Nair S.
      • Mason A.
      • Eason J.
      • Loss G.
      • Perrillo R.P.
      Is obesity an independent risk factor for hepatocellular carcinoma in cirrhosis?.
      USA659(HCC), total N = 19,271Cirrhotic patients receiving liver transplantationsNAMeasuredHistologic finding1–3, 35
      Calle et al. (2003)
      • Calle E.E.
      • Rodriguez C.
      • Walker-Thurmond K.
      • Thun M.J.
      Overweight, obesity, and mortality from cancer in a prospectively studied cohort of US adults.
      USA965(PLC), Total N = 900,053Cancer Prevention Study II,16Self-reportedDeath certificates1, 4, 5, 9, 11–13, 20–22
      Samanic et al. (2004)
      • Samanic C.
      • Gridley G.
      • Chow W.H.
      • et al.
      Obesity and cancer risk among white and black United States veterans.
      USA5140(PLC), Total: N = 4500,700(M)White and black veterans12Discharge diagnosisCancer registry1, 18
      Batty et al. (2005)
      • Batty G.D.
      • Shipley M.J.
      • Jarrett R.J.
      • et al.
      Obesity and overweight in relation to organ-specific cancer mortality in London (UK): findings from the original Whitehall study.
      UK51(PLC), total N = 18,403(M)Non- industrial London-based government employees35MeasuredDeath certificates1, 4, 11, 14, 21
      Kuriyama et al. (2005)
      • Kuriyama S.
      • Tsubono Y.
      • Hozawa A.
      • et al.
      Obesity and risk of cancer in Japan.
      Japan31(PLC), total N = 27,539Population subjects7.6Self-reportedCancer Registry1, 4, 5, 12, 32
      Oh et al. (2005)
      • Oh S.W.
      • Yoon Y.S.
      • Shin S.A.
      Effects of excess weight on cancer incidences depending on cancer sites and histologic findings among men: Korea National Health Insurance Corporation Study.
      Korea2410(HCC), total N = 781,283(M)Civil servants and private school workers and their dependants9.9MeasuredHistologic finding1,4, 5, 10, 11, 17
      Rapp et al. (2005)
      • Rapp K.
      • Schroeder J.
      • Klenk J.
      • et al.
      Obesity and incidence of cancer: a large cohort study of over 145,000 adults in Austria.
      Austrilia57(PLC), total N = 67,447(M)Adult Vorarlberg residents10MeasuredHistologic finding1, 4, 14
      N’Kontchou et al. (2006)
      • N’Kontchou G.
      • Paries J.
      • Htar M.T.
      • et al.
      Risk factors for hepatocellular carcinoma in patients with alcoholic or viral C cirrhosis.
      France220(HCC), total N = 771Compensated alcoholic/HCV cirrhosis4.2Self-reportedHistologic finding or AFP ⩾ 400 ng/Ml + positive image1–3
      Samanic et al. (2006)
      • Samanic C.
      • Chow W.H.
      • Gridley G.
      • Jarvholm B.
      • Fraumeni Jr., J.F.
      Relation of body mass index to cancer risk in 362,552 Swedish men.
      Sweden194(HCC), total N = 362,552(M)Workers of construction Industry19MeasuredCancer Registry1, 4
      Ioannou et al. (2007)
      • Ioannou G.N.
      • Splan M.F.
      • Weiss N.S.
      • et al.
      Incidence and predictors of hepatocellular carcinoma in patients with cirrhosis.
      USA100(HCC), total N = 2120Cirrhotic veterans3.6MeasuredCancer Registry1, 4–6
      Chen et al. (2008)
      • 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.
      Taiwan291(HCC), N = 23,567Residents of 7 townships14MeasuredHistologic finding or AFP ⩾ 400 ng/Ml + positive image1, 2, 4–6, 13
      Jee et al. (2008)
      • Jee S.H.
      • Yun J.E.
      • Park E.J.
      • et al.
      Body mass index and cancer risk in Korean men and women.
      Korea10520(HCC), total N = 1213,829National Health Insurance Corporation10.8MeasuredCancer registry or hospital admission diagnosis1, 4
      Ohishi et al. (2008)
      • Ohishi W.
      • Fujiwara S.
      • Cologne J.B.
      • et al.
      Risk factors for hepatocellular carcinoma in a Japanese population: a nested case-control study.
      Japan224(HCC), total N = 20,000Adult Health Study longitudinal cohort in HiroshiNAMeasuredCancer registry or histologic finding1, 3–6, 9, 33
      Joshi et al. (2008)
      • Joshi S.
      • Song Y.M.
      • Kim T.H.
      • Cho S.I.
      Socio-economic status and the risk of liver cancer mortality: a prospective study in Korean men.
      Korea998(PLC) total N = 548,530Civil service workers6MeasuredDeath registry1, 3–6
      Ohki et al. (2008)
      • Ohki T.
      • Tateishi R.
      • Sato T.
      • et al.
      Obesity is an independent risk factor for hepatocellular carcinoma development in chronic hepatitis C patients.
      Japan341(HCC), total N = 1431Positive for HCV-RNA6.1MeasuredHistologic finding or AFP ⩾ 400 ng/Ml + positive image1, 2, 5, 7, 15, 16, 23, 24
      Batty et al. (2009)
      • Batty G.D.
      • Barzi F.
      • Huxley R.
      • et al.
      Obesity and liver cancer mortality in Asia: the Asia Pacific Cohort Studies Collaboration.
      APCSC445(PLC), total N = 405799Austrilia/New Zealand residents4MeasuredDeath registries1–5, 19, 25, 26
      Inoue et al. (2009)
      • Inoue M.
      • Noda M.
      • Kurahashi N.
      • et al.
      Impact of metabolic factors on subsequent cancer risk: results from a large-scale population-based cohort study in Japan.
      Japan1858 (PLC), total N = 27,724Inhabitants10.2MeasuredCancer registries1, 4, 5, 19
      Wang et al. (2009)
      • Wang C.S.
      • Yao W.J.
      • Chang T.T.
      • Wang S.T.
      • Chou P.
      The impact of type 2 diabetes on the development of hepatocellular carcinoma in different viral hepatitis statuses.
      Taiwan111(HCC), total N = 5929Villager8MeasuredCancer registries1–6
      Inoue et al. (2009)
      • Inoue M.
      • Kurahashi N.
      • Iwasaki M.
      • et al.
      Metabolic factors and subsequent risk of hepatocellular carcinoma by hepatitis virus infection status: a large-scale population-based cohort study of Japanese men and women (JPHC Study Cohort II).
      Japan102(HCC), total N = 17,590Inhabitants12.7MeasuredDeath Registry1, 2, 4–6, 9
      Hart et al. (2010)
      • Hart C.L.
      • Batty G.D.
      • Morrison D.S.
      • Mitchell R.J.
      • Smith G.D.
      Obesity, overweight and liver disease in the Midspan prospective cohort studies.
      UK69(PLC), total N = 27,121General population26MeasuredCancer Registry1, 3, 4, 14, 25, 29, 30
      Loomba et al. (2010)
      • Loomba R.
      • Yang H.I.
      • Su J.
      • et al.
      Obesity and alcohol synergize to increase the risk of incident hepatocellular carcinoma in men.
      Taiwan135(HCC), total N = 2260Positive for HBV18.5MeasuredHistologic finding or AFP ⩾ 400 ng/Ml + positive image1, 4–6, 16
      Chao et al. (2011)
      • Chao L.T.
      • Wu C.F.
      • Sung F.Y.
      • et al.
      Insulin, glucose and hepatocellular carcinoma risk in male hepatitis B carriers: results from 17-year follow-up of a population-based cohort.
      Taiwan124(HCC), total N = 1142(M)Originally healthy, HBsAg-carriers8MeasuredHistologic finding or AFP ⩾ 400 ng/Ml + positive image1, 3–6, 10
      Hung et al. (2011)
      • Hung C.H.
      • Lee C.M.
      • Wang J.H.
      • et al.
      Impact of diabetes mellitus on incidence of hepatocellular carcinoma in chronic hepatitis C patients treated with interferon-based antiviral therapy.
      Taiwan87(HCC), total N = 1470Chronic HCV infection4.4MeasuredCancer registries1–3, 7, 15
      Abbreviations: RR, relative risk; CI, confidence interval; NA, data not applicable; m, male; f, female; PLC, primary liver cancer; HCC, hepatocellular carcinoma; HBV, hepatitis B virus; HCV, hepatitis C virus.
      1, age; 2, sex; 3, diabetes; 4, smoking; 5, alcohol; 6, hepatitis B virus and/or hepatitis C virus; 7, AFP; 8, CLC; 9, coffee use; 10, family history of cancer; 11, physical activity; 12, diet; 13, education; 14, socioeconomic status; 15, Platelet count; 16, alanine aminotransferase 17, place of birth; 18, calendar year; 19, study centre; 20, HRT; 21, marital status; 22, NSAIDs use; 23, albumin; 24 bilirubin;25 blood pressure; 26 serum cholesterol; 27 birth year; 28, MetS score; 29, bronchitis; 30, angina,31, the time of blood draw; 32, type of health insurance; 33, radiation dose; 34, fibrosis stage; 35, race.

      3.2 Quantitative data synthesis

      The combined results based on all studies showed that there was a statistically significant link between EBW, overweight or obesity and PLC risk, with significant heterogeneity among studies (EBW, SRR = 1.49, 95% CIs = 1.31–1.68, Q = 122.23, Ph < 0.001, I2 = 83.6, n = 21; overweight, SRR = 1.18, 95% CIs = 1.06–1.31, Q = 33.71, Ph = 0.001, I2 = 61.4, n = 14; obesity, SRR = 1.83, 95% CIs = 1.59–2.11, Q = 56.14, Ph < 0.001, I2 = 75.0, n = 19) (Fig. 1A–C).
      Figure thumbnail gr1
      Fig. 1Forest plots of risk of primary liver cancer associated with excess body weight, overweight and obesity. Squares represent the study-specific relative risk. Diamonds represent the summary relative risks (SRRs). Horizontal lines represent 95% confidence intervals (CIs). (A) Forest plots of risk of primary liver cancer associated with excess body weight (EBW, body mass index (BMI) ⩾25 kg/m2). (B) Forest plots of risk of primary liver cancer associated with overweight (BMI ⩾25 and <30 kg/m2). (C) Forest plots of risk of primary liver cancer associated with obesity (BMI ⩾ 30 kg/m2).
      We then conducted subgroup meta-analyses by gender, geographic locations, ascertainment of exposure and outcome, the number of cases, duration of follow-up and confounders. The links between EBW and obesity and PLC risk were positive in all strata (Table 2).
      Table 2Stratified meta-analyses of excess body weight (BMI ⩾25 kg/m2) and obesity (BMI ⩾30 kg/m2) and risk of primary liver cancer.
      CharacteristicExcess body weightObesity
      Studies, nCases, nSRR (95% CI)PhPdI2,%Studies, nCases, nSRR (95% CI)PhPdI2, %
      All2119,3411.48(1.31–1.67)<0.00183.61922,3781.83(1.59–2.11)<0.00175.0
      Sex
      Male1112,4791.42(1.22–1.65)<0.00178.11213,6041.91(1.51–2.41)<0.00178.1
      Female521751.18(1.08–1.30)0.6500.0410622061.55(1.30–1.85)0.6760.0270
      Geographic location
      Asia1317,2401.35(1.18–1.54)<0.00178.8814,8371.54(1.33–1.78)0.32613.3
      Non-Asia821011.65(1.36–2.02)<0.0010.11774.61175412.09(1.69–2.59)<0.0010.0278.6
      No. of cases
      <120924741.65(1.32–2.08)0.02454.685051.95(1.66–2.29)0.4450
      ⩾1201216,8671.39(1.21–1.60)<0.0010.33087.61121,8731.78(1.48–2.13)<0.0010.74677.3
      BMI ascertainment
      Self-reported413351.58(1.10–2.26)<0.00185.5312162.02(1.38–2.94)0.03869.4
      Measured1718,0061.44(1.27–1.64)<0.0010.68580.51621,1621.78(1.49–2.14)0.0010.54160.7
      Outcome ascertainment
      Cancer/death registry1149001.49(1.24–1.80)<0.00181.81177451.86(1.51–2.31)<0.00176.4
      Histological finding or non-invasive diagnosis1014,4411.48(1.23–1.77)<0.0010.88085.8814,6331.78(1.49–2.14)0.0710.75746.4
      Duration of follow-up
      The duration of follow-up in one study29 was not available.
      <10947561.45(1.17–1.80)<0.00187.3842691.81(1.42–2.30)0.01958.2
      ⩾1012145851.47(1.25–1.73)<0.0010.84680.31018,1091.88(1.54–2.30)<0.0010.81275.1
      Adjustment for confounders
      Alcohol use
      No7111981.53(1.13–2.07)<0.00188.21016,9961.98(1.60–2.46)<0.00177.5
      Yes1481431.46(1.25–1.69)<0.0010.81781.7953821.69(1.41–2.04)0.0780.27343.5
      HBV and/or HCV
      No9147421.28(1.14–1.43)<0.00173.11220,1821.81(1.52–2.14)<0.00171.1
      Yes1245991.74(1.35–2.25)<0.0010.0386.5721961.89(1.43–2.50)0.0150.79661.8
      Diabetes
      No15181721.40(1.23–1.59)<0.00182.51521,3191.77(1.51–2.07)<0.00168.4
      Yes611691.70(1.27–2.27)<0.0010.25576.9410592.06(1.53–2.78)0.0770.37956.2
      Bold values indicate statistical significance at the p value equal to 0.10 level.
      Abbreviations: RR, relative risk; CI, confidence interval; HBV, hepatitis B virus; HCV, hepatitis C virus; BMI, body mass index; Ph, p value for heterogeneity; Pd, p value for difference.
      low asterisk The duration of follow-up in one study
      • Nair S.
      • Mason A.
      • Eason J.
      • Loss G.
      • Perrillo R.P.
      Is obesity an independent risk factor for hepatocellular carcinoma in cirrhosis?.
      was not available.
      Interestingly, for studies of EBW,
      • 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.
      • Jee S.H.
      • Yun J.E.
      • Park E.J.
      • et al.
      Body mass index and cancer risk in Korean men and women.
      • Joshi S.
      • Song Y.M.
      • Kim T.H.
      • Cho S.I.
      Socio-economic status and the risk of liver cancer mortality: a prospective study in Korean men.
      • Ohishi W.
      • Fujiwara S.
      • Cologne J.B.
      • et al.
      Risk factors for hepatocellular carcinoma in a Japanese population: a nested case-control study.
      • Ohki T.
      • Tateishi R.
      • Sato T.
      • et al.
      Obesity is an independent risk factor for hepatocellular carcinoma development in chronic hepatitis C patients.
      • Batty G.D.
      • Barzi F.
      • Huxley R.
      • et al.
      Obesity and liver cancer mortality in Asia: the Asia Pacific Cohort Studies Collaboration.
      • Inoue M.
      • Kurahashi N.
      • Iwasaki M.
      • et al.
      Metabolic factors and subsequent risk of hepatocellular carcinoma by hepatitis virus infection status: a large-scale population-based cohort study of Japanese men and women (JPHC Study Cohort II).
      • Hart C.L.
      • Batty G.D.
      • Morrison D.S.
      • Mitchell R.J.
      • Smith G.D.
      Obesity, overweight and liver disease in the Midspan prospective cohort studies.
      • Loomba R.
      • Yang H.I.
      • Su J.
      • et al.
      Obesity and alcohol synergize to increase the risk of incident hepatocellular carcinoma in men.
      • Yu M.W.
      • Yang Y.C.
      • Yang S.Y.
      • et al.
      Hormonal markers and hepatitis B virus-related hepatocellular carcinoma risk: a nested case-control study among men.
      • Calle E.E.
      • Rodriguez C.
      • Walker-Thurmond K.
      • Thun M.J.
      Overweight, obesity, and mortality from cancer in a prospectively studied cohort of US adults.
      • Batty G.D.
      • Shipley M.J.
      • Jarrett R.J.
      • et al.
      Obesity and overweight in relation to organ-specific cancer mortality in London (UK): findings from the original Whitehall study.
      • Kuriyama S.
      • Tsubono Y.
      • Hozawa A.
      • et al.
      Obesity and risk of cancer in Japan.
      • Oh S.W.
      • Yoon Y.S.
      • Shin S.A.
      Effects of excess weight on cancer incidences depending on cancer sites and histologic findings among men: Korea National Health Insurance Corporation Study.
      • Rapp K.
      • Schroeder J.
      • Klenk J.
      • et al.
      Obesity and incidence of cancer: a large cohort study of over 145,000 adults in Austria.
      • N’Kontchou G.
      • Paries J.
      • Htar M.T.
      • et al.
      Risk factors for hepatocellular carcinoma in patients with alcoholic or viral C cirrhosis.
      • Samanic C.
      • Chow W.H.
      • Gridley G.
      • Jarvholm B.
      • Fraumeni Jr., J.F.
      Relation of body mass index to cancer risk in 362,552 Swedish men.
      • Ioannou G.N.
      • Splan M.F.
      • Weiss N.S.
      • et al.
      Incidence and predictors of hepatocellular carcinoma in patients with cirrhosis.
      • Inoue M.
      • Noda M.
      • Kurahashi N.
      • et al.
      Impact of metabolic factors on subsequent cancer risk: results from a large-scale population-based cohort study in Japan.
      • Chao L.T.
      • Wu C.F.
      • Sung F.Y.
      • et al.
      Insulin, glucose and hepatocellular carcinoma risk in male hepatitis B carriers: results from 17-year follow-up of a population-based cohort.
      • Hung C.H.
      • Lee C.M.
      • Wang J.H.
      • et al.
      Impact of diabetes mellitus on incidence of hepatocellular carcinoma in chronic hepatitis C patients treated with interferon-based antiviral therapy.
      there was significant difference in RR between the strata of genders and confounder (infection with HBV and/or HCV). When stratifying for gender, we found that males with EBW had a higher risk of PLC development than females with EBW (SRR = 1.42, 95% CI 1.22–1.65, n = 11 for males versus SRR = 1.18, 95% CI 1.08–1.30, n = 5 for females; Pd = 0.041). The SRRs of PLC with EBW for studies adjusted for infection with HBV and/or HCV were significantly stronger than those for studies not adjusted for it (SRRs, 1.74 versus 1.28; Pd = 0.03). There was no difference in PLC risk with EBW between strata in ascertainment of exposure and outcome, the number of cases, duration of follow-up and confounders (alcohol consumption, history of DM) (Table 2).
      Similarly, for studies on the association between obesity and PLC,
      • 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.
      • Jee S.H.
      • Yun J.E.
      • Park E.J.
      • et al.
      Body mass index and cancer risk in Korean men and women.
      • Joshi S.
      • Song Y.M.
      • Kim T.H.
      • Cho S.I.
      Socio-economic status and the risk of liver cancer mortality: a prospective study in Korean men.
      • Ohki T.
      • Tateishi R.
      • Sato T.
      • et al.
      Obesity is an independent risk factor for hepatocellular carcinoma development in chronic hepatitis C patients.
      • Hart C.L.
      • Batty G.D.
      • Morrison D.S.
      • Mitchell R.J.
      • Smith G.D.
      Obesity, overweight and liver disease in the Midspan prospective cohort studies.
      • Loomba R.
      • Yang H.I.
      • Su J.
      • et al.
      Obesity and alcohol synergize to increase the risk of incident hepatocellular carcinoma in men.
      • Moller H.
      • Mellemgaard A.
      • Lindvig K.
      • Olsen J.H.
      Obesity and cancer risk: a Danish record-linkage study.
      • Wolk A.
      • Gridley G.
      • Svensson M.
      • et al.
      A prospective study of obesity and cancer risk (Sweden).
      • Nair S.
      • Mason A.
      • Eason J.
      • Loss G.
      • Perrillo R.P.
      Is obesity an independent risk factor for hepatocellular carcinoma in cirrhosis?.
      • Calle E.E.
      • Rodriguez C.
      • Walker-Thurmond K.
      • Thun M.J.
      Overweight, obesity, and mortality from cancer in a prospectively studied cohort of US adults.
      • Samanic C.
      • Gridley G.
      • Chow W.H.
      • et al.
      Obesity and cancer risk among white and black United States veterans.
      • Batty G.D.
      • Shipley M.J.
      • Jarrett R.J.
      • et al.
      Obesity and overweight in relation to organ-specific cancer mortality in London (UK): findings from the original Whitehall study.
      • Kuriyama S.
      • Tsubono Y.
      • Hozawa A.
      • et al.
      Obesity and risk of cancer in Japan.
      • Oh S.W.
      • Yoon Y.S.
      • Shin S.A.
      Effects of excess weight on cancer incidences depending on cancer sites and histologic findings among men: Korea National Health Insurance Corporation Study.
      • Rapp K.
      • Schroeder J.
      • Klenk J.
      • et al.
      Obesity and incidence of cancer: a large cohort study of over 145,000 adults in Austria.
      • N’Kontchou G.
      • Paries J.
      • Htar M.T.
      • et al.
      Risk factors for hepatocellular carcinoma in patients with alcoholic or viral C cirrhosis.
      • Samanic C.
      • Chow W.H.
      • Gridley G.
      • Jarvholm B.
      • Fraumeni Jr., J.F.
      Relation of body mass index to cancer risk in 362,552 Swedish men.
      • Ioannou G.N.
      • Splan M.F.
      • Weiss N.S.
      • et al.
      Incidence and predictors of hepatocellular carcinoma in patients with cirrhosis.
      • Wang C.S.
      • Yao W.J.
      • Chang T.T.
      • Wang S.T.
      • Chou P.
      The impact of type 2 diabetes on the development of hepatocellular carcinoma in different viral hepatitis statuses.
      obese males had a stronger risk of PLC development than obese females (males: SRR = 1.91, 95% CI 1.51–2.41, n = 12; females: SRR = 1.55, 95% CI 1.30–1.85, n = 6; Pd = 0.027). In addition, geographic locations were also found to significantly modify the association between obesity and PLC risk. The SRRs were significantly higher in non-Asian studies (Europen/North American) than that in Asian studies (non-Asia: SRRs 2.09, 95% CI 1.69–2.59; Asia: SRRs 1.54, 95% CI: 1.33–1.78; Pd = 0.02). However, no differences in the association between obesity and the risk of PLC were found between strata in ascertainment of exposure and outcome, the number of cases, duration of follow-up and confounders (alcohol use, history of DM and infection with HBV and/or HCV) (Table 2).
      We then conducted meta-regression analyses to investigate the sources of heterogeneity among studies according to the above subgroups. For studies of EBW, in univariate meta-regression analyses, only confounder (adjustment for infection with HBV and/or HCV; P = 0.077) was found to be a significant factor. The between-study variance was reduced from 0.0894 to 0.0802 based on REML estimate, and the heterogeneity explained by this confounder was 10.2%. For studies of obesity, geographic location was the only significant factor (P = 0.06) and the heterogeneity explained by geographic location was 13.2%.
      We investigated the effect of EBW and obesity on PLC risk in population of specific liver diseases (patients with HBV and/or HCV infection or cirrhosis) (Fig. 2A and B). For studies assessing EBW and PLC risk (Fig. 2A), the SRRs of this association for participants with specific liver diseases (3222 cases of PLC) were comparable to those for general population (specific liver diseases: SRR 1.73, 95% CI 1.28–2.35, n = 9 versus general population: SRR 1.36, 95% CI 1.20–1.53, n = 17; Pd = 0.149). Further analysis indicated that patients with HCV infection (SRR 2.15, 95% CI 1.50–3.09, n = 4, 2337 cases of PLC) had a significantly stronger risk of PLC associated with EBW than general population with EBW had (Pd = 0.059). Similarly, the SRRs of this association for cirrhotic patients were 2.41 (95% CI 1.95–2.98, n = 2320 cases of PLC), which were also higher than those for the counterparts of general population (Pd = 0.002). However, the SRRs of this association for patients with HBV infection were not the case (SRR 1.27, 95% CI 0.93–1.73, n = 4, 565 cases of PLC; Pd = 0.687). For studies assessing the association between obesity and PLC risk (Fig. 2B), the SRRs of this association were also similar for participants with specific liver diseases (1693 cases of PLC) with those for general population (specific liver diseases: SRR 2.05, 95% CI 1.50–2.80, n = 5 versus general population: SRR 1.78, 95% CI 1.50–2.08, n = 14; Pd = 0.432). Further analysis found that patients with HCV infection (392 cases of PLC) had a stronger risk of PLC associated with obesity than general population with obesity had (Pd = 0.082), however, patients with HBV infection (322 cases of PLC) or with cirrhosis (979 cases of PLC) had a similar risk compared with counterparts of general population (Pd = 0.163 for HBV and Pd = 0.319 for cirrhosis, respectively).
      Figure thumbnail gr2
      Fig. 2The pooled estimates of the association between excess body weight (EBW, body mass index (BMI) ⩾25 kg/m2 (A) and obesity (BMI ⩾30 kg/m2, (B) and primary liver cancer risk in population of specific liver diseases (patients with HBV or HCV infection or cirrhosis) and counterparts of the general population.
      We also conducted a sensitivity analysis by omitting one study at a time and calculating the pooled RRs for the remainder of studies, and found that there were no changes in the direction of effect when any one study was excluded. For example, when study by Jee et al.
      • Jee S.H.
      • Yun J.E.
      • Park E.J.
      • et al.
      Body mass index and cancer risk in Korean men and women.
      was excluded (which seemed to have a strong influence on the meta-analysis estimate of effect), the pooled RR remained the same (SRR 1.68, 95% CI 1.46–1.90).
      We found no indication of publication bias for studies on the association between BMI and PLC risk in all the analyses, Begg’s test showed P = 0.216 for EBW and PLC, 0.228 for overweight, and 0.529 for obesity.

      4. Discussion

      In this meta-analysis, we found that overweight, obesity and EBW were associated with 18%, 83% and 48% increased risk of PLC, respectively. This increased risk of liver cancer seemed to be independent of gender, geographic locations, case size, ascertainment of exposure and outcome, duration of follow-up and confounders. Like the previous meta-analysis, a higher risk of PLC with EBW or obesity was seen in males than that in females. Importantly, patients with HCV infection or cirrhosis had a higher risk of PLC with EBW than the counterparts of general population did.
      The exact biologic mechanisms underlying the association between EBW and increased risk of PLC remain unclear, but certainly involve the development of non-alcoholic fatty liver disease (NAFLD) and subsequent non-alcoholic steatohepatitis (NASH). NAFLD is the chief hepatic manifestation of obesity, diabetes mellitus and metabolic syndrome, all of which are related to insulin resistance.
      • Farrell G.C.
      • Larter C.Z.
      Nonalcoholic fatty liver disease: from steatosis to cirrhosis.
      • Borena W.
      • Strohmaier S.
      • Lukanova A.
      • et al.
      Metabolic risk factors and primary liver cancer in a prospective study of 578,700 adults.
      Population-based estimates for the prevalence of NAFLD are approximately 30% in the USA.
      • Browning J.D.
      • Szczepaniak L.S.
      • Dobbins R.
      • et al.
      Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity.
      Individuals with NAFLD and steatosis or with NASH progressing to cirrhosis may develop HCC.
      • Borena W.
      • Strohmaier S.
      • Lukanova A.
      • et al.
      Metabolic risk factors and primary liver cancer in a prospective study of 578,700 adults.
      • Guzman G.
      • Brunt E.M.
      • Petrovic L.M.
      • et al.
      Does nonalcoholic fatty liver disease predispose patients to hepatocellular carcinoma in the absence of cirrhosis?.
      • Hashimoto E.
      • Yatsuji S.
      • Tobari M.
      • et al.
      Hepatocellular carcinoma in patients with nonalcoholic steatohepatitis.
      Insulin resistance and the subsequent inflammatory cascade likely contribute to the development of NAFLD–NASH–HCC histopathogenic pathway.
      • Borena W.
      • Strohmaier S.
      • Lukanova A.
      • et al.
      Metabolic risk factors and primary liver cancer in a prospective study of 578,700 adults.
      Insulin resistance leads to elevated levels of the pro-inflammatory cytokine, such as tumor necrosis factor (TNF) and interleukin (IL)-6, which favour the development of hepatic steatosis and inflammation and subsequent cancer within the liver.
      • Papa S.
      • Bubici C.
      • Zazzeroni F.
      • Franzoso G.
      Mechanisms of liver disease: cross-talk between the NF-kappaB and JNK pathways.
      • Park E.J.
      • Lee J.H.
      • Yu G.Y.
      • et al.
      Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression.
      In addition, hyperinsulinemia may up-regulate the production of insulin-like growth factor-1 (IGF-1), which stimulates cellular proliferation and inhibits apoptosis within the liver.
      • Weng C.J.
      • Hsieh Y.H.
      • Tsai C.M.
      • et al.
      Relationship of insulin-like growth factors system gene polymorphisms with the susceptibility and pathological development of hepatocellular carcinoma.
      • Longato L.
      • de la Monte S.
      • Kuzushita N.
      • et al.
      Overexpression of insulin receptor substrate-1 and hepatitis Bx genes causes premalignant alterations in the liver.
      To our knowledge, the strengths of this study include as follows: (1) our meta- analysis was based on 26 prospective studies, which might minimize the possibility of recall or selection bias. (2) All the included studies evaluated multiple potential confounders and the relationships between BMI and PLC risk in each study were derived from regression after adjustment at least for age, and most of the studies were adjusted for the important risk factors for PLC, such as alcohol use, infection of HBV and/or HCV, a history of DM. (3) The large number of studies with different populations expand prior observational studies by permitting additional evaluation of subgroups (e.g. by gender and sources of population), which may permit us to more precisely evaluate risk with EBW or obesity on different subgroups, and to make some inferences with regards to the different population, especially patients with specific liver disease.
      As with any meta-analysis of observational studies, our study has limitations. First, great heterogeneity was presented across studies, which would throw some doubt on the reliability of the summary RR estimates. The significant heterogeneity may exist in terms of geographic location, ascertainment of anthropometry and outcome, duration of follow-up, sources of population and confounders. We used subgroup and REML meta-regression analyses to explore the sources of heterogeneity, and confounder (infection with HBV and/or HCV) or geographic location was found to be significant factor, and accounted for only 10.2% or 13.2% of heterogeneity across studies. Second, the possibility that the observed relationship between EBW and PLC risk due to unmeasured or residual confounding should be considered, since inadequate control for confounders may bias the results towards exaggeration or underestimation of risk estimates. Obesity tends to be associated with unhealthy behaviours linked to increased risk of PLC, such as heavy alcohol consumption and a history of DM, both of which are associated with increased PLC risk. However, a positive association between BMI and PLC risk persisted when we restricted the meta-analysis to studies that controlled for both confounders, respectively. These results exclude the possibility that the association between obesity and PLC is explained by diabetic status and alcohol use. Third, several studies in this meta-analysis relied on self-reported anthropometric measures, which may have led to some underestimation of the true associations. However, the SRR estimates for the studies that had measured weight and height were similar with those for studies that relied on self-reporting. Finally, as in any meta-analysis, it is possible that an observed association is the result of publication bias, because small studies with null results tend not to be published. However, the results obtained from funnel plot analysis and formal statistical tests did not provide evidence for such bias.
      In agreement with previous meta-analysis by Larrson et al.
      • Larsson S.C.
      • Wolk A.
      Overweight, obesity and risk of liver cancer: a meta-analysis of cohort studies.
      we also found that the summary RR of PLC for obesity was statistically significantly higher for men (SRR = 1.91) than for women (SRR = 1.55). These results were based on more researches and confirm previous conclusions. The reasons for the apparent sex difference in the associations for EBW remain elusive, but might be related to differences between males and females in the association between adiposity and steroid hormone concentrations. Obesity is inversely related to testosterone concentrations in males
      • Muller M.
      • den Tonkelaar I.
      • Thijssen J.H.
      • Grobbee D.E.
      • van der Schouw Y.T.
      Endogenous sex hormones in men aged 40–80 years.
      but positively related to those in females.
      • Key T.J.
      • Appleby P.N.
      • Reeves G.K.
      • et al.
      Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women.
      Moreover, findings from a meta-analysis indicated that high testosterone concentrations were associated with a higher risk of type 2 DM in females but with a lower risk in males.
      • Ding E.L.
      • Song Y.
      • Malik V.S.
      • Liu S.
      Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis.
      Given insulin resistance is one of the important mechanisms linking obesity to risk of PLC, a reduction in testosterone concentrations due to obesity in males may be one reason for the stronger association of obesity with PLC risk in males than in females. Adiposity is positively associated with circulating concentrations of estradiol in postmenopausal females and males.
      • Muller M.
      • den Tonkelaar I.
      • Thijssen J.H.
      • Grobbee D.E.
      • van der Schouw Y.T.
      Endogenous sex hormones in men aged 40–80 years.
      • Key T.J.
      • Appleby P.N.
      • Reeves G.K.
      • et al.
      Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women.
      In addition, epidemiological studies have demonstrated a clear male predominance in the diagnosis of NAFLD, while higher prevalence rates of NAFLD in postmenopausal women.
      • Clark J.M.
      • Brancati F.L.
      • Diehl A.M.
      Nonalcoholic fatty liver disease.
      NASH males have higher PLC rates than NASH females in almost all populations, with male:female ratios usually averaging between 1.6:1 and 4:1.
      • Yasui K.
      • Hashimoto E.
      • Komorizono Y.
      • et al.
      Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma.
      • El-Serag H.B.
      • Rudolph K.L.
      Hepatocellular carcinoma: epidemiology and molecular carcinogenesis.
      Other potential explanations for the sex difference might be related to sex-specific differences in exposure to risk factors. Men are more likely to be infected with hepatitis B and C viruses, consume alcohol and smoke cigarettes.
      • El-Serag H.B.
      • Rudolph K.L.
      Hepatocellular carcinoma: epidemiology and molecular carcinogenesis.
      In a subgroup analysis stratified by Asians and non-Asians, we found that obesity was associated with a significantly higher risk of PLC among non-Asians than that among Asians. The difference in the prevalence of obesity and incidence of PLC between Asians and non-Asians may partly explain the difference between Asians and non-Asians.
      We found a higher summary RR estimate of PLC in EBW individuals with HCV infection than that in general population with EBW (P = 0.059). Although it is well established that patients with HCV infection are at increased risk for the development of HCC, it is unclear what role steatosis plays in the development of HCC. Prior data have shown an association of chronic HCV infection and hepatic steatosis in a large portion of cases, which has also been shown to be a risk factor for liver disease progression.
      • Pekow J.R.
      • Bhan A.K.
      • Zheng H.
      • Chung R.T.
      Hepatic steatosis is associated with increased frequency of hepatocellular carcinoma in patients with hepatitis C-related cirrhosis.
      Moreover, animal models have demonstrated that steatosis induces chronic hepatic inflammation, reactive oxygen species, and DNA damage.
      • Cai D.
      • Yuan M.
      • Frantz D.F.
      • et al.
      Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB.
      • Arkan M.C.
      • Hevener A.L.
      • Greten F.R.
      • et al.
      IKK-beta links inflammation to obesity-induced insulin resistance.
      In HCV transgenic mice that develop HCC, carcinogenesis is preceded by the development of steatosis.
      • Moriya K.
      • Fujie H.
      • Shintani Y.
      • et al.
      The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice.
      • 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.
      In humans, steatosis may be a common mediator of HCC in hepatitis C through enhanced oxidative stress, increased susceptibility to apoptosis and activation of subsinusoidal stellate cells.
      • Powell E.E.
      • Jonsson J.R.
      • Clouston A.D.
      Steatosis: co-factor in other liver diseases.
      In summary, findings of this meta-analysis provide evidence that EBW may significantly increase PLC risk, and suggest that PLC may, at least partly, be prevented by maintaining a healthy body weight.

      Conflict of interest statement

      None declared.

      References

        • Polesel J.
        • Zucchetto A.
        • Montella M.
        • et al.
        The impact of obesity and diabetes mellitus on the risk of hepatocellular carcinoma.
        Ann Oncol. 2009; 20: 353-357
        • Kant P.
        • Hull M.A.
        Excess body weight and obesity–the link with gastrointestinal and hepatobiliary cancer.
        Nat Rev Gastroenterol Hepatol. 2011; 8: 224-238
        • Renehan A.G.
        • Soerjomataram I.
        • Leitzmann M.F.
        Interpreting the epidemiological evidence linking obesity and cancer: a framework for population-attributable risk estimations in Europe.
        Eur J Cancer. 2010; 46: 2581-2592
        • Renehan A.G.
        • Soerjomataram I.
        • Tyson M.
        • et al.
        Incident cancer burden attributable to excess body mass index in 30 European countries.
        Int J Cancer. 2010; 126: 692-702
        • Ohishi W.
        • Fujiwara S.
        • Cologne J.B.
        • et al.
        Impact of radiation and hepatitis virus infection on risk of hepatocellular carcinoma.
        Hepatology. 2011; 53: 1237-1245
        • El-Serag H.B.
        • Mason A.C.
        Risk factors for the rising rates of primary liver cancer in the United States.
        Arch Intern Med. 2000; 160: 3227-3230
        • Yu M.C.
        • Yuan J.M.
        Environmental factors and risk for hepatocellular carcinoma.
        Gastroenterology. 2004; 127: S72-S78
        • El-Serag H.B.
        • Tran T.
        • Everhart J.E.
        Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma.
        Gastroenterology. 2004; 126: 460-468
        • Batty G.D.
        • Shipley M.J.
        • Kivimaki M.
        • et al.
        Obesity and overweight in relation to liver disease mortality in men: 38 year follow-up of the original Whitehall study.
        Int J Obes (Lond). 2008; 32: 1741-1744
        • 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
        • 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
        • Jee S.H.
        • Yun J.E.
        • Park E.J.
        • et al.
        Body mass index and cancer risk in Korean men and women.
        Int J Cancer. 2008; 123: 1892-1896
        • Joshi S.
        • Song Y.M.
        • Kim T.H.
        • Cho S.I.
        Socio-economic status and the risk of liver cancer mortality: a prospective study in Korean men.
        Public Health. 2008; 122: 1144-1151
        • Ohishi W.
        • Fujiwara S.
        • Cologne J.B.
        • et al.
        Risk factors for hepatocellular carcinoma in a Japanese population: a nested case-control study.
        Cancer Epidemiol Biomarkers Prev. 2008; 17: 846-854
        • 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
        • Batty G.D.
        • Barzi F.
        • Huxley R.
        • et al.
        Obesity and liver cancer mortality in Asia: the Asia Pacific Cohort Studies Collaboration.
        Cancer Epidemiol. 2009; 33: 469-472
        • Inoue M.
        • Kurahashi N.
        • Iwasaki M.
        • et al.
        Metabolic factors and subsequent risk of hepatocellular carcinoma by hepatitis virus infection status: a large-scale population-based cohort study of Japanese men and women (JPHC Study Cohort II).
        Cancer Causes Control. 2009; 20: 741-750
        • Hart C.L.
        • Batty G.D.
        • Morrison D.S.
        • Mitchell R.J.
        • Smith G.D.
        Obesity, overweight and liver disease in the Midspan prospective cohort studies.
        Int J Obes (Lond). 2010; 34: 1051-1059
        • Loomba R.
        • Yang H.I.
        • Su J.
        • et al.
        Obesity and alcohol synergize to increase the risk of incident hepatocellular carcinoma in men.
        Clin Gastroenterol Hepatol. 2010; 8 (898 e1-2): 891-898
        • Nkontchou G.
        • Bastard J.P.
        • Ziol M.
        • et al.
        Insulin resistance, serum leptin, and adiponectin levels and outcomes of viral hepatitis C cirrhosis.
        J Hepatol. 2010; 53: 827-833
        • Arano T.
        • Nakagawa H.
        • Tateishi R.
        • et al.
        Serum level of adiponectin and the risk of liver cancer development in chronic hepatitis C patients.
        Int J Cancer. 2012;
        • DerSimonian R.
        • Laird N.
        Meta-analysis in clinical trials.
        Control Clin Trials. 1986; 7: 177-188
        • Higgins J.P.
        • Thompson S.G.
        Quantifying heterogeneity in a meta-analysis.
        Stat Med. 2002; 21: 1539-1558
        • Higgins J.P.
        • Thompson S.G.
        Controlling the risk of spurious findings from meta-regression.
        Stat Med. 2004; 23: 1663-1682
        • Begg C.B.
        • Mazumdar M.
        Operating characteristics of a rank correlation test for publication bias.
        Biometrics. 1994; 50: 1088-1101
        • Moller H.
        • Mellemgaard A.
        • Lindvig K.
        • Olsen J.H.
        Obesity and cancer risk: a Danish record-linkage study.
        Eur J Cancer. 1994; 30A: 344-350
        • Wolk A.
        • Gridley G.
        • Svensson M.
        • et al.
        A prospective study of obesity and cancer risk (Sweden).
        Cancer Causes Control. 2001; 12: 13-21
        • Yu M.W.
        • Yang Y.C.
        • Yang S.Y.
        • et al.
        Hormonal markers and hepatitis B virus-related hepatocellular carcinoma risk: a nested case-control study among men.
        J Natl Cancer Inst. 2001; 93: 1644-1651
        • Nair S.
        • Mason A.
        • Eason J.
        • Loss G.
        • Perrillo R.P.
        Is obesity an independent risk factor for hepatocellular carcinoma in cirrhosis?.
        Hepatology. 2002; 36: 150-155
        • Calle E.E.
        • Rodriguez C.
        • Walker-Thurmond K.
        • Thun M.J.
        Overweight, obesity, and mortality from cancer in a prospectively studied cohort of US adults.
        N Engl J Med. 2003; 348: 1625-1638
        • Samanic C.
        • Gridley G.
        • Chow W.H.
        • et al.
        Obesity and cancer risk among white and black United States veterans.
        Cancer Causes Control. 2004; 15: 35-43
        • Batty G.D.
        • Shipley M.J.
        • Jarrett R.J.
        • et al.
        Obesity and overweight in relation to organ-specific cancer mortality in London (UK): findings from the original Whitehall study.
        Int J Obes (Lond). 2005; 29: 1267-1274
        • Kuriyama S.
        • Tsubono Y.
        • Hozawa A.
        • et al.
        Obesity and risk of cancer in Japan.
        Int J Cancer. 2005; 113: 148-157
        • Oh S.W.
        • Yoon Y.S.
        • Shin S.A.
        Effects of excess weight on cancer incidences depending on cancer sites and histologic findings among men: Korea National Health Insurance Corporation Study.
        J Clin Oncol. 2005; 23: 4742-4754
        • Rapp K.
        • Schroeder J.
        • Klenk J.
        • et al.
        Obesity and incidence of cancer: a large cohort study of over 145,000 adults in Austria.
        Br J Cancer. 2005; 93: 1062-1067
        • N’Kontchou G.
        • Paries J.
        • Htar M.T.
        • et al.
        Risk factors for hepatocellular carcinoma in patients with alcoholic or viral C cirrhosis.
        Clin Gastroenterol Hepatol. 2006; 4: 1062-1068
        • Samanic C.
        • Chow W.H.
        • Gridley G.
        • Jarvholm B.
        • Fraumeni Jr., J.F.
        Relation of body mass index to cancer risk in 362,552 Swedish men.
        Cancer Causes Control. 2006; 17: 901-909
        • Ioannou G.N.
        • Splan M.F.
        • Weiss N.S.
        • et al.
        Incidence and predictors of hepatocellular carcinoma in patients with cirrhosis.
        Clin Gastroenterol Hepatol. 2007; 5 (945 e1–4): 938-945
        • Inoue M.
        • Noda M.
        • Kurahashi N.
        • et al.
        Impact of metabolic factors on subsequent cancer risk: results from a large-scale population-based cohort study in Japan.
        Eur J Cancer Prev. 2009; 18: 240-247
        • Wang C.S.
        • Yao W.J.
        • Chang T.T.
        • Wang S.T.
        • Chou P.
        The impact of type 2 diabetes on the development of hepatocellular carcinoma in different viral hepatitis statuses.
        Cancer Epidemiol Biomarkers Prev. 2009; 18: 2054-2060
        • Chao L.T.
        • Wu C.F.
        • Sung F.Y.
        • et al.
        Insulin, glucose and hepatocellular carcinoma risk in male hepatitis B carriers: results from 17-year follow-up of a population-based cohort.
        Carcinogenesis. 2011; 32: 876-881
        • Hung C.H.
        • Lee C.M.
        • Wang J.H.
        • et al.
        Impact of diabetes mellitus on incidence of hepatocellular carcinoma in chronic hepatitis C patients treated with interferon-based antiviral therapy.
        Int J Cancer. 2011; 128: 2344-2352
        • Farrell G.C.
        • Larter C.Z.
        Nonalcoholic fatty liver disease: from steatosis to cirrhosis.
        Hepatology. 2006; 43: S99-S112
        • Borena W.
        • Strohmaier S.
        • Lukanova A.
        • et al.
        Metabolic risk factors and primary liver cancer in a prospective study of 578,700 adults.
        Int J Cancer. 2011; ([Epub ahead of print])https://doi.org/10.1002/ijc.26338
        • Browning J.D.
        • Szczepaniak L.S.
        • Dobbins R.
        • et al.
        Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity.
        Hepatology. 2004; 40: 1387-1395
        • Guzman G.
        • Brunt E.M.
        • Petrovic L.M.
        • et al.
        Does nonalcoholic fatty liver disease predispose patients to hepatocellular carcinoma in the absence of cirrhosis?.
        Arch Pathol Lab Med. 2008; 132: 1761-1766
        • Hashimoto E.
        • Yatsuji S.
        • Tobari M.
        • et al.
        Hepatocellular carcinoma in patients with nonalcoholic steatohepatitis.
        J Gastroenterol. 2009; 44: 89-95
        • Papa S.
        • Bubici C.
        • Zazzeroni F.
        • Franzoso G.
        Mechanisms of liver disease: cross-talk between the NF-kappaB and JNK pathways.
        Biol Chem. 2009; 390: 965-976
        • Park E.J.
        • Lee J.H.
        • Yu G.Y.
        • et al.
        Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression.
        Cell. 2010; 140: 197-208
        • Weng C.J.
        • Hsieh Y.H.
        • Tsai C.M.
        • et al.
        Relationship of insulin-like growth factors system gene polymorphisms with the susceptibility and pathological development of hepatocellular carcinoma.
        Ann Surg Oncol. 2010; 17: 1808-1815
        • Longato L.
        • de la Monte S.
        • Kuzushita N.
        • et al.
        Overexpression of insulin receptor substrate-1 and hepatitis Bx genes causes premalignant alterations in the liver.
        Hepatology. 2009; 49: 1935-1943
        • Muller M.
        • den Tonkelaar I.
        • Thijssen J.H.
        • Grobbee D.E.
        • van der Schouw Y.T.
        Endogenous sex hormones in men aged 40–80 years.
        Eur J Endocrinol. 2003; 149: 583-589
        • Key T.J.
        • Appleby P.N.
        • Reeves G.K.
        • et al.
        Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women.
        J Natl Cancer Inst. 2003; 95: 1218-1226
        • Ding E.L.
        • Song Y.
        • Malik V.S.
        • Liu S.
        Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis.
        Jama. 2006; 295: 1288-1299
        • Clark J.M.
        • Brancati F.L.
        • Diehl A.M.
        Nonalcoholic fatty liver disease.
        Gastroenterology. 2002; 122: 1649-1657
        • Yasui K.
        • Hashimoto E.
        • Komorizono Y.
        • et al.
        Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma.
        Clin Gastroenterol Hepatol. 2011; 9 ([quiz e50]): 428-433
        • El-Serag H.B.
        • Rudolph K.L.
        Hepatocellular carcinoma: epidemiology and molecular carcinogenesis.
        Gastroenterology. 2007; 132: 2557-2576
        • Pekow J.R.
        • Bhan A.K.
        • Zheng H.
        • Chung R.T.
        Hepatic steatosis is associated with increased frequency of hepatocellular carcinoma in patients with hepatitis C-related cirrhosis.
        Cancer. 2007; 109: 2490-2496
        • Cai D.
        • Yuan M.
        • Frantz D.F.
        • et al.
        Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB.
        Nat Med. 2005; 11: 183-190
        • Arkan M.C.
        • Hevener A.L.
        • Greten F.R.
        • et al.
        IKK-beta links inflammation to obesity-induced insulin resistance.
        Nat Med. 2005; 11: 191-198
        • Moriya K.
        • Fujie H.
        • Shintani Y.
        • et al.
        The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice.
        Nat Med. 1998; 4: 1065-1067
        • 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
        • Powell E.E.
        • Jonsson J.R.
        • Clouston A.D.
        Steatosis: co-factor in other liver diseases.
        Hepatology. 2005; 42: 5-13