Keywords

1 Introduction

Sodium is the most abundant electrolyte in extracellular fluid and as such has a major role in the regulation of body fluid volume, plasma osmolality, and cell membrane potential. In the course of evolution, the human body has developed powerful mechanisms to preserve its sodium and chloride content and to maintain the sodium concentration in the extracellular fluid within a relatively narrow range [1]. Up to approximately 5,000 years ago, the sodium content in the human diet was extremely low since the salt content of natural foods is quite modest [2]. Switching to a much higher salt intake occurred as a result of the discovery that the addition of salt to many foods was useful to preserve them from rapid deterioration [3]; this high salt intake has been sustained since then despite the widespread availability of modern technologies for food preservation. The current unjustifiably large excess in dietary salt intake has meanwhile been recognized as a major worldwide hazard to community health being causally associated with epidemic disorders such as hypertension [4, 5], cardiovascular accidents [6], renal dysfunction [7], nephrolithiasis [8], and osteoporosis [9].

Gastric cancer is a common neoplasia and is the third leading cause of death from cancer worldwide [10, 11, 12]. Although there are large geographic and ethnic differences in its incidence and its overall rate has been slowly decreasing over recent decades, this disease is still an important public health burden and, at least partly, a preventable public health problem throughout the world [10, 11, 12]. Evidence has been provided for more or less strong associations between gastric cancer and a few dietary factors, among which is the dietary salt content and the habitual consumption of salt-rich foods. In this regard, many case-control studies detected an adverse effect of high salt consumption on the risk of gastric cancer WCRF [13]. Also, a number of prospective studies have been performed to investigate the relationship between salt or salted food consumption and risk of stomach cancer. A recent meta-analysis of these studies has shown that dietary salt intake is directly associated with the risk of gastric cancer, with progressively increasing risk across increasing levels of habitual consumption [14]. This epidemiological evidence is supported by the results of clinical and experimental studies which found that high salt intake may alter the viscosity of the gastric protective mucous barrier [15] and increase the colonization by Helicobacter pylori (HP), a recognized risk factor for gastric cancer [16]. High intra-gastric sodium concentrations were shown to cause mucosal damage and inflammation, which in turn has been reported to increase cell proliferation and endogenous mutations [17, 18].

This chapter will focus mainly on recent epidemiological advances concerning the association between excess salt intake and risk of gastric cancer and will also touch on the possible mechanisms whereby excess salt may promote the development of gastric cancer.

2 Salt Intake and Gastric Cancer: Epidemiological Evidence

Incidence rates of gastric cancer are different among geographic regions, and this variability may be due to lifestyle and/or environmental factors in addition to genetic susceptibility. Migration studies have focused on the association between salt and gastric cancer. Analyses of Japanese migrants showed a higher rate of decrease in gastric cancer events in Japanese individuals resident in Hawaii than in those who migrated to Brazil, whose rate in turn was similar to the rate of those who stayed in Japan [19]. These differences might indeed be explained by changes occurring in the habitually high dietary salt intake that migrant populations continued or not to maintain in host countries.

Earlier ecological investigations had also shown an adverse effect of high salt consumption on the risk of gastric cancer: The INTERSALT study, including 24 countries, showed a significant direct association between 24 h urinary sodium excretion (a valid proxy for dietary salt intake) and mortality from gastric cancer [20]. Also, the results of the analysis of 65 rural Chinese counties indicated a positive relationship between consumption of salt-preserved vegetables and mortality from stomach cancer [21]. Similar results were obtained in five Japanese areas, where the authors found a positive association between 24 h urinary sodium excretion and mortality from gastric cancer [22, 23].

While there are remarkable differences in the prevalence of gastric cancer in different countries, a large number of case-control studies suggested an adverse effect of high dietary salt intake or habitual consumption of salted foods on the risk of gastric cancer not only in Asian countries [24, 25], but also in American [26, 27] and European populations [28, 29, 30]. In particular, a most recent European case-control investigation supported the conclusion that high salt consumption is an important risk factor for gastric cancer, with no differences according to HP infection and virulence, tumor site, and histological type [31]. A consensus document of the World Cancer Research Fund International in 2007 supported a relationship between salt consumption and risk of gastric cancer and reported the results of a meta-analysis of the case-control studies available at that time WCRF [13]. In particular, this analysis showed that habitual salted food consumption was positively associated with gastric cancer, with a fivefold increase in risk for each single serving per day.

Finally, as previously mentioned, a number of prospective studies estimated the predictive role of dietary salt intake on the risk of gastric cancer. The majority of these studies were carried out in Japan. Here, a large cohort including 39,065 male and female participants followed for an average of 11 years showed a significant association between total salt intake, assessed by questionnaire, and rate of gastric cancer in men (RR = 2.23) and a positive but not significantly similar trend in women (RR = 1.32) [32]. In addition, another two Japanese investigations detected a similar relationship between high salt intake and rate of gastric cancer, over 11 and 14 years of follow-up, respectively [33, 34]. At variance with these results, the analysis of a cohort of 12,000 male and female participants followed for 15 years in Hawaii demonstrated a positive trend only in women [35]. A large population study carried out in the Netherlands was also not able to detect a significant association between total reported salt intake and risk of gastric cancer (RR = 1.18) [36].

Prospective studies focusing on the consumption of particular salt-rich foods in general demonstrated an adverse effect of elevated consumption on the risk of stomach cancer. Thus, a strong positive association between processed meat consumption and gastric cancer was found in a very large European cohort, including 520,000 male and female participants, in which greater intake was associated with 68 % greater risk compared with lower consumption [37]. A similarly adverse effect of greater processed meat consumption was found in both men and women by the prospective investigation of a large American population sample including 970,000 individuals followed for an average of 14 years [38].

Similar results were found with regard to the consumption of salted fish. Thus, in a sample of 17,600 American men, greater consumption of salted fish correlated with higher mortality for gastric cancer (RR = 1.90) [39]. In a Japanese cohort, greater salted fish consumption was significantly associated with higher gastric cancer incidence in men (RR = 1.77), while in women there was only a nonsignificant trend (RR = 1.17) [32]. However, the authors also reported that higher pickled food intake was associated with greater risk of gastric cancer accidents both in male and in female participants [32]. In another Japanese cohort composed of over 55,000 atomic bomb survivors, there was also a positive trend between higher intake of pickled foods and risk of gastric cancer after 20 years of follow-up, which, however, did not attain statistical significance (RR = 1.11) [40].

In addition, studies on another common Asian dietary salt-rich food, that is, miso-soup, showed a nonsignificant positive trend between elevated habitual consumption of this type of food and gastric cancer events both in a small American cohort [35] and in a large Japanese population [41].

A recent systematic review of all the prospective studies available has shown unequivocally a direct and significant association between higher salt intake and risk of gastric cancer [14]. This meta-analysis was based on the results of seven studies published between 1998 and 2008 and included 270,000 people and 1,474 events. Pooled estimates based on a follow-up period ranging from 6 to 15 years indicated that there was a graded positive association between habitual salt consumption and incidence of gastric cancer. “High” salt intake and “moderately high” salt intake were associated with 68 and 41 % greater risk of gastric cancer, respectively, compared with “low” salt consumption (Fig. 1). The relationship was not significantly different in men and women, and likewise was not affected by the length of follow-up, the year of publication, and the participants’ age at enrollment. Salt consumption was a particularly strong predictor of gastric cancer in the studies carried out in Japanese populations. Separate analyses indicated that the risk of gastric cancer was greater in individuals who reported to be habitual eaters of salt-rich foods: In particular, elevated consumption of pickled foods, salted fish, and processed meat were significantly associated with 27, 24, and 24 % greater risk of gastric cancer, respectively, whereas high miso-soup consumption showed a similarly nonsignificant trend (RR = 1.05) (Fig. 2).

Fig. 1
figure 1

Salt intake and risk of gastric cancer. a “High” salt intake: Forest plot of the risk of gastric cancer associated with “high” salt intake compared to “low” salt intake in 10 population cohorts from 7 published prospective studies. b “Moderately high” salt intake: forest plot of the risk of gastric cancer associated with “moderately high” salt intake compared to “low” salt intake in 10 population cohorts from 7 published prospective studies. Total population, n = 268,718; events, n = 1,474. Results are expressed as relative risk (RR) and 95 % confidence intervals (95 % C.I.). (Adapted from Ref. [14])

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Fig. 2
figure 2figure 2

Salt-rich foods intake and risk of gastric cancer. a Pickled foods: forest plot of the risk of gastric cancer associated with “high” pickled foods intake compared to “low” intake in 11 population cohorts from 7 published prospective studies. Total population, n = 242,568; events, n = 2,858. b Salted fish: forest plot of the risk of gastric cancer associated with “high” salted fish intake compared to “low” intake in 13 population cohorts from 8 published prospective studies. Total population, n = 209,704; events, n = 1,447. c Processed meat: Forest plot of the risk of gastric cancer associated with “high” processed meat intake compared to “low” intake in 7 population cohorts from 5 published prospective studies. Total population, n = 1,578,092; events, n = 2,002. d Miso-soup: Forest plot of the risk of gastric cancer associated with “high” miso-soup intake compared to “low” intake in 12 population cohorts from 8 published prospective studies. Total population, n = 249,931; events, n = 3,022. Results are expressed as relative risk (RR) and 95 % confidence intervals (95 % C.I.). (Adapted from Ref. [14])

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Finally, Dias-Neto et al. [42] analyzed the association between salted food consumption, preference for salted foods (or the use of table salt), and gastric intestinal metaplasia. The study, that included cohort, case-control and cross-sectional investigations, showed a trend toward an adverse effect of high salt consumption that, however, did not reach statistical significance.

3 Salt Intake and Helicobacter Pylori Infection

Helicobacter pylori (HP), infection is one of the main predisposing factors for gastric cancer development. High salt intake increases the colonization by HP [16] and induces mucosal damage on persistent HP infection [16]. A few studies suggested a possible causal link between excess salt intake, HP infection, and carcinogenesis [34, 43, 44].

A cross-sectional study of 634 Japanese men (aged 40–49 years) reported that habitual consumption of salt-rich foods, in particular miso-soup and pickled vegetables, was associated with high prevalence of HP infection [45]. This association was also reported by EUROGAST, an international study that related the rate of national HP infection to the 24 h urinary sodium excretion levels assessed by the INTERSALT project. A positive relationship between HP infection rates and urinary sodium excretion was detected in almost of all age and gender categories [46].

Two small case-control studies assessed Helicobacter pylori (HP), infection and salt intake in Japanese [44] and Korean [34] samples, after the development of gastric cancer. The authors found that the combination of high salt intake and HP infection was associated with gastric cancer compared to the combination of low salt diet and no HP infection. In addition, the combination of high salt and HP infection was better associated with the risk of gastric cancer than the combination of Helicobacter pylori (HP), infection and low salt intake in a Japanese population sample [44].

The potential association between salted food consumption and HP infection in humans was also evaluated in a Japanese prospective study, which showed a positive association between high salt intake and gastric cancer only in the HP infection-positive group [34]. Moreover, the results indicated a strong effect of high salt intake on gastric carcinogenesis in individuals with both atrophic gastritis and HP infection.

Finally, the synergistic effects of dietary high salt intake and HP infection on gastric carcinogenesis were also found in animal studies. Helicobacter pylori (HP), infection exacerbated gastric mucosal damage on a salty diet in mice [47]. Moreover, in a study of Mongolian gerbils with HP infection, the cocarcinogenic effect of a high salt diet was confirmed, and high salt consumption was associated with elevated titers of anti-HP antibodies, hypergastrinemia, and inflammatory cell infiltration [43].

4 Other Biological Mechanisms and Experimental Evidence

A number of experimental studies addressed the question of the possible mechanisms of the adverse effect of excess salt intake toward susceptibility to gastric cancer. As previously mentioned, a powerful interaction has been detected between excess salt intake and HP infection, with high salt intake increasing the rate of colonization of the gastric mucosa by HP [16], enhancing surface mucous cells, and reducing gland mucous cell mucin [43]. A study in rats showed that high dietary salt intake reduced cell yield and produced an increase in the number of S phase cells, susceptible to mutagenesis [17]. In the same species, salt administration induced dose-dependent damage of the surface mucous cell layer and an increase in replicative DNA synthesis [18]. Moreover, in gerbils with HP infection, high dietary salt up-regulated the expression of COX-2 and iNOS [48], potentiated the effects of HP infection, and caused gastric cancer progression [49]. High salt intake was found to potentiate CagA expression (HP gene), increase the capacity of this gene to translocate into gastric epithelial cells, and improve the capacity of HP to alter the function of epithelial cells [50].

In addition, both hypergastrinemia induced by high salt intake in the presence of HP infection [43] and the synergic effect of this chronic hypergastrinemia and HP infection may contribute to parietal cell loss and gastric cancer progression [51].

A number of studies suggested that elevated salt intake may promote and/or enhance the effect of food-derived carcinogens, for example N-nitroso compounds [1, 15, 52], potent carcinogen that may induce tumors in several sites [53], by affecting the viscosity of the protective mucous barrier [43] and damaging the gastric epithelium.

Finally, some experimental investigations on animal models showed a synergistic effect of high salt intake and chemical carcinogens (MNNG and MNU) in the development of gastric cancer [54, 55].

5 Perspectives

Gastric cancer remains one of the most common forms of cancer worldwide with approximately 870,000 new cases [56, 57] accounting for about 9.9 % of new cancers [58]. The mortality from this form of cancer remains high with more than 628,000 deaths (12.1 %) worldwide, equally represented in developed and developing countries [59]. While the worldwide incidence of gastric cancer has declined rapidly throughout recent decades, in particular in Western countries, in China, and other countries in East Asia, the decline has been less substantial than for other countries. In fact, an increased incidence has been observed in the oldest and youngest age groups [60]. Moreover, the age at onset of gastric cancer in the Chinese population is lower than in the West, and this may signal the effect of new environmental factors.

Most adult populations around the world have average daily salt intakes higher than 6 g (MRC [1, 61, 62], and for many in eastern Europe and Asia higher than 12 g [63], while WHO recommendations suggest that average population salt intake should be less than 5 g per day [64]. A population reduction in salt intake is recognized as a global priority for a highly cost-effective prevention of the epidemic of cardiovascular disease in both developed and developing countries [1, 65, 66, 67, 68, 69]. There is ample evidence suggesting the potential for further benefit by this policy in addition to its effects on cardiovascular disease [70].