Annals of Oncology Advance Access originally published online on August 22, 2008
Annals of Oncology 2009 20(2):353-357; doi:10.1093/annonc/mdn565
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epidemiology |
The impact of obesity and diabetes mellitus on the risk of hepatocellular carcinoma
1 S.O.C. Epidemiologia e Biostatistica, IRCCS, Centro di Riferimento Oncologico, Aviano
2 Epidemiology Service, Istituto Tumori "Fondazione Pascale," Naples
3 Department of Epidemiology, Istituto di Ricerche Farmacologiche "Mario Negri"
4 Istituto di Statistica Medica e Biometria, Università degli Studi di Milano, Milan, Italy
5 International Agency for Research on Cancer, Lyon, France
* Correspondence to: Dr J. Polesel, S.O.C., Epidemiologia e Biostatistica, IRCCS, Centro di Riferimento Oncologico, Via Franco Gallini 2, 33081 Aviano, Pordenone, Italy. Tel: +39-0434-659354; Fax: +39-0434-659231; E-mail: polesel{at}cro.it
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abstract |
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Background: Obesity has been associated to increased hepatocellular carcinoma (HCC) risk, but studies on the topic do not fully account for hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. Likewise, an increased risk has been reported for diabetes mellitus (DM) but whether DM is an independent risk factor has not been established yet. To evaluate the association of obesity and DM with HCC risk, we conducted a hospital-based, case–control study in two Italian areas.
Patients and methods: From 1999 to 2003, 185 HCC cases and 404 hospital controls were enrolled. Blood samples were obtained for HBV and HCV screening.
Results: After allowance for known risk factors, body mass index 
30 kg/m2 [odds ratio (OR) = 1.9, 95% confidence interval (CI) 0.9–3.9] and DM (OR = 3.7, 95% CI 1.7–8.4) were associated to HCC risk. These associations persisted (OR = 3.5, 95% CI 1.6–7.7 for obesity; OR = 3.5, 95% CI 1.3–9.2 for DM) among subjects without HBV and/or HCV infection. Overall, 23% of HCC cases seemed attributable to these conditions, and this figure rose to 37% among subjects without HBV and/or HCV infections.
Conclusions: The present study provides further evidence that obesity and DM increase HCC risk and that these factors may explain a relevant proportion of cases among subjects without markers of HBV/HCV infection.
Key words: attributable risk, diabetes mellitus, HBV, HCV, hepatocellular carcinoma, obesity
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introduction |
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Hepatocellular carcinoma (HCC) is a highly fatal disease that, in Italy, accounts for 6% of all cancer deaths among men and for 5% among women [1]. Infection with hepatitis C (HCV) and/or hepatitis B (HBV) viruses and elevated alcohol consumption are the leading risk factors for HCC, accounting for
90% of cases [2]. Other factors may also be relevant, including medical conditions, smoking habits, and diet. Over the last two or three decades, upward trends in HCC incidence and mortality have been reported in the United States [3] and in several European countries [4]. Similar trends in obesity prevalence have suggested a possible association of HCC risk with excessive weight. A recent meta-analysis [5], summarizing the evidence from cohort studies, found increased HCC risks of 17% for overweight people and of 90% for obese ones, compared with those in regular weight. The authors, however, recognized the lack of allowance for potential confounders—in particular chronic HBV and HCV infections and alcohol abuse—as a potential limitation.
It is well known that diabetes mellitus (DM) and obesity are related medical conditions. Epidemiological data showed a three-fold increased HCC risk among diabetics [6], but most of previous studies did not fully establish whether DM preceded HCC or whether both HCC and DM might be due to other factors, particularly chronic liver disease [7]. Thus, we further investigated the association between obesity, DM and HCC risk, controlling for known risk factors like HCV and/or HBV infections, drinking, and smoking habits.
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patients and methods |
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From January 1999 to July 2002, we conducted a case–control study on HCC and lymphomas in the province of Pordenone, Northeast Italy, and in the town of Naples, South Italy [8]. Cases were patients <85 years of age with incident HCC, who had not yet received any cancer treatment at study entry. In Northeast Italy, cases were admitted at the ‘Centro di Riferimento Oncologico’ National Cancer Institute, Aviano, and at the ‘Santa Maria degli Angeli’ General Hospital, Pordenone; in South Italy, they were admitted at the ‘Fondazione Pascale’ National Cancer Institute and four General Hospitals, Naples. Out of 261 identified HCC cases, three subjects refused study participation, 29 did not supply blood samples, and additional 44 HCC cases did not have anthropometric measurements at cancer diagnosis. For the remaining 185 HCC cases (median age 66 years, range 43–84 years), both comprehensive questionnaire information and blood samples were available. Histological or cytological confirmation was available for 78% of HCC cases, whereas the remaining cases were diagnosed by ultrasound and/or tomography (12%) and by elevated
-fetoprotein (10%). The comparison group included patients aged 40–82 years (median age 65 years), who were admitted for a wide spectrum of acute conditions to the same hospitals where HCC cases had been interviewed. Specifically excluded from the control group were patients whose hospital admission was due to diseases related to alcohol and tobacco use (e.g. respiratory diseases, peptic ulcer, lung cancer, and head and neck cancer), hepatitis viruses (e.g. hepatitis, cirrhosis, and oesophageal varices), or chronic diseases that might have resulted in substantial lifestyle modifications (e.g. diabetes, cardio-, and cerebral vascular diseases). However, comorbidity for such diseases was not an exclusion criterion. Overall, 467 controls were contacted and 462 accepted to participate. Blood samples were available for 431 controls and 404 provided information on body size measures during interview. Twenty-seven percent of controls admitted to the hospital for traumas, 25% for acute surgical conditions, 24% for nontraumatic orthopedic diseases, 14% for eye diseases, and 10% for other illnesses. Controls were more often female and were younger than HCC cases as matching was conducted according to the distribution by age and gender of cancer cases in the entire study, which also included lymphomas [9]. All study participants signed an informed consent, in agreement with the recommendations of the Board of Ethics of the Aviano National Cancer Institute approving the study.
Each case and each control provided a 15-ml blood sample the day the interview took place for detecting infections with hepatitis viruses (i.e. anti-HCV positivity and HBsAg positivity). Sera were screened for anti-HCV using a third-generation MEIA (AxSYM HCV, version 3.0; Abbott, Wiesbaden, Germany) and for HBsAg using micro particle enzyme immunoassay (AxSYM HBsAg version 2.0, Abbott Diagnostic Division, Wiesbaden, Germany).
Cases and controls were approached during their hospital stay and they were interviewed by trained nurses. A structured questionnaire was used to collect information on education and other socioeconomic factors, diet, and history of cancer in first-degree relatives. Smoking and drinking habits were assessed in separate sections; drinkers were asked to report any change in alcohol beverage intake, as to compute the maximal lifetime alcohol intake [8]. The questionnaire also included a problem-oriented medical history to assess the history of clinically relevant diseases—including cirrhosis, DM, and treated hypertension—up to 1 year before cancer diagnosis/interview. In a detailed section of the questionnaire, study subjects were asked to report their height and weight 1 year before cancer diagnosis or interview (in controls) and weight at 30 and 50 years of age. Body mass index (BMI) was computed as weight (kg) divided by squared height (m2).
Adjusted odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were calculated by means of unconditional multiple logistic regression models including age, gender, study centre, years of education, HBsAg and/or anti-HCV positivity, smoking habits, cigarettes per day, drinking habits, and lifetime maximal alcohol intake, when mentioned [10]. Since current drinking habits among cases may be influenced by early symptoms of cancer, maximal lifetime alcohol intake, rather than the present alcohol consumption, was considered for adjustments [8]. Percent attributable risks were computed using the distribution of the risk factors in HCC cases and corresponding 95% CIs were obtained [11].
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results |
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The distribution of cases and controls according to major anthropometric measures 1 year before diagnosis/interview and history of lifetime body size measures is reported in Table 1. Compared with subjects with a BMI <25 kg/m2, obese subjects (BMI
30 kg/m2) showed an approximately two-fold increased HCC risk (OR = 1.9, 95% CI 0.9–3.9). BMI at ages 30 and 50 years and absolute variation since those particular ages were not significantly associated to HCC risk. Results did not change when patients with DM were excluded from the analysis (data not shown). No association emerged for hypertension (Table 1).
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Cases reported more frequently than controls a history of DM (20% and 6%, respectively; Table 2). After adjusting for potential confounding factors, DM was associated to a nearly four-fold increased HCC risk (OR = 3.7, 95% CI 1.7–8.4), and the strength of the association did not significantly vary according to time since diagnosis of DM. Five per cent of cases and 2% of controls were obese individuals with DM; their HCC risk was five-fold increased, as compared with nonobese subjects without DM (Table 2).
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The association between obesity, DM, and HCC risk was further investigated among subjects without serological evidence of HBV and/or HCV infections (Table 3). Among HBsAg-negative and anti-HCV-negative subjects, obesity and DM were confirmed to increase HCC risk (OR = 3.5 for both obesity and DM), and these two conditions combined led to a 10-fold increase in risk (OR = 11.8 for diabetics with BMI
30 kg/m2 versus nondiabetic with BMI <30 kg/m2). DM and obesity accounted for 14% and 9% of HCC cases, respectively, after allowance for HCV/HBV infection, drinking, and smoking habits—while both factors accounted for 23% of HCC cases (Table 3). The proportion of HCC cases attributable to obesity and DM was higher (37%) among subjects who had negative HBsAg and anti-HCV test, and this effect was more evident for obesity (from 9% to 28%) (Table 3).
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discussion |
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The present study found increased HCC risk in the obese and diabetic subjects, after controlling for infections with HCV and/or HBV, drinking, and smoking habits. In particular, it is worth stressing that the effect of obesity and DM persisted in persons without hepatitis virus infections (HBsAg negative and anti-HCV negative) and that obesity and DM in these persons may explain a relevant proportion of HCC cases.
The association between HCC risk and obesity, though not significant, was consistent with OR estimates reported in recent meta-analyses of cohort studies [5, 12]. Investigations on selected subgroups confirmed increased HCC risks for obese persons [13, 14]. Likewise, a two- to four-fold increased risk of HCC among diabetics emerged from cohort [15–17] and case–control studies [18–20]. However, a temporal relationship—i.e. whether DM preceded HCC and any other liver disease predisposing to HCC—could not be fully established in most of these studies. DM is common in subjects with cirrhosis [21, 22] or hepatitis infection [23], two conditions which cause various degrees of liver failure. In the present study as in another case–control investigation [20], however, DM was a risk factor for HCC also among subjects without evidence of HCV and HBV infections, thus pointing to a real association. In the present study, >20% of HCC cases were attributable to obesity and diabetes, and this figure rose to 37% in HBsAg-negative and anti-HCV-negative patients. Although these figures might have overestimated the actual values, they may explain a relevant proportion of HCC cases not attributable to HCV/HBV infection, alcohol abuse, and heavy smoking [2, 8].
Among obese and diabetic patients, metabolic disorders are common and hepatocellular injuries may occur because of elevated fat accumulation in the liver. Nonalcoholic fatty liver disease (NAFLD) is extremely frequent among these patients [6], and excessive weight is associated to an advanced disease [24]. Liver steatosis has been reported in 60% of obese subjects, whereas a relevant proportion of these subjects had more severe histological abnormalities like nonalcoholic steatohepatitis (25%) and cirrhosis (3%) [24]. Among major pathogenic factors in NAFLD, lipid peroxidation has been recognized to induce mutagens from reactive oxygen species, thus favoring the development of cancer-promoting mutations [6]. Among these, mutations of p53 tumor suppressor gene have been documented, in particular among diabetics [25]. In addition, both obesity and diabetes were associated with insulin resistance and elevated insulin-like growth factor, which stimulate cell growth and may promote cancer cells proliferation [26].
Availability of serological testing against HCV and HBV, as well as detailed information on smoking and drinking habits, are among the strengths of the present study. Fine adjustments for drinking status and maximal lifetime alcohol intake were made to address potential confounding due to the fact that elevated alcohol consumption is a risk factor for both diabetes and HCC.
The main limitation of the present study is its sample size, which affected ORs precision and did not allow more detailed analysis according to selected strata. In particular, we were not able to evaluate the effect of obesity and DM among HBsAg-negative/anti-HCV-negative subjects without history of alcohol abuse since the number of HCC cases (n = 15) was not sufficient to support statistical models. An additional potential limitation is the use of hospital controls, which may differ from the general population and may lead to selection bias if controls had higher prevalence of obesity or diabetes than the source population. However, according to study design, great attention was paid in excluding controls admitted to hospital for diseases that might have been associated to DM or which might have led to dietary modifications. Information bias was also minimized by administering the questionnaire to cases and controls in a hospital setting through the same interviewers and by the nearly complete participation of identified cases and controls. Moreover, information on medical conditions provided by hospital controls has been shown to be satisfactorily reliable for the present structured questionnaire, with overall agreement >90% for diabetes [27].
In conclusion, the present study provides further evidence that obesity and DM increase the risk of HCC and that these factors may explain a relevant proportion of cases especially among subjects without HBV and/or HCV infections.
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Italian Association for Cancer Research (AIRC); the Italian League against Cancer (LILT).
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acknowledgements |
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Dr Carlo La Vecchia was a Senior Fellow at the International Agency for the Research on Cancer. The authors wish to thank Mrs O. Volpato for study coordination, Ms G. Bessega, L. Zaina, M. Grimaldi, and S. Desicato for their help in data collection, and Ms L. Mei for editorial assistance. We are also grateful to Drs P. Casarin, F. Izzo, R. Mele, A. Grandi, L. Forner., P. Ascierto, R. Magri, and R. Di Lauro for providing cases and hospital control patients and to laboratory technicians of the Divisione di Microbiologia e Immunologia, General Hospital of Pordenone for virological testing.
Received for publication April 29, 2008. Accepted for publication July 18, 2008.
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