The Role of Diet and Nutrition Related Indicators in Biliary Diseases: An Umbrella Review of Systematic Review and Meta-Analysis

Wang et al.
Nutrition & Metabolism (2022) 19:51

https://doi.org/10.1186/s12986-022-00677-1
REVIEW Open Access
The role of diet and nutrition related

indicators in biliary diseases: an umbrella review
of systematic review and meta‑analysis
Yaoqun Wang†, Jiong Lu†, Ningyuan Wen, Guilin Nie, Dingzhong Peng, Xianze Xiong, Nansheng Cheng* and
Bei Li*
Abstract
Background: Diet and nutrition, as a modifiable risk factor, have been demonstrated to play a significant role in the
etiology of biliary diseases, whereas few comprehensive studies have been able to evaluate the strength and qual-
ity of these evidence. This umbrella review aims to evaluate the evidence pertaining risk factors for biliary diseases in
terms of diet and nutrition-related indicators.
Methods: An umbrella review method was adopted: evidence from observational studies up to 22 November 2021
were identified using PubMed, Web of Science, the Cochrane database, as well as manual screening. Eligible system-
atic reviews and meta-analyses were screened according to inclusion and exclusion criteria. The inclusion criteria
were: (1) meta analysis or systematic review; (2) The theme of the study is the relationship between diet or nutri-
tion and biliary tract diseases; (3) Summarized and reported OR, RR or HR values and corresponding 95% CI; (4) No
restrictions on the use of participants and languages; (5) Only extract the data of biliary tract diseases from multiple
health outcomes; (6) Only the most recent studies on the same subject were included. This study had been registered
at PROSPERO (CRD42021293908). For each eligible systematic review and meta-analysis, we extracted the data of
general characteristics and the main findings. The methodological quality of the meta-analyses included in our study
were assessed by AMSTAR2 and the quality of evidence was evaluated by the GRADE.
Results: A total of 323 articles were searched, among which 24 articles with 83 unique outcomes were identified
as eligible. 35 of these outcomes were downgraded in GRADE evaluation as they reported heterogeneity. In short,
among 83 unique outcomes, 5 were rated as moderate, 16 as low, and the rest as very low. For the prevention of bil-
iary tract diseases, emphasis should be placed on appropriately increasing the intake of fruits, vegetables, coffee and
tea, and reducing the intake of alcohol, raw fish and foods with high nitrate. Meanwhile, weight, blood sugar and lipid
levels should be controlled, and diabetes should be actively prevented and treated. Drinking is not recommended to
prevent gallstones, although studies have shown that it may reduce the risk of cholecystolithiasis.
Conclusions: Our study summarizes the current multifaceted evidence on the relationship between dietary and
nutritional indicators and biliary diseases, but the quality of all evidence was not high. Evidence from additional high-
quality prospective studies are needed in the future.
†
Yaoqun Wang and Jiong Lu share Co-first authorship
*Correspondence: nanshengcheng@yeah.net; libei445@163.com
Division of Biliary Surgery, Department of General Surgery, West China
Hospital of Sichuan University, No. 37 Guo Xue Xiang, Chengdu 610041,
Sichuan Province, China
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Wang et al. Nutrition & Metabolism (2022) 19:51 Page 2 of 33
Keywords: Diet, Biliary diseases, Umbrella review, Meta-analysis, Systematic review
Introduction Meanwhile, to date, there have been few comprehen-

Gallbladder cancer and cholangiocarcinoma are major sive studies on the strength and quality of the evidence.
malignancies of the biliary tract. Additionally, according Umbrella reviews provide a structured and critical sum-
to anatomical position, bile duct cancer can be further mary of existing evidence, and enable the grading of evi-
divided into intrahepatic cholangiocarcinoma (iCCA) dence by specific criteria including sample size, strength
and extrahepatic cholangiocarcinoma (eCCA). Biliary and precision of the association, and assessment of the
cancer is one of the very lethal malignancies arising from presence of biases. Hence, in order to better evaluate the
the gallbladder or biliary duct epithelium, representing existing evidence on the relationship between diet and
approximately 3–5% of all cancers of the gastrointestinal nutrition-related indicators and biliary cancer risk, we
system [1]. Despite the low incidence of biliary cancers, conducted an umbrella review of the latest evidence from
cholangiocarcinoma is the second most common pri- existing systematic reviews and meta-analyses.
mary liver cancer after hepatocellular carcinoma (HCC), In addition, cholecystolithiasis and other benign gall-
accounting for approximately 10% of primary liver can- bladder diseases, as the most common disease of the
cers [1]. Although the treatment of biliary cancer has biliary system (up to 20% of adults develop gallstones at
improved in recent years, long-term survival still needs some point in their lives [14]), is closely related to the
to be improved, with a dismal 5-year survival rate of occurrence of biliary tract tumors. As we all know, diet
about 5% [2]. Biliary cancer can be related to chronic bil- related factors are also closely related to the occurrence
iary tract or gallbladder inflammation owing to gallstone, of gallstones. Therefore, we also included cholecystolithi-
choledocholithiasis, or primary sclerosing cholangitis, asis/gallbladder diseases in this umbrella review to more
but the exact etiology remains poorly understood [3]. comprehensively summarize the relationship between
Clearly, for the general public, these risk factors do not diet related factors and biliary diseases.
provide appropriate recommendations for biliary tumor Previous studies have found that there are extensive
prevention. links between drinking and common biliary diseases, and
Diet and nutrition, as modifiable risk factors, play an there are also some disputes. Therefore, we will elaborate
important role in the prevention of cardiovascular and drinking and biliary diseases as a separate topic.
cerebrovascular diseases [4], metabolic diseases, cancer
etc. [5, 6]. For example, Guevara Cruz et al. [7] found that Methods
optimizing the diet pattern can reduce serum triglyc- Study design
eride and glucose tolerance of patients with metabolic Umbrella review is a summary of existing systematic
syndrome. The randomized controlled trial conducted review and meta-analysis, which aims to summarize the
by Prentice et al. [8]. Confirmed that the low-fat diet pat- evidence from multiple studies around a research topic
tern and can reduce the incidence rate of ovarian cancer [15, 16]. We conducted this umbrella review to assess
in postmenopausal women. This also reveals that dietary the relationship between diet and nutritional indicators
factors may be related to the occurrence of malignant and the risk of biliary tract diseases, such as gallbladder
tumors. In addition, different dietary and nutritional cancer, bile duct cancer, cholecystolithiasis or gallbladder
factors have been proved to play a role in promoting diseases.
or inhibiting cancer in malignant tumors of the biliary The protocol of this umbrella review was registered on
system [9]. For example, Larsson et al. [10] found that PROSPERO (CRD42021293908).
modified diet approach to stop hypertension (MDASH)
diet and a modified Mediterranean (MMED) diet play Literature search strategy
a positive role in reducing the risk of extrahepatic BTC. Two of the authors (Yaoqun Wang and Ningyuan Wen)
A cohort study in Japan reported that fruit and vegeta- independently conducted a comprehensive literature
bles intake tended to be associated with a reduced risk of search using PubMed, Web of Science, and the Cochrane
eCCA [11]. Database of Systematic Reviews. We searched studies
Although there have been a number of meta-analyses published from database inception to 22 November 2021
summarizing evidence of the association between diet to identify systematic reviews and meta analyses of retro-
and nutrition-related factors (eg, daily foods, coffee, and spective or prospective studies.
alcohol) and the risk of biliary tract cancer, some evi- The search algorithm used the following terms/
dence for the same factor varies considerably [12, 13]. keywords:
• Gallbladder cancer: (diet OR dietary OR food OR recent study with the largest number of studies and effect
nutrition OR nutritional factors) AND (gallblad- size was included.
der cancer OR gallbladder carcinoma OR gallblad- The exclusion criteria were: (1) Animal studies; (2) Nar-
der neoplasms OR gallbladder tumor OR gallblad- rative reviews, original studies, conference proceedings
der neoplasm OR gallbladder mass OR gallbladder and letters to editors; (3) Systematic reviews or meta-
masses) AND (meta-analysis OR systematic review analyses targeting other non-biliary diseases; (4) Studies
OR systematic overview). in which diet, nutritional factors, or nutritional indica-
• Bile duct cancer: (diet OR dietary OR food OR nutri- tors were not the exposure of interest; (5) Studies that did
tion OR nutritional factors) AND (biliary Cancer OR not provide study specific data: Odds Ratios(OR), Rela-
biliary tumor OR biliary neoplasms OR biliary neo- tive Rates(RR) or Hazard Ratios (HR) and corresponding
plasm OR biliary mass OR biliary masses OR chol- 95% confidence interval (CI).
angiocarcinoma OR bile duct cancer OR bile duct
tumor OR bile duct neoplasms OR bile duct neo- Data extraction
plasm OR bile duct mass OR bile duct masses) AND Two authors (Yaoqun Wang and Ningyuan Wen)
(meta-analysis OR systematic review OR systematic extracted data separately.
overview). Any disagreement in the extracted data was re-evalu-
• Gallstone: (diet OR dietary OR food OR nutrition OR ated by a third author (Jiong Lu). For each eligible sys-
nutritional factors) AND (cholecystolithiasis OR gall- tematic review and meta-analysis, we first extracted the
stone OR gallbladder stone) AND (meta-analysis OR following general characteristics: (1) the first author; (2)
systematic review OR systematic overview). the publication year; (3) original article retrieval time;
(4) journal; (5) dietary factor or nutrition related indica-
Furthermore, manual searches on the reference lists of tors in the study; (6) number of studies included;(7) out-
the identified publications, references of other nutrition comes of interest investigated (disease type), country or
related umbrella reviews and research registration plat- region of original studies and the number of correspond-
form were also conducted to identify additional studies ing studies; (8) study design(cohort, case–control, cross-
relevant to our umbrella review. Disagreements were sectional, Nested case–control); (9) number of cases/
resolved by discussion between the two authors. Detailed total participants; (10) quality assessment of each eligible
search strategies and manual searches results can be systematic review or meta-analysis.
found in Additional file 1: Table S1. Furthermore, the main findings of each study were also
abstracted: (1) the type of effect model; (2) meta-analysis
Selection and exclusion criteria metric; (3) estimated summary effect (OR: Odds Ratios,
The topic of our study is the association between diet and RR: Relative Rates or HR: Hazard Ratios), 95% confidence
nutrition-related factors and disease, which is not appli- intervals (CIs) and p-value of test for estimated summary
cable to randomized controlled studies. Hence, our study effect; (4) heterogeneity (I 2) and p-value; (5) publication
mainly included systematic reviews and meta-analyses bias by Egger’s test and small study effect; (6) subgroup
based on cohort or case–control studies. analyses; (7) type of comparison (e.g. high vs. low analysis
The inclusion criteria were as follows: (1) Meta analyses or dose–response analysis) was abstracted when possible.
and systematic reviews of retrospective or prospective
studies adhering to PRISMA guidelines; (2) Evaluated the Quality evaluation
association of diet and nutrition related factors and risk AMSTAR2 is a practical tool for evaluating the qual-
of biliary tract disease. Eligible dietary factors included ity of systematic reviews and meta analyses. The revised
daily foods, beverages (including alcohol) etc. Eligible AMSTAR2 [17] consists of 16 items, which covers the
nutrition related indicators included BMI, glycemic index whole process of systematic reviews and meta-analy-
(including diabetes), blood lipids etc.; (3) Summarized ses, including topic selection, design, registration, data
and reported Odds Ratios(OR), Relative Rates(RR) or extraction, statistical analysis and discussion. The details
Hazard Ratios (HR) and corresponding 95% confidence of AMSTAR2 scale are shown in Table 5. Among these 16
interval (CI) from studies; (4) No participants and lan- items, items 2, 4, 7, 9, 11, 13 and 15 are critical items. The
guage restriction were used in the selection of eligible detailed grading criteria of AMSTAR2 scale for system-
studies; (5) Whenever there were multiple health out- atic review and meta-analysis are as follows [17]:
comes, we only extract the data of the diseases concern-
ing biliary system; (6) If there are multiple meta-analysis • High: No or one non-critical weakness: the sys-
and/or systematic review on the same topic, the most tematic review provides an accurate and compre-
hensive summary of the results of the available Results

studies that address the question of interest [17]. Characteristics of the included meta‑analyses
• Moderate: More than one non-critical weakness*: The process of literature screening is shown in Fig. 1.
the systematic review has more than one weakness Two authors independently and systematically retrieved
but no critical flaws. It may provide an accurate 323 articles respectively. Overall, 24 articles with 83
summary of the results of the available studies that unique outcomes were included by eligibility criteria. A
were included in the review [17]. list of all the excluded articles and the reason for exclu-
• Low: One critical flaw with or without non-critical sion was provided in Additional file 2: Table S2.
weaknesses: the review has a critical flaw and may Table 1 shows the characteristics of these 24 stud-
not provide an accurate and comprehensive sum- ies. Among all included articles, nine did not conduct
mary of the available studies that address the ques- methodological quality assessment for original studies
tion of interest [17]. [21–28], the remaining 15 articles used the Newcastle
• Critically low: More than one critical flaw with Ottawa Quality Assessment scale(NOS) for assessment.
or without non-critical weaknesses: the review The included studies covered 43 significant associations
has more than one critical flaw and should not be between 83 diet, nutrition related indicators and biliary
relied on to provide an accurate and comprehen- diseases risk. All systematic reviews and meta-analyses
sive summary of the available studies [17]. were published between 2008 and 2021. Among these
articles, four included only case–control studies [1,
When evaluating the quality of evidence,the GRADE 27, 29–31], six included only cohort studies [25, 26,
[18, 19] was adopted to rate the strength of evidence 32–35], and the remaining thirteen included different
for each outcome in each meta-analysis. According types of original studies, encompassing case–control
to the GRADE classification, evidence from rand- studies, cohort studies, nested case–control studies
omized controlled trials was defined as high quality and cross-sectional studies. The number of original
without degradation, while evidence from observa- studies included in these articles ranged from 2 to 26.
tional studies is automatically reduced by two levels at Except that only one article could not obtain the exact
the beginning, defined as low-quality evidence. Next, number of participants and cases [24], the number of
evidence was comprehensively evaluated according participants in other studies were at least 435, at most
to five factors that may lead to the reduction of evi- 10,786,685, and the number of cases were at least 105,
dence quality (risk of bias, Indirectness, inconsistency, at most 61,071.
imprecision and publication bias) and three factors Tables 2, 3 and 4 respectively show the relationship
that may upgrade evidence quality (large effect, dose– between dietary factors, nutrition related indicators,
response gradient and plausible confounding). Finally, alcohol and biliary diseases. Among the included articles,
evidence was divided into four levels according to its 4 focused on gallbladder cancer, 8 on cholangiocarci-
quality (high, moderate, low and very low). noma, 9 on cholecystolithiasis/gallbladder diseases, and
3 on both gallbladder cancer and cholangiocarcinoma.
Seventeen of twenty-four studies focused on fourteen
Statistical analysis food items, including alcohol, coffeee, high spicy food,
For each meta-analysis included in our study, we tea, vegetable, fruit, raw fish, fermented fish, glutinous
abstracted exposure, outcome and the estimated sum- rice, meat, betel nut, fermented meats, high nitrate foods
mary effect (OR: Odds Ratios, RR: Relative Rates or and rice. Seven studies focused on 11 nutrition related
HR: Hazard Ratios) with its corresponding 95% CI and indicators, including overweight, obesity, diabetes mel-
p-value. Cochran’s Q test and the I2 metric were used litus, glycemic index rate, glycemic load rate, every 5
to assess the heterogeneity between different studies. unit increment of BMI, every 10 cm increment of waist
The selection of random or fixed effect models was circumference, every 0.1 unit increment in waist-to-
adopted from the original models in the selected meta- hip ratio, triglycerides, HDL cholesterol and Non-HDL
analyses. We did not conduct a secondary analysis. cholesterol.
Egger’s test [20] was used to calculate publication bias
or small study effect, and when p-value < 0.1, we con-
sidered occurrence of publication bias. For other sta- Gallbladder cancer
tistical tests, the significance threshold was still set as In the studies we included, there were some dietary fac-
p < 0.05. The dose–response analyses were abstracted tors, such as all spicy food [29], chili pepper [29] and tea
from the articles when possible. [22] intake, which were not related to the risk of gallblad-
der cancer.
Fig. 1 Literature screening process of this study
Type two diabetes mellitus was associated with an Due to the limited number of studies, no further study
increased risk of gallbladder cancer (RR = 1.56, 95% has investigated the effect of different types of tea
CI 1.36–1.79) [41]. Compared with normal subjects, intake on reducing the risk of bile duct cancer.
T2DM increased the risk of gallbladder cancer by 56%. For fruit and vegetable consumption, we found that
Overweight and obesity are also risk factors for gall- they have a significant effect on reducing the incidence
bladder cancer. Being overweight increased the risk by of bile duct cancer [37]. In terms of vegetables consump-
17% (RR = 1.17, 95% CI 1.07–1.28), while in obesity this tion, the summary RR was 0.48 (95%CI 0.22–0.74). For
figure rose to 62% (RR = 1.62, 95% CI 1.49–1.75) [42]. dose–response analysis, every 100 g increment of vegeta-
These results are in good agreement with the results of bles consumed per day was associated with a 69 percent
subgroup analyses of different study models (case control reduction in the risk of bile duct cancer (RR = 0.31, 95%
and cohort studies) in the meta-analysis. CI 0.20–0.47, p < 0.001). In term of fruits consumption,
the summary RR was 0.47 (95% CI 0.32–0.61) and the
Bile duct cancer summary RR every 100 g increment a day was not sta-
The consumption of tea was related to a reduced risk tistically significant. Although the summary data show
of bile duct cancer [36] (RR = 0.66,95% CI 0.48–0.85), that vegetable and fruits consumption can reduce the risk
although this was not apply to gallbladder cancer. of bile duct cancer, a cohort study in this meta-analysis
According to dose–response analyses, the risk of bile showed that neither consumption were associated with a
duct cancer decreased by 4% with each additional cup reduced risk of bile duct cancer. Therefore, the relation-
of tea per day (RR = 0.96, 95% CI 0.93–0.98, p = 0.001). ship between vegetable or fruit consumption and the risk
Table 1 The general characteristics of the 24 systematic reviews and meta-analyses
First author, Original article Journal Dietary factor No. of studies Disease type; continent/ Type of studies Study Sample size Quality
year retrieval time or nutrition included in this region/country; no. of design(number) assessment
related review related studies
indicators to our topic
Bagnardi [21] Up to September British Journal of Alcohol 8 studies GBC; Meta-analysis Cohort(4) 880 GBC cases NA
2012 Cancer North America(3), Asia(5) Case–control(4)
Clements [1] NA Journal of Hepa- Alcohol 15 studies iCCA; Systematic Case–control(15) 13,986 cases and NOS
tology China(5);America(5);South review and 780,565 controls
Korea(2); Denmark(1); meta-analysis
Wang et al. Nutrition & Metabolism
Italy(1); Japan(1)
Alcohol 11 studies eCCA: Case–control(11) 8,293 cases and
China(6);South Korea(1) 452,450 controls
Godos [13] Up to March Nutrients Coffeee 5 publications on BTC; Meta-analysis Cohort(15) 726 cases among NOS
2017 17 studies America(11);Japan(3); of prospective Case–control(2) 1,375,626 partici-
(2022) 19:51
Sweden(3) cohort studies pants

Chen [29] Up to June 2017 Chinese Medical High Spicy Food 3 publications on GBC; Meta-analysis Case–control(6) 219 cases and NOS
Journal 6 studies Hungary(2),Chile(2),India(2) of case–control 245 controls
studies
Xiong [36] NA Oncotarget Tea 8 studies BTC; Systematic Cohort(3) 7968 BTC cases NOS
West(4);East(4) review and Case–control(5)
meta-analysis
ZHU [22] NA Molecular and Tea 6 studies GBC; Meta-analysis Cohort(2) 753 cases among NA
Clinical Oncology China(2), America(1), Italy(1), Case–control(4) 115,349 partici-
Japan(1),Poland(1) pants
Huai [37] Up to 31 May Nutrition and Vegetable 10 studies BTC; Meta-analysis Case–control(8) 2620 cases NOS
2020 Cancer-an Inter- Thailand(4),Japan(2),Italy(1) Cohort(1) among
national Journal ,Netherland(1), Hungary(1), Nested case–con- 90,829 partici-
India(1) trol(1) pants
Fruit 13 studies BTC; Case–control(11) 2926 cases
Thailand(5),Japan(2), Cohort(1) among
India(2),Italy(1),Chili(1), Nested case–con- 90,866 partici-
Nepal(1), Hungary(1) trol(1) pants
Kamsa-ard [30] Up to 4 March Asian Pacific Raw Fish 3 studies CCA; Systematic Case–control(3) 1920 participants NOS
2016 Journal of Cancer Thailand(3) review and
Prevention Fermented Fish 2 studies CCA; meta-analysis Case–control(2) 435 participants
Thailand(2)
Glutinous Rice 3 studies CCA; Case–control(3) 842 participants
Thailand(3)
Meat 2 studies CCA; Case–control(2) 616 participants
Thailand(2)
Betel nut 3 studies CCA; Case–control(3) 709 participants
Thailand(3)
Page 6 of 33
Table 1 (continued)
Steele [23] Up to 8 February Infectious Dis- Fermented Meats 3 studies CCA; Systematic Case–control(2) 471 cases and NA
2015 eases of Poverty Thailand(3) review and Nested case– 690 controls
meta-analysis control(1)
High Nitrate 5 studies CCA; Case–control(3) 682 cases and
Foods Thailand(5) Nested case–con- 901 controls
trol(2)
Rice 2 studies CCA; Case–control(2) 232 cases and
Thailand(2) 232 controls
Daniel [26] NA Scandinavian Triglycerides 2 studies Gallstone; a cohort study Cohort(2) 298 cases among NA
Denmark(1),Sweden(1) and a systematic 3038 participants
(2022) 19:51
Journal of Gastro- HDL cholesterol

enterology review with meta
Non-HDL choles- analysis
terol
Byung [38] Up to 01 March Gut and Liver Alcohol 24 studies Gallstone; Meta-analysis of Cohort(9) 22,401 cases NOS
2018 America and Europe(19), case–control and Case–control(15) among
Asia(4),Australia(1) cohort Studies 76,185 partici-
pants
Zhang [39] Up to June 2015 Alimentary Coffee 6 publications on Gallstone; Systematic Cohort(7) 11,477 cases NOS
Pharmacology & 8 studies America(2),Italy(2),Sweden(1 review and Case–control(1) among
Therapeutics ),Britain(1) meta-analysis 227,749 partici-
pants
Zhang [40] Up to March Medicine Vegetable 14 studies Gallstone; Systematic Cohort(9) Case– 33,983 cases NOS
2018 America(5),Italy(1),Iran(1), review and control(4) among
French(1),Sweden(1), Britain meta-analysis Cross-sectional(1) 1,533,752 partici-
(1),Korea(1),Indian(1),Germ pants
any(1), Argentina(1)
Fruit 5 studies Gallstone; Cohort(4) 20,599 cases
America(2),French(1),Swede Case–control(1) among
n(1),Korea(1) 1,223,147 partici-
pants
Ying Li [31] Up to February PLOS ONE Alcohol 2 studies GBC; Systematic Case–control(2) 467 cases and NOS
2010 China(2) review and 1315 controls
2 studies VPC; meta-analysis Case–control(2) 105 cases and
China(2) 1331 controls
2 studies eCCA; China(2) Case–control(2) 228 cases and
753 controls
Page 7 of 33
Table 1 (continued)
Emma E. McGee NA Jnci-Journal of Alcohol Total 26 studies GBC; A Pooling Project Cohort(26) 1104 cases NA
[27] the National NA and meta- among
(2022) 19:51
Cancer Institute analysis 230,0628 partici-

pants
Total 26 studies iCCA; 613 cases among
NA 230,0628 partici-
pants
Total 26 studies eCCA; 928 cases among
pants
Total 26 studies VPC; 521 cases among
pants
Xiao-Hua Ye [35] Up to 31 May World Journal of Alcohol 7 studies eCCA; Meta-analysis Case–control(6) 783 cases among NOS
2013 Gastroenterology America(3); China(3); Cohort(1) 1770 participants
Turkey(1)
Jiantao Wang Up to May 2016 European Journal Alcohol 18 studies Gallstone; Meta-analysis Case–control(10) 29,680 cases NA
[28] of Gastroenterol- Europe(11); America(3); Cohort(8) among
ogy &Hepatology Asia(2); Oceania(2) 415,747 partici-
pants
Gu [41] Up to 31 August Diabetes-Metab- T2DM 20 studies GBC; Systematic Cohort(12) 4106 cases NOS
2014 olism Research East Asia(6),America(6), review and Case–control(8) among
and Reviews Europe(6),India (n = 1), Israel meta-analysis of 4,223,350 partici-
(n = 1), observational pants
studies
Page 8 of 33
Table 1 (continued)
Li [42] Up to August Obesity Overweight 17 studies GBC; Meta-analysis of Cohort(9) 6285 cases NOS
2015 Europe(7),Asia(7),Americas(3) observational Case–control(8) among
studies 6,183,691 partici-
pants
Obesity 22 studies GBC; Cohort(13) 6761 cases
Europe(10),Asia(8),Ameri Case–control(9) among

cas(4) 10,786,685
participants
Overweight 8 studies eCCA; Cohort(4) 1938 cases
Europe(4),Asia(3),Ameri Case–control(4) among
(2022) 19:51
cas(1), 1,614,375 partici-

pants
Obesity 16 studies eCCA; Cohort(7) 5819 cases
Europe(6),Americas(6),Asia(4) Case–control(9) among
6,479,962 par-
ticipants
Aune [33] Up to 9 January Journal of DM 10 studies GBD; Systematic Cohort(10) 223,651 cases NOS
2015 Diabetes and its America(6),China(2),Italy(1), review and among
Complications Britain(1) meta-analysis 7,365,198 partici-
of prospective pants
studies
Barclay [25] Up to March American Journal Glycemic index 2 studies Gallstone:America(2) Meta analysis Cohort(2) 114,933 partici- NA
2007 of Clinical Nutri- rate pants
tion Glycemic load
rate
Dagfinn Aune Up to 9 January European Journal BMI 17 studies GBD; Meta analysis Cohort(17) 55,670 cases NOS
[34] 2015 of Epidemiology America(9),Europe(7),Ch among
ina(1) 1,921,103 partici-
pants
Waist Circumfer- 5 studies GBD; Cohort(5) 15,523 cases
ence America(4),Europe(1) among
284,095 partici-
pants
Waist-to-Hip 4 studies GBD; Cohort(4) 14,458 cases
Ratio America(4) among
230,166 partici-
pants
Page 9 of 33
(2022) 19:51
Table 1 (continued)
Petrick [24] Up to 5 Septem- American Journal Obesity 4 studies iCCA; Pooling Project Cohort(1) NA NA
ber 2017 of Gastroenterol- America(3),Europe(1) and meta- Nested case–con-
ogy analysis trol(3)
DM 6 studies iCCA; Cohort(2) NA
America(3),Europe(2),Asia(1) Nested case–con-
trol(4)
Page 10 of 33
Table 2 The relationship between dietary factors and biliary diseases
First author, No. of Type of study Dietary factor Effects model MA metric Estimates 95%CI Test for I2% (p-value) Egger test Publication
Year included (Subgroup or overall effect (p-value) bias and small-
studies Dose response) (p-value) study effect
Gallbladder cancer
Chen [29] 6 Case–control All spicy food random OR 1.78 (0.83–3.83) NA 75 (0.001) 0.714 No publication
bias
Chen [29] 6 Case–control Chili pepper random OR 1.78 (0.83–3.83) NA 75 (0.001) 0.714 No publication
bias
ZHU [22] 6 Case–control(4);Cohort(2) Tea random OR 0.67 (0.40–1.12) 0.13 82 (< 0.0001) Only funnel No publication
plot (N) bias
ZHU [22] 4 Case–control(3);Cohort(1) Tea (highest vs. random OR 0.57 (0.25–1.29) 0.18 82 (0.001) Only funnel No publication
lowest/none) plot (N) bias
ZHU [22] 4 Case–control(3);Cohort(1) Tea (moderate vs. random OR 0.62 (0.33–1.14) 0.12 77 (0.004) Only funnel No publication
low/none) plot (N) bias
(2022) 19:51
Biliary tract cancer

Godos [13] 8 Total Cohort(5);Case–con- Coffee random OR 0.83 (0.64–1.08) NA 0 (0.58) Only funnel No publication
trol(3) plot (N) bias
Godos [13]# 5 Cohort(5) Coffee random OR 0.74 (0.34–1.63) NA 0 (0.82) Only funnel No publication
plot (N) bias
Godos [13]# 3 Case–control(3) Coffee random OR 0.84 (0.61–1.15) NA 22 (0.27) Only funnel No publication
plot (N) bias
Xiong [36] 8 Total Case– Tea random RR 0.66 (0.48–0.85) NA 81.1 (0.000) > 0.05 No publication
control(5);Cohort(3) bias
Xiong [36]# 3 Cohort Tea random RR 0.62 (0.44–0.80) NA 55.8 (0.009) > 0.05 No publication
bias
Xiong [36]# 5 Case–control Tea random RR 0.84 (0.77–0.90) NA 60 (0.001) > 0.05 No publication
bias
Xiong [36] 8 Total Case– Tea (every 1cup/ – RR 0.96 (0.93–0.98) 0.001 NA > 0.05 No publication
control(5);Cohort(3) day increment) bias
Huai [37] 10 Total Case– Vegetable random RR 0.48 (0.22–0.74) NA 86.8 (0.000) 0.84 No publication
control(8);Cohort(1); bias
Nested case–control(1)
Huai [37]# 8 Case–control Vegetable random RR 0.45 (0.14–0.75) NA 88 (< 0.001) 0.84 No publication
bias
Huai [37]# 1 Cohort Vegetable – RR 0.96 (0.37–1.55) NA – 0.84 No publication
bias
Huai [37]# 1 Nested case–control Vegetable – RR 0.40 (0.23–0.76) NA – 0.84 No publication
bias
Huai [37] 8 Case–control(6);Cohort(1); Vegetable (every – RR 0.31 (0.20–0.47) < 0.001 NA 0.84 No publication
Nested case–control(1) 100 g/day incre- bias
ment)
Page 11 of 33
Table 2 (continued)
Huai [37] 13 Total Case– Fruit random RR 0.47 (0.32–0.61) NA 63.3 (0.001) 0.64 No publication
control(11);Cohort(1); bias
Huai [37]# 11 Case–control Fruit random RR 0.41 (0.26–0.56) NA 61.6 (0.004) 0.64 No publication
bias
Huai [37]# 1 Cohort Fruit – RR 0.87 (0.47–1.27) NA – 0.64 No publication
bias
Huai [37]# 1 Nested case–control Fruit – RR 0.60 (0.33–0.98) NA – 0.64 No publication
bias
(2022) 19:51
Huai [37] 8 Case–control(6);Cohort(1); Fruit (every – RR 0.89 (0.66–1.18) 0.35 NA 0.64 No publication
Nested case–control(1) 100 g/day incre- bias
ment)
Kamsa-ard [30] 3 Case–control Raw Fish fixed OR 2.54 (1.94–3.35) < 0.00001 0 (0.80) NA NA
Kamsa-ard [30] 2 Case–control Fermented Fish fixed OR 1.61 (0.76–3.41) 0.21 45 (0.18) NA NA
Kamsa-ard [30] 3 Case–control Glutinous Rice fixed OR 1.30 (0.85–2.01) 0.23 62 (0.07) NA NA
Kamsa-ard [30] 2 Case–control Meat random OR 1.03 (0.57–1.85) 0.92 59 (0.06) NA Na
Kamsa-ard [30] 3 Case–control Betel nut fixed OR 1.45 (0.69–3.02) 0.33 60 (0.06) NA NA
Steele [23] 3 Total Case–control(2) Fermented Meats random OR 1.81 (0.96–3.39) 0.066 17 (0.28) NA NA
Steele [23] 5 Total Case–control(3) High Nitrate random OR 1.41 (1.05–1.91) 0.024 46 (0.01) NA NA
Nested case–control(2) Foods
Steele [23] 2 Case–control Rice random OR 0.88 (0.48–1.63) 0.688 34 (0.22) NA NA
Cholecystolithiasis/gallbladder diease
Zhang [39] 7 Cohort Coffee random RR 0.83 (0.76–0.89) NA 35.9 (0.154) 0.39 No publication
bias
Zhang [39] 4 Cohort Coffee (every – RR 0.95 (0.91–1.00) 0.049 54.4 (0.019) 0.39 No publication
1Cup/Day incre- bias
ment)
Zhang [40] 14 Total Case– Vegetables random RR 0.83 (0.74–0.94) NA 82.5 (0.000) 0.682 No publication
control(4);Cohort(9);Cross bias
sectional(1)
Zhang [40]# 9 Cohort Vegetables random RR 0.92 (0.82–1.02) NA 80.2 (0.001) 0.682 No publication
bias
Zhang [40]# 4 Case–control Vegetables random RR 0.39 (0.24–0.62) NA 59.8 (0.058) 0.682 No publication
bias
Zhang [40]# 1 Cross sectional Vegetables random RR 0.92 (0.80–1.07) NA – 0.682 No publication
bias
Page 12 of 33
(2022) 19:51
Table 2 (continued)
Zhang [40] 6 Cohort Vegetables(every – RR 0.96 (0.93–0.98) 0.001 NA 0.682 No publication

200 g/Day incre- bias
ment)
Zhang [40] 5 Cohort Fruits random RR 0.88 (0.83–0.92) NA 0 (0.456) 0.735 No publication
bias
Zhang [40] 4 Cohort Fruits (every – RR 0.97 (0.96–0.98) NA 0.735 No publication
200 g/Day incre- bias
ment)
#: Subgroup analysis of the different study design types of the corresponding study
Page 13 of 33
Table 3 The relationship between nutrition related indicators and biliary diseases
First author, No. of Type of study Nutrition Effects model MA metric Estimates 95%CI Test for overall I2% (p-value) Egger test Publication bias
year included related effect (p-value) (p-value) and small-study
studies indicators effect
Gallbladder cancer
Gu [41] 20 Total Case– Type 2 DM random RR 1.56 (1.36–1.79) NA 43.5 (0.01) < 0.001 Exist publication
control(8); bias
Cohort(12)
Gu [41]# 8 Case–control Type 2 DM random RR 1.52 (1.09–2.11) NA 38.8 (0.109) < 0.001 Exist publication
bias
Gu [41]# 12 Cohort Type 2 DM random RR 1.57 (1.35–1.83) NA 48.7 (0.013) < 0.001 Exist publication
bias
Li [42] 17 Total Case–con- Overweight random RR 1.17 (1.07–1.28) NA 32.6 (0.03) 0.375 No publication
trol(8); Cohort(9) bias
Li [42]# 8 Case–control Overweight random RR 1.24 (1.07–1.44) NA 0 (0.877) 0.375 No publication
(2022) 19:51
bias
Li [42]# 9 Cohort Overweight random RR 1.15 (1.02–1.30) NA 56.9 (0.004) 0.375 No publication
bias
Li [42] 22 Total Case– Obesity random RR 1.62 (1.49–1.75) NA 0 (0.524) 0.375 No publication
control(9); bias
Cohort(13)
Li [42]# 9 Case–control Obesity random RR 1.48 (1.26–1.74) NA 0 (0.544) 0.375 No publication
bias
Li [42]# 13 Cohort Obesity random RR 1.67 (1.52–1.83) NA 0 (0.492) 0.375 No publication
bias
Li [42] 8(eCCA) Total Case–con- Overweight random RR 1.26 (1.14–1.39) NA 0 (0.452) 0.478 No publication
Li [42]# 4(eCCA) Case–control Overweight random RR 1.11 (0.89–1.39) NA 10.3 (0.350) 0.478 No publication
bias
Li [42]# 4(eCCA) Cohort Overweight random RR 1.31 (1.16–1.47) NA 0 (0.596) 0.478 No publication
bias
Li [42] 16(eCCA) Total Case–con- Obesity random RR 1.48 (1.21–1.81) NA 68 (0.000) 0.478 No publication
Li [42]# 9(eCCA) Case–control Obesity random RR 1.27 (1.03–1.55) NA 53.6 (0.011) 0.478 No publication
bias
Li [42]# 7(eCCA) Cohort Obesity random RR 1.81 (1.29–2.53) NA 62.7 (0.004) 0.478 No publication
bias
Petrick [24] 4(iCCA) Total Nested Obesity random RR 1.49 (1.32–1.70) < 0.001 0 (0.70) 0.09 Exist publication
case–control(3); bias
Cohort(1)
Petrick [24]# 3(iCCA) Nested case– Obesity random RR 1.46 (1.27–1.69) < 0.001 0 (0.60) 0.09 Exist publication
control bias
Page 14 of 33
Table 3 (continued)
First author, No. of Type of study Nutrition Effects model MA metric Estimates 95%CI Test for overall I2% (p-value) Egger test Publication bias
year included related effect (p-value) (p-value) and small-study
studies indicators effect
Petrick [24]# 1(iCCA) Cohort Obesity random RR 1.62 (1.23–2.12) < 0.001 – 0.09 Exist publication
bias
Petrick [24] 6(iCCA) Total Nested DM random RR 1.53 (1.31–1.78) < 0.001 67.3 (0.009) 0.9 No publication
case–control(4); bias
Cohort(2)
Petrick [24]# 4(iCCA) Nested case– DM random RR 1.59 (1.47–1.72) < 0.001 0 (0.40) 0.9 No publication
control bias
(2022) 19:51
Petrick [24]# 2(iCCA) Cohort DM random RR 1.45 (0.99–2.13) 0.06 81.1 (0.02) 0.9 No publication
bias
Aune [33] 10 Cohort DM random RR 1.56 (1.26–1.93) NA 99.4 (< 0.0001) 0.70 No publication
bias
Barclay [25] 2 Cohort Glycemic index fixed RR 1.26 (1.13–1.40) < 0.0001 NA Only funnel plot No publication
rate (highest vs. (N) bias
lowest)
Barclay [25] 2 Cohort Glycemic load fixed RR 1.41 (1.25–1.60) < 0.0001 NA Only funnel plot No publication
rate (highest vs. (N) bias
lowest)
Dagfinn Aune 17 Cohort Every 5 unit random RR 1.63 (1.49–1.78) NA 98 (< 0.0001) 0.13 No publication
[34] increment of BMI bias
Dagfinn Aune 5 Cohort Every 10 cm random RR 1.46 (1.24–1.72) NA 98 (< 0.0001) NA NA
[34] increment of
waist circumfer-
ence
Dagfinn Aune 4 Cohort Every 0.1 unit random RR 1.44 (1.26–1.64) NA 92 (< 0.0001) NA NA
[34] increment in
waist-to-hip ratio
Daniel [26] 2 Cohort Triglycerides fixed OR 1.10 (0.99–1.22) NA 0 (NA) NA NA
Daniel [26] 2 Cohort HDL cholesterol fixed OR 0.87 (0.62–1.23) NA 0 (NA) NA NA
Daniel [26] 2 Cohort Non-HDL choles- fixed OR 1.19 (1.07–1.32) NA 81 (NA) NA NA
terol
Page 15 of 33
Table 4 The relationship between alcohol consumption and biliary diseases
First author, No. of Type of study Dietary factor Effects MA metric Estimates 95%CI Test for I2% (p-value) Egger test Publication
Year included (subgroup or model overall effect (p-value) bias and small-
studies dose response) (p-value) study effect
Gallbladder cancer
Bagnardi [16] 8 Case–control(4); Alcohol (Light Random RR 1.23 (0.84 − 1.83) NA 18 (NA) NA NA
Cohort(4) vs. none)c
Ying Li [50] 2 Case–control Alcohol (drinker Fixed OR 0.7 99%CI(0.49– 0.009 16 (0.27) NA NA
vs. non-drinker) 1.00)
Emma E. Total 26 stud- Cohort Alcohol (> 0–0.5 Random HR 1.07 (0.91–1.26) NA 0 (NA) NA NA
McGee [35] ies vs. 0 drink/d)a
(2022) 19:51
Emma E. Total 26 stud- Cohort Alcohol (> 0.5–1 Random HR 1.1 (0.87–1.39) NA 0 (NA) NA NA
Emma E. Total 26 stud- Cohort Alcohol (1– < 3 Random HR 0.94 (0.74–1.21) NA 0 (NA) NA NA
Emma E. Total 26 stud- Cohort Alcohol (3– < 5, Random HR 1.16 (0.69–1.94) NA 0 (0.57) NA NA
Emma E. Total 26 stud- Cohort Alcohol (> 5 vs. 0 Random HR 2.39 (0.63–9.12) NA 64.9 (0.02) NA NA
McGee [35] ies drink/d)a
Emma E. Total 26 stud- Cohort Alcohol (every – HR 0.98 (0.92–1.05) 0.31 12 (NA) NA NA
McGee [35] ies 1drink/d
increment)a
Ying Li [50] 2(eCCA) Case–control Alcohol (drinker Fixed OR 1.14 99%CI(0.75– 0.41 0 (0.81) NA NA
Ying Li [50] 2(VPC) Case–control Alcohol (drinker Random OR 0.68 99%CI(0.20– 0.43 77 (0.04) NA NA
Emma E. Total 26 Cohort Alcohol (> 0–0.5 Random HR 0.79 (0.62–1.00) NA 0 (NA) NA NA
McGee [35] studies(iCCA) vs. 0 drink/d)a
Emma E. Total 26 Cohort Alcohol (> 0.5–1 Random HR 0.91 (0.65–1.26) NA 0 (NA) NA NA
Emma E. Total 26 Cohort Alcohol (1– < 3 Random HR 0.98 (0.73–1.31) NA 0 (NA) NA NA
Emma E. Total 26 Cohort Alcohol (3– < 5, Random HR 1.25 (0.77–2.02) NA 8.5 (0.37) NA NA
Emma E. Total 26 Cohort Alcohol (> 5 vs. 0 Random HR 2.35 (1.46–3.78) NA 0 (0.52) NA NA
McGee [35] studies(iCCA) drink/d)a
Page 16 of 33
Table 4 (continued)
Emma E. Total 26 Cohort Alcohol (every – HR 1.03 (1.01–1.06) 0.04 0 (NA) NA NA

McGee [35] studies(iCCA) 1drink/d
increment)a
Emma E. Total 26 Cohort Alcohol (> 0–0.5 Random HR 0.87 (0.68–1.12) NA 30.8 (NA) NA NA
McGee [35] studies(eCCA) vs. 0 drink/d)a
Emma E. Total 26 Cohort Alcohol (> 0.5–1 Random HR 1.14 (0.82–1.58) NA 28.4 (NA) NA NA

Emma E. Total 26 Cohort Alcohol (1– < 3 Random HR 1.08 (0.74–1.58) NA 48.3 (NA) NA NA
Emma E. Total 26 Cohort Alcohol (3– < 5, Random HR 1.82 (0.98–3.39) NA 57.2 (0.01) NA NA
(2022) 19:51
McGee [35] studies(eCCA) drink/d)a
Emma E. Total 26 Cohort Alcohol (every – HR 1.03 (0.98–1.08) 0.84 25.3 (NA) NA NA
McGee [35] studies(eCCA) 1drink/d
increment)a
Emma E. Total 26 Cohort Alcohol (> 0–0.5 Random HR 1.08 (0.80–1.45) NA 13.7 (NA) NA NA
McGee [35] studies(VPC) vs. 0 drink/d)a
Emma E. Total 26 Cohort Alcohol (> 0.5–1 Random HR 0.99 (0.69–1.41) NA 0 (NA) NA NA
Emma E. Total 26 Cohort Alcohol (1– < 3 Random HR 1.33 (0.99–1.80) NA 0 (NA) NA NA
Emma E. Total 26 Cohort Alcohol (3– < 5, Random HR 1.16 (0.66–2.01) NA 0 (0.93) NA NA
McGee [35] studies(VPC) drink/d)a
Emma E. Total 26 Cohort Alcohol (every – HR 1.00 (0.95–1.04) 0.35 0 (NA) NA NA
McGee [35] studies(VPC) 1drink/d
increment)a
Xiao-Hua Ye 7(eCCA) Total case– Alcohol (drinker Random RR 1.09 (0.87–1.37) NA 0 (0.575) 0.296 No publication
[51] control(6);Cohort(1) vs. non-drinker) bias
Xiao-Hua Ye 6(eCCA) Case–control(6) Alcohol (drinker Random RR 1.10 (0.86–1.41) NA 0 (0.447) 0.296 No publication
[51]# vs. non-drinker) bias
Xiao-Hua Ye 1(eCCA) Cohort(1) Alcohol (drinker Random RR 1.06 (0.60–1.87) NA – 0.296 No publication
[51]# vs. non-drinker) bias
Clements [1] 15(iCCA) Case–control Alcohol (drinker Random OR 3.15 (2.24–4.41) NA 87 (NA) Only funnel No publication
vs. non-drinker) plot (N) bias
Page 17 of 33
Table 4 (continued)
Clements [1] 11(eCCA) Case–control Alcohol (drinker Random OR 1.75 (1.20–2.55) NA 87 (NA) Only funnel No publication
vs. non-drinker) plot (N) bias
Jiantao Wang 18 Total case– Alcohol (highest Random RR 0.62 (0.49–0.78) NA 94.6 (0.000) 0.836 No publication
[52] control(10);Cohort(8) vs. lowest) bias
Jiantao Wang 10 Case–control(10) Alcohol (highest Random RR 0.58 (0.45–0.73) NA 37.8 (0.107) 0.836 No publication
[52]# vs. lowest) bias
Jiantao Wang 8 Cohort(8) Alcohol (highest Random RR 0.66 (0.48–0.91) NA 96.8 (0.000) 0.836 No publication
[52]# vs. lowest) bias
Jiantao Wang 3 Case– Alcohol (types Random RR 0.64 (0.52–0.78) NA 0 (0.368) 0.836 No publication
[52] control(1);Cohort(2) of drink beer bias
(2022) 19:51
highest vs. low-

est)b
Jiantao Wang 3 Case– Alcohol (types Random RR 0.72 (0.54–0.96) NA 44.1 (0.167) 0.836 No publication
[52] control(1);Cohort(2) of drink wine bias
highest vs. low-
est)b
Jiantao Wang 2 Cohort(2) Alcohol (types Random RR 0.71 (0.64–0.85) NA 1 (0.421) 0.836 No publication
[52] of drink liquor bias
highest vs. low-
est)b
Byung [27] 23 Case– Alcohol (drinker Random RR 0.84 (0.79–0.89) NA 61 (< 0.01) 0.009 Exist publica-
control(14);Cohort(9) vs. non-drinker) tion bias
Byung [27] 11 Total case– Alcohol (Light Random RR 0.96 (0.94–0.99) NA 0 (0.75) 0.383 No publication
control(5);Cohort(6) vs. none)d bias
Byung [27]# 5 Case–control Alcohol (Light Random RR 0.98 (0.95–1.01) NA 0 (0.99) 0.383 No publication
vs. none)d bias
Byung [27]# 6 Cohort Alcohol (Light Random RR 0.94 (0.89–0.98) NA 0 (0.51) 0.383 No publication
vs. none)d bias
Byung [27] 14 Total case– Alcohol (Moder- Random RR 0.80 (0.75–0.85) NA 17 (0.27) 0.523 No publication
control(8);Cohort(6) ate vs. none)d bias
Byung [27]# 8 Case–control Alcohol (Moder- Random RR 0.76 (0.72–0.80) NA 0 (0.70) 0.523 No publication
ate vs. none)d bias
Byung [27]# 6 Cohort Alcohol (Moder- Random RR 0.85 (0.80–0.91) NA 0 (0.57) 0.523 No publication
ate vs. none)d bias
Byung [27] 14 Total case– Alcohol (Heavy Random RR 0.66 (0.56–0.79) NA 61 (< 0.01) 0.602 No publication
control(8);Cohort(6) vs. none)d bias
Page 18 of 33
(2022) 19:51
Table 4 (continued)
Byung [27]# 8 Case–control Alcohol (Heavy Random RR 0.58 (0.40–0.85) NA 54 (0.03) 0.602 No publication
vs. none)d bias
Byung [27]# 6 Cohort Alcohol (Heavy Random RR 0.73 (0.68–0.79) NA 0 (0.61) 0.602 No publication
vs. none)d bias
a: Alcoholic drinks per day(0 [referent], > 0–0.5, > 0.5–1, 1– < 3, 3– < 5, > 5 drink/d) and continuously (analyzed per one drink), One alcoholic drink was defined as 14 g of ethanol
b: The types of drink: wine, beer and liquor
c: The author decided to consider as light, moderate and heavy drinking every interval whose midpoint was respectively ≤ 12.5 g, ≤ 50 g and > 50 g per day of alcohol
d: Drinking level for each category: light, F < 7 and M < 14 g/day; moderate, F 7–17 and M 14–18 g/day; high, F > 14 and M > 28 g/day. F, female; M, male, B, both
Page 19 of 33
of bile duct cancer remains to be further evaluated by Glycemic load rate [25] (RR = 1.41, 95% CI 1.25–1.60,
larger and more comprehensive clinical studies. p < 0.0001), diabetes mellitus [33] (RR = 1.41, 95% CI
In addition, some studies from Thailand have shown 1.56, 1.26–1.93), every 5 unit increment of BMI [34]
that eating raw fish [30] (RR = 2.54, 95% CI 1.94–3.35, (RR = 1.63, 95% CI 1.49–1.78), every 10 cm increment
p < 0.00001) and high-nitrate foods [23] (RR = 1.41, 95% of waist circumference [34] (RR = 1.46, 95% CI 1.24–
CI 1.05–1.91, p = 0.024) increases the risk of bile duct 1.72), every 0.1 unit increment in waist-to-hip ratio [34]
cancer. Because these studies are meta-analyses of ret- (RR = 1.44, 95% CI 1.26–1.64) and non-HDL cholesterol
rospective case–control studies and the sample size is [26] (RR = 1.19, 95% CI 1.07–1.32).
small, the evidence they can provide is very limited.
There was no obvious significant association of coffee Alcohol consumption and biliary tract diseases
[13], fermented fish [30], glutinous rice [30], meat [30], Our study included eight meta-analyses that discussed
betel nut [30], fermented meats [23] and rice [23] con- the relationship between alcohol consumption and bil-
sumption with bile duct cancer. iary diseases.
Similarly, some nutritional indicators are also associ- In these studies, three meta-analyses reported the rela-
ated with the risk of bile duct cancer. Both overweight tionship between alcohol consumption and gallbladder
and obesity increase the risk of eCCA [42]. Overweight cancer [21, 27, 31]. Bagnardi et al. [21] defined daily alco-
increased the risk of eCCA by 26% (RR = 1.26, 95% hol intake ≦12.5 g, ≦50 g and ≧50 g as light, moderate,
CI 1.14–1.39), while obesity increased the risk by 48% and heavy alcohol consumption, respectively. Their meta
(RR = 1.48, 95% CI 1.21–1.81). Although subgroup analy- analysis found that heavy drinking was associated with a
sis of case–control studies showed that overweight was marked increased risk of gallbladder cancer (RR = 2.64,
not associated with the risk of eCCA, we had more rea- 95% CI 1.62–4.30). The association between alcohol
son to believe the evidence provided by cohort studies. consumption and gallbladder cancer risk was not statis-
Obesity and diabetes are also risk factors for iCCA [24], tically significant for light (RR = 1.23, 95% CI 0.84–1.83)
in obese and diabetic subjects, the RR values of iCCA to moderate (RR = 0.88, 95% CI 0.68–1.13) drinkers. In a
were 1.49 (95%CI 1.32–1.70, p < 0.001) and 1.53 (95%CI meta-analysis based on cohort studies, Emma E. McGee
1.31–1.78, p < 0.001) respectively. et al. [27] further divided the aggregated cohort studies
into 6 subgroups (0,0–0.5,0.5–1,1–3,3–5, > 5 drink/d),
Cholecystolithiasis/gallbladder diseases based on drink/d (14 g of ethanol/d). The subgroups
Since many studies did not separate cholecystolithiasis were compared with the 0 drink/d group and no statisti-
from other gallbladder diseases such as acute cholecysti- cal association was found between alcohol consumption
tis, some of the studies we included may not be limited to and the risk of gallbladder cancer. There was no dose–
cholecystolithiasis. response effect between alcohol consumption and gall-
Although studies have confirmed that coffee consump- bladder cancer, either. In another meta-analysis, Li et al.
tion has no obvious relationship with the incidence of [31]. found a 30% reduction in gallbladder cancer among
biliary cancers, coffee consumption is a protective factor drinkers compared to non-drinkers (OR = 0.7, 99%CI
in the formation of gallstones [39]. Overall, the combined 0.49–1.00, p = 0.009).
RR was 0.83 (95% CI 0.76–0.89), and each additional cup In the study of intrahepatic cholangiocarcinoma,
of coffee consumed per day was associated with a 5% Emma E. McGee et al. [27] found that the risk of iCCA
(RR = 0.95, 95% CI 0.91–1.00, p = 0.049) reduction in was reduced in patients with > 0–0.5 drink/d compared
cholecystolithiasis risk. As for the relationship between with non-drinkers (HR = 0.79, 95%CI 0.62–1.00). When
vegetable and fruit consumption and cholecystolithiasis, drinking > 5 drink/d, The risk of iCCA was 1.35 times
current evidence suggests that vegetable consumption higher than that of non-alcohol consumption (HR = 2.35,
is associated with a 17% (RR = 0.83, 95% CI 0.74–0.94) 95%CI 1.46–3.78), and there was a dose–response effect
lower risk and fruit with a 12% (RR = 0.83, 95% CI 0.83– between the risk of iCCA and the amount of alcohol
0.92) lower risk [40]. Moreover, there is a dose–response consumed (every 1drink/d increment, HR = 1.03, 95%CI
relationship between the intake of vegetables and fruits 1.01–1.06, p = 0.04).Similarly, in the meta-analysis con-
and the risk of disease, that is, for each additional 200 g ducted by Clements et al. [1]., drinkers had an approxi-
per day, the corresponding risk of disease will be reduced mately 2.15-fold increased risk for iCCA (OR = 3.35,
by 4% (RR = 0.96, 95% CI 0.93–0.98, p = 0.001) and 3% 95%CI 2.24–4.41) and a approximately 0.75-fold
(RR = 0.97, 95% CI 0.96–0.98, p = 0.001). increased risk for eCCA (OR = 1.75, 95%CI 1.20–2.55)
In addition, some nutritional indicators may be related compared to non-drinkers.
to the occurrence of gallstone, such as Glycemic index As for cholecystolithiasis or gallbladder disease,
rate [25] (RR = 1.26, 95% CI 1.13–1.40, p < 0.0001), although drinking is a risk factor for biliary cancers,
Byung et al. [38]. found that drinking can reduce the risk evidence and finally determine the strength of each evi-
of cholecystolithiasis by 16% (RR = 0.84, 95% CI = 0.79– dence level was decided.
0.89). At the same time, compared with non-drinkers, the In this umbrella review, we summarized 83 independ-
risk of cholecystolithiasis decreased gradually with the ent outcomes (Table 5). Regarding the risk of bias, 44
increase of alcohol consumption. In mild, moderate and outcomes were downgraded due to inadequate control
severe drinkers, the risk decreased by 4% (RR = 0.96, 95% for confounding factors (including inaccuracy in meas-
CI = 0.94–0.99), 20% (RR = 0.80, 95% CI = 0.75–0.85) uring all known prognostic factors; Prognostic factors
and 34% (RR = 0.66, 95% CI = 0.56–0.79) respectively. were not matched and/or not adjusted in the statistical
Similarly, we also found the same conclusion in the study analysis). We judged the imprecision of evidence by the
of Jiantao Wang et al. [28] (Alcohol consumption high- 95% confidence interval of each evidence and the opti-
est vs. lowest, RR = 0.62, 95%CI 0.49–0.78). In addition, mal information size (OIS). If the sample size of evidence
they also studied the consumption of different types of was lower than the OIS standard, the confidence inter-
alcoholic beverages and the risk of cholecystolithiasis. vals contained invalid values, or the confidence intervals
The results showed that increased consumption of beer did not exclude significant benefits or harms (95%CI con-
(RR = 0.64, 95%CI 0.52–0.78), wine (RR = 0.72, 95%CI tained 1, with lower limit < 0.75, upper limit > 1.25), the
0.54–0.96), and liquor (RR = 0.71, 95%CI 0.64–0.85) quality level of evidence would be reduced. We found a
tended to reduce the risk of gallstones. total of 38 outcomes of Imprecision and downgraded
one level. The inconsistency and publication bias were
Heterogeneity, publication bias and small study effect mainly evaluated according to the I2 and Egger’s test of
Of all the items we summarized (all items in Tables 2, meta-analyses included in our study. In our study, 35
3 and 4), 52 items presented low heterogeneity outcomes were downgraded due to inconsistencies and
(I2 < 25%); 36 items had moderate-to-high heterogeneity 45 outcomes were downgraded due to suspected publi-
(25% < I2 < 75%), and 19 items had very high levels hetero- cation bias. None of the outcomes was downgraded due
geneity (I2 > 75%). In addition, there were 7 items that did to indirectness. In terms of upgrading factors, seven of
not report heterogeneity. For evidence with significant the outcomes were upgraded due to large effect (Relative
heterogeneity (p < 0.05), the quality of evidence will be effect > 2 or < 0.5), 14 due to dose response gradient, and
degraded in the evaluation of evidence quality. 0 due to plausible confounding.
This umbrella review used Egger’s test to summarize In short, among 83 independent outcomes, 5 were
publication bias and small study effects in meta-analyses. rated as moderate, 16 as low, and the rest as very low
Of the 24 meta-analyses, 7 studies did not measure pub- (Table 6).
lication bias, 3 reported significant publication bias, and
the remaining did not report significant publication bias Discussion
(Table 1). Main findings and interpretation of evidence
To promote the general population’s understanding of
AMSTAR2 and GRADE classification the impact of dietary and nutritional indicators on biliary
The methodological quality of the meta-analyses included disease risk, our study provide a comprehensive overview
in our study were assessed using AMSTAR2 scale, and of the reported associations between diet and nutrition-
the results of the review were rated as high, moder- related factors and biliary disease risk by incorporating
ate, low, and critically low. Overall, the vast majority (21 evidence from existing systematic reviews and meta-
studies, 87.5%) of methodological qualities of the meta- analyses. Overall, we included 24 articles that included
analyses were assessed as “critically low” by AMSTAR2 83 risk estimates of dietary and nutrition-related factors
scale (Table 5). The remaining three meta-analyses were associated with the incidence of gallbladder cancer, bile
assessed as “low” and no one was assessed “moderate” or duct cancer, and gallstones. There was no high evidence
“high”. to support an association among all the evidence evalu-
Since the studies we included were all meta-analyses ated. Only 5 associations were supported by moder-
based on retrospective studies, all evidence was first low- ate evidence and 16 associations were supported by low
ered by two grades, from high level to low level during evidence.
GRADE evaluation. Next, we decided whether to con- In this umbrella review, the evaluation tools we used
tinue to downgrade the evidence according to whether include AMSTAR2 and GRADE. The methodological
there was risk of bias, indirectness, inconsistency, impre- quality of the meta-analyses included in this umbrella
cision and publication bias. After checking whether there review was assessed by AMSTAR2. It mainly includes
were large effects, dose–response gradients and plausible the following aspects of evaluation: research questions,
confounding of evidence, whether to upgrade the level of inclusion standard PICO elements, system review plan,
Table 5 Methodological quality of the systematic review and meta-analyses were assessed using the AMSTAR2 scale
Study Q1 Q2* Q3 Q4* Q5 Q6 Q7* Q8 Q9* Q10 Q11* Q12 Q13* Q14 Q15* Q16 AMSTAR-2
overall
quality
Bagnardi [21] Y N N Y N Y N PY PY N Y Y Y Y N Y Critically low

Clements [1] Y N N Y N N N PY PY N Y N N N Y Y Critically low
Godos [13] Y N N PY Y Y Y Y PY N Y N Y Y Y Y Low
Chen [29] Y N N Y Y Y N Y PY N Y Y Y N Y Y Critically low
Xiong [36] Y N N PY N Y N Y Y N N N N N Y Y Critically low
ZHU [22] Y N N Y N Y N PY PY N Y N N Y Y Y Critically low
Huai [37] Y N N Y Y Y N PY PY N Y N Y Y Y Y Critically low
Kamsa-ard [30] Y N N N Y Y N N PY N N N N N N Y Critically low
Steele [23] Y N N Y N Y N PY N N N N Y N N Y Critically low
Daniel [26] Y Y N Y Y Y N Y Y N N N N N N Y Critically low
Byung [38] Y N Y Y Y Y N PY PY N N N Y N Y Y Critically low
Zhang [39] Y N N Y Y Y N Y Y N Y Y Y Y Y Y Critically low
Zhang [40] Y N N Y Y Y N PY Y N Y Y Y Y Y Y Critically low
Ying Li [31] Y N N Y N Y N PY PY N Y N N Y N Y Critically low
Emma E. McGee [27] Y N N N N N N PY PY N Y N N N N Y Critically low
Xiao-Hua Ye [35] Y N N Y Y Y N PY PY N Y Y N Y Y Y Critically low
Jiantao Wang [28] Y N N Y N Y N PY PY N Y N N Y Y Y Critically low
Gu [41] Y N N Y Y Y N Y Y N Y Y Y Y Y Y Critically low
Li [42] Y N N Y Y N N Y Y N N Y N N Y Y Critically low
Aune [33] Y N N Y N N Y Y Y N Y Y Y Y Y Y Low
Barclay [25] Y N N Y Y Y N Y N N N Y N N Y Y Critically low
Dagfinn Aune [34] Y N Y Y N N Y Y Y N Y Y Y Y Y Y Low
Petrick [24] Y N N PY Y Y N Y N N N Y Y N Y Y Critically low
AMSTAR-2 items: Q1: Did the research questions and inclusion criteria for the review include the components of PICO? Q2: Did the report of the review contain
an explicit statement that the review methods were established prior to the conduct of the review, and did the report justify any signifificant deviations from
the protocol? Q3: Did the review authors explain their selection of the study designs for inclusion in the review? Q4: Did the review authors use a comprehensive
Literature search strategy? Q5: Did the review authors perform study selection in duplicate? Q6: Did the review authors perform data extraction in duplicate? Q7: Did
the review authors provide a list of excluded studies and justify the exclusions? Q8: Did the review authors describe the included studies in adequate detail? Q9: Did
the review authors use a satisfactory technique for assessing the risk of bias (RoB) in individual studies that were included in the review? Q10: Did the review authors
report on the sources of funding for the studies included in the review? Q11: If meta-analysis was performed, did the review authors use appropriate methods for
statistical combination of results? Q12: If meta-analysis was performed, did the review authors assess the potential impact of RoB in individual studies on the results of
the meta-analysis or other evidence synthesis? Q13: Did the review authors account for RoB in primary studies when interpreting/discussing the results of the review?
Q14: Did the review authors provide a satisfactory explanation for, and discussion of, any heterogeneity observed in the results of the review? Q15: If they performed
quantitative synthesis, did the review authors carry out an adequate investigation of publication bias (small study bias) and discuss its likely impact on the results of
the review? Q16: Did the review authors report any potential sources of conflflict of interest, including any funding they received for conducting the review?
included study design type, literature search strategy, lit- namely large effect, dose–response gradient and plausi-
erature screening, data extraction, exclusion of specific ble confounding, we divided the quality of evidence of
details of literature, assessment of bias risk, assessment systematic evaluation into four grades: high, moderate,
of the rationality of statistical analysis, assessment of the low and very low [18, 19].
accuracy of interpretation of results, and assessment of Based on available evidence, our study did not found
financial support and conflict of interest. Based on the that food or nutrition consumption (except alcohol con-
evaluation of the above projects, the results of the review sumption) was associated with increased risk of gallblad-
is rated as high, moderate, low, and critically low [17]. der cancer. Our study found that overweight, obesity and
The application of GRADE in the systematic reviews and diabetes can increase the risk of gallbladder cancer, but
meta analyses is to analyze the quality of the evidence, the quality of evidence was rated low or very low. That
that is, to what extent the authenticity of the prognostic doesn’t mean the conclusion is wrong. At present, exist-
outcome can be assured. By examining five demotion fac- ing studies have proposed the biological pathogenesis of
tors, including risk of bias, Indirectness, inconsistency, gallbladder cancer caused by the above factors. It is gen-
imprecision and publication bias, three upgrade factors, erally believed that overweight and obesity contribute to
Table 6 AMSTAR2 and GRADE classification of the evidence
Summary of findings Certainty assessment(degradation factor) Certainty assessment (Escalation Importance Grade AMSTAR2
factors)
First author,Dietary and Study Outcome Relative Risk Inconsistency Indirectness Imprecision Publication Large Plausible Dose
Year nutrition related design(number) effect (95% of bias effect confounding response
factor CI) bias gradient
Chen [19] All spicy food Case–control(6) Gallbladder OR 1.78 Seri- Seriousf Not serious Seriousg Undetected No No No 6-Important ⨁◯◯◯ Critically low
cancer (0.83–3.83) ouse Very low
Chen [19] Chili pepper Case–control(6) Gallbladder OR 1.78 Seri- Seriousf Not serious Seriousg Undetected No No No 6-Important ⨁◯◯◯ Critically low
cancer (0.83–3.83) ouse Very low

ZHU [20] Tea Case– Gallbladder OR 0.67 Seri- Seriousf Not serious Seriousg Undetected No No No 6-Important ⨁◯◯◯ Critically low
control(4);Cohort(2) cancer (0.40–1.12) ouse Very low
ZHU [20] Tea (highest vs. Case– Gallbladder OR 0.57 Seri- Seriousf Not serious Seriousg Undetected No No No 6-Important ⨁◯◯◯ Critically low
lowest/none) control(3);Cohort(1) cancer (0.25–1.29) ouse Very low
(2022) 19:51
ZHU [20] Tea (moderate vs. Case– Gallbladder OR 0.62 Seri- Seriousf Not serious Seriousg Undetected No No No 6-Important ⨁◯◯◯ Critically low
low/none) control(3);Cohort(1) cancer (0.33–1.14) ouse Very low
Godos [8] Coffee Cohort(5);Case–con- Biliary tract OR 0.83 Not Not serious Not serious Seriousg Undetected No No No 6-Important ⨁◯◯◯ Low
trol(3) cancer (0.64–1.08) seri- Very low
ous
Xiong [21] Tea Case– Biliary tract RR 0.66 Seri- Seriousf Not serious Not serious Undetected No No Yes 7-Critical ⨁◯◯◯ Critically low
control(5);Cohort(3) cancer (0.48–0.85) ouse Very low
Xiong [21] Tea (every 1cup/ Case– Biliary tract RR 0.96 Seri- Seriousf Not serious Not serious Undetected No No Yes 7-Critical ⨁◯◯◯ Critically low
day increment) control(5);Cohort(3) cancer (0.93–0.98) ouse Very low
Huai [22] Vegetable Case– Biliary tract RR 0.48 Not Seriousf Not serious Not serious Undetected Yes No Yes 7-Critical ⨁⨁⨁◯ Critically low
control(8);Cohort(1); cancer (0.22–0.74) seri- Moderate
Nested case–con- ous
trol(1)
Huai [22] Vegetable (every Case– Biliary tract RR 0.31 Not Seriousf Not serious Not serious Undetected Yes No Yes 7-Critical ⨁⨁⨁◯ Critically low
100 g/day incre- control(6);Cohort(1); cancer (0.20–0.47) seri- Moderate
ment) Nested case–con- ous
trol(1)
Huai [22] Fruit Case– Biliary tract RR 0.47 Not Seriousf Not serious Not serious Undetected Yes No No 7-Critical ⨁⨁◯◯ Critically low
control(11);Cohort(1); cancer (0.32–0.61) seri- Low
trol(1)
Huai [22] Fruit (every 100 g/Case– Biliary tract RR 0.89 Not Seriousf Not serious Seriousg Undetected No No Yes 6-Important ⨁◯◯◯ Critically low
day increment) control(6);Cohort(1); cancer (0.66–1.18) seri- Very low
trol(1)
Kamsa-ard Raw Fish Case–control(3) Biliary tract OR 2.54 Seri- Not serious Not serious Not serious Strongly Yes No No 7-Critical ⨁◯◯◯ Critically low
[23] cancer (1.94–3.35) ouse suspected Very low
Kamsa-ard Fermented Fish Case–control(2) Biliary tract OR 1.61 Seri- Not serious Not serious Seriousg Strongly No No No 6-Important ⨁◯◯◯ Critically low
Kamsa-ard Glutinous Rice Case–control(3) Biliary tract OR 1.3 Seri- Not serious Not serious Seriousg Strongly No No No 6-Important ⨁◯◯◯ Critically low
Page 23 of 33
Table 6 (continued)
factors)
Kamsa-ard Meat Case–control(2) Biliary tract OR 1.03 Seri- Not serious Not serious Seriousg Strongly No No No 6-Important ⨁◯◯◯ Critically low
Kamsa-ard Betel nut Case–control(3) Biliary tract OR 1.45 Seri- Not serious Not serious Seriousg Strongly No No No 6-Important ⨁◯◯◯ Critically low
Steele [24] Fermented Meats Total case–control(2) Biliary tract OR 1.81 Seri- Not serious Not serious Seriousg Strongly No No No 6-Important ⨁◯◯◯ Critically low
@Nested case–con- cancer (0.96–3.39) ouse suspected Very low
trol(1)
Steele [24] High Nitrate Total case–control(3) Biliary tract OR 1.41 Seri- Seriousf Not serious Not serious Strongly No No No 7-Critical ⨁◯◯◯ Critically low
(2022) 19:51
Foods @Nested case–con- cancer (1.05–1.91) ouse suspected Very low

trol(2)
Steele [24] Rice Case–control(2) Biliary tract OR 0.88 Seri- Not serious Not serious Seriousg Strongly No No No 6-Important ⨁◯◯◯ Critically low
cancer (0.48–1.63) ouse suspected Very low
Zhang [28] Coffee Cohort(7) Cholecys- RR 0.83 Not Not serious Not serious Not serious Undetected No No Yes 7-Critical ⨁⨁⨁◯ Critically low
tolithiasis/ (0.76–0.89) seri- Moderate
gallbladder ous
diease
Zhang [28] Coffee (every Cohort(4) Cholecys- RR 0.95 Not Seriousf Not serious Not serious Undetected No No Yes 7-Critical ⨁⨁◯◯ Critically low
1Cup/Day incre- tolithiasis/ (0.91–1.00) seri- Low
ment) gallbladder ous
diease
Zhang [29] Vegetables Case– Cholecys- RR 0.83 Not Seriousf Not serious Not serious Undetected No No Yes 7-Critical ⨁⨁◯◯ Critically low
control(4);Cohort(9); tolithiasis/ (0.74–0.94) seri- Low
@Cross sectional(1) gallbladder ous
diease
Zhang [29] Vegetables(every Cohort(6) Cholecys- RR 0.96 Not Seriousf Not serious Not serious Undetected No No Yes 7-Critical ⨁⨁◯◯ Critically low
200 g/Day incre- tolithiasis/ (0.93–0.98) seri- Low
diease
Zhang [29] Fruits Cohort(5) Cholecys- RR 0.88 Not Not serious Not serious Not serious Undetected No No Yes 7-Critical ⨁⨁⨁◯ Critically low
tolithiasis/ (0.83–0.92) seri- Moderate
gallbladder ous
diease
Zhang [29] Fruits (every Cohort(4) Cholecys- RR 0.97 Not Not serious Not serious Not serious Undetected No No Yes 7-Critical ⨁⨁⨁◯ Critically low
200 g/Day incre- tolithiasis/ (0.96–0.98) seri- Moderate
diease
Gu [17] Type 2 DM Case–control(8); Gallbladder RR 1.56 Not Seriousf Not serious Not serious Strongly No No No 7-Critical ⨁◯◯◯ Critically low
Cohort(12) cancer (1.36–1.79) seri- suspected Very low
ous
Page 24 of 33
Table 6 (continued)
factors)
Li [18] Overweight Case–control(8); Gallbladder RR 1.17 Not Seriousf Not serious Not serious Undetected No No No 7-Critical ⨁◯◯◯ Critically low
Cohort(9) cancer (1.07–1.28) seri- Very low
ous
Li [18] Obesity Case–control(9); Gallbladder RR 1.62 Not Not serious Not serious Not serious Undetected No No No 7-Critical ⨁⨁◯◯ Critically low
Cohort(13) cancer (1.49–1.75) seri- Low
ous
Li [18] Overweight Case–control(4); Biliary tract RR 1.26 Not Not serious Not serious Not serious Undetected No No No 7-Critical ⨁⨁◯◯ Critically low
Cohort(4) cancer- (1.14–1.39) seri- Low
eCCA ous
(2022) 19:51
Li [18] Obesity Case–control(9); Biliary tract RR 1.48 Not Seriousf Not serious Not serious Undetected No No No 7-Critical ⨁◯◯◯ Critically low
Cohort(7) cancer- (1.21–1.81) seri- Very low
eCCA ous
Petrick [25] Obesity Nested case–con- Biliary tract RR 1.49 Not Not serious Not serious Not serious Undetected No No No 7-Critical ⨁⨁◯◯ Critically low
trol(3); Cohort(1) cancer-iCCA(1.32–1.70) seri- Low
ous
Petrick [25] DM Nested case–con- Biliary tract RR 1.53 Not Seriousf Not serious Not serious Undetected No No No 7-Critical ⨁◯◯◯ Critically low
trol(4); Cohort(2) cancer-iCCA(1.31–1.78) seri- Very low
ous
Aune [31] DM Cohort(10) Cholecys- RR 1.56 Not Seriousf Not serious Not serious Undetected No No No 7-Critical ⨁◯◯◯ Low
tolithiasis/ (1.26–1.93) seri- Very low
gallbladder ous
diease
Barclay [30] Glycemic index Cohort(2) Cholecys- RR 1.26 Seri- Seriousf Not serious Not serious Undetected No No No 7-Critical ⨁◯◯◯ Critically low
rate (highest vs. tolithiasis/ (1.13–1.40) ouse Very low
lowest) gallbladder
diease
Barclay [30] Glycemic load Cohort(2) Cholecys- RR 1.41 Seri- Seriousf Not serious Not serious Undetected No No No 7-Critical ⨁◯◯◯ Critically low
rate (highest vs. tolithiasis/ (1.25–1.60) ouse Very low
lowest) gallbladder
diease
Dagfinn Every 5 unit incre- Cohort(17) Cholecys- RR 1.63 Not Seriousf Not serious Not serious Undetected No No Yes 7-Critical ⨁⨁◯◯ Low
Aune [32] ment of BMI tolithiasis/ (1.49–1.78) seri- Low
gallbladder ous
diease
Dagfinn Every 10 cm Cohort(5) Cholecys- RR 1.46 Not Seriousf Not serious Not serious Strongly No No Yes 7-Critical ⨁◯◯◯ Low
Aune [32] increment of tolithiasis/ (1.24–1.72) seri- suspected Very low
waist circumfer- gallbladder ous
ence diease
Page 25 of 33
Table 6 (continued)
factors)
Dagfinn Every 0.1 unit Cohort(4) Cholecys- RR 1.44 Not Seriousf Not serious Not serious Strongly No No Yes 7-Critical ⨁◯◯◯ Low
Aune [32] increment in tolithiasis/ (1.26–1.64) seri- suspected Very low
waist-to-hip ratio gallbladder ous
diease
Daniel [33] Triglycerides Cohort(2) Cholecys- OR 1.1 Not Not serious Not serious Not serious Strongly No No No 6-Important ⨁◯◯◯ Critically low
tolithiasis/ (0.99–1.22) seri- suspected Very low
gallbladder ous
diease
Daniel [33] HDL cholesterol Cohort(2) Cholecys- OR 0.87 Not Not serious Not serious Seriousg Strongly No No No 6-Important
(2022) 19:51
⨁◯◯◯ Critically low

tolithiasis/ (0.62–1.23) seri- suspected Very low
gallbladder ous
diease
Daniel [33] Non-HDL cho- Cohort(2) Cholecys- OR 1.19 Not Seriousf Not serious Not serious Strongly No No No 7-Critical ⨁◯◯◯ Critically low
lesterol tolithiasis/ (1.07–1.32) seri- suspected Very low
gallbladder ous
diease
Ying Li [50] Alcohol(drinker Case–control(2) Gallbladder OR 0.7 Seri- Not serious Not serious Not serious Strongly No No No 7-Critical ⨁◯◯◯ Critically low
vs. non-drinker) cancer @99%CI(0.49– ouse suspected Very low
1.00)
Emma E. Alcohol(>0–0.5 Cohort(26) Gallbladder HR 1.07 Seri- Not serious Not serious Seriousg Strongly No No No 6-Important ⨁◯◯◯ Critically low
McGee, vs. 0 drink/d)a cancer (0.91–1.26) ouse suspected Very low
2019 [35]
Emma E. Alcohol(>0.5–1 Cohort(26) Gallbladder HR 1.1 Seri- Not serious Not serious Seriousg Strongly No No No 6-Important ⨁◯◯◯ Critically low
McGee, vs. 0 drink/d)a cancer (0.87–1.39) ouse suspected Very low
2019 [35]
Emma E. Alcohol(1–<3 vs. Cohort(26) Gallbladder HR 0.94 Seri- Not serious Not serious Seriousg Strongly No No No 6-Important ⨁◯◯◯ Critically low
McGee [35] 0 drink/d)a cancer (0.74–1.21) ouse suspected Very low
Emma E. Alcohol(3–<5, vs. Cohort(26) Gallbladder HR 1.16 Seri- Not serious Not serious Seriousg Strongly No No No 6-Important ⨁◯◯◯ Critically low
Emma E. Alcohol(>5 vs. 0 Cohort(26) Gallbladder HR 2.39 Seri- Seriousf Not serious Seriousg Strongly No No No 6-Important ⨁◯◯◯ Critically low
McGee [35] drink/d)a cancer (0.63–9.12) ouse suspected Very low
Emma E. Alcohol(every Cohort(26) Gallbladder HR 0.98 Seri- Not serious Not serious Not serious Strongly No No No 6-Important ⨁◯◯◯ Critically low
McGee [35] 1drink/d cancer (0.92–1.05) ouse suspected Very low
increment)a
Bagnardi Alcohol (Light vs. Case– Gallbladder RR 1.23 Not Not serious Not serious Seriousg Strongly No No No 6-Important ⨁◯◯◯ Critically low
[16] none)c control(4);Cohort(4) cancer (0.84 − 1.83) seri- suspected Very low
ous
Bagnardi Alcohol (Moder- Case– Gallbladder RR 0.88 Not Not serious Not serious Seriousg Strongly No No No 6-Important ⨁◯◯◯ Critically low
[16] ate vs. none)c control(4);Cohort(4) cancer (0.68 − 1.13) seri- suspected Very low
ous
Page 26 of 33
Table 6 (continued)
factors)
Bagnardi Alcohol (Heavy vs.Case– Gallbladder RR 2.64 Not Not serious Not serious Not serious Strongly Yes No No 7-Critical ⨁⨁◯◯ Critically low
[16] none)c control(4);Cohort(4) cancer (1.62 − 4.30) seri- suspected Low
ous
Ying Li [50] Alcohol(drinker Case–control(2) Biliary tract OR 1.14 Seri- Not serious Not serious Seriousg Strongly No No No 6-Important ⨁◯◯◯ Critically low
vs. non-drinker) cancer- 99%CI(0.75– ouse suspected Very low
eCCA 1.75)
Ying Li [50] Alcohol(drinker Case–control(2) Biliary tract OR 0.68 Seri- Seriousf Not serious Seriousg Strongly No No No 6-Important ⨁◯◯◯ Critically low
vs. non-drinker) cancer-VPC 99%CI(0.20– ouse suspected Very low
2.37)
(2022) 19:51
Emma E. Alcohol(> 0–0.5 Cohort(26) Biliary tract HR 0.79 Seri- Not serious Not serious Seriousg Strongly No No No 7-Critical ⨁◯◯◯ Critically low
McGee [35] vs. 0 drink/d)a cancer (0.62–1.00) ouse suspected Very low
Emma E. Alcohol(> 0.5–1 Cohort(26) Biliary tract HR 0.91 Seri- Not serious Not serious Seriousg Strongly No No No 6-Important ⨁◯◯◯ Critically low
Emma E. Alcohol(1– < 3 vs. Cohort(26) Biliary tract HR 0.98 Seri- Not serious Not serious Seriousg Strongly No No No 6-Important ⨁◯◯◯ Critically low
Emma E. Alcohol(3– < 5, vs. Cohort(26) Biliary tract HR 1.25 Seri- Not serious Not serious Seriousg Strongly No No No 6-Important ⨁◯◯◯ Critically low
Emma E. Alcohol(> 5 vs. 0 Cohort(26) Biliary tract HR 2.35 Seri- Not serious Not serious Not serious Strongly Yes No No 7-Critical ⨁◯◯◯ Critically low
Emma E. Alcohol(every Cohort(26) Biliary tract HR 1.03 Seri- Not serious Not serious Not serious Strongly No No No 7-Critical ⨁◯◯◯ Critically low
increment)a
Emma E. Alcohol(> 0–0.5 Cohort(26) Biliary tract HR 0.87 Seri- Not serious Not serious Seriousg Strongly No No No 6-Important ⨁◯◯◯ Critically low
Emma E. Alcohol(1– < 3 vs. Cohort(26) Biliary tract HR 1.08 Seri- Seriousf Not serious Seriousg Strongly No No No 6-Important ⨁◯◯◯ Critically low
Emma E. Alcohol(3– < 5, vs. Cohort(26) Biliary tract HR 1.82 Seri- Seriousf Not serious Seriousg Strongly No No No 6-Important ⨁◯◯◯ Critically low
Emma E. Alcohol(> 5 vs. 0 Cohort(26) Biliary tract HR 1.02 Seri- Not serious Not serious Seriousg Strongly No No No 6-Important ⨁◯◯◯ Critically low
Emma E. Alcohol(every Cohort(26) Biliary tract HR 1.03 Seri- Not serious Not serious Not serious Strongly No No No 6-Important ⨁◯◯◯ Critically low
increment)b
Emma E. Alcohol(> 0–0.5 Cohort(26) Biliary tract HR 1.08 Seri- Not serious Not serious Seriousg Strongly No No No 6-Important ⨁◯◯◯ Critically low
Page 27 of 33
Table 6 (continued)
factors)
Emma E. Alcohol(1– < 3 vs. Cohort(26) Biliary tract HR 1.33 Seri- Not serious Not serious Seriousg Strongly No No No 6-Important ⨁◯◯◯ Critically low
Emma E. Alcohol(3– < 5, vs. Cohort(26) Biliary tract HR 1.16 Seri- Not serious Not serious Seriousg Strongly No No No 6-Important ⨁◯◯◯ Critically low
Emma E. Alcohol(> 5 vs. 0 Cohort(26) Biliary tract HR 1.59 Seri- Not serious Not serious Seriousg Strongly No No No 6-Important ⨁◯◯◯ Critically low
(2022) 19:51
Emma E. Alcohol(every Cohort(26) Biliary tract HR 1 Seri- Not serious Not serious Not serious Strongly No No No 6-Important ⨁◯◯◯ Critically low
increment)a
Xiao-Hua Ye Alcohol(drinker Case– Biliary tract RR 1.09 Not Not serious Not serious Seriousg Undetected No No No 6-Important ⨁⨁◯◯ Critically low
[51] vs. non-drinker) control(6);Cohort(1) cancer- (0.87–1.37) seri- Low
eCCA ous
Clements [1] Alcohol(drinker Case–control(15) Biliary tract OR 3.15 Not Seriousf Not serious Not serious Undetected Yes No No 7-Critical ⨁⨁◯◯ Critically low
vs. non-drinker) cancer-iCCA(2.24–4.41) seri- Low
ous
Clements [1] Alcohol(drinker Case–control(11) Biliary tract OR 1.75 Not Seriousf Not serious Not serious Undetected No No No 7-Critical ⨁◯◯◯ Critically low
vs. non-drinker) cancer- (1.20–2.55) seri- Very low
eCCA ous
Jiantao Alcohol(highest Case– Cholecys- RR 0.62 Not Seriousf Not serious Not serious Undetected No No No 7-Critical ⨁◯◯◯ Critically low
Wang [52] vs. lowest) control(10);Cohort(8) tolithiasis/ (0.49–0.78) seri- Very low
gallbladder ous
diease
Jiantao Alcohol(types of Case–control(1); Cholecys- RR 0.64 Not Not serious Not serious Not serious Undetected No No No 7-Critical ⨁⨁◯◯ Critically low
Wang drink beer highestCohort(2) tolithiasis/ (0.52–0.78) seri- Low
vs. lowest)b gallbladder ous
diease
Jiantao Alcohol(types of Case–control(1); Cholecys- RR 0.72 Not Not serious Not serious Not serious Undetected No No No 7-Critical ⨁⨁◯◯ Critically low
Wang [52] drink wine high- Cohort(2) tolithiasis/ (0.54–0.96) seri- Low
est vs. lowest)b gallbladder ous
diease
Jiantao Alcohol(types of Cohort(2) Cholecys- RR 0.71 Not Not serious Not serious Not serious Undetected No No No 7-Critical ⨁⨁◯◯ Critically low
Wang [52] drink liquor high- tolithiasis/ (0.64–0.85) seri- Low
est vs. lowest)b gallbladder ous
diease
Page 28 of 33
Table 6 (continued)
factors)
(2022) 19:51
Byung [27] Alcohol (drinker Case– Cholecys- RR 0.84 Not Seriousf Not serious Not serious Strongly No No No 7-Critical ⨁◯◯◯ Critically low
vs. non-drinker) control(14);Cohort(9) tolithiasis/ (0.79–0.89) seri- suspected Very low
gallbladder ous
diease
Byung [27] Alcohol (Light vs. Case– Cholecys- RR 0.96 Not Not serious Not serious Not serious Undetected No No No 7-Critical ⨁⨁◯◯ Critically low
none)d control(5);Cohort(6) tolithiasis/ (0.94–0.99) seri- Low
gallbladder ous
diease
Byung [27] Alcohol (Moder- Case– Cholecys- RR 0.8 Not Not serious Not serious Not serious Undetected No No No 7-Critical ⨁⨁◯◯ Critically low
ate vs. none)d control(8);Cohort(6) tolithiasis/ (0.75–0.85) seri- Low
gallbladder ous
diease
Byung [27] Alcohol (Heavy vs.Case– Cholecys- RR 0.66 Not Seriousf Not serious Not serious Undetected No No No 7-Critical ⨁◯◯◯ Critically low
none)d control(8);Cohort(6) tolithiasis/ (0.56–0.79) seri- Very low
gallbladder ous
diease
a: Alcoholic drinks per day(0 [referent], > 0–0.5, > 0.5–1, 1– < 3, 3– < 5, > 5 drink/d) and continuously (analyzed per one drink), One alcoholic drink was defined as 14 g of ethanol
b: The types of drink: wine, beer and liquor
c: The author decided to consider as light, moderate and heavy drinking every interval whose midpoint was respectively ≤ 12.5 g, ≤ 50 g and > 50 g per day of alcohol
d: Drinking level for each category: light, F < 7 and M < 14 g/day; moderate, F 7–17 and M 14–18 g/day; high, F > 14 and M > 28 g/day. F, female; M, male, B, both
e: Failure to adequately control for confounding
f: Conclusions significant heterogeneity was reported
g:The credible interval contains invalid values and the credible interval does not exclude significant benefits or harms
Page 29 of 33
gallbladder cancer by interfering with the metabolism of risk of bile duct cancer. Furthermore, other studies have
lipids and endogenous hormones, affecting the move- shown that some specific dietary patterns can also affect
ment of the gallbladder and increasing the risk of gall- the occurrence of bile duct cancer. For example, in a
stones [43]. Other studies also believe that obesity will cohort study [10], a Mediterranean (MED) diet and the
inevitably increase the accumulation of fat in the gall- Dietary Approaches to Stop Hypertension (DASH) sig-
bladder, leading to fatty gallbladder disease and aggra- nificantly reduced the risk of bile duct cancer. Similarly,
vating local inflammation, which is also an important this research was not included in this umbrella review
mechanism to promote the occurrence of gallbladder because it was not further studied by evidence-based
cancer [44]. In type 2 diabetes, the possible mechanisms medicine.
contributing to gallbladder cancer include: Hyperinsu- Cholelithiasis or gallbladder diease is also one of the
linemia and up-regulation of insulin-like growth fac- most common diseases of the biliary system. There has
tor-1 (IGF-1) levels promote cell proliferation and inhibit been clear epidemiological evidence that gallstone is
apoptosis. Hyperglycemia stimulates tumor growth by a risk factor for gallbladder cancer [47]. Therefore, the
inducing the increase of insulin and IGF-1 levels. In addi- research on the risk factors of gallstone is of great sig-
tion, some studies have suggested that other dietary fac- nificance both from the perspective of prevention of
tors, such as the consumption of green onions, seaweed gallbladder cancer and health economics. In our study,
and kelp, are negatively correlated with gallbladder and we found 3 moderate intensity outcomes, 4 low inten-
bile duct cancer, while pickled vegetables and meats sity outcomes, and the other outcomes levels were very
are positively correlated [45]. These studies were not low. Based on the available evidence, we recommend
included in this umbrella review because there was no proper intake of coffee, fruits and vegetables to reduce
meta-analysis to evaluate these results. the risk of gallstones. In the evidence of nutrition related
As for bile duct cancer, it is important to note that in indicators we included, almost all the evidence related
bile duct cancer studies, some have included gallbladder to cholelithiasis (blood glucose related indicators and
and bile duct cancer together, or have not performed a BMI related indicators) were consistent with the corre-
subgroup analysis by bile duct cancer type. Subgroup sponding evidence of gallbladder cancer or cholangio-
analysis were not reworked because of limited data avail- carcinoma, but the level of all evidence were not high.
ability. Our study found that drinking tea is a protective Recent studies have pointed out that high fructose, low
factor of cholangiocarcinoma [36]. In terms of the biolog- fiber, high fat and low vitamin C will increase the risk of
ical mechanism by which tea drinking can reduce the risk gallstone formation. On the other hand, a high intake of
of cancer, studies have confirmed that tea contains a large monounsaturated fats and fiber, moderate intake of olive
amount of tea polyphenols, which can inhibit cell prolif- oil, fish, plant proteins, fruit, coffee, and vitamin C sup-
eration, enhance apoptosis, inhibit cell invasion, angio- plementation were all protective [48]. Furthermore, dif-
genesis and metastasis by inhibiting enzyme activity and ferent dietary patterns can also affect the formation of
signal transduction pathway [46]. Although the level of gallstones. A recent cohort study, with an average follow-
this evidence is very low, it still has certain suggestive up of 13.85 years, reported a positive correlation between
significance. We observed a strong inverse association vegetarians and symptomatic gallstone disease compared
between fruit and vegetable consumption and bile duct with non vegetarians [49]. A case–control study on the
cancer incidence [37]. Two outcomes related to vegetable relationship between dietary intake and different types of
consumption were rated as moderate, and two outcomes gallstone formation showed that a high consumption of
related to fruit consumption were rated as low and very beef, pork and fried food increased the risk of cholesterol
low respectively. Fruits and vegetables are not only high stones, while excessive consumption of carbohydrates
in fiber, but also have anti-tumor properties of micro- increased the risk of pigment stones [50].As we did not
nutrients and macronutrients; As such, they are reason- find the corresponding meta-analysis of the above stud-
able targets for dietary prevention. In two meta-analyses ies. Therefore, our research does not cover these aspects.
from Thailand [23, 30], raw fish and high nitrate food Since the relationship between alcohol consumption
consumption were suspected risk factors for bile duct and biliary tract diseases is complex and controver-
cancer. Because the studies included in these two meta- sial, we conducted a separate study on this topic. First
analyses were limited to Thailand, the possibility of pub- of all, as far as drinking is concerned, studies have con-
lication bias were high and the number of cases included firmed that alcohol is an important risk factor for the
was small, the conclusions of these studies were relatively occurrence of upper gastrointestinal malignancies. For
limited. Among the nutrition-related indicators associ- example, Boffetta et al. [51] reported that acetaldehyde,
ated with bile duct cancer, similar to gallbladder cancer, as the main metabolite of ethanol, may play a role in
higher body mass index and diabetes still increased the the occurrence of upper gastrointestinal tumors. While
alcohol consumption has been shown to be a risk factor unified classification of the diseases in our study, which
for cancers of the liver, colon and esophagus, it remains also affected the research results to some extent.
controversial when it comes to gallbladder cancer [21].
Of the evidence we reviewed, one suggested that alcohol
consumption reduced the risk of gallbladder cancer, one Conclusions
suggested that heavy alcohol consumption increased the Diet and nutrition, as modifiable risk factors, have
risk, and the rest did not suggest an association between important implications for prevention, including can-
alcohol consumption and gallbladder cancer. So far, there cer and other non-communicable diseases. Our study
is still a lack of high-quality evidence to further clarify the summarizes the current multifaceted evidence on the
correlation between the two. For cholangiocarcinoma, relationship between dietary and nutritional indica-
we did not find moderate or high-grade evidence, but tors and biliary diseases. For the prevention of biliary
evidence suggests that low alcohol consumption may be tract diseases, emphasis should be placed on appropri-
a protective factor for cholangiocarcinoma, while heavy ately increasing the intake of fruits, vegetables, coffee
alcohol consumption may increase the risk of both intra- and tea, and reducing the intake of alcohol, raw fish
hepatic and extrahepatic cholangiocarcinoma. and foods with high nitrate. Meanwhile, weight, blood
Surprisingly, in terms of cholecystolithiasis/gallblad- sugar and lipid levels should be controlled, and diabetes
der diease, regardless of the level of alcohol consumption should be actively prevented and treated. Drinking is
or the intake of different types of alcoholic beverages, all not recommended to prevent gallstones, although stud-
evidence suggests that drinking is a protective factor for ies have shown that it may reduce the risk of cholecys-
the incidence of cholecystolithiasis/gallbladder diease, tolithiasis. Overall, the quality of all evidence was not
although the level of evidence is not high. But overall, high. Evidence from additional high-quality prospective
given that many studies have reported that drinking is studies are needed in the future.
harmful to health, we do not recommend drinking to
prevent cholecystolithiasis/gallbladder diease. Supplementary Information
The online version contains supplementary material available at https://doi.
org/10.1186/s12986-022-00677-1.
Strengths and limitations

Additional file 1: Table S1. Search terms utilized in the umbrella review.
Umbrella reviews is one of the highest level of evidence-
Additional file 2: Table S2. List of excluded studies and exclusion reason.
based medical evidence at present. It critically evaluates
all published meta-analyses and systematic reviews on a
medical topic and summarizes evidence from multiple Acknowledgements
Not applicable.
sources [52, 53]. In recent years, the publication of sys-
tematic review and meta-analysis research results has Author contributions
increased rapidly. Although this has filled a large num- (i) Conception and design: YW, BL, NC; (ii) Administrative support: BL, NC; (iii)
Collection and assembly of data: YW, JL, NW; (iv) Data analysis and interpreta-
ber of evidence gaps in clinical decision-making, it also tion: YW, JL, GN, DP; (v) Manuscript writing: YW, JL, XX; (vi) All authors read and
brings difficulties for clinicians in medical decision-mak- approved the final manuscript.
ing. Therefore, umbrella reviews are becoming increas-
Funding
ingly influential in the field of evidence-based medicine. This work was supported by 1·3·5 project for disciplines of excellence–Clini-
However, possible limitations should be taken into cal Research Incubation Project, West China Hospital, Sichuan University
account in the interpretation of this topic. Firstly, our (20HXFH021), National Natural Science Foundation of China (Grant No.
81900516).
umbrella review relied only on published systematic
reviews and meta-analyses. Some missing individual stud- Availability of data and materials
ies may have had an impact on our results, but the impact Not applicable.
was slight because the meta-analyses we included were
the most recent, with highest number of studies included. Declarations
Secondly, for some of the associations we included in this Ethics approval and consent to participate
study, the number of original studies included in the cor- Not applicable.
responding meta-analysis was small, which is likely to
Consent for publication
result in publication bias. Finally, due to the close cor- Not applicable.
relation between the biliary diseases we studied, and
different studies have different classification standards Competing interests
The authors declare that they have no competing interests.
for biliary diseases, we could not achieve a completely
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Wang et al.

Nutrition & Metabolism (2022) 19:51

REVIEW Open Access

The role of diet and nutrition related

Keywords: Diet, Biliary diseases, Umbrella review, Meta-analysis, Systematic review

Introduction Meanwhile, to date, there have been few comprehen-

hensive summary of the results of the available Results

Fig. 1 Literature screening process of this study

Sweden(3) cohort studies pants

Journal of Gastro- HDL cholesterol

Cancer Institute analysis 230,0628 partici-

Europe(10),Asia(8),Ameri Case–control(9) among

cas(1), 1,614,375 partici-

Biliary tract cancer

Zhang [40] 6 Cohort Vegetables(every – RR 0.96 (0.93–0.98) 0.001 NA 0.682 No publication

Emma E. Total 26 Cohort Alcohol (every – HR 1.03 (1.01–1.06) 0.04 0 (NA) NA NA

McGee [35] studies(eCCA) vs. 0 drink/d)a

highest vs. low-

Bagnardi [21] Y N N Y N Y N PY PY N Y Y Y Y N Y Critically low

cancer (0.83–3.83) ouse Very low

Foods @Nested case–con- cancer (1.05–1.91) ouse suspected Very low

⨁◯◯◯ Critically low

Strengths and limitations

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