Nutrition 32 (2016) 3–8
Contents lists available at ScienceDirect
Nutrition journal homepage: www.nutritionjrnl.com
Meta-analysis
Green tea and liver cancer risk: A meta-analysis of prospective cohort studies in Asian populations Ya-Qing Huang M.D. a, Xin Lu M.D. b, Han Min M.D. a, Qian-Qian Wu M.D. a, Xiao-Ting Shi M.D. a, Kang-Qi Bian M.D. a, Xiao-Ping Zou M.D., Ph.D. a, * a b
Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 9 February 2015 Accepted 20 May 2015
Objectives: The aim of this meta-analysis was to investigate whether an association existed between green tea consumption and the risk for liver cancer in prospective cohort studies in Asian populations. Methods: Relevant studies were identified by searching PubMed, EMBASE, ISI Web of Science, and the Chinese Bio-medicine Database published before April 2015. Study-specific risk estimates for the highest versus non- or lowest and increment of daily cup of green tea consumption levels were combined based on fixed- or random-effects models. STATA 11.0 (Stata Corporation, College Station, TX, USA) software was used for statistical analysis. Results: Nine prospective cohort articles involving 465,274 participants and 3694 cases of liver cancer from China, Japan, and Singapore were included. The summary relative risk (RR) indicated a significant association between the highest green tea consumption and reduced risk for liver cancer (summary RR, 0.88; 95% confidence interval [CI], 0.81–0.97). However, no statistically significant association was observed when analyzing daily consumption of one cup (summary RR, 0.97; 95% CI, 0.95–1.00). When stratified by sex, the protective effect of green tea consumption on risk for liver cancer was observed only in the group of women (summary RR, 0.78; 95% CI, 0.64– 0.96), but not in men (summary RR, 0.89; 95% CI, 0.79–1.00). Conclusions: The present analysis indicated the preventive effects of green tea intake on the risk for liver cancer in female Asian populations. However, additional studies are needed to make a convincing case for this association. Ó 2016 Elsevier Inc. All rights reserved.
Keywords: Green tea Liver cancer Meta-analysis Cohort studies Asian populations
Introduction Primary liver cancer is the sixth most common cancer and, because of its poor prognosis, the second most common cause of cancer death [1]. An estimated 782,000 new primary liver cancer cases and 745,000 deaths occurred worldwide in 2012. In addition to hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, which are major etiologic determinants, other possible The authors declare that they have no competing interests. Y-QH and X-PZ designed the research. Y-QH and XL performed the literature research and extracted the data. HM contributed analytical tools. Y-QH, X-TS, and Q-QW analyzed the data. All of the authors helped interpret the results and write and revise the manuscript. * Corresponding author. Tel./fax: þ86 137 707 71661. E-mail address: [email protected] (X.-P. Zou). http://dx.doi.org/10.1016/j.nut.2015.05.021 0899-9007/Ó 2016 Elsevier Inc. All rights reserved.
environmental risk factors such as dietary aflatoxin, excessive alcohol intake, cigarette smoking, obesity, and diabetes play a key role in the development of liver cancer [2]. Brewed from the Camellia sinensis plant, tea is one of the most popular beverages consumed worldwide. According to the level of fermentation, tea can be classified into three major commercial types: green tea (nonfermented), black tea (fermented), and oolong tea (half fermented). Among these types, green tea contains a much higher level of polyphenols known as catechins, which have been shown to have antimutagenic, antigenotoxic, and anticarcinogenic activities [3]. A major polyphenol of green tea, epigallocatechin-3-gallate (EGCG), has generated interest for its antitumor effects [4]. Numerous animal and in vitro experiments have been carried out to support the possibility that green tea has preventive effects against liver cancer [5,6]. EGCG, as the
4
Y.-Q. Huang et al. / Nutrition 32 (2016) 3–8
major polyphenol of green tea, is proven to inhibit the growth of all liver cancer cell lines [7]. However, the molecular mechanisms of the chemopreventive effects of green tea remain uncertain. Over the past 2 decades, several epidemiologic studies have been conducted to investigate the association between green tea consumption and risk for liver cancer, but with varying results. One review [8] declared very limited support for green tea consumption in reducing the risk for liver cancer. A previous meta-analysis [9] suggested that high green tea intake might be associated with lower risk for liver cancer, resulting from the combination of cohort and case–control studies. However, it was limited because true differences in the level and range of intake between studies were not taken into account. Considering that the results of subsequent published cohort studies tended to show a weak correlation between green tea intake and liver cancer risk, we therefore conducted this exploratory metaanalysis to update and summarize the results from prospective studies for deriving a more precise estimation of this topic and to further evaluate whether there is a dose–response relationship between green tea intake and the risk for liver cancer. Materials and methods Data sources and searches Pertinent studies were identified by a computerized Pubmed, EMBASE, ISI Web of Science, and Chinese Bio-medicine Database search that included the years 1966 through April 2015. We used the search terms green tea, tea, polyphenol, or catechin combined with liver neoplasm, liver cancer, and hepatocellular carcinoma in the full-text option. The search was done on studies conducted on human species, without restriction on language. The reference lists of reviews and retrieved articles were hand searched at the same time. The titles and abstracts were scanned to exclude any studies that were clearly irrelevant. The full texts and tables of the remaining articles were retrieved and perused to determine the relevance of the study design and data, according to the inclusion criteria detailed here. Furthermore, references from the retrieved articles were reviewed to make sure that all the relevant bibliographies published were reviewed. Two authors (Y-QH and XL) conducted all searches independently.
Statistical analysis The measure of effect of interest was the RR and the corresponding 95% CI and the HR was considered as RR directly. Study-specific RRs and 95% CIs for highest versus non- or lowest green tea consumption level were extracted from each study, and then log RRs were weighted by the inverse of their variances to obtain summary RRs and 95% CIs. If the study provided separate RR estimates for men and women, we treated them as two different studies in statistical analysis. Studies were combined by using the DerSimonian and Laird random-effects model, which incorporates both within- and between-study variability [20]. Statistical heterogeneity among studies was evaluated using the Q and I2 statistics [21]; P < 0.10 and I2 > 50% were considered statistically significant [22]. When there was significant heterogeneity among study results, the randomeffects model was used to calculate summary RR, whereas the fixed-effects model was used to calculate summary RR among studies with homogeneous results. Additionally, subgroup analysis was carried out to investigate the influence of geographic area (China versus Japan), sex, the number of liver cancer cases (
Contents lists available at ScienceDirect
Nutrition journal homepage: www.nutritionjrnl.com
Meta-analysis
Green tea and liver cancer risk: A meta-analysis of prospective cohort studies in Asian populations Ya-Qing Huang M.D. a, Xin Lu M.D. b, Han Min M.D. a, Qian-Qian Wu M.D. a, Xiao-Ting Shi M.D. a, Kang-Qi Bian M.D. a, Xiao-Ping Zou M.D., Ph.D. a, * a b
Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 9 February 2015 Accepted 20 May 2015
Objectives: The aim of this meta-analysis was to investigate whether an association existed between green tea consumption and the risk for liver cancer in prospective cohort studies in Asian populations. Methods: Relevant studies were identified by searching PubMed, EMBASE, ISI Web of Science, and the Chinese Bio-medicine Database published before April 2015. Study-specific risk estimates for the highest versus non- or lowest and increment of daily cup of green tea consumption levels were combined based on fixed- or random-effects models. STATA 11.0 (Stata Corporation, College Station, TX, USA) software was used for statistical analysis. Results: Nine prospective cohort articles involving 465,274 participants and 3694 cases of liver cancer from China, Japan, and Singapore were included. The summary relative risk (RR) indicated a significant association between the highest green tea consumption and reduced risk for liver cancer (summary RR, 0.88; 95% confidence interval [CI], 0.81–0.97). However, no statistically significant association was observed when analyzing daily consumption of one cup (summary RR, 0.97; 95% CI, 0.95–1.00). When stratified by sex, the protective effect of green tea consumption on risk for liver cancer was observed only in the group of women (summary RR, 0.78; 95% CI, 0.64– 0.96), but not in men (summary RR, 0.89; 95% CI, 0.79–1.00). Conclusions: The present analysis indicated the preventive effects of green tea intake on the risk for liver cancer in female Asian populations. However, additional studies are needed to make a convincing case for this association. Ó 2016 Elsevier Inc. All rights reserved.
Keywords: Green tea Liver cancer Meta-analysis Cohort studies Asian populations
Introduction Primary liver cancer is the sixth most common cancer and, because of its poor prognosis, the second most common cause of cancer death [1]. An estimated 782,000 new primary liver cancer cases and 745,000 deaths occurred worldwide in 2012. In addition to hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, which are major etiologic determinants, other possible The authors declare that they have no competing interests. Y-QH and X-PZ designed the research. Y-QH and XL performed the literature research and extracted the data. HM contributed analytical tools. Y-QH, X-TS, and Q-QW analyzed the data. All of the authors helped interpret the results and write and revise the manuscript. * Corresponding author. Tel./fax: þ86 137 707 71661. E-mail address: [email protected] (X.-P. Zou). http://dx.doi.org/10.1016/j.nut.2015.05.021 0899-9007/Ó 2016 Elsevier Inc. All rights reserved.
environmental risk factors such as dietary aflatoxin, excessive alcohol intake, cigarette smoking, obesity, and diabetes play a key role in the development of liver cancer [2]. Brewed from the Camellia sinensis plant, tea is one of the most popular beverages consumed worldwide. According to the level of fermentation, tea can be classified into three major commercial types: green tea (nonfermented), black tea (fermented), and oolong tea (half fermented). Among these types, green tea contains a much higher level of polyphenols known as catechins, which have been shown to have antimutagenic, antigenotoxic, and anticarcinogenic activities [3]. A major polyphenol of green tea, epigallocatechin-3-gallate (EGCG), has generated interest for its antitumor effects [4]. Numerous animal and in vitro experiments have been carried out to support the possibility that green tea has preventive effects against liver cancer [5,6]. EGCG, as the
4
Y.-Q. Huang et al. / Nutrition 32 (2016) 3–8
major polyphenol of green tea, is proven to inhibit the growth of all liver cancer cell lines [7]. However, the molecular mechanisms of the chemopreventive effects of green tea remain uncertain. Over the past 2 decades, several epidemiologic studies have been conducted to investigate the association between green tea consumption and risk for liver cancer, but with varying results. One review [8] declared very limited support for green tea consumption in reducing the risk for liver cancer. A previous meta-analysis [9] suggested that high green tea intake might be associated with lower risk for liver cancer, resulting from the combination of cohort and case–control studies. However, it was limited because true differences in the level and range of intake between studies were not taken into account. Considering that the results of subsequent published cohort studies tended to show a weak correlation between green tea intake and liver cancer risk, we therefore conducted this exploratory metaanalysis to update and summarize the results from prospective studies for deriving a more precise estimation of this topic and to further evaluate whether there is a dose–response relationship between green tea intake and the risk for liver cancer. Materials and methods Data sources and searches Pertinent studies were identified by a computerized Pubmed, EMBASE, ISI Web of Science, and Chinese Bio-medicine Database search that included the years 1966 through April 2015. We used the search terms green tea, tea, polyphenol, or catechin combined with liver neoplasm, liver cancer, and hepatocellular carcinoma in the full-text option. The search was done on studies conducted on human species, without restriction on language. The reference lists of reviews and retrieved articles were hand searched at the same time. The titles and abstracts were scanned to exclude any studies that were clearly irrelevant. The full texts and tables of the remaining articles were retrieved and perused to determine the relevance of the study design and data, according to the inclusion criteria detailed here. Furthermore, references from the retrieved articles were reviewed to make sure that all the relevant bibliographies published were reviewed. Two authors (Y-QH and XL) conducted all searches independently.
Statistical analysis The measure of effect of interest was the RR and the corresponding 95% CI and the HR was considered as RR directly. Study-specific RRs and 95% CIs for highest versus non- or lowest green tea consumption level were extracted from each study, and then log RRs were weighted by the inverse of their variances to obtain summary RRs and 95% CIs. If the study provided separate RR estimates for men and women, we treated them as two different studies in statistical analysis. Studies were combined by using the DerSimonian and Laird random-effects model, which incorporates both within- and between-study variability [20]. Statistical heterogeneity among studies was evaluated using the Q and I2 statistics [21]; P < 0.10 and I2 > 50% were considered statistically significant [22]. When there was significant heterogeneity among study results, the randomeffects model was used to calculate summary RR, whereas the fixed-effects model was used to calculate summary RR among studies with homogeneous results. Additionally, subgroup analysis was carried out to investigate the influence of geographic area (China versus Japan), sex, the number of liver cancer cases (
