Food groups and risk of hepatocellular carcinoma: A multicenter case-control study in Italy
International Journal of Cancer Dec 2006
Renato Talamini 1 *, Jerry Polesel 1, Maurizio Montella 2, Luigino Dal Maso 1, Anna Crispo 2, Luigi G. Tommasi 1, Francesco Izzo 3, Marina Crovatto 4, Carlo La Vecchia 5 6, Silvia Franceschi 7
1Unità di Epidemiologia e Biostatistica, Centro di Riferimento Oncologico, Istituto Nazionale Tumori, Aviano, Italy
2Servizio di Epidemiologia, Istituto Tumori Fondazione Pascale, Cappella dei Cangiani, Naples, Italy
3Divisione di Chirurgia D, Istituto Tumori Fondazione Pascale, Cappella dei Cangiani, Naples, Italy
4Divisione di Microbiologia e Immunologia, Ospedale S. Maria degli Angeli, Pordenone, Italy
5Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
6Istituto di Statistica Medica e Biometria, Università degli Studi di Milano, Milan, Italy
7International Agency for Research on Cancer, Lyon, France
Hepatocellular carcinoma (HCC) is a frequent malignancy in many regions of the world. Over the last few decades, increasing incidence and mortality have been reported in the United States, Japan and in several European countries, including Italy, though rates have been levelling off since the mid 1990s. Infection with hepatitis B virus and (HBV) and hepatitis C virus (HCV) and heavy alcohol drinking are the major risk factors for HCC in developed countries. However, other factors, including diet, may be relevant, but the evidence is still unclear, except for aflatoxin contamination.
At least 16 epidemiological studies have examined the relation between diet and HCC risk. Ten were case-control studies, 1 was a cross-sectional ecological survey, and 5 were cohort studies. Among these, an Italian case-control study reported a decreased risk of HCC with milk intake, whereas studies from Japan and United States did not. Correlation data from an ecological study suggested an inverse association between wheat intake and HCC risk, but results from case-control studies did not support this finding.
Inverse associations were observed for vegetable intake in several studies, as well as for fresh fruits, while few investigations did not find any association. Meat and animal protein consumptions were associated with increased risk of HCC in a cohort, and a case-control study, but not in others. Inverse relations were observed with consumption of fish in some studies, but other did not confirm this finding. Likewise, for egg consumption, 2 studies reported an inverse relation with HCC risk, while 3 others reported an increased risk.
To provide further insights on the relation between food and risk of HCC, we analysed data derived from a multicentre Italian case-control study.
The role of diet, except for alcohol drinking and aflatoxin contamination, in the etiology of hepatocellular carcinoma (HCC) is unclear. A hospital-based case-control study was conducted in Italy in 1999-2002, including 185 incident, histologically-confirmed cases of HCC. Controls were 412 subjects admitted to hospitals for acute, nonneoplastic diseases unrelated to diet. Dietary habits were assessed using a validated food-frequency questionnaire. Odds ratios (ORs) and the corresponding 95% confidence intervals (CI) were computed using unconditional multiple logistic regression, adjusting for hepatitis B (HBV) and hepatitis C (HCV) virus infection and alcohol drinking. Energy adjustment was carried out by means of the residual model. A significant inverse relation was found between intakes of milk and yoghurt (OR = 0.28; 95% CI: 0.13-0.61), white meats (OR = 0.44; 95% CI: 0.20-0.95), eggs (OR = 0.31; 95% CI: 0.14-0.69), and fruits (OR = 0.48; 95% CI: 0.22-1.05) and HCC risk. The favourable effect of high intakes of milk and yoghurt, white meats, eggs and fruits was consistent across strata of HBV and HCV infections. The present study supports the hypothesis of a role of diet in HCC aetiology. Dietary modifications may be indicated in subjects at high-risk for HCC.
The present study showed a significant inverse association between consumptions of milk and yoghurt, white meats, eggs and fruits and HCC risk. Decreased risk of HCC with the highest milk intakes (OR = 0.7, for the highest vs. lowest quartile) was also reported in another case-control study from Italy, while a case-control study in Japan found a higher risk with greater than average consumption of milk (OR = 1.9, in men; OR = 2.6 in women). No associations were found in relation to milk consumption in other studies: a cross-sectional ecological survey, a case-control, and a cohort study. Only in the study by Kuper et al., which studied jointly milk and dairy products, these appeared to have an inverse association with HCC risk (OR = 0.70 one-quintile increment, 95% CI: 0.49-1.01). All these studies were able to control for potentially important confounding effects of HBsAg or history of hepatitis C and B. Our data showed that the relation with milk and yoghurt were consistent across strata of age and HBV and HCV serological markers.
In our study, a significant inverse association was also found with white meat consumption, but previous results for meat consumption and HCC risk were inconsistent. Four case-control studies did not find a relation with meat consumption. However, one study suggested a decreased risk of HCC with high vs. low intake of pork. In an ecological study in China, no relation between meat intake and HCC risk was reported. In contrast, an increased risk was observed between daily meat consumption and HCC risk in a cohort study in Japan; this association was apparently stronger in men.
An inverse association of HCC risk with egg consumption was found in our study. This remained significant across strata of age, but only among HBsAg- and antiHCV- subjects. Intakes of eggs were investigated in some previous studies. The two case-control studies examining the effect of egg consumption and HCC risk gave conflicting results. In a previous Italian study, a significant inverse dose-risk relation was reported (OR = 0.51). However, in a Japanese study, an increased risk of HCC was observed for higher egg consumption among men only (OR = 1.9), after adjustment for age only. Different dietary habits between Italian and Japanese populations, including fat for cooking, may partly account for those differences but, most likely, eggs are a different diet indicator in Italy and in Japan. The inverse relation with diary products, and eggs may be due to their retinol content, since serum retinol levels have been inversely related to HCC risk in a case-control study from China. Retinol is found in foods of animal origin, such as liver, milk, diary products, and eggs. In particular for the Italian diet, dairy products and eggs are among the main sources of retinol, with an average retinol contents of 400 g/100 g and 850 g/100 g, respectively.
An inverse association between fruit and HCC risk was found in our study. Our data showed that the favourable effect of fruit was consistent across strata of age, HBV and HCV serological markers. Two case-control studies reported a decrease in risk with higher consumption of fruit, but 2 additional studies reported no association. A case-control study conducted in northern Italy found that the population attributable-risk for HCC risk was 40% for low vegetable and fruit consumptions. Vegetables and fruits contain several compounds, such as flavonoids, which have several biological activities that include antimutagenic, antiproliferative, and antioxidant effects, as well as involvement in cell signalling, cell cycle regulation, and angiogenesis. Consequently, flavonoids may have an important role in explaining the favourable effects of vegetables and fruits against cancer (e.g., lung, breast, prostate and colorectal cancers). However, the possible role of the antioxidant properties of vegetables and fruits against HCC risk remains speculative.
The present study showed a nonsignificant inverse association with vegetables. A protective effect of high vegetable intakes has been found in some, but not all, studies. A major problem in the interpretation of our case-control study, as well as similar previous studies on HCC, is reverse causation. HCC is generally preceded by chronic hepatitis and cirrhosis that can lead to dietary modifications. A good example of this is the excess of former drinkers among HCC cases compared to controls. However, with the possible exception of eggs, none of the food groups that showed inverse association with HCC risk belong to groups whose consumption would have been discouraged in the presence of liver diseases.
With reference to other possible sources of bias, information on diet and liver cancer was limited in the Italian public at the time of the study, as the issue had not received media attention. Although this study was not population-based, the catchments areas were comparable for cases and controls. Dietary habits of hospital controls may have differed from those of the general population; however, by study design, great attention was paid in excluding all diagnoses that might have been associated to or had determined special dietary habits in control subjects. Moreover, to reduce the possibility of recall bias due to changes in diet related to disease onset, we elicited information on food intake during the 2 years before the interview. The questionnaire was administered to cases and controls by the same interviewers under similar conditions in a hospital setting, thus minimizing information bias. In addition, our findings are strengthened by the almost complete participation of identified cases and controls and by the reliance on a validated food-frequency questionnaire. Adjustments for gender, age, centre, education, place of birth, drinking habits, total energy intake, and HBsAg and/or antiHCV were made to address potential confounding.
In conclusion, our study indicated that diet has a relevant role in HCC risk. In particular, the beneficial effect dietary products, white meats, eggs and fruits was independent from other major risk factors (i.e., HBV- and HCV-infections), addressing the importance of indications towards a diet modification for subjects at high-risk of HCC.
Material and methods
Data derived from a case-control study conducted between January 1999 and July 2002, in the province of Pordenone, Northeast of Italy, and in Naples, South of Italy, to assess the association of HBV and HCV with HCC and lymphohaematopoietic neoplasms.
Cases were patients below the age of 85 years with incident HCC, who had not yet received any cancer treatment at study entry. They were admitted to the National Cancer Institute, Aviano, the 'Santa Maria degli Angeli' General Hospital, Pordenone, the Pascale National Cancer Institute, and 4 General Hospitals in Naples. A total of 261 HCC cases were identified. Three cases refused to participate in the study, 29 HCC cases did not provide a blood sample, and 44 were not questioned on dietary habits, thus leaving 185 eligible cases (median age: 66, range: 43-84 years) with available questionnaires and blood samples. Histological or cytological confirmation was available for 78.2% of HCC cases, and for the remaining ones the diagnosis was based on ultrasound, tomography, and elevated a-fetoprotein levels.
Controls were patients aged below 85 years admitted, to the same hospitals where HCC cases had been interviewed for a wide spectrum of acute conditions. Patients, whose hospital admission was due to diseases related to alcohol and tobacco use (e.g., respiratory diseases, peptic ulcer, lung cancer, head and neck cancer, etc.) or hepatitis viruses (e.g., hepatitis, cirrhosis, oesophageal varices, etc.) were specifically excluded from the control group, as were those hospitalised for any chronic diseases that might have lead to substantial lifestyle modifications (e.g., diabetes, cardio- and cerebro-vascular diseases, etc.). Of the 467 controls contacted, 462 accepted to participate. Blood samples were available for 431 controls and 412 provided comprehensive information on dietary habits; of these, 27% were admitted for trauma, 24% for nontraumatic orthopaedic diseases, 25% for acute surgical conditions, 13% for eye diseases and 11% for other illnesses. Controls were more often females, were younger than HCC cases, more often recruited in the study centre of Aviano/Pordenone as matching was conducted according to the distribution by age, gender and study centre of cancer cases in the entire study, which also included lymphohaematopoietic neoplasms. In the present analyses, however, the control group was restricted to subjects above age 40 (n = 412; median age: 65, range: 40-82 years), as no HCC case below age 40 years had been identified. All study participants signed an informed consent form, according to the recommendations of the Ethical Committee of the Aviano National Cancer Institute.
The same interview-based, structured questionnaire and coding manual were used in each study centre. Centrally trained and supervised interviewers identified and questioned patients in hospitals. On average, about 1% of cases and controls refused the interview. The data were checked centrally for consistency. Each case and control provided a 15 ml sample of blood on the day the interview took place. Sera were screened for antibodies against HCV (antiHCV) using a third-generation MEIA (AxSYM HCV, version 3.0; Abbott, Wiesbaden, Germany) and for HBV surface antigen (HBsAg) using microparticle enzyme immunoassay (AxSYM HBsAg version 2.0, Abbott Diagnostic Division, Wiesbaden, Germany).
A validated food frequency questionnaire (FFQ) was employed to assess subjects' habitual diet and to estimate their total energy intake 2 years before cancer diagnosis or, for the controls, hospital admission. The FFQ included information on age, education and other sociodemographic characteristics, anthropometrics measures, tobacco smoking, history of selected diseases, lifestyle factors and exposures that entailed risk of HCV transmission. The dietary section included 63 foods, food groups or recipes divided into 7 sections: (i) milk, yoghurt, coffee, tea, sugar and artificial sweeteners; (ii) bread and cereals (first courses); (iii) meat and foods used as meat substitutes (second courses); (iv) vegetables (side dishes); (v) fruits; (vi) sweets, desserts and soft drinks; (vii) alcoholic beverages.
For fruit and vegetables subject to seasonal variation, consumption in season and the corresponding duration were elicited. For 22 food items, serving size was defined either in 'natural' units (e.g., 1 teaspoon of sugar, 1 egg) or as an average serving in the Italian diet (e.g., 80 g pasta or rice with tomato or meat sauce; 250 g pizza; 120-150 g red meat). Intake lower than once a week but at least once a month was coded as 0.5 per week. Some questionnaire items and recipes were allocated to 2 food groups, according to their contents (e.g., pizza was apportioned into both bread and cheese for one half each). The FFQ allowed estimation of total energy intake using the Italian food-composition database. Odds ratios (OR) and the corresponding 95% confidence intervals (CI) were computed by unconditional multiple logistic regression, including age in quinquennia (<45, 45-49, 50-54, 55-59, 60-64, 65-69, 70-74, >75), sex, center, years of education (<7, 7-11, >12 years), place of birth (North-Center and South), drinking habits (abstainer, former, current), maximal lifetime alcohol intake (<21 vs. >21 drinks/week), and total energy intake (Kcal/day, in continuous, energy from alcohol included). As prevalence of HBV infection was very low among controls (n = 4, 1%), for the sake of adjustment for seroprevalence of HBV and HCV infections, information on hepatitis viruses were combined and a dummy variable (HBsAg+ and /or antiHCV+ vs. HBsAg- and antiHCV-) was included in the model. Adjustment for energy was made using the residual model. Food groups were entered in the model as quartile of intake based on the distribution of cases and controls combined. The test for trend was based on the likelihood-ratio test between the models with and without linear terms for each variable of interest. Heterogeneity of risk estimates across strata was evaluated by Wald X2 test.
Table I shows the distribution of HCC cases and controls by sociodemographic factors and selected variables, and the corresponding ORs unadjusted and adjusted for major confounding factors. An inverse relation was found with educational level (OR for >12 vs. <7 years was 0.30, 95% CI: 0.16-0.58). Compared to never drinkers, former drinkers seemed to be at higher risk than current ones (ORs was 5.42 and 0.62, respectively). Maximal lifetime alcohol intake >21 drinks/week (former and current drinkers combined) was related to HCC risk (OR = 2.38; 95% CI: 1.13-5.01). Fifteen percent of cases, compared to 1% of controls, were chronically infected with HBV (HBsAg+ vs. HBsAg-, OR = 17.20; 95% CI: 5.40-54.76), whereas being positive to Anti-HCV test was associated to an increased risk of HCC (OR = 18.42; 95% CI: 11.20-30.29, Table I). Patients who were positive for markers of HBV or HCV infections (80% of cases and 11% of controls) showed a 30-fold increased risk of HCC (HBsAg+ and/or AntiHCV+, OR = 30.36; 95% CI: 17.98-51.25, data not shown). An increased risk was found for the highest (>2650 Kcal/day) vs. lowest quartile (<1868 Kcal/day) of total energy intake (OR = 2.37; 95% CI: 1.35-4.17).
Table II shows the upper limits of intake in quartiles of the food groups considered, and the corresponding multivariate ORs and relative 95% CI values. A significant inverse trend in risk was found for intake of milk and yoghurt (OR for highest vs. lowest quartile =0.28, 95% CI: 0.13-0.61; p for trend < 0.01), white meats (OR = 0.44, 95% CI: 0.20-0.95; p = 0.01), eggs (OR = 0.31, 95% CI: 0.14-0.69; p < 0.01), and fruits (OR = 0.48, 95% CI: 0.22-1.05; p = 0.04). Intakes of bread, pasta/rice, soup, read meats, pork and processed meat, fish, cheese, vegetables, potatoes and dessert were not significantly related to HCC risk.
When separate analysis of food groups associated to HCC risk was conducted across strata of age (<65 vs. >65 years), no differences emerged for highest vs. lowest consumption of milk and yoghurt (ORs: 0.20 and 0.30, respectively), eggs (ORs: 0.28 and 0.26, respectively) (data not shown). However, a nonsignificant modifying effect for white meats (ORs: 0.62 and 0.31, respectively), and fruits (ORs: 1.01 and 0.31, respectively) was found. No considerable differences emerged between study centres (Aviano/Pordenone vs. Naples, data not shown).
Food groups significantly associated to HCC risk were further investigated in separate strata according to HBV and/or HCV infection (Table III). No clear modifying effect of HBV and/or HCV emerged (p for heterogeneity > 0.05). In particular, among subjects who were HBsAg+ and/or anti-HCV+, a reduction in HCC risk was confirmed for high intakes of milk and yoghurt (OR = 0.53), white meats (OR = 0.32), eggs (OR = 0.67) and fruits (OR = 0.64).
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