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Emrani A S, Mirjalili F, Yekrang Safakar H, Forootani B, Salehi-abargouei A. The Association between Dietary Polyphenols Intake and Risk of Liver Cancer: A Systematic Review and Meta-Analysis of Observational Studies. JNFS 2025; 10 (2) :328-337
URL: http://jnfs.ssu.ac.ir/article-1-1074-en.html
URL: http://jnfs.ssu.ac.ir/article-1-1074-en.html
Arezoo sadat Emrani 
, Fatemeh Mirjalili , Hooman Yekrang Safakar , Bita Forootani , Amin Salehi-abargouei *
, Fatemeh Mirjalili , Hooman Yekrang Safakar , Bita Forootani , Amin Salehi-abargouei *
Yazd Cardiovascular Research Center, Non-communicable Diseases Research Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
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1 Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran; 2 Research Center for Food Hygiene and Safety, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran; 3 Student Research Committee, Shahid Sadoughi University of Medical Sciences, Yazd, Iran; 4 Yazd Cardiovascular Research Center, Non-communicable Diseases Research Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
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The Association between Dietary Polyphenols Intake and Risk of Liver Cancer: A Systematic Review and Meta-Analysis of Observational Studies
Arezoo sadat Emrani; MSc1,2, Fatemeh Mirjalili; MSc1,2,3, Hooman Yekrang Safakar; MSc1,2,
Bita Forootani; MSc1,2 & Amin Salehi-abargouei; PhD*1,2,4
Bita Forootani; MSc1,2 & Amin Salehi-abargouei; PhD*1,2,4
1 Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran; 2 Research Center for Food Hygiene and Safety, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran; 3 Student Research Committee, Shahid Sadoughi University of Medical Sciences, Yazd, Iran; 4 Yazd Cardiovascular Research Center, Non-communicable Diseases Research Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
| ARTICLE INFO | ABSTRACT | |
| SYSTEMATIC REVIEW and META-ANALYSIS | Background: The current data on the association between dietary polyphenols intake and liver cancer are not conclusive. Therefore, we aimed to perform a systematic review and meta-analysis of observational studies on the association between dietary polyphenol intake and liver cancer. Methods: A systematic search of online databases, including PubMed/MEDLINE, Scopus, and Web of Science, was conducted until August 2024. Observational studies that investigated the association between dietary intake of polyphenols and the risk of liver cancer were included. The overall effects were assessed using the random effects model. Results: Totally, four studies were eligible to be included in the systematic review, and for meta-analysis, 3 studies with 4 effect sizes were included. The overall association between dietary intake of isoflavones and the risk of liver cancer was not significant (P=0.35, 95% CI: 0.58-1.21). Conclusion: No significant association was found between dietary polyphenols intake and liver cancer risk. Further observational studies are suggested to confirm these findings. | |
| Article history: Received: 31 May 2024 Revised: 8 Oct 2024 Accepted: 18 Oct 2024 |
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| *Corresponding author abargouei@ssu.ac.ir Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd. Postal code: 8915173160 Tel: +98 35 38209119 |
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| Keywords Polyphenols; Isoflavones; Liver neoplasms; Hepatocellular cancer. |
Introduction
Liver cancer is the third leading cause of cancer-related death worldwide (Sung et al., 2021). The prevalence of liver cancer is highly increasing, and new-diagnosed cases and cancer mortality in 2017 were more than twice the statistics in 1990 (Lin et al., 2020). Although the prevalence of this cancer is decreasing in Asia, it still has a higher rate than in European and American countries (Dasgupta et al., 2020). About 75 to 90% of primary liver cancers are hepatocellular carcinomas (HCC), which are often malignant and have a poor prognosis (London and McGlynn, 2006). One of the reasons for the high prevalence of liver cancer in Asia, especially in East and Southeast Asia, is the endemicity of hepatitis B virus infection, which is an important risk factor for this cancer (Petrick et al., 2020). Contamination of food with toxins such as aflatoxin, alcohol drinking, smoking, non-alcoholic fatty liver disease, obesity, and diabetes, genetic and also dietary factors are mentioned as other risk factors in the incidence of liver cancer (Mohammadian et al., 2018).
Evidence suggests that plant-based dietary patterns are associated with a reduced risk of liver cancer (Zhang et al., 2013). A study in Chinese adults found that adherence to a dietary pattern rich in fruits, vegetables, fish, and herbal tea may diminish the risk of liver cancer (Lan et al., 2018). Studies have also shown that the intake of certain food items, such as tea, coffee, and soy products which are rich sources of polyphenols, may be inversely related to the risk of liver cancer (Yang et al., 2020). Polyphenols are compounds that
have been claimed to have numerous benefits, including antioxidant, anti-inflammatory,
anti-atherosclerosis, and anti-cancer activities (Costea et al., 2019). So far, many polyphenols are known, which are divided into 4 main structural groups including flavonoids, phenolic acids, lignans, and stilbenes (Papuc et al., 2017, Wu et al., 2021). Due to their pharmacological effects on oxidative stress, lipid metabolism, and inflammation (Li et al., 2014), nowadays, polyphenols are considered an adjuvant treatment for liver diseases. However, few human studies have been conducted on the association between dietary polyphenols and the risk of liver cancer. An in-vitro study stated that flavonoids can increase the apoptosis of liver cancer cells (Mansoor et al., 2011). A randomized, double-blinded, and placebo-controlled trial demonstrated that green tea polyphenols may be protective for liver cancer by decreasing oxidative DNA damage in high-risk individuals (Luo et al., 2005). It was also suggested by Lagiou et al. that flavones intake may be inversely related to HCC risks (Lagiou et al., 2008). However, another study showed an increased risk of HCC in women with isoflavone consumption (Kurahashi et al., 2009). Moreover, recent studies have suggested conducting a systematic review to find out the association between different polyphenols and liver disease (Li et al., 2018).
To the best of our knowledge, no systematic review and meta-analysis has been conducted on the association between polyphenols and liver cancer risk. Therefore, the present study investigated the relationship between dietary intake of polyphenols and risk of liver cancer.
Materials and Methods
The present study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines (Moher et al., 2015). The study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (http://www.crd. york.ac.uk/PROSPERO) with the following registration number: CRD42023487302
Search strategy
The search strategy was applied in online databases until August 2024, including, PubMed/MEDLINE, Web of Science, and Scopus. To find related articles, two authors screened titles and abstracts independently (B Forootani & H Yekrang Safakar). The references of the selected articles were also checked to find additional studies.
Evidence suggests that plant-based dietary patterns are associated with a reduced risk of liver cancer (Zhang et al., 2013). A study in Chinese adults found that adherence to a dietary pattern rich in fruits, vegetables, fish, and herbal tea may diminish the risk of liver cancer (Lan et al., 2018). Studies have also shown that the intake of certain food items, such as tea, coffee, and soy products which are rich sources of polyphenols, may be inversely related to the risk of liver cancer (Yang et al., 2020). Polyphenols are compounds that
have been claimed to have numerous benefits, including antioxidant, anti-inflammatory,
anti-atherosclerosis, and anti-cancer activities (Costea et al., 2019). So far, many polyphenols are known, which are divided into 4 main structural groups including flavonoids, phenolic acids, lignans, and stilbenes (Papuc et al., 2017, Wu et al., 2021). Due to their pharmacological effects on oxidative stress, lipid metabolism, and inflammation (Li et al., 2014), nowadays, polyphenols are considered an adjuvant treatment for liver diseases. However, few human studies have been conducted on the association between dietary polyphenols and the risk of liver cancer. An in-vitro study stated that flavonoids can increase the apoptosis of liver cancer cells (Mansoor et al., 2011). A randomized, double-blinded, and placebo-controlled trial demonstrated that green tea polyphenols may be protective for liver cancer by decreasing oxidative DNA damage in high-risk individuals (Luo et al., 2005). It was also suggested by Lagiou et al. that flavones intake may be inversely related to HCC risks (Lagiou et al., 2008). However, another study showed an increased risk of HCC in women with isoflavone consumption (Kurahashi et al., 2009). Moreover, recent studies have suggested conducting a systematic review to find out the association between different polyphenols and liver disease (Li et al., 2018).
To the best of our knowledge, no systematic review and meta-analysis has been conducted on the association between polyphenols and liver cancer risk. Therefore, the present study investigated the relationship between dietary intake of polyphenols and risk of liver cancer.
Materials and Methods
The present study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines (Moher et al., 2015). The study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (http://www.crd. york.ac.uk/PROSPERO) with the following registration number: CRD42023487302
Search strategy
The search strategy was applied in online databases until August 2024, including, PubMed/MEDLINE, Web of Science, and Scopus. To find related articles, two authors screened titles and abstracts independently (B Forootani & H Yekrang Safakar). The references of the selected articles were also checked to find additional studies.
| Table 1. Characteristics of studies that assessed the association between dietary polyphenols intake and risk of liver cancer | |||||||||
| First author, year | Country | Design/follow up (year) | Cases/Controls or cohort size | Dietary assessment | Polyphenols | Contrast | Adjusted OR | Adjustments | Quality score |
| Raul Zamora-Ros et al., 2013 | Denmark, France, Germany, Greece, Italy, Norway, Spain, Sweden, the Netherlands and United Kingdom | Cohort/11.4 | 191/477015 | FFQa | Total flavonoids Flavanols Flavan-3-ol monomers Proanthocyanidins Theaflavins Anthocyanidins Flavonols Flavanones Flavones Isoflavones Lignans |
T3b vs. T1 |
0.65 (0.4-1.04)
0.62 (0.39-0.99) 0.65 (0.39-1.07)
0.6 (0.35-1.03)
1.2 (0.78-1.87) 0.79 (0.47-1.32) 1.1 (0.75-1.62) 1.06 (0.69-1.62) 0.74 (0.44-1.26) 1.37 (0.8-2.35) |
Center, sex, age, total energy, educational level, smoke intensity, alcohol lifetime and alcohol baseline, body mass index, self-reported diabetes at baseline, physical activity, fiber and coffee intake. | 9 |
| Pagona Lagiou et al., 2008 | Greece | Case-Control | 250/360 | FFQ | Flavanones Flavan-3-ols Flavonols Anthocyanidins Flavones Isoflavones Total flavonoids |
Q5c vs. Q1 | 1.18 (0.56-2.47) 1.14 (0.5-2.58) 1.11 (0.51-2.43) 1.73 (0.74-4.04) 0.41 (0.16-1.06) 0.85 (0.39-1.86) 0.96 (0.43-2.12) |
Gender, age, education, tobacco smoking, and total energy intake | 6 |
| Norie Kurahashi et al., 2008 (men) | Japan | Cohort/11.8 | 69/7146 | FFQ | Genistein Daidzein |
T3 vs. T1 | 1.13 (0.6-2.11) 1.09 (0.58-2.05) |
Age, area, HCV, HBsAg, smoking status, alcohol consumption, and intake of coffee and vegetables | 9 |
| Norie Kurahashi et al., 2008 (women) | Japan | Cohort/11.8 | 32/12751 | FFQ | Genistein Daidzein |
T3 vs T1 | 3.19 (1.13-9) 3.9 (1.3-11.69) |
Age, area, HCV, HBsAg, smoking status, alcohol consumption, and intake of coffee and vegetables | 9 |
| Wei Zhang et al., 2019 (men) | China | Nested case-control | 131/262 | FFQ | Isoflavone Daidzein Genistein Glycitein |
Q4d vs. Q1 | 1.36 (0.57-3.21) 1.27 (0.55-2.96) 1.24 (0.52-2.93) 0.72 (0.3-1.74) |
Total energy intake, education level, regular physical activity during past 5 years, history of viral hepatitis, history of chronic liver disease or cirrhosis, history of diabetes, history of cholelithiasis or cholecystectomy, and family history of liver cancer, regular alcohol drinker, body mass index, dietary fat intake | 8 |
| Wei Zhang et al., 2019 (women) | China | Nested case-control | 86/165 | FFQ | Isoflavone Daidzein Genistein Glycitein |
Q4 vs. Q1 | 0.63 (0.2-1.97) 0.68 (0.22-2.08) 0.64 (0.21-1.96) 0.63 (0.18-2.26) |
Total energy intake, education level, regular physical activity during past 5 years, history of viral hepatitis, history of chronic liver disease or cirrhosis, history of diabetes, history of cholelithiasis or cholecystectomy, and family history of liver cancer, regular alcohol drinker, body mass index, dietary fat intake | 8 |
| a: Food frequency questionnaire ; b:P-tertile; c: Quintile; d: Quartile . | |||||||||
Eligibility criteria
Articles were included in the study if they: 1) were a cohort, case-control, or cross-sectional study; 2) assessed the association between dietary polyphenols and risk of liver cancer; 3) reported risk estimates with a 95% confidence interval (CI); and, 4) were performed on adults. Articles were excluded if they: 1) examined polyphenols in plasma or urine, 2) had a review or trial design; or 3) were done on animals.
Data extraction
The following characteristics were extracted from each included study: the last name of the first author, publication year, study location, study design, gender, number of participants, age, type and the average intake of polyphenols, hazard ratio (HR), relative risk (RR) or odds ratio (OR) of the fully adjusted models with their 95% CI for each level of polyphenol intake. A.E extracted the data, and it was rechecked by the second author (F Mirjalili).
Risk of bias assessment
The Newcastle-Ottawa Scale was used to assess the quality of the eligible studies (Wells, 2000). In this scale, there are three main domains, including “selection”, “comparability”, and “outcome” to evaluate the quality of the studies. Studies would be classified as high quality if they got 7 stars or more. If a study got less than 5 stars, it would be classified as low quality. A study with 6 stars would be in the moderate quality category (Wells, 2000). Two authors (AS Emrani & F Mirjalili) performed the quality assessment independently.
The overall quality of the meta-analysis
The Grading of Recommendation Assessment, Development and Evaluation (GRADE) system was used to assess the overall quality of the present meta-analysis (Guyatt et al., 2008). The GRADE system evaluates the certainty of the evidence according to the risk of bias, consistency, directness, precision, publication bias, and study design of the included articles in the meta-analysis.
Data analysis
All statistical analysis was performed using Stata version 17 (STATA Corp., College Station, Texas). All reported HRs, RRs, and ORs (with their 95% CI) were used to calculate RR and its standard error. The overall effect size was calculated by using a random effects model. Using Cochran’s Q test and I2 statistic, between-study heterogeneity was assessed. Publication bias was checked by looking over Begg’s funnel plot and asymmetry tests (Begg’s test and Egger’s test). P-values less than 0.05 were considered statistically significant.
Results
Literature search
In this systematic search, 14230 articles were identified from PubMed/MEDLINE, Scopus, and Web of Science. There were 3790 duplicates and 9521 ineligible articles after screening through the title and abstract. By reading 919 full texts of potentially relevant studies, 651 irrelevant records were excluded, and 268 related reports were assessed for eligibility. Finally, 264 articles were excluded for the following reasons: 237 studies were performed on other cancers, 4 studies were reviews, 4 studies reported urinary or plasma concentration, 3 articles did not report any data for polyphenols or reported mixed polyphenols, and 16 articles were not observational studies. Therefore, 4 studies were included in the present systematic review and meta-analysis (Kurahashi et al., 2009, Lagiou et al., 2008, Zamora‐Ros et al., 2013, Zhang et al., 2013) (Figure 1).
Articles were included in the study if they: 1) were a cohort, case-control, or cross-sectional study; 2) assessed the association between dietary polyphenols and risk of liver cancer; 3) reported risk estimates with a 95% confidence interval (CI); and, 4) were performed on adults. Articles were excluded if they: 1) examined polyphenols in plasma or urine, 2) had a review or trial design; or 3) were done on animals.
Data extraction
The following characteristics were extracted from each included study: the last name of the first author, publication year, study location, study design, gender, number of participants, age, type and the average intake of polyphenols, hazard ratio (HR), relative risk (RR) or odds ratio (OR) of the fully adjusted models with their 95% CI for each level of polyphenol intake. A.E extracted the data, and it was rechecked by the second author (F Mirjalili).
Risk of bias assessment
The Newcastle-Ottawa Scale was used to assess the quality of the eligible studies (Wells, 2000). In this scale, there are three main domains, including “selection”, “comparability”, and “outcome” to evaluate the quality of the studies. Studies would be classified as high quality if they got 7 stars or more. If a study got less than 5 stars, it would be classified as low quality. A study with 6 stars would be in the moderate quality category (Wells, 2000). Two authors (AS Emrani & F Mirjalili) performed the quality assessment independently.
The overall quality of the meta-analysis
The Grading of Recommendation Assessment, Development and Evaluation (GRADE) system was used to assess the overall quality of the present meta-analysis (Guyatt et al., 2008). The GRADE system evaluates the certainty of the evidence according to the risk of bias, consistency, directness, precision, publication bias, and study design of the included articles in the meta-analysis.
Data analysis
All statistical analysis was performed using Stata version 17 (STATA Corp., College Station, Texas). All reported HRs, RRs, and ORs (with their 95% CI) were used to calculate RR and its standard error. The overall effect size was calculated by using a random effects model. Using Cochran’s Q test and I2 statistic, between-study heterogeneity was assessed. Publication bias was checked by looking over Begg’s funnel plot and asymmetry tests (Begg’s test and Egger’s test). P-values less than 0.05 were considered statistically significant.
Results
Literature search
In this systematic search, 14230 articles were identified from PubMed/MEDLINE, Scopus, and Web of Science. There were 3790 duplicates and 9521 ineligible articles after screening through the title and abstract. By reading 919 full texts of potentially relevant studies, 651 irrelevant records were excluded, and 268 related reports were assessed for eligibility. Finally, 264 articles were excluded for the following reasons: 237 studies were performed on other cancers, 4 studies were reviews, 4 studies reported urinary or plasma concentration, 3 articles did not report any data for polyphenols or reported mixed polyphenols, and 16 articles were not observational studies. Therefore, 4 studies were included in the present systematic review and meta-analysis (Kurahashi et al., 2009, Lagiou et al., 2008, Zamora‐Ros et al., 2013, Zhang et al., 2013) (Figure 1).
Characteristics of the included studies
The characteristics of all four eligible studies are presented in Table 1. These studies were published between 2008 and 2019. One study was conducted in China (Zhang et al., 2013), one in Japan (Kurahashi et al., 2009), one in Greece (Lagiou et al., 2008), and one of the studies was multi-center research conducted in Denmark, France, Germany, Greece, Italy, Norway, Spain, Sweden, the Netherlands, and United Kingdom (Zamora‐Ros et al., 2013). Two studies were cohorts (Kurahashi et al., 2009, Zamora‐Ros et al., 2013), one study had a case-control design (Lagiou et al., 2008) and one of them was a nested case-control (Zhang et al., 2013). All studies were performed on both genders. However, in the studies conducted by Norie Kurahashi et al. (Kurahashi et al., 2009) and Wei Zhang et al. (Zhang et al., 2013), results were reported for men and women separately; therefore, we obtained two effect sizes from the study by Wei Zhang et al.. This meta-analysis was only conducted for the association between dietary intake of isoflavones and liver cancer risk. Since Norie Kurahashi et al. (Kurahashi et al., 2009) did not report any data for total isoflavones, this study was not included in the present meta-analysis.
Risk of bias assessment
According to the Newcastle-Ottawa quality assessment scale, all studies were categorized as high quality except one. This case-control study (Lagiou et al., 2008) had moderate quality, mainly because the non-response rate was different in the case and control groups.
The overall quality of the meta-analysis
We assessed the certainty of the evidence for the association between isoflavone intake and the risk of liver cancer based on the GRADE system. The GRADE certainty of evidence was very low for this association.
Findings from systematic review
In a study conducted by Raul Zamora-Ros et al. (Zamora‐Ros et al., 2013), the association between total flavonoids, flavanols, flavan-3-ol monomers, proanthocyanidins, theaflavins, anthocyanidins, flavonols, flavanones, flavones, and lignans and the risk of liver cancer was assessed. In this study, only dietary intake of flavanols was inversely related to liver cancer risk. In a case-control study (Lagiou et al., 2008), Pagona Lagiou et al. examined the role of flavanones, flavan-3-ols, flavonols, anthocyanidins, flavones, and total flavonoids in the etiology of liver cancer. They found that flavones may be related to the reduced risk of hepatocellular carcinoma. Another cohort study in Japan investigated the relationship between isoflavones (genistein and daidzein) and the incidence of hepatocellular carcinoma (Kurahashi et al., 2009). They concluded that genistein and daidzein may be related to an increased risk of liver cancer in women. However, this relation was non-significant in men. Finally, a nested case-control study evaluated the association between dietary and urinary isoflavones (genistein, daidzein, and glycitein) and the odds of liver cancer (Zhang et al., 2013). They did not observe any significant relation between dietary intake of isoflavones and liver cancer risk.
Findings from meta-analysis
Three articles reported data on the relationship between dietary intake of isoflavones and liver cancer risk (Lagiou et al., 2008, Zamora‐Ros et al., 2013, Zhang et al., 2013). The overall results did not show any significant association between dietary consumption of isoflavones and the odds of liver cancer (P=0.35, 95% CI: 0.58-1.21, Figure 2). Between-study heterogeneity was not significant (P=0.65, I2=0.00%).
The characteristics of all four eligible studies are presented in Table 1. These studies were published between 2008 and 2019. One study was conducted in China (Zhang et al., 2013), one in Japan (Kurahashi et al., 2009), one in Greece (Lagiou et al., 2008), and one of the studies was multi-center research conducted in Denmark, France, Germany, Greece, Italy, Norway, Spain, Sweden, the Netherlands, and United Kingdom (Zamora‐Ros et al., 2013). Two studies were cohorts (Kurahashi et al., 2009, Zamora‐Ros et al., 2013), one study had a case-control design (Lagiou et al., 2008) and one of them was a nested case-control (Zhang et al., 2013). All studies were performed on both genders. However, in the studies conducted by Norie Kurahashi et al. (Kurahashi et al., 2009) and Wei Zhang et al. (Zhang et al., 2013), results were reported for men and women separately; therefore, we obtained two effect sizes from the study by Wei Zhang et al.. This meta-analysis was only conducted for the association between dietary intake of isoflavones and liver cancer risk. Since Norie Kurahashi et al. (Kurahashi et al., 2009) did not report any data for total isoflavones, this study was not included in the present meta-analysis.
Risk of bias assessment
According to the Newcastle-Ottawa quality assessment scale, all studies were categorized as high quality except one. This case-control study (Lagiou et al., 2008) had moderate quality, mainly because the non-response rate was different in the case and control groups.
The overall quality of the meta-analysis
We assessed the certainty of the evidence for the association between isoflavone intake and the risk of liver cancer based on the GRADE system. The GRADE certainty of evidence was very low for this association.
Findings from systematic review
In a study conducted by Raul Zamora-Ros et al. (Zamora‐Ros et al., 2013), the association between total flavonoids, flavanols, flavan-3-ol monomers, proanthocyanidins, theaflavins, anthocyanidins, flavonols, flavanones, flavones, and lignans and the risk of liver cancer was assessed. In this study, only dietary intake of flavanols was inversely related to liver cancer risk. In a case-control study (Lagiou et al., 2008), Pagona Lagiou et al. examined the role of flavanones, flavan-3-ols, flavonols, anthocyanidins, flavones, and total flavonoids in the etiology of liver cancer. They found that flavones may be related to the reduced risk of hepatocellular carcinoma. Another cohort study in Japan investigated the relationship between isoflavones (genistein and daidzein) and the incidence of hepatocellular carcinoma (Kurahashi et al., 2009). They concluded that genistein and daidzein may be related to an increased risk of liver cancer in women. However, this relation was non-significant in men. Finally, a nested case-control study evaluated the association between dietary and urinary isoflavones (genistein, daidzein, and glycitein) and the odds of liver cancer (Zhang et al., 2013). They did not observe any significant relation between dietary intake of isoflavones and liver cancer risk.
Findings from meta-analysis
Three articles reported data on the relationship between dietary intake of isoflavones and liver cancer risk (Lagiou et al., 2008, Zamora‐Ros et al., 2013, Zhang et al., 2013). The overall results did not show any significant association between dietary consumption of isoflavones and the odds of liver cancer (P=0.35, 95% CI: 0.58-1.21, Figure 2). Between-study heterogeneity was not significant (P=0.65, I2=0.00%).
Publication bias
There was no publication bias for the meta-analysis of the association between dietary intake of isoflavones and the risk of liver cancer (Begg’s test, P=0.73; Egger’s tests, P=0.75).
Discussion
In the present systematic review and meta-analysis, no significant association was found between dietary intake of isoflavones and the risk of liver cancer. Many health properties have been attributed to isoflavones, such as hormone-like properties, immunity, antioxidant, anti-tumor, and anti-inflammatory functions (Ko, 2014). Evidence has shown that isoflavones may have a protective association with cancer due to their anti-tumor and antioxidant properties (Ko, 2014). These protective effects occur through blocking endoplasmic reticulum (ER-a) protein, suppression of DNA transcription, and stopping carcinogenesis pathways by protein tyrosine kinase inhibition (Ko, 2014). A review has stated that polyphenols have protective effects on the liver, and by affecting the metabolism they can inhibit liver cancer (Li et al., 2023). Moreover, this review suggested that flavonoids enter the liver by binding to albumin and cause changes in glucose uptake, gene expression of glucose transporter, and its metabolism in the liver (Li et al., 2023). Another review study in 2018 showed that polyphenols through different mechanisms such as regulating mitochondrial and signaling pathways can induce apoptosis in liver cancer cells (Li et al., 2018).
In the case of liver cancer, there are few human studies, the results of in-vitro studies showed the reducing effects of isoflavones on the proliferation of hepatocellular cancer cells in rats (Gu et al., 2005, Su et al., 2003). Researchers found higher levels of genistein and daidzein (which are common isoflavones) in rats’ liver than in plasma (Janning et al., 2000, McClain et al., 2006). Moreover, genistein may be used as an adjuvant treatment for liver disease, since it has shown protective effects on liver fibrosis in rat models (Leija Salas et al., 2007, Salas et al., 2007). Contrary to the results obtained in the present meta-analysis, a case-control study found a decreasing association between the intake of miso soup and tofu (which contain a high amount of soybeans) and the risk of HCC (Sharp et al., 2005). In a cohort study conducted on the Japanese population, unlike the current study, intake of genistein and daidzein was positively related to the HCC risk in women, while this relationship was non-significant in men (Kurahashi et al., 2009). This study suggests that the effects of isoflavones intake may differ in populations based on gender. Studies have shown that estrogen can be effective in HCC prevention (Kurahashi et al., 2009). On the other hand, isoflavones can have anti-estrogenic effects due to competition with estradiol (Bingham et al., 1998), and this may be one of the reasons for the difference in isoflavones impact in men and women. Consistent with the present study results, two observational studies found no association between dietary isoflavone intake and the risk of liver cancer (Lagiou et al., 2008, Zamora‐Ros et al., 2013).
The present study is the first systematic review and meta-analysis to investigate the association between dietary polyphenols intake and liver cancer risk. A complete and unrestricted search was performed in the study. However, this study has some limitations. Since the studies relating to dietary polyphenol intake and liver cancer risk were limited, a meta-analysis could not be performed for all polyphenols. Meta-analysis was only possible for the relationship between dietary intake of isoflavones and the incidence of liver cancer. In addition, the small number of included articles made it impossible to perform subgroup analysis. Moreover, the design of the included studies was observational, which can lead to recall bias. Finally, the range of polyphenol intake and confounding variables adjusted in the final models were different in the included studies.
Conclusion
There was no significant association between dietary isoflavones intake and the risk of liver cancer. There are limited observational studies assessing the relationship between polyphenol intake and the odds of liver cancer. On the other hand, liver cancer is one of the most fatal cancers worldwide, and it is important to examine its risk and protective factors. Therefore, it is highly recommended that future research investigate the relationship between polyphenols and liver cancer risk.
Acknowledgement
The authors would like to thank the Research Development Center of Shahid Sadoughi Hospital, Shahid Sadoughi University of Medical Sciences, for their close collaboration and scientific input.
Authors' contributions
B Forootani and A Salehi-abargouei conceived the study. H Yekrang Safakar and B Forootani designed the search strategy and conducted the systematic search and study selection. AS Emrani and F Mirjalili did data extraction and statistical analyses. AS Emrani wrote the first draft of the manuscript. A Salehi-abargouei critically revised the manuscript. All authors read and approved the final version of the manuscript.
Conflicts of Interest
The authors declare that they have no conflict of interest.
Funding
No founding.
References
Bingham S, Atkinson C, Liggins J, Bluck L & Coward A 1998. Phyto-oestrogens: where are we now? British journal of nutrition. 79 (5): 393-406.
Costea T, Nagy P, Ganea C, Szöllősi J & Mocanu M-M 2019. Molecular Mechanisms and Bioavailability of Polyphenols in Prostate Cancer. International journal of molecular sciences. . 20 (5): 1062.
Dasgupta P, et al. 2020. Global trends in incidence rates of primary adult Liver cancers: A systematic review and mMeta-analysis. Frontiers in oncology. 10: 171.
Gu Y, Zhu C-F, Iwamoto H & Chen J-SJWjogW 2005. Genistein inhibits invasive potential of human hepatocellular carcinoma by altering cell cycle, apoptosis, and angiogenesis. World journal of gastroenterology. 11 (41): 6512.
Guyatt GH, et al. 2008. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. British medical journal. 336 (7650): 924-926.
Janning P, et al. 2000. Toxicokinetics of the phytoestrogen daidzein in female DA/Han rats. Archives of toxicology. 74: 421-430.
Ko K-P 2014. Isoflavones: chemistry, analysis, functions and effects on health and cancer. Asian Pacific journal of cancer prevention. 15 (17): 7001-7010.
Kurahashi N, et al. 2009. Isoflavone consumption and subsequent risk of hepatocellular carcinoma in a population-based prospective cohort of Japanese men and women. International journal of cancer. 124 (7): 1644-1649.
Lagiou P, et al. 2008. Flavonoid intake and liver cancer: a case–control study in Greece. Cancer causes & control. 19 (8): 813-818.
Lan Q-Y, et al. 2018. Dietary patterns and primary liver cancer in Chinese adults: a case-control study. Oncotarget. 9 (45): 27872.
Leija Salas A, Díaz Montezuma T, Garrido Fariña G, Reyes-Esparza J & Rodríguez-Fragoso LJP 2007. Genistein modifies liver fibrosis and improves liver function by inducing uPA expression and proteolytic activity in CCl4-treated rats. Pharmacology. 81 (1): 41-49.
Li A-N, et al. 2014. Resources and biological activities of natural polyphenols. Nutrients. 6 (12): 6020-6047.
Li S, et al. 2018. The potential and action mechanism of polyphenols in the treatment of liver diseases. Oxidative medicine cellular longevity. 2018 (1): 8394818.
Li S, et al. 2023. Polyphenols as potential metabolism mechanisms regulators in liver protection and liver cancer prevention. Cell proliferation. 56 (1): e13346.
Lin L, et al. 2020. The burden and trends of primary liver cancer caused by specific etiologies from 1990 to 2017 at the global, regional, national, age, and sex level results from the global burden of disease study 2017. Liver cancer. 9 (5): 563-582.
London W & McGlynn K 2006. Liver cancer. Cancer epidemiology and prevention. 3: 763-786.
Luo H, et al. 2005. Phase IIa chemoprevention trial of green tea polyphenols in high-risk individuals of liver cancer: modulation of urinary excretion of green tea polyphenols and 8-hydroxydeoxyguanosine. Carcinogenesis. 27 (2): 262-268.
Mansoor TA, et al. 2011. Isoflavones as apoptosis inducers in human hepatoma HuH-7 Cells. Phytotherapy research. 25 (12): 1819-1824.
McClain RM, et al. 2006. Acute, subchronic and chronic safety studies with genistein in rats. Food and chemical toxicology. 44 (1): 56-80.
Mohammadian M, Mahdavifar N, Mohammadian-Hafshejani A & Salehiniya H 2018. Liver cancer in the world: epidemiology, incidence, mortality and risk factors. World cancer research journal 5(2): e1082.
Moher D, et al. 2015. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Systematic reviews. 4: 1-9.
Papuc C, Goran GV, Predescu CN, Nicorescu V & Stefan G 2017. Plant polyphenols as antioxidant and antibacterial agents for shelf-life extension of meat and meat products: classification, structures, sources, and action mechanisms. Comprehensive reviews in food science and food safety. 16 (6): 1243-1268.
Petrick J, et al. 2020. International trends in hepatocellular carcinoma incidence, 1978-2012. International journal of cancer. 147 (2): 317-330.
Salas AL, Ocampo G, Fariña GG, Reyes-Esparza J & Rodríguez-Fragoso LJAoH 2007. Genistein decreases liver fibrosis and cholestasis induced by prolonged biliary obstruction in the rat. Annals of hepatology. 6 (1): 41-47.
Sharp GB, et al. 2005. Relationship of hepatocellular carcinoma to soya food consumption: A cohort‐based, case‐control study in Japan. International journal of cancer. 115 (2): 290-295.
Su S-J, et al. 2003. Effects of soy isoflavones on apoptosis induction and G2-M arrest in human hepatoma cells involvement of caspase-3 activation, Bcl-2 and Bcl-XL downregulation, and Cdc2 kinase activity. Nutrition and cancer. 45 (1): 113-123.
Sung H, et al. 2021. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Cancer journal for clinicians. 71 (3): 209-249.
Wells G 2000. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. In In 3rd Symposium on Systematic Reviews: Beyond the Basics, . Oxford: UK, 3-5 July 2000 2000.
Wu M, et al. 2021. Potential implications of polyphenols on aging considering oxidative stress, inflammation, autophagy, and gut microbiota. Critical reviews in food science and nutrition. 61 (13): 2175-2193.
Yang W-S, et al. 2020. Diet and liver cancer risk: a narrative review of epidemiological evidence. British journal of nutrition. 124 (3): 330-340.
Zamora‐Ros R, et al. 2013. Dietary flavonoid, lignan and antioxidant capacity and risk of hepatocellular carcinoma in the European prospective investigation into cancer and nutrition study. International journal of cancer. 133 (10): 2429-2443.
Zhang W, et al. 2013. Vegetable-based dietary pattern and liver cancer risk: Results from the Shanghai Women's and Men's Health Studies. Cancer science. 104 (10): 1353-1361.
There was no publication bias for the meta-analysis of the association between dietary intake of isoflavones and the risk of liver cancer (Begg’s test, P=0.73; Egger’s tests, P=0.75).
Discussion
In the present systematic review and meta-analysis, no significant association was found between dietary intake of isoflavones and the risk of liver cancer. Many health properties have been attributed to isoflavones, such as hormone-like properties, immunity, antioxidant, anti-tumor, and anti-inflammatory functions (Ko, 2014). Evidence has shown that isoflavones may have a protective association with cancer due to their anti-tumor and antioxidant properties (Ko, 2014). These protective effects occur through blocking endoplasmic reticulum (ER-a) protein, suppression of DNA transcription, and stopping carcinogenesis pathways by protein tyrosine kinase inhibition (Ko, 2014). A review has stated that polyphenols have protective effects on the liver, and by affecting the metabolism they can inhibit liver cancer (Li et al., 2023). Moreover, this review suggested that flavonoids enter the liver by binding to albumin and cause changes in glucose uptake, gene expression of glucose transporter, and its metabolism in the liver (Li et al., 2023). Another review study in 2018 showed that polyphenols through different mechanisms such as regulating mitochondrial and signaling pathways can induce apoptosis in liver cancer cells (Li et al., 2018).
In the case of liver cancer, there are few human studies, the results of in-vitro studies showed the reducing effects of isoflavones on the proliferation of hepatocellular cancer cells in rats (Gu et al., 2005, Su et al., 2003). Researchers found higher levels of genistein and daidzein (which are common isoflavones) in rats’ liver than in plasma (Janning et al., 2000, McClain et al., 2006). Moreover, genistein may be used as an adjuvant treatment for liver disease, since it has shown protective effects on liver fibrosis in rat models (Leija Salas et al., 2007, Salas et al., 2007). Contrary to the results obtained in the present meta-analysis, a case-control study found a decreasing association between the intake of miso soup and tofu (which contain a high amount of soybeans) and the risk of HCC (Sharp et al., 2005). In a cohort study conducted on the Japanese population, unlike the current study, intake of genistein and daidzein was positively related to the HCC risk in women, while this relationship was non-significant in men (Kurahashi et al., 2009). This study suggests that the effects of isoflavones intake may differ in populations based on gender. Studies have shown that estrogen can be effective in HCC prevention (Kurahashi et al., 2009). On the other hand, isoflavones can have anti-estrogenic effects due to competition with estradiol (Bingham et al., 1998), and this may be one of the reasons for the difference in isoflavones impact in men and women. Consistent with the present study results, two observational studies found no association between dietary isoflavone intake and the risk of liver cancer (Lagiou et al., 2008, Zamora‐Ros et al., 2013).
The present study is the first systematic review and meta-analysis to investigate the association between dietary polyphenols intake and liver cancer risk. A complete and unrestricted search was performed in the study. However, this study has some limitations. Since the studies relating to dietary polyphenol intake and liver cancer risk were limited, a meta-analysis could not be performed for all polyphenols. Meta-analysis was only possible for the relationship between dietary intake of isoflavones and the incidence of liver cancer. In addition, the small number of included articles made it impossible to perform subgroup analysis. Moreover, the design of the included studies was observational, which can lead to recall bias. Finally, the range of polyphenol intake and confounding variables adjusted in the final models were different in the included studies.
Conclusion
There was no significant association between dietary isoflavones intake and the risk of liver cancer. There are limited observational studies assessing the relationship between polyphenol intake and the odds of liver cancer. On the other hand, liver cancer is one of the most fatal cancers worldwide, and it is important to examine its risk and protective factors. Therefore, it is highly recommended that future research investigate the relationship between polyphenols and liver cancer risk.
Acknowledgement
The authors would like to thank the Research Development Center of Shahid Sadoughi Hospital, Shahid Sadoughi University of Medical Sciences, for their close collaboration and scientific input.
Authors' contributions
B Forootani and A Salehi-abargouei conceived the study. H Yekrang Safakar and B Forootani designed the search strategy and conducted the systematic search and study selection. AS Emrani and F Mirjalili did data extraction and statistical analyses. AS Emrani wrote the first draft of the manuscript. A Salehi-abargouei critically revised the manuscript. All authors read and approved the final version of the manuscript.
Conflicts of Interest
The authors declare that they have no conflict of interest.
Funding
No founding.
References
Bingham S, Atkinson C, Liggins J, Bluck L & Coward A 1998. Phyto-oestrogens: where are we now? British journal of nutrition. 79 (5): 393-406.
Costea T, Nagy P, Ganea C, Szöllősi J & Mocanu M-M 2019. Molecular Mechanisms and Bioavailability of Polyphenols in Prostate Cancer. International journal of molecular sciences. . 20 (5): 1062.
Dasgupta P, et al. 2020. Global trends in incidence rates of primary adult Liver cancers: A systematic review and mMeta-analysis. Frontiers in oncology. 10: 171.
Gu Y, Zhu C-F, Iwamoto H & Chen J-SJWjogW 2005. Genistein inhibits invasive potential of human hepatocellular carcinoma by altering cell cycle, apoptosis, and angiogenesis. World journal of gastroenterology. 11 (41): 6512.
Guyatt GH, et al. 2008. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. British medical journal. 336 (7650): 924-926.
Janning P, et al. 2000. Toxicokinetics of the phytoestrogen daidzein in female DA/Han rats. Archives of toxicology. 74: 421-430.
Ko K-P 2014. Isoflavones: chemistry, analysis, functions and effects on health and cancer. Asian Pacific journal of cancer prevention. 15 (17): 7001-7010.
Kurahashi N, et al. 2009. Isoflavone consumption and subsequent risk of hepatocellular carcinoma in a population-based prospective cohort of Japanese men and women. International journal of cancer. 124 (7): 1644-1649.
Lagiou P, et al. 2008. Flavonoid intake and liver cancer: a case–control study in Greece. Cancer causes & control. 19 (8): 813-818.
Lan Q-Y, et al. 2018. Dietary patterns and primary liver cancer in Chinese adults: a case-control study. Oncotarget. 9 (45): 27872.
Leija Salas A, Díaz Montezuma T, Garrido Fariña G, Reyes-Esparza J & Rodríguez-Fragoso LJP 2007. Genistein modifies liver fibrosis and improves liver function by inducing uPA expression and proteolytic activity in CCl4-treated rats. Pharmacology. 81 (1): 41-49.
Li A-N, et al. 2014. Resources and biological activities of natural polyphenols. Nutrients. 6 (12): 6020-6047.
Li S, et al. 2018. The potential and action mechanism of polyphenols in the treatment of liver diseases. Oxidative medicine cellular longevity. 2018 (1): 8394818.
Li S, et al. 2023. Polyphenols as potential metabolism mechanisms regulators in liver protection and liver cancer prevention. Cell proliferation. 56 (1): e13346.
Lin L, et al. 2020. The burden and trends of primary liver cancer caused by specific etiologies from 1990 to 2017 at the global, regional, national, age, and sex level results from the global burden of disease study 2017. Liver cancer. 9 (5): 563-582.
London W & McGlynn K 2006. Liver cancer. Cancer epidemiology and prevention. 3: 763-786.
Luo H, et al. 2005. Phase IIa chemoprevention trial of green tea polyphenols in high-risk individuals of liver cancer: modulation of urinary excretion of green tea polyphenols and 8-hydroxydeoxyguanosine. Carcinogenesis. 27 (2): 262-268.
Mansoor TA, et al. 2011. Isoflavones as apoptosis inducers in human hepatoma HuH-7 Cells. Phytotherapy research. 25 (12): 1819-1824.
McClain RM, et al. 2006. Acute, subchronic and chronic safety studies with genistein in rats. Food and chemical toxicology. 44 (1): 56-80.
Mohammadian M, Mahdavifar N, Mohammadian-Hafshejani A & Salehiniya H 2018. Liver cancer in the world: epidemiology, incidence, mortality and risk factors. World cancer research journal 5(2): e1082.
Moher D, et al. 2015. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Systematic reviews. 4: 1-9.
Papuc C, Goran GV, Predescu CN, Nicorescu V & Stefan G 2017. Plant polyphenols as antioxidant and antibacterial agents for shelf-life extension of meat and meat products: classification, structures, sources, and action mechanisms. Comprehensive reviews in food science and food safety. 16 (6): 1243-1268.
Petrick J, et al. 2020. International trends in hepatocellular carcinoma incidence, 1978-2012. International journal of cancer. 147 (2): 317-330.
Salas AL, Ocampo G, Fariña GG, Reyes-Esparza J & Rodríguez-Fragoso LJAoH 2007. Genistein decreases liver fibrosis and cholestasis induced by prolonged biliary obstruction in the rat. Annals of hepatology. 6 (1): 41-47.
Sharp GB, et al. 2005. Relationship of hepatocellular carcinoma to soya food consumption: A cohort‐based, case‐control study in Japan. International journal of cancer. 115 (2): 290-295.
Su S-J, et al. 2003. Effects of soy isoflavones on apoptosis induction and G2-M arrest in human hepatoma cells involvement of caspase-3 activation, Bcl-2 and Bcl-XL downregulation, and Cdc2 kinase activity. Nutrition and cancer. 45 (1): 113-123.
Sung H, et al. 2021. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Cancer journal for clinicians. 71 (3): 209-249.
Wells G 2000. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. In In 3rd Symposium on Systematic Reviews: Beyond the Basics, . Oxford: UK, 3-5 July 2000 2000.
Wu M, et al. 2021. Potential implications of polyphenols on aging considering oxidative stress, inflammation, autophagy, and gut microbiota. Critical reviews in food science and nutrition. 61 (13): 2175-2193.
Yang W-S, et al. 2020. Diet and liver cancer risk: a narrative review of epidemiological evidence. British journal of nutrition. 124 (3): 330-340.
Zamora‐Ros R, et al. 2013. Dietary flavonoid, lignan and antioxidant capacity and risk of hepatocellular carcinoma in the European prospective investigation into cancer and nutrition study. International journal of cancer. 133 (10): 2429-2443.
Zhang W, et al. 2013. Vegetable-based dietary pattern and liver cancer risk: Results from the Shanghai Women's and Men's Health Studies. Cancer science. 104 (10): 1353-1361.
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Received: 2024/05/31 | Published: 2025/05/30 | ePublished: 2025/05/30
Received: 2024/05/31 | Published: 2025/05/30 | ePublished: 2025/05/30
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