Gastroenterology Research and Practice

Volume 2012 (2012), Article ID 808120, 11 pages

doi:10.1155/2012/808120

Research Article

Association between Habitual Dietary Salt Intake and Risk of Gastric Cancer: A Systematic Review of Observational Studies

Sheng Ge, Xiaohui Feng, Li Shen, Zhanying Wei, Qiankun Zhu, and Juan Sun

Department of Clinical Nutrition, Shanghai Sixth People’s Hospital, Shanghai Jiaotong University, Shanghai 200233, China

Received 20 April 2012; Accepted 11 June 2012

Academic Editor: Jin-Lian Chen

Copyright © 2012 Sheng Ge et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Purpose. Systematic reviews of case-control and prospective studies showed a positive association between habitual salt intake and gastric cancer. Given new studies published thereafter, we carried out a meta-analysis to assess the association between dietary salt intake and gastric cancer. Methods. Case-control studies and cohort studies published between January 1992 and January 2012 on PubMed and Embase were searched. We quantified associations between salt intake and gastric cancer with meta-analysis. Results. Eleven studies (7 case controls and 4 cohorts) finally were included in the meta-analysis (total population: ; events: ). The combined odds ratio showed significantly positive association between high salt intake and gastric cancer compared with low salt intake (OR = 2.05, 95% CI [1.60, 2.62]; ). In subgroup meta-analysis, findings were slightly different when analyses were restricted to salty food intake (OR = 2.41, 95% CI [2.08, 2.78]; ) as well as in Asia (OR = 1.27 95% CI [1.22, 1.32]; ). There was no evidence that sample size, exposure assessment substantially influenced the estimate of effects. Conclusions. The systemic review supports the hypothesis that dietary salt intake is positively associated with the risk of gastric cancer.

1. Introduction

Dietary factors are important environmental risk determinants for cancer development. The role of dietary factors in gastric cancer was studied in the last 40 years and received particularly attention recently. It is difficult to establish a causal relationship between salt intake and gastric cancer due to methodological limitations among which is the valid measurement of accurate salt intake. Therefore, the conclusion is still unclear. In 2007, the Second Expert Report from the World Cancer Research Fund [1] supported the view that salt intake is significantly related to gastric cancer. From then on, two meta-analyses have been published addressing the association between salt intake and gastrointestinal metaplasia or gastric cancer. The study [2] on salt intake and gastrointestinal metaplasia revealed a positive trend but no statistical significance was observed. Another meta-analysis [3] included 7 prospective studies in total, and four out of seven were carried out in Japan. Although it demonstrated a positive association between salt consumption and incidence rate of gastric cancer, the limitation in geographic location prevents its generalization. Although prospective studies have more power in controlling confounders than case-control studies, the tendency of using baseline salt intake to represent the subsequent salt consumption causes inaccuracy in actual salt intake. Therefore, we carried out this systematic review to assess the relationship between habitual dietary salt intake and risk of gastric cancer.

2. Materials and Methods

2.1. Data Sources and Searches

This paper was planned, conducted, and reported according to the PRISMA statement [4]. We performed a systematic search for publications using MEDLINE and Embase databases (from 1992 to 2012). The following keywords were used in searching: “salt or sodium or salty or sodium chloride” and “gastric cancer or stomach cancer.” Moreover, we searched for the keywords in titles, abstracts and performed a manual search of references cited in the selected articles and published reviews.

2.2. Eligibility Criteria

Citations selected from the initial search were subsequently screened for eligibility. The list of references was independently screened by two reviewers. Cohort and case-control studies were included in the systematic review when all the following criteria were met: (1) original research addressing the association between the consumption of salt or salted foods and the occurrence of gastric cancer in humans; (2) prospective design; (3) adult population; (4) exposure defined as salt or salted foods by the authors of each study or including foods with high contents of salt as defined in the latest report of the World Cancer Research Fund and the American Institute for Cancer Research (processed foods such as processed meat; salty foods such as potato crisps or chips, salted nuts, and salty snack foods; salted foods such as bacon, sausages, and ham; salt-preserved foods such as salted meat, fish, vegetables, and fruits); (5) diagnosis of gastric cancer determined prospectively as outcome (gastric cancer incidence and/or mortality rate); (6) indication of the number of participants exposed and the rate or number of events in different categories of salt/sodium intake; (7) articles written in English.

2.3. Data Extraction and Quality Assessment

We designed a data collection form before selecting eligible studies. The following data were extracted independently by two authors using a unified data form, the first author’s full name, year of publication, country, gender, age, range of followup, study population, the events and mortality of gastric cancer, types of estimate of habitual sodium intake, and factors controlled and matched or adjusted variables in the design or data analysis. The results of the two authors were compared, and a consensus result would be achieved if there were any disagreement.

The Newcastle-Ottawa Scale [5] was used by two authors independently to evaluate the quality of the included studies. The Coding Manual for Case-Control Studies (an 8-stars system) was used to assess the quality of case-control studies, in which a study was judged on 3 broad perspectives as follows: (a) the selections of both study groups, (b) the comparability of study groups, and (c) exposure levels of study groups. The Coding Manual for Cohort Studies (a 9-star system) was used to assess the quality of cohort studies, as well as in case-control study. Each cohort study was judged on 3 broad perspectives as follows: (a) the selections of both study groups, (b) the comparability of study groups, and (c) outcome of the two study groups. The results of the two authors were compared, and a consensus result would be received if there was any disagreement.

2.4. Statistical Methods

We evaluated the differences between low salt consumption and high salt consumption on the occurrence of gastric cancer. The original data from the studies was used to calculate the summary OR with its 95% confidence intervals (CIs) in all analyses. A random-effects model was used to account for between-study heterogeneity and publication bias.

The method of Mantel-Haenszel test [6] was used to assess the pooled OR and corresponding 95% confidence intervals (CIs) across studies. Forest plots were used to visually assess the results of Mantel-Haenszel test.

To assess the heterogeneity of ORs across studies, the Cochran Q statistic [7] (significance level of ) and the statistic [8] (which quantifies the percentage of variation attributable to heterogeneity) were calculated. Subgroup analyses were carried out by region and food items to assess the relationship between salt intake and gastric cancer. The Begg test [9] and funnel plot [10] were used to assess the possibility of publication bias.

3. Results

3.1. Literature Search

Our search strategy yielded 1580 articles: 810 from Embase and 770 from Pubmed. A flow diagram that detailed the process is presented in Figure 1. The main details of the flow diagraph are as follows: after the first step, only 492 articles with full-text access are reserved. There were 159 reviews, 14 letters or editorial, and 50 duplicated articles among the 492 articles. 242 articles were excluded after we had reviewed titles and abstracts, and only 27 articles are reserved. 16 articles were excluded after reviewing the full text, because there were no original data. Finally, 11 studies (7 case-control studies [11–17] and 4 cohort studies [18–21]) were included in the meta-analysis.

Figure 1: Process of study selection for salt intake and risk of gastric cancer.

3.2. Characteristics of the Included Studies

The characteristics of the studies included in our meta-analysis are showed in Table 1 [11–21]. The total number of participants was 2076498 [11–20, 20, 21]. The study design types were as follows: case-control study ( [11–17, 21]) and cohort study ( [18–21]). Studies were conducted in Japan ( [19–21]), Korea ( [16, 18]), China ( [17]), Spain ( [14]), Portugal ( [11]), Colombia ( [12]), Iran ( [13]), and Mexico ( [15]). Only 2 [18, 20] of the final 11 studies reported women and men independently. Total salt intake was used to assess sodium intake in 4 studies [11–13, 20]. Salted food was used in 6 studies [14–17, 20, 21]. Salt preference was used in the last 1 study [18].

Table 1: The characteristics of the studies included in the meta-analysis.

First author

Gastric cancer ()
Type of estimate of habitual sodium intake
Factors controlled for in multivariate analysis

Publication year
Location
Study period
Sex
Age (years)
Study population

()
Events
Mortality

Peleteiro [11]
2011
Portugal
2001–2006
F/M
18–92
1071
422
~
Total salt intake
Age, gender, education, smoking, H. pylori infection, and total energy intake

Campos [12]
2006
Colombia
2000–2002
F/M
49–75
647
216
30
Total salt intake
Age, gender, and hospital

Pourfarzi [13]
2009
Iran
2003–2005
F/M
65.46 ± (11.5)
611
217
~
Total salt intake
Age, gender, residence, education, and family history on cancer

Kim [18]
2010
Korea
1996–2003
F/M
30–80
2248129
12393
~
Salt preference
Age, sex, BMI, smoking habits, alcohol consumption, physical activity, and family history of cancer

Ramón et al. [14]
2002
Spain
1986–1989
F/M
32–80
305
165
12
Smoked and pickled foods, salt
Age, gender

Shikata [19]
2006
Japan
1998–2002
F/M
>40
2467
93

Total salt intake
Age, sex, Helicobacter pylori infection, atrophic gastritis, medical history of peptic ulcer, family history of cancer, body mass index, diabetes mellitus, total vitamin B2, vitamin C and dietary fiber intake, smoking habits and dietary factors intake of total energy, total protein, carbohydrate, vitamin B1, cholesterol, physical activity, and alcohol

Ngoan [20]
2002
Japan
1986–2001
F/M
>15
13250
116
116
Pickled food
Age, sex, smoking, and other dietary factors

Ward [15]
1999
Mexico
1989–1990
F/M
~
972
220
~
Salty snacks
Age, gender, and total calories

Tsugane [21]
2004
Japan
1990–2001
F/M
40–59
39065
486
361
Salted food consumption (miso soup, pickled vegetables, salted fish roe, salted fish preserves, and dried or salted fish)
Age, gender, cigarette smoking, fruit and vegetable intake, drinking history, and personal medical history

Lee [16]
2003
Korea
1999.3–1999.9
F/M
~
268
69
~
Salt-fermented fish
Age, sex, education, family history of gastric cancer, smoking, alcohol drinking, and H. pylori infection

Yang [17]
2011
China
2006–2010
F/M
40–75
900
300

Salted food (meat and fishes, pickled vegetable)
Age, sex, smoking, drinking, fresh fruit, and fresh vegetables

The study quality scores were listed in Table 2: 6 studies got a score of 8 (4 case-control studies and 2 cohort studies), 5 studies got 7 points (3 case-control studies and 2 cohort studies).

Table 2: The study quality scores of the studies included in meta-analysis.

First author, year of publication (reference)
Objects selection
Comparability
Exposure/result
Total quality scores

Adequate definition/exposed cohort representat-iveness
Representativeness of cases/nonexposed cohort
Controls selection/exposure ascertainment
Controls definition/outcome not present

Exposure ascertainment/outcome assessment
cases and controls ascertainment method/followup length
Nonresponse rate/adequate followup

Campos, 2006 [12]
⋆
⋆
0
⋆
⋆ ⋆
⋆
⋆
0
7

Tsugane, 2004 [21]
⋆
⋆
⋆
⋆
⋆ ⋆
⋆
⋆
0
8

Peleteiro, 2011 [11]
⋆
⋆
⋆
⋆
⋆ ⋆
⋆
⋆
0
8

Pourfarzi, 2009 [13]
⋆
⋆
⋆
⋆
⋆ ⋆
⋆
⋆
0
8

Yang, 2011 [17]
⋆
⋆
⋆
⋆
⋆ ⋆
⋆
⋆
0
8

Shikata, 2006 [19]
0
⋆
⋆
⋆
⋆ ⋆
⋆
⋆
0
7

Ward, 1999 [15]
0
⋆
⋆
⋆
⋆ ⋆
⋆
⋆
0
7

Ngoan, 2002 [20]
0
⋆
⋆
⋆
⋆ ⋆
⋆
⋆
0
7

Ramón et al., 1993 [14]
⋆
⋆
⋆
⋆
⋆ ⋆
⋆
⋆
0
8

Lee, 2003 [16]
⋆
⋆
⋆
⋆
⋆ ⋆
⋆
⋆
0
8

Kim, 2010 [18]
⋆
⋆
⋆
⋆
⋆ ⋆
⋆
⋆
0
8

3.3. The Risk of Gastric Cancer of High Salt Intake and Low Salt Intake

The multivariable-adjusted ORs for each study and combination of all studies for the high versus low categories of salt intake are shown in Table 3. The summary OR of all studies, using a random-effects model, showed that the high salt intake was significantly associated with a 105% greater risk of gastric cancer compared with low salt intake (OR = 2.05 95% CI [1.60, 2.62]; = 154.7; ). However, there was statistically significant heterogeneity across the studies (; ), regarding the methods were used to evaluate the exposure, the food items evaluated, the consumption categories considered for analysis, and the degree of adjustment for possible confounders. Subgroup analysis was used for categorical variables.

Table 3: High versus low categories of salt and gastric cancer.

Study or subgroup
High salt
Low salt

Odds ratio
Odds ratio

Events
Total
Events
Total
Weight
M-H, fixed, 95% CI
M-H, fixed, 95% CI

Peleteiro et al. 2011 [11]
144
364
132
346
2.0%
1.06 [0.78, 1.44]

Pourfarzi et al. 2009 [13]
121
213
95
394
0.7%
4.14 [2.90, 5.91]

Campos et al. 2006 [12]
19
30
197
617
0.2%
3.68 [1.72, 7.89]

Kim et al. (men) 2010 [18]
2261
302734
5874
890825
73.9%
1.13 [1.08. 1.19]

Kim et al. (women) 2010 [22]
518
136400
1796
560116
17.5%
1.19 [1.07, 1.31]

Jose M. Ramón et al. 1993 [14]
27
63
33
108
0.3%
1.70 [0.89, 3.25]

Shikata et al. 2006 [19]
30
564
12
663
0.3%
3.05 [1.55, 6.01]

Ngoan et al. (men) 2002 [20]
7
341
27
2039
0.2%
1.56 [0.67, 3.62]

Ngoan et al. (women) 2002 [20]
1
316
8
2876
0.0%
1.14 [0.14, 9.13]

Ward and López-Carrillo 1999 [15]
105
355
75
435
1.2%
2.02 [1.44,2.83]

Tsugane et al. 2004 [21]
130
89048
58
86483
1.5%
2.18 [1.60, 2.97]

Lee et al. 2003 [16]
47
69
22
199
0.1%
17.19 [8.77, 33.68]

Yang et al. 2011 [17]
180
482
120
418
2.0%
1.48 [1.12, 1.96]

Total (95% CI)

530979

1545519
100.0%
1.22 [1.17, 1.27]

Total events
3590

8449

Heterogeneity: Chi² = 154.77, df = 12 (); = 92%

Test for overall effect: = 9.64 ()

A trend toward a direct association between salt intake and gastric cancer risk was detected in all 11 individual studies that were included in the meta-analysis and statistically significant in 9 of them.

3.4. Subgroup Analysis

Stratifying by geographic region, the pooled ORs of gastric cancer for the high versus low categories of salt intake were 1.15 (95% CI, [0.88, 1.52]) for studies conducted in Europe, there was no statistically significant heterogeneity among studies of salt intake in Europe ( and ) (Table 4); and 1.27 (95% CI, [1.22, 1.32]) for studies conducted in Asia with stratification according to geographic region, and there was statistically significant heterogeneity among studies of salt intake in Asia ( and ) (Table 5). So separate analysis of the studies reporting further analyses was carried out to check for potential sources of heterogeneity that might explain the association between dietary salt intake and gastric cancer events in Japan. The OR was 2.61 (95% CI, [2.02, 3.38]) for studies conducted in Japan (Table 6).

Table 4: High versus low categories of salt and gastric cancer in Europe.

Study or subgroup
High salt
Low salt

Odds ratio
Odds ratio

Events
Total
Events
Total
Weight
M-H, fixed, 95% CI
M-H, fixed, 95% CI

Peleteiro et al. 2011 [23]
144
364
132
346
85.5%
1.06 [0.78, 1.44]

Jose M. Ramón 1993 [14]
27
63
33
108
14.5%
1.70 [0.89, 3.25]

Total (95% CI)

427

454
100.0%
1.15 [0.88, 1.52]

Total events
171

165

Heterogeneity: Chi² = 1.70, df = 1 (); = 41%

Test for overall effect: = 1.03 ()

Table 5: High versus low categories of salt and gastric cancer in Asia.

Study or subgroup
High salt
Low salt

Odds ratio
Odds ratio

Events
Total
Events
Total
Weight
M-H, fixed, 95% CI
M-H, fixed, 95% CI

Pourfarzi et al. 2009 [13]
121
213
95
394
0.8%
4.14 [2.90, 5.91]

Campos et al. 2006 [12]
19
30
197
617
0.2%
3.68 [1.72, 7.89]

Kim et al. 2010 [18]
2779
439134
7670
1450941
94.7%
1.20 [1.15, 1.25]

Shikata et al. 2006 [19]
30
564
12
663
0.3%
3.05 [1.55, 6.01]

Ngoan et al. 2002 [20]
8
657
35
4915
0.2%
1.72 [0.79, 3.72]

Tsugane et al. 2004 [21]
130
89048
58
86483
1.6%
2.18 [1.60, 2.97]

Lee et al. 2003 [16]
47
69
22
199
0.1%
17.19 [8.77, 33.68]

Yang et al. 2011 [17]
180
482
120
418
2.2%
1.48 [1.12, 1.96]

Total (95% CI)

530197

1544630
100.0%
1.27 [1.22, 1.32]

Total events
3314

8209

Heterogeneity: Chi² = 133.98, df = 7 (); = 95%

Test for overall effect: = 11.22 ()

Table 6: High versus low categories of salt and gastric cancer in Japan.

Study or subgroup
High salt
Low salt

Odds ratio
Odds ratio

Events
Total
Events
Total
Weight
M-H, fixed, 95% CI
M-H, fixed, 95% CI

Campos et al. 2006 [12]
19
30
197
617
8.7%
3.68 [1.72, 7.89]

Shikata et al. 2006 [19]
30
564
12
663
13.6%
3.05 [1.55, 6.01]

Ngoan et al. 2002 [20]
8
65
35
4915
1.0%
19.57 [8.69, 44.04]

Tsugane et al. 2004 [21]
130
89048
58
86483
76.6%
2.18 [1.60, 2.97]

Total (95% CI)

89707

92678
100.0%
2.61 [2.02, 3.38]

Total events
187

302

Heterogeneity: Chi² = 25.98, df = 3 ();

Test for overall effect: = 7.29 ()

We also conducted analyses that were stratified according to the food items, using studies that reported results on gastric cancer in relation to food items. The OR for salt was 1.20 (95% CI, [1.15, 1.26]), and there was statistically significant heterogeneity among these studies ( and ) (Table 7). The OR for salty food was 2.41 (95% CI, [2.08, 2.78]), statistically significant heterogeneity was also found among these studies ( 01 and ) (Table 8). The results showed that different sources of salt intake (salt or food items) had different risks on gastric cancer.

Table 7: High versus low categories of salt and gastric cancer through salt.

Study or subgroup
High salt
Low salt

Odds ratio
Odds ratio

Events
Total
Events
Total
Weight
M-H, fixed, 95% CI
M-H, fixed, 95% CI

Peleteiro et al. 2011 [11]
144
364
132
346
2.2%
1.06 [0.78, 1.44]

Kim et al. 2010 [18]
2779
439134
7670
1450841
97.1%
1.20 [1.15, 1.25]

Jose M. Ramón et al. 1993 [14]
27
63
33
108
0.4%
1.70 [0.89, 3.25]

Shikata et al. 2006 [19]
30
564
12
663
0.3%
3.05 [1.55, 6.01]

Total (95% CI)

440125

1451958
100.0%
1.20 [1.15,  1.26]

Total events
2980

7847

Heterogeneity: Chi² = 9.01, df = 3 (); = 67%

Test for overall effect: = 8.43 ()

Table 8: High versus low categories of salt and gastric cancer through salty food.

Study or subgroup
High salt
Low salt

Odds ratio
Odds ratio

Events
Total
Events
Total
Weight
M-H, fixed, 95% CI
M-H, fixed, 95% CI

Pourfarzi et al. 2009 [13]
121
213
95
394
12.3%
4.14 [2.90, 5.91]

Campos et al. 2006 [12]
19
30
197
617
2.9%
3.68 [1.72, 7.89]

Ngoan et al. (men) 2002 [20]
8
657
35
4915
3.5%
1.72 [0.79, 3.72]

Mary H. Ward 1999
105
355
75
435
20.3%
2.02 [1.44, 2.83]

Tsugane et al. 2004 [21]
130
89048
58
86483
25.1%
2.18 [1.60, 2.97]

Lee et al. 2003 [16]
47
69
22
199
1.5%
17.19 [8.77, 33.68]

Yang et al. 2011 [17]
180
482
120
418
34.4%
1.48 [1.12, 1.96]

Total (95% CI)

90854

93461
100.0%
2.41 [2.08, 2.78]

Total events
610

602

Heterogeneity: Chi² = 56.59, df = 6 (); = 89%

Test for overall effect: = 11.75; ()

4. Discussion

Diet is considered to be associated with carcinogenesis. In this meta-analysis, we attempted to collect the evidence to identify the relationship between dietary salt intake and gastric cancer. Findings from the current study suggested that, compared with low salt intake, high salt intake showed significantly positive association with gastric cancer (overall OR = 2.05, 95% CI [1.60, 2.62]; ). However, there was a significant heterogeneity among the included studies. In subgroup analysis by category of salt intake, geographical regions, and sex, however, the significantly positive association was not changed.

Although we observed a positive association, there were many methodological limitations in human studies which prevent valid measurements used to assess salt consumption effectively [24]. For example, there are greater recall and selection biases in case-control studies because of their retrospective nature. In these studies, gastric cancer patients were more likely to change their dietary behavior as well as salty foods for their health. Then their earlier long-term dietary habit may have been strongly influenced by the recent diet. Because of different methods used to assess and report salt consumption across studies, we could not evaluate a dose-response relation between salt consumption and gastric cancer. We cannot be able to exclude the other confounding factors, such as mutagens in the salty foods or processed food.

The World Cancer Research Fund and the American Institute for Cancer Research published in 2007 a large systematic review and meta-analysis, which concerned the effect of salt in the development of gastric cancer [1]. A 17-article systematic review and meta-analyses on addressing the association between dietary salt exposure and gastric intestinal metaplasia received a positive association [2]. A meta-analysis (7 articles included) to assess the association between habitual salt intake and risk of gastric cancer in prospective studies also got a positive association [3]. However, there was a significant heterogeneity among the included studies in the three articles.

4.1. Potential Mechanisms

Several mechanisms which suggested that salt intake may increase gastric cancer risk have been postulated although there has been no consistent conclusion.

4.1.1. The Destruction of the Mucosal Barrier

Intragastric high salt concentration destroys the mucosal barrier, through the increase of surface mucous cell mucin and decrease of gland mucous cell mucin [25], leading to inflammation and damage such as diffuse erosion and degeneration [21], produces atrophic gastritis and decreases the acidity of the stomach. It creates a condition favoring H. pylori infection [12].

4.1.2. Intestinal Metaplasia

Intestinal metaplasia is also an important risk factor of gastric cancer. Mucosal damage in the stomach increases the rate of mitosis, leading to excessive cell replication [22] and hyperplasia of the gastric pit epithelium with increased potential for mutations [23]. Intestinal metaplasia characterized by the presence of caliciform cells in glands and in foveolar gastric mucosa was detected near regenerative hyperplasia foci high NaCl diets animals [26]. High salt intake will increase concentration of NaCl in the stomach; then it may accelerate the procedure of intestinal metaplasia and increase the risk of gastric cancer in the future.

4.1.3. Hypergastrinemia

Gastrin itself may mediate epithelial cell growth in H. pylori-colonized mucosa [27] and induce hypergastrinemia [28]. Chronic hypergastrinemia can synergize with Helicobacter infection and lead to eventual parietal cell loss and progression to gastric cancer [29].

4.1.4. H. pylori

H. pylori is one of the important recognized risk factors of gastric cancer. The damage caused by salt may also increase gastric H. pylori colonization. H. pylori responds to changes in the concentration of NaCl in its environment in such a way that growth, cell morphology, survival, and virulence factor expression are all altered by increased salt concentration [30]. Elevated salt concentrations result in alterations in expression of the virulence factor CagA in H. pylori strain 26695 and enhance the ability of CagA to translocate into gastric epithelial cells and enhance the ability of H. pylori to alter gastric epithelial cell function [31].

4.1.5. Endogenous Mutations

Salt may also directly damage gastric mucus, improve inflammatory responses of the gastric epithelium [32], which may increase epithelial cell proliferation as part of the repair process, potentiate the action of carcinogens [33], and increase the probability of endogenous mutations [34].

4.1.6. Exposure to Carcinogens

High dietary salt intake damages the stomach mucosa that protects the stomach and increases the susceptibility of the mucosal cells to carcinogens from foods, such as N-nitroso compounds. And its repair is associated with inflammatory changes [35] and leads to cell death [36]. But the studies included in the current meta-analysis did not report the potential carcinogens of the salty foods or processed food. Future observational studies should pay more attention in this area.

4.2. Limitations

Despite these advantages, the current meta-analysis, however, had limitations.

First, the majority of included studies used questionnaire to assess habitual salt intake which had limited value [37]. Only few studies used 24 h urinary sodium excretion as indictor of salt consumption which is recommended by the World Cancer Research Fund as the best measurement of salt intake[38]. The information derived from the questionnaire is subjective, qualitative and had not covered all the sources of sodium intake [39]. In most studies, the consumption of salted food which is high in salt and nitrites as well was recorded as a source of sodium intake. It is well known that nitrite is a mutagen that is closely related to gastric carcinogenesis [40, 41]. These methodological limitations compromised the association between salt intake and gastric cancer, either toward exaggeration or underestimation of risk estimates.

Second, due to the huge heterogeneity of the related data presented in the studies, the number of studies involved in the meta-analysis was relatively small. Therefore, subgroup analyses were difficult to perform.

Third, the current meta-analysis is unable to rule out the possible influence of confounding factors on the revealed association. Some confounders were inherent in the included studies. Although each study recruited some known risk factors for adjustment for gastric cancer, these covariates were not consistent and unknown confounders such as mutagens in salted foods cannot be excluded as a potential explanation for the observed findings.

Fourth, the cutoff values corresponding to the low and high categories for salt intake variedwidely among the studies, which might also affect the obtained results.

In conclusion, the overall current literature on dietary salt intake and the risk of gastric cancer suggested significantly positive association. Due to the nature of the association, more well-designed prospective studies that use unified measures of dietary salt intake are needed to fully characterize such an association, and it is impossible to perform a large randomized, controlled clinical trial to clarify the cause-effect relationship. Therefore, future observational study with recommended salt assessment method and maximized exclusion of confounders from salted foods is necessary.

Conflict of Interests

The authors declare that there was no conflict of interests.

References

World Cancer Research Fund, American Institute for Cancer Research: Food, Nutrition, Physical Activity, and the Prevention of Cancer: A global perspective. Washington, DC, USA, American Institute for Cancer Research, 2007

M. Dias-Neto, M. Pintalhão, M. Ferreira, and N. Lunet, “Salt intake and risk of gastric intestinal metaplasia: systematic review and meta-analysis,” Nutrition and Cancer, vol. 62, no. 2, pp. 133–147, 2010.

L. D'Elia, G. Rossi, R. Ippolito, F. P. Cappuccio, and P. Strazzullo, “Habitual salt intake and risk of gastric cancer: a meta-analysis of prospective studies,” Clinical Nutrition, vol. 1, no. 3, pp. 1–10, 2012.

D. Moher, A. Liberati, J. Tetzlaff, et al., “Preferred reporting items for systematic review and meta-analyses: the PRISMA statement,” PLoS Medicine, vol. 6, no. 6, Article ID e1000097, 2009.

A. Stang, “Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses,” European Journal of Epidemiology, vol. 25, no. 9, pp. 603–605, 2010.

N. Mantel and W. Haenszel, “Statistical aspects of the analysis of data from retrospective studies of disease,” National Cancer Institute, vol. 22, pp. 719–748, 1959.

R. DerSimonian and N. Laird, “Meta-analysis in clinical trials,” Controlled Clinical Trials, vol. 7, no. 3, pp. 177–188, 1986.

J. P. T. Higgins, S. G. Thompson, J. J. Deeks, and D. G. Altman, “Measuring inconsistency in meta-analyses,” British Medical Journal, vol. 327, no. 7414, pp. 557–560, 2003.

C. B. Begg and M. Mazumdar, “Operating characteristics of a rank correlation test for publication bias,” Biometrics, vol. 50, no. 4, pp. 1088–1101, 1994.

M. Egger, G. D. Smith, M. Schneider, and C. Minder, “Bias in meta-analysis detected by a simple, graphical test,” British Medical Journal, vol. 315, no. 7109, pp. 629–634, 1997.

B. Peleteiro, C. Lopes, C. Figueiredo, and N. Lunet, “Salt intake and gastric cancer risk according to Helicobacter pylori infection, smoking, tumour site and histological type,” British Journal of Cancer, vol. 104, no. 1, pp. 198–207, 2011.

F. Campos, G. Carrasquilla, C. Koriyama et al., “Risk factors of gastric cancer specific for tumor location and histology in Cali, Colombia,” World Journal of Gastroenterology, vol. 12, no. 36, pp. 5772–5779, 2006.

F. Pourfarzi, A. Whelan, J. Kaldor, and R. Malekzadeh, “The role of diet and other environmental factors in the causation of gastric cancer in Iran— a population based study,” International Journal of Cancer, vol. 125, no. 8, pp. 1953–1960, 2009.

Jose M. Ramón, L. Serra, C. Cerdü, and J. Orom, “Dietary factors and gastric cancer risk. A case-control study in Spain,” Cancer, vol. 71, no. 5, pp. 1731–1735, 1993.

M. H. Ward and L. López-Carrillo, “Dietary factors and the risk of gastric cancer in Mexico City,” American Journal of Epidemiology, vol. 149, no. 10, pp. 925–932, 1999.

S. A. Lee, D. Kang, K. N. Shim, J. W. Choe, W. S. Hong, and H. Choi, “Effect of diet and Helicobacter pylori infection to the risk of early gastric cancer,” Journal of Epidemiology, vol. 13, no. 3, pp. 162–168, 2003.

W. G. Yang, C. B. Chen, Z. X. Wang et al., “A case-control study on the relationship between salt intake and salty taste and risk of gastric cancer,” World Journal of Gastroenterology, vol. 17, no. 15, pp. 2049–2053, 2011.

J. Kim, S. Park, and B. H. Nam, “Gastric cancer and salt preference: a population-based cohort study in Korea,” American Journal of Clinical Nutrition, vol. 91, no. 5, pp. 1289–1293, 2010.

K. Shikata, Y. Kiyohara, M. Kubo et al., “A prospective study of dietary salt intake and gastric cancer incidence in a defined Japanese population: the Hisayama study,” International Journal of Cancer, vol. 119, no. 1, pp. 196–201, 2006.

L. T. Ngoan, T. Mizoue, Y. Fujino, N. Tokui, and T. Yoshimura, “Dietary factors and stomach cancer mortality,” British Journal of Cancer, vol. 87, no. 1, pp. 37–42, 2002.

S. Tsugane, S. Sasazuki, M. Kobayashi, and S. Sasaki, “Salt and salted food intake and subsequent risk of gastric cancer among middle-aged Japanese men and women,” British Journal of Cancer, vol. 90, no. 1, pp. 128–134, 2004.

J. Kim, S. Park, and B. H. Nam, “Gastric cancer and salt preference: a population-based cohort study in Korea,” American Journal of Clinical Nutrition, vol. 91, no. 5, pp. 1289–1293, 2010.

B. Peleteiro, C. Lopes, C. Figueiredo, and N. Lunet, “Salt intake and gastric cancer risk according to Helicobacter pylori infection, smoking, tumour site and histological type,” British Journal of Cancer, vol. 104, no. 1, pp. 198–207, 2011.

V. W. Chen, R. R. Abu-Elyazeed, D. E. Zavala et al., “Risk factors of gastric precancerous lesions in a high-risk Colombian population. I. Salt,” Nutrition and Cancer, vol. 13, no. 1-2, pp. 59–65, 1990.

S. Kato, T. Tsukamoto, T. Mizoshita et al., “High salt diets dose-dependently promote gastric chemical carcinogenesis in Helicobacter pylori-infected Mongolian gerbils associated with a shift in mucin production from glandular to surface mucous cells,” International Journal of Cancer, vol. 119, no. 7, pp. 1558–1566, 2006.

A. Vences-Mejía, H. Caballero-Ortega, V. Dorado-González et al., “Cytochrome P450 expression in rat gastric epithelium with intestinal metaplasia induced by high dietary NaCl levels,” Environmental Toxicology and Pharmacology, vol. 20, no. 1, pp. 57–64, 2005.

R. M. Peek Jr., H. Wirth, S. F. Moss et al., “Helicobacter pylori alters gastric epithelial cell cycle events and gastrin secretion in Mongolian gerbils,” Gastroenterology, vol. 118, no. 1, pp. 48–59, 2000.

X. Q. Wang, P. D. Terry, and H. Yan, “Review of salt consumption and stomach cancer risk: epidemiological and biological evidence,” World Journal of Gastroenterology, vol. 15, no. 18, pp. 2204–2213, 2009.

T. C. Wang, C. A. Dangler, D. Chen et al., “Synergistic interaction between hypergastrinemia and Helicobacter infection in a mouse model of gastric cancer,” Gastroenterology, vol. 118, no. 1, pp. 36–47, 2000.

H. Gancz, K. R. Jones, and D. S. Merrell, “Sodium chloride affects Helicobacter pylori growth and gene expression,” Journal of Bacteriology, vol. 190, no. 11, pp. 4100–4105, 2008.

J. T. Loh, V. J. Torres, and T. L. Cover, “Regulation of Helicobacter pylori cagA expression in response to salt,” Cancer Research, vol. 67, no. 10, pp. 4709–4715, 2007.

M. Takahashi and R. Hasegawa, “Enhancing effects of dietary salt on both initiation and promotion stages of rat gastric carcinogenesis.,” Princess Takamatsu Symposia, vol. 16, pp. 169–182, 1985.

J. Kim, S. Park, and B. H. Nam, “Gastric cancer and salt preference: a population-based cohort study in Korea,” American Journal of Clinical Nutrition, vol. 91, no. 5, pp. 1289–1293, 2010.

C. Furihata, H. Ohta, and T. Katsuyama, “Cause and effect between concentration-dependent tissue damage and temporary cell proliferation in rat stomach mucosa by NaCl, a stomach tumor promoter,” Carcinogenesis, vol. 17, no. 3, pp. 401–406, 1996.

G. Charnley and S. R. Tannenbaum, “Flow cytometric analysis of the effect of sodium chloride on gastric cancer risk in the rat,” Cancer Research, vol. 45, no. 11, pp. 5608–5616, 1985.

P. A. Van Den Brandt, A. A. M. Botterweck, and R. A. Goldbohm, “Salt intake, cured meat consumption, refrigerator use and stomach cancer incidence: a prospective cohort study (Netherlands),” Cancer Causes and Control, vol. 14, no. 5, pp. 427–438, 2003.

P. Correa, “Human gastric carcinogenesis: a multistep and multifactorial process— first American Cancer Society Award lecture on cancer epidemiology and prevention,” Cancer Research, vol. 52, no. 24, pp. 6735–6740, 1992.

M. Tatematsu, M. Takahashi, S. Fukush- ima, M. Hananouchi, and T. Shirai, “Effects in rats of sodium chloride on experimental gas t r i c cancer s induced by N-methyl -N-nitro- Nnitrosoguanidine or 4-nitroqu- inoline-1-oxide,” Journal of the National Cancer Institute, vol. 55, pp. 101–106, 1975.

V. W. Chen, R. R. Abu-Elyazeed, D. E. Zavala et al., “Risk factors of gastric precancerous lesions in a high-risk Colombian population. I. Salt,” Nutrition and Cancer, vol. 13, no. 1-2, pp. 59–65, 1990.

W. Chen, J. H. Weisburger, E. S. Fiala et al., “Gastric carcinogenesis: 2-Chloro-4-methylthiobutanoic acid, a novel mutagen in salted, pickled sanma hiraki fish, or similarly treated methionine,” Chemical Research in Toxicology, vol. 9, no. 1, pp. 58–66, 1996.

World Cancer Research Fund, American Institute for Cancer Research: Food, Nutrition, Physical Activity, and the Prevention of Cancer: A global perspective, Washington, DC, USA, American Institute for Cancer, 2007