Review of salt consumption and stomach cancer risk: Epidemiological and biological evidence

Abstract

Stomach cancer is still the fourth most common cancer; thus, it remains an important public health burden worldwide, especially in developing countries. The remarkable geographic variations in the rates of stomach cancer indicate that dietary factors, including a range of food groups to which salt and/or nitrates have been added, may affect stomach cancer risk. In this paper, we review the results from ecologic, case-control and cohort studies on the relationship between salt or salted foods and stomach cancer risk. The majority of ecological studies indicated that the average salt intake in each population was closely correlated with gastric cancer mortality. Most case-control studies showed similar results, indicating a moderate to high increase in risk for the highest level of salt or salted food consumption. The overall results from cohort studies are not totally consistent, but are suggestive of a moderate direct association. Since salt intake has been correlated with Helicobacter pylori (H pylori) infection, it is possible that these two factors may synergize to promote the development of stomach cancer. Additionally, salt may also cause stomach cancer through directly damaging gastric mucus, improving temporary epithelial proliferation and the incidence of endogenous mutations, and inducing hypergastrinemia that leads to eventual parietal cell loss and progression to gastric cancer. Based on the considerable evidence from ecological, case-control and cohort studies worldwide and the mechanistic plausibility, limitation on salt and salted food consumption is a practical strategy for preventing gastric cancer.

Key Words: Disease prevention; Helicobacter pylori infection; Salt consumption; Stomach cancer

INTRODUCTION

Stomach cancer is the fourth most common cancer and is the third leading cause of cancer death worldwide[1–3]. The estimated number of stomach cancer cases worldwide was 933 900 in 2002, with two-thirds occurring in developing countries[3]. Tremendous variation in both incidence and mortality rates exists across geographic regions, with > 10-fold differences observed between low-risk and high-risk areas[4]. Although stomach cancer incidence rates have been decreasing slowly over recent decades in China, it was estimated that there were 0.4 million new cases diagnosed and 0.3 million deaths from this malignancy in 2005[5]. Therefore, this disease remains an important public health burden throughout the world, especially in developing counties including China.

Several risk factors for stomach cancer have been identified, including Helicobacter pylori (H pylori) infection, salt-preserved foods, dietary nitrite, smoking, alcohol, obesity, radiation, and family history[67]. Researchers also found that the incidence rates of stomach cancer varied across different geographic regions and this variation may be associated with genetic, lifestyle or environmental factors, including diet[8]. Salt intake was first reported as a possible risk factor for stomach cancer in 1959[9]. In some early studies, using refrigerators for food storage, which may be an indicator of less salted food consumption or decreased salt intake, was found to be correlated with a reduction in stomach cancer rates[1011], leading researchers to hypothesize that salt intake may play a role in the development of stomach cancer. A Japanese ecological study suggested a nearly linear correlation between the cumulative mortality rate of stomach cancer and the median 24 h urine salt excretion level[1213]. Experimental studies[1415], including rodent models, have also suggested that salt may play an important role in the etiology of stomach cancer. Based on the available experimental and epidemiological data, a report from World Health Organization (WHO)/Food and Agriculture Organization (FAO) Expert Consultation in 2003 concluded that “salt-preserved foods and salt probably increase the risk of stomach cancer”[16].

The purpose of this paper was to review the current literature on salt consumption and the risk of stomach cancer. We obtained the relevant papers and identified our literature search through PubMed from SCI papers. All cohort papers were selected with cohort size more than 2000; case-control papers were filtered out with case sample size around or more than 100. At the end, we summarized the evidence from epidemiological perspectives regarding salt intake and stomach cancer risk.

EPIDEMIOLOGICAL STUDIES OF SALT AND STOMACH CANCER RISK

When evaluating epidemiologic studies on the relationship between salt or salted food consumption and stomach cancer risk, it is essential to consider the diversity of salted foods. Some studies analyzed overall dietary salt intake, whereas others evaluated stomach cancer risk associated with salt intake in various categories, such as table salt or salted fish.

Ecologic studies

Several ecologic studies reported positive associations between different indicators of salt consumption and stomach cancer mortality at the population level[17–21]. In an ecologic study of 24 countries, median urinary sodium levels, ascertained on randomly selected samples from each country, were significantly correlated with stomach cancer mortality (r = 0.70 in men; 0.74 in women) (both P < 0.001)[17]. Another study evaluated correlations between both salt intake and 24 h urinary sodium excretion and stomach cancer mortality among men in four geographic regions of Japan, and reported a strong correlation between stomach cancer mortality and salt excretion, but not with dietary salt intake[21]. An ecologic study of stomach cancer mortality in 65 Chinese counties observed significant, yet modest, correlations for intake of salt-preserved vegetables (r = 0.26 in men and 0.36 in women)[18]. A Japanese study administered a 38-item food frequency questionnaire to a sample of 634 men and the wives of 373 of these men from five districts in Japan. The rank correlation coefficient between gastric cancer mortality and pickled vegetable consumption was 0.36[19]. In a similar study of 207 Japanese men and the wives of 165 of the men, average daily sodium consumption, estimated using a 3 d weighed food record, was correlated with stomach cancer mortality rates (partial rank r = 0.45)[20].

In summary, the majority of ecological studies indicated that the average salt intake in each population was closely correlated with gastric cancer mortality. However, employing dietary assessment methods in these studies has some limitations, such as variation of the questionnaire validity in different population, and use of the same composition table calculating salt intake in diverse dietary cultures. One validated questionnaire used by one population may not be appropriate or valid for another population; thus in population based studies, dietary estimates may not be highly accurate and the association between dietary factors and disease may be much compromised. Applying the same composition table to calculate the same food in different dietary culture may cause bias, since the same food in different areas may have different salt content. For example, the regional average salt content of miso in 39 regions of 20 prefectures across Japan ranged from 9.1% to 18.2%[22]. Furthermore, as with all ecologic studies, diet and stomach cancer were neither measured nor analyzed on the individual level. Rather, the diets of sampled individuals were used to represent entire populations or geographic regions. Thus, misclassification is an obvious concern. Furthermore, associations observed at the population level cannot be assumed to hold at the individual level, and causality cannot be inferred from this type of study.

Case-control studies

Forty two case-control studies on salt consumption in relation to stomach cancer are presented in Table 1[23–64]. Of these, twenty two studied overall salt, table salt or sodium[2324–44], twelve estimated salted/dried fish and/or salted fish gut or cod roe[253945–54], six investigated salted or pickled vegetables[253252–55], three focused on salty snacks[415657], and twelve studied salted foods in general[293032525458–64].

Table 1 Summary of 45 case-control studies that evaluated the association between salt consumption and stomach cancer risk.

Author and year	No. of cases	No. of controls	Factors evaluated	Exposure levels and OR (95% CI)1
SALT AND SODIUM INTAKE
Modan et al, 1974: Israel[23]	166	429	Salt	No association
Risch et al, 1985: Canada[24]	246	246	Salt	No association
You et al, 1988: China[25]	564	1131	Salt (per capita household)	≤ 13 kg/yr, ≤ 19 kg/yr, ≤ 20 kg/yr, > 20 kg/yr
				1.0, 1.2, 1.1, 1.1 (0.8-1.4); NS
Negri et al, 1990: Italy[26]	526	1223	Salt	Low, intermediate, salty
				1.0, 1.3, 1.2 (0.8-1.7); NS
Wu-Willians et al, 1990: USA[27]	137 male	137	Add salt	Rarely, often, always
				1.0, 1.4, 1.2 (Na); NS
Nazario et al, 1993: Puerto Rico[28]	136	151	Salt	≤ 6.979 g/wk; 6.98-18.66 g/wk; 18.67-43.26 g/wk; ≥ 43.27g/wk
				1.0, 2.9, 4.5, 5.0 (2.1-12.0); P < 0.05
Ramón et al, 1993: Spain[29]	117	234	Salt	Quartiles 1 through 4
				1.0, 1.2, 1.8, 2.1 (1.2-7.1); P for trend < 0.01
Lee et al, 1995: Korea[30]	213	213	Salt	Tertile 3 vs 1
				3.7 (1.1-12.5); P < 0.05
La Vecchia c et al, 1997: Italy[31]	746	2053	Salt	Low, intermediate or high
				1.0, 1.5 (1.0-2.2); P < 0.05
Ye et al, 1998: China[32]	272	544	Salt	0.25 kg/m; > 0.25 kg/m
				1.0, 1.3 (1.0-1.6); NS
López-Carrillo et al, 1999: Mexico[33]	220	752	Salt	Never, sometimes (adding salt after tasting the food)
				Positive association; P < 0.05
Liu et al, 2001: China[34]	189	189	Heavy salt	Low to high half
				1.0, 2.0 (1.3-3.2); P < 0.05
Machida-Montani et al, 2004: Japan[35]	122	235	Salt	Tertiles 1 through 3
				1.0, 1.3, 1.5 (0.6-3.7); N
Qiu et al, 2004: China[36]	103	133	Salt	Positive association; P < 0.05
La Vecchia et al, 1987: Italy[37]	206	474	Table salt	Tertile 3 vs 1
				1.5 (Na); NS
Tuyns et al, 1988: Belgium[38]	293	2851	Table salt	Never, sometimes, always
				1.0, 1.0, 1.8 (1.2-2.8); P < 0.05
Buiatti et al, 1989: Italy[39]	1016	1159	Table salt	Seldom, always
				1.5 (1.3-1.9); NS
Coggon et al, 1989: England[40]	95	190	Table salt	Low to high half
				1.0, 6.2 (2.0-18.9); P < 0.05
Boeing et al, 1991: Germany[41]	143	579	Table salt	No association
Boeing et al, 1991: Poland[42]	741	741	Table salt	Low to high half
				1.0, 1.6 (1.2-2.3); P < 0.05
Graham et al, 1990: USA[43]			Sodium intake	≤ 73.2 g/mo; 73.2-98.8 g/mo; ≤ 98.9-127.3 g/mo; > 127.3 g/mo
	186 male	181		1.0, 1.8, 2.6, 3.1 (1.7-5.8); P for trend = 0.001
				≤ 66.9; 67.0-88.5; > 88.5
	107 female	104		1.0, 1.8, 4.7 (2.3-9.6); P for trend = 0.0001
Harrison et al, 1997: USA[44]		132	Sodium intake	Low to high half
	60 intestinal			1.0, 1.3 (0.8-1.9); NS
	31 diffuse			1.0, 1.4 (0.9-2.1); NS
SALTY FOODS
Salted fish
Haenszel et al, 1972: Japan[45]	220	440	Salted/dried fish	None, use both, 2 times/mo; 3-5 times/mo; 6 times/mo
				1.0, 2.0, 1.5, 2.5, 2.6 (Na); P < 0.05
Haenszel et al, 1976: Japan[46]	783	1566	Salted/dried fish	None; < 4 times/mo; 4-9 times/mo; ≥ 10 times/mo
				1.0, 1.1, 1.1, 1.2 (Na); NS
Tajima et al, 1985: Japan[47]	93	186	Salted/dried fish	Low to high half
				1.0, 2.6 (Na); P < 0.01
You et al, 1988: China[25]	564	1131	Sated fish	≤ 0.5 kg/yr, ≤ 1 kg/yr, > 1 kg/yr
				1.0, 1.0, 1.4 (0.8-1.5); NS
Buiatti et al, 1989: Italy[39]	1016	1159	Salted/dried fish	Tertile 3 vs 1
				1.4 (Na); P for trend = 0.001
Kato et al, 1990: Japan[48]				< 2-3 times/wk; ≥ 2-3 times/wk
	289 male	1247	Salted/dried fish	1.0, 1.2 (0.9-1.7); NS
			Salted fish gut, cod roe	1.0, 1.5 (1.1-2.1); P < 0.05
	138 female	1767	Salted/dried fish	1.0, 0.7 (0.5-1.0); NS
			Salted fish gut, cod roe	1.0, 0.5 (0.3-1.0); NS
González et al, 1991: Spain[49]	354	354	Salted fish	Low to high half
				1.0, 1.5 (0.9-2.6); NS
Palli et al, 1992: Italy[50]		1159	Salted/dried fish	Tertile 3 vs 1
	68 cardia			1.7 (0.9-3.1); NS
	855 others			1.5 (1.2-1.8); NS
Hansson et al, 1993: Sweden[51]	338	669	Salted fish	None, ≤ 0.9 times/mo; ≤ 3 times/mo; ≤ 7 times/mo; ≤ 11 times/mo
				1.0, 1.0, 0.9, 0.9, 1.3 (0.8-2.1); NS (adolescence)
				None, ≤ 0.9 times/mo; ≤ 3 times/mo; ≤ 7 times/mo
				1.0, 1.0, 0.8, 0.8 (0.5-1.3); NS (20 yr prior to interview)
Kim et al, 2002: Korea[52]	136	136	Salted fish	Tertiles 1 through 3
				1.0, 0.8, 0.8 (0.4-1.6); NS
Cai et al, 2003: China[53]	381	222	Salty fish	< times/mo, < 3 times/wk, ≥ 3 times/wk
				1.0, 1.0, 5.5 (1.4-19.5); NS
Strumylaite et al, 2006: Lithuania[54]	379	1137	Salted fish	Almost do not use, 1-3 times/mo
				1.0, 0.7 (0.5-0.9); P for trend = 0.002
Salted vegetable
You et al, 1988: China[25]	564	1131	Sated vegetables	< daily, daily
				1.0, 1.1 (0.7-1.8); NS
Ye et al, 1998: China[32]	272	544	Salted vegetables	< 2 kg/yr; > 2 kg/yr
				1.0, 1.4 (1.1-1.8); P < 0.05
Kim et al, 2002: Korea[52]	136	136	Salted vegetables	Tertiles 1 through 3
				1.0, 0.9, 1.5 (0.8-2.9); NS
Xibin et al, 2002: China[55]	210	630		Low to high half
			Pickled or salted vegetables	1.0, 4.0 (1.6-9.8); P < 0.05
			Preference for a high salt vegetables	1.0, 2.6 (1.6-4.3); P < 0.05
Cai et al, 2003: China[53]	381	222	Pickled vegetables	< times/M, < 3 times/w, ≥ 3 times/wk
				1.0, 1.3, 1.8 (1.0-3.0); P for trend = 0.038
Strumylaite et al, 2006: Lithuania[54]	379	1137	Pickled vegetables with salt and oil	Almost do not use, 1-3 times/mo, ≥ 1-2 times/wk
			Pickled vegetables with salt and vinegar	1.0, 0.6, 0.8 (0.6-2.1); NS
			Salted mushrooms	Almost do not use, 1-3 times/mo, ≥ 1-2 times/wk
				1.0,0.7, 0.8 (0.6-1.0); NS
				1-3 times/mo, ≥ 1-2 times/wk
				1.0, 1.6 (1.1-2.4); NS
Salted snacks
Boeing et al, 1991: Germany[41]	143	579	Pretzels, salty snacks	Tertiles 1 through 3
				1.0, 0.7, 1.5 (1.0-2.2); NS
Ward et al, 1999: Mexico[56]	220	752	Salty snacks	Never, ≤ 2, > 2 times/mo
				1.0, 1.3, 1.8 (1.2-2.8); P for trend = 0.008
Chen et al, 2002: Nebraska[57]	124	449	Salty snacks	Quartiles 1 through 4
				1.0, 1.4, 1.2, 0.7 (0.3-1.6);NS
Salted foods in general
Hu et al, 1988: China[58]	241	241	Salted and fermented soya paste	< 2 kg/yr; > 2 kg/yr
				1.0, 1.5 (1.0-2.2); NS
Kono et al, 1988: Japan[59]	139	2852	Salty foods	None or 1-3 times/mo; 1-3 times/mo; once/do more
				1.0, 0.8, 1.4 (Na): NS
Demirer et al, 1990: Turkey[60]	100	100	Salted foods	Less than once or twice/wk; once or twice/wk vs
				1.0, 3.8 (2.1-6.9); P < 0.001
Hoshiyama et al,1992: Japan[61]	294	294 (general population)	Salty foods	No, moderate, yes
		202 (hospital control)		1.0, 1.7, 2.3 (1.5-3.4); P < 0.01
				1.0, 1.3, 1.1 (0.7-1.9); NS
Ramón et al, 1993: Spain[29]	117	234	Pickled foods	Quartiles 1 through 4
				1.0, 1.2, 2.1, 3.7 (Na); P for trend < 0.01
Ji et al, 1998: China[62]	1124	1451	Salted foods	Occasionally, sometimes, frequently
				1.0, 1.4, 1.7 (1.3-2.4); P for trend = 0.001
Lee et al, 1995: Korea[30]	213	213	Salted side dishes	Tertile 3 vs 1
				4.5 (2.5-8.0); P < 0.05
Ye et al, 1998: China[32]	272	544	Salted fermented sea foods	< 1.5 kg/yr; > 1.5 kg/yr
				1.0, 1.6 (1.2-2.0); P < 0.01
Kim et al, 2002: Korea[52]	136	136	Salty foods	Tertiles 1 through 3
				1.0, 1.1, 0.9 (0.4-1.8); NS
De Stefani et al, 2004: Uruguay[63]	240	960	Salted meat	Tertiles 1 through 3 1.0, 1.3, 2.0 (1.4-2.9); P for trend = 0.0003
Campos et al, 2006: Colombia[64]	368	431	Salting meals before tasting	No, yes
				1.0, 3.5 (1.6-7.3); P for trend = 0.001
Strumylaite et al, 2006: Lithuania[54]	379	1137	Salted meat	Almost do not use, 1-3 times/mo, ≥ 1-2 times/wk
				1.0, 1.5, 3.0 (2.2-4.0); P for trend < 0.001

¹OR, Odds ratio; CI: Confidence interval; Na: No association.

Among the sixteen studies that estimated overall dietary salt or sodium intake, eight in Puerto Rico, Spain, Korea, Italy, Mexico, China (two) and USA have shown strong statistically significant increases in risk (OR = 1.5-5.0 for the highest intake levels)[28–343643]. Seven of them reported statistically non-significant OR of 1.1 to 1.5 for consumption in the upper half of overall salt or sodium intake[24–27323544], and the remaining study reported no association[23]. Six of the studies specifically examined the use of table salt, with three studies (in Belgium, England, and Poland) reporting statistically significant increases in risk with OR = 1.6, 1.8, 6.2, respectively[384042]. Two other studies each reported statistically non-significant odds ratios of 1.5 for consumption of the upper half of the table salt intake distribution[3739]; the remaining study reported no association[41].

Of the twelve studies that estimated salted fish intake, four found strong statistically significant increases in risk (OR = 1.4-5.5 for the highest intake levels)[39454748]. One Japanese study reported a statistically significant increase in risk for high consumption of salted fish gut and cod roe in males, but not females, and no significant association for salted/dried fish for both genders[48]. Seven other studies reported statistically non-significant correlations[254649–53]; the remaining study reported a statistically significant inverse association with odds ratios of 0.7 for consumption in the upper half of the salted fish intake distribution[54].

Six studies in Table 1 examined salted vegetables; of these, three reported statistically significant increases in risk with higher intakes of salted vegetables[325355], the remaining three studies in China, Korea and Lithuania showed no relationship to stomach cancer risk[255254]. Additionally, three studies reported on salted snacks. Of them, only one study in Mexico reported a statistically significant relationship to stomach cancer[56], with the other two reporting no substantial associations[4157].

Twelve studies examined consumption of salted soya paste, salted side dishes and salty foods in general[293032525458–64]. Nine of them observed a moderate increase in risk with higher consumption (OR = 1.6-4.5)[293032546061–64], the remaining three reported no association[525859].

In summary, many case-control studies found similar results, indicating a moderate to high increase in risk for the highest level of salt or salted food consumption. Given the large number of studies that reported data on salt, sodium and salty foods consumption, some inconsistent results were to be expected. The inconsistencies may be due, at least in part, to the retrospective assessment of salt exposure, which might have changed after the diagnosis of stomach cancer. Furthermore, the degree to which each of these measures reflects total salt intake varies, and it is therefore not surprising that results would vary.

Cohort studies

Eleven cohort studies, investigating salt or salted food consumption and stomach cancer risk in the US, Japan, Sweden, and the Netherlands have produced inconsistent results (Table 2)[65–75]. When viewed separately in the Table, the results were inconsistent for both salt intake and intake of salty foods. Four Japanese studies reported statistically significant associations (range of RR = 2.2-5.4 for the highest intake level)[67687375], including one study that reported significantly elevated risks in both men and women after 10 years follow up of 20 300 men and 21 812 women[73]. Another study, conducted in rural Japan with 8035 subjects and 76 stomach cancer deaths, reported a significantly elevated relative risk for the most frequent intake of highly salted foods compared with the least frequent intake (RR = 5.4; 1.8-16.3; P for trend < 0.01)[75]. In a study that examined 18 684 men and 20 381 women and included 486 histologically confirmed stomach cancer cases (358 men and 128 women), there was a dose-dependent association between salt consumption and stomach cancer risk in men (P for trend < 0.001), but not in women (P for trend = 0.48)[67]. Shikata et al[68] categorized 2476 subjects into four groups according to daily salt intake. After 14 years of follow-up, the age- and sex-adjusted incidence was significantly higher in the second to fourth groups than in the first group (RR = 2.4, 95% CI: 1.2-4.7; RR = 2.1, 95% CI: 1.0-4.3; RR = 3.0, 95% CI: 1.5-5.8, respectively). With the exception of these positive findings, the remaining seven cohort studies showed no substantial associations[656669–7274]. It is perhaps noteworthy that four studies with statistically significant positive results were conducted in Japan, which may be related to a potentially higher range of salt intake in that country.

Table 2 Summary of 11 cohort studies that evaluated the association between salt consumption and stomach cancer risk.

Author and yr	Size of cohort	No. of cases	Length of follow-up (yr)	Factors evaluated	Exposure levels and RR (95% CI)1
Salt
Nomura et al, 1990: USA[65]	7990 male	150	4	Table salt/shoyu	Never-seldom, after tasting, always
					1.0, 1.4, 1.0 (0.6-1.6); NS
van den Brandt et al, 2003: Netherlands[66]	120 852	282	6.3	Dietary salt	Quintiles 1 through 5
					1.0, 1.5, 1.0, 1.5, 1.2 (0.8-1.8); NS
				Table salt	Never, seldom, sometimes, often/very often
					1.0, 1.1, 0.7, 0.9 (0.6-1.4); NS
Tsugane et al, 2004: Japan[67]			12	Salt	Quintiles 1 through 5
	18 684	358			Male: 1.0, 1.7, 2.0, 2.3, 2.2 (1.5-3.4); P for trend < 0.001
	20 381	128			Female:1.0, 0.9, 1.0, 0.6, 1.3 (0.8-2.3); NS
Shikata et al, 2006: Japan[68]	2476	93	14	Dietary salt	< 10.0, 10.0-12.9, 13.0-15.9, ≤ 16.0 1.0, 2.1, 1.9, 2.7 (1.4-5.2); P for trend = 0.01
Sjödahl et al, 2008: Sweden[69]	73 133	313	18	Dietary salt	Low to high half
					1.0, 1.0 (0.7-1.4); NS
Salty foods
Kneller et al, 1991: USA[70]	17 633 male	75	20	Salted fish	Never, < 1, ≥ 1 1.0, 1.0, 1.9 (1.0-3.6); NS
Galanis et al, 1998: USA[71]	11 907	108	14.8 (average)	Dried or salted fish	None, 1 or more times/wk
				High-salt foods	1.0, 1.0 (0.6-1.7); NS
					None, 1-3 times/wk, 4 or more times/wk
					1.0, 1.0, 1.1, (0.7-1.8); NS
Ngoan et al, 2002: Japan[72]	13 000	116	10	Salted food	Low, median, high
					1.0, 1.0, 1.4 (0.6-3.2); NS
Kim et al, 2004: Japan[73]		400	10	Salted food	Quartiles 1 through 4
	20 300			(traditional type)	Male:1.0, 2.0, 2.5, 2.9 (1.8-4.7); P for trend < 0.0001
	21 812				Female: 1.0, 1.7, 1.3, 2.4 (1.3-4.4); P for trend = 0.007
Tokui et al, 2005: Japan[74]	110 792		12	Preference for salty food	No, a little, somewhat, much, very much
		574			Male: 1.0, 0.9, 1.1, 1.1, 1.4 (0.7-2.8); NS
		285			Female: 1.0, 1.6, 1.8, 1.5, 1.9 (0.6-5.8); NS
				Dried or salty fish	None, 1-2/mo, 1-2/wk, 3-4/wk, 1+/d
		574			Male: 1.0, 0.9, 0.9, 0.9, 1.1 (0.7-1.8); NS
		285			Female:1.0, 0.6, 0.7, 0.7, 0.9 (0.5-1.6); NS
Kurosawa et al, 2006: Japan[75]	8035	76	11	Salted food	Low, intermediate, high
					1.0, 4.0, 5.4 (1.8-16.3); P for trend < 0.01

¹RR: Relative risk.

In summary, some cohort studies suggest that a higher intake of salt or of salted food, as estimated by validated food frequency questionnaires, may be directly associated (or at least indirectly linked) with subsequent development of stomach cancer. Although the overall results from cohort studies are not totally consistent, they are suggestive of a moderate direct association.

EVIDENCE ON INTERACTIONS BETWEEN SALT OR SALTED FOODS AND HELICOBACTER PYLORI INFECTION

Even though H pylori infection is the strongest risk factor for stomach cancer, it cannot completely explain the worldwide distribution of this disease. It is very important to evaluate the potential joint effects of H pylori infection and other factors, including salt intake, in stomach cancer carcinogenesis.

Few epidemiological studies have investigated H pylori infection in relation to salt consumption. In an international ecologic study[76], statistically significant correlations between national H pylori infection rates and national salt excretion levels were found in older (age 50-64) men and women (r = 0.73 and r = 0.83, respectively) and in younger (age 20-34) men (r = 0.73), but not in younger women (r = 0.52). A cross-sectional study of 634 Japanese men[77] reported that daily consumption of miso soup was associated with the prevalence of H pylori (OR = 1.60, P< 0.05). Similarly, increasing consumption of pickled vegetables was associated with increased H pylori infection risk (OR = 1.90 for the highest level, P for trend = 0.02). Despite limitations inherent in these types of studies, they can nevertheless provide information on potential associations between salted foods and H pylori infection in humans, which may be evaluated more fully in case-control and cohort studies.

Three previous epidemiological studies have examined the potential synergistic relationship between salt consumption and H pylori infection in the development of stomach cancer; however, the results are inconsistent[356878]. A case-control study in Japan analyzing the independent and joint effects of diet and H pylori infection found that subjects with H pylori infection and with high salt intake (OR = 14.2) had a higher odds ratio compared with subjects with H pylori infection and low salt intake (OR = 9.7) (reference group was no H pylori infection and low salt intake), but there was not a statistically significant interaction between the two risk factors[35]. A Korean case-control study investigating the role of salt and H pylori infection in stomach cancer found that subjects with H pylori infection and high salt consumption had a 10-fold risk of early stomach cancer compared with subjects without H pylori infection and with a low salt consumption (P = 0.047)[78]. These two case-control studies have some limitations, including issues of possible recall bias and misclassification. For example, both H pylori and salt intake were assessed after the development of stomach cancer. Advancing stomach cancer can combine with the loss of infection characterized by a fall in circulating anti-H pylori antibodies and changes in salt exposure (or in recollection of dietary exposures prior to the onset of disease). Only one cohort study, conducted in Japan, evaluated the potential interaction between diet and H pylori, and found that the positive association between increased salt intake and gastric cancer was statistically significant among subjects with H pylori infection only[68]. The relative risks were similar, however, and the authors note that findings for dietary salt were most pronounced in subjects who had both H pylori infection and atrophic gastritis. The three studies discussed above have relatively small sample sizes, ranging from 69 to 122 stomach cancer cases, and thus the estimation of relative risk is imprecise and results should be interpreted cautiously, especially in the analyses of effect modification (interaction). Finally, the tendency of case-control studies to show stronger associations than cohort studies suggests the possibility that some degree of recall bias and/or selection bias may have influenced the results of the former.

Critical issues in interpreting salt consumption with stomach cancer risk

Most epidemiological data suggest an association between salt intake and the development of stomach cancer. When interpreting these data, several issues must be considered.

Assessment of salt intake is difficult and prone to some potential biases. Many commonly used dietary assessment methods, such as food frequency questionnaires and diet records, have reported only moderate reproducibility in epidemiological studies, and thus some misclassification of dietary intake is inevitable[7980]. This may be particularly true of total salt intake, given its nearly ubiquitous addition to most processed foods. In addition, use of different salt assessment methods may lead to different conclusions. For example, both 24 h urinary excretion and 3 d dietary record methods for salt intake estimation were used in one Japanese ecologic study. Only urinary salt excretion level showed a strong correlation with stomach cancer mortality, while dietary salt was weakly and non-significantly correlated[21]. Although 24 h urine collection may be an optimal method in estimating routine salt intake, it is impracticable for a large-scale population study, especially a cohort study with long-term follow-up.

Another critical issue in interpreting salt consumption in relation to stomach cancer risk is the variation in the salt consumption levels across the population. To date, there is no standard method for salt intake categorization, and several studies have reasonably compared categories, such as quintiles for the application in the specific study population. Because average salt intake varies across different populations, salt consumption levels considered “high” in one study might be considered “low” in another study. For example, in a study conducted in Japan, subjects reporting once per week consumption of salted food were in the lowest exposure category[48]; in contrast, the subjects in a Turkish study reporting once per week were classified into the highest exposure level (defined as ≥1-2 times/week)[60]. Finally, in some studies[75], salted food levels were calculated from the sum of the scores of foods belonging to the food items (pickled vegetable + foods deep-boiled in soy sauce), making it impossible to compare effects at similar levels of consumption across studies.

Because of the complexity of diets, the traditional approach with a single nutrient may potentially be confounded by the interactions between food components that are likely to be interactive or synergistic[81]. It is possible that the increased risks in stomach cancer could be due to compounds other than salt in foods that were produced during the preservation process[56]. In East Asia, salted foods and sauces are also high in NO₃, a chemical carcinogen, which may either be added to the foods or synergize from amino acids during fermentation. Nitrite and salt may work at an early stage[82] in a synergistic fashion on stomach cancer carcinogenesis[17] that might cause the strong associations between highly salted foods and gastric cancer[67]. However, nitrite was not clearly related with stomach cancer risk[83] and its function may be influenced by other factors. For example, when lower salt intake was combined with higher NO₃ intake, stomach cancer mortality rates tended to be lower[17]. However, this might be explained by a higher intake of fresh fruits and vegetables, which are the major source of nitrate and also protect against cancer[8485].

Moreover, it may be difficult to separate the effects of salt from other nutrients that may contribute to stomach cancer risk. The absence of adjustment for confounding factors (such as age, sex, smoking and dietary habit) can hamper the statistical estimation causing over- or underestimation of the real association between salt or salted food and stomach cancer. In Tables 1 and 2, few studies have controlled for dietary factors in their analyses of salt consumption, which makes it difficult to compare the different studies according to the dietary variables adjusted in the analysis. However, the study results that were adjusted by a wide range of potentially confounding variables, such as age, sex, H pylori infection, atrophic gastritis, medical history of peptic ulcer, family history of cancer, body mass index, diabetes, total cholesterol, physical activity, alcohol intake, smoking habit and other dietary factors[68], showed no difference from the crude results. Studies with adjustment for some or most of the above potential confounding factors[66687273] showed no systematically apparent differences from the studies with adjustment for a few or several confounders.

BIOLOGICAL MECHANISMS

Several mechanisms by which salt intake may increase stomach cancer risk have been postulated, although to date there has been no consistent conclusion. High dietary salt intake may potentiate the colonization of H pylori[86], a known risk factor for stomach cancer, through the increase of surface mucous cell mucin and decrease of gland mucous cell mucin[87]. At the molecular level, high dietary salt intake may potentiate CagA (H pylori gene) expression 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[15]. Another explanation for the potential effect of high salt intake in gastric carcinogenesis is that high dietary salt intake helps to change the mucous viscosity protecting the stomach, potentiate exposure to carcinogens such as N-nitroso compounds, and lead to cell death[88]. In addition, high salt intake can cause damage to, and inflammatory responses of, the gastric epithelium[14], which may increase epithelial cell proliferation as part of the repair process and increase the probability of endogenous mutations[8990]. One mechanism of high salt action in gastric carcinogenesis has been considered to induce hypergastrinemia in H pylori-infected gerbils[87]. Gastrin itself may mediate epithelial cell growth in H pylori-colonized mucosa[91] and chronic hypergastrinemia can synergize with Helicobacter infection and lead to eventual parietal cell loss and progression to gastric cancer[92].

ANIMAL STUDIES OF SALT AND STOMACH CANCER

Most published animal studies focus on the relationship between gastric cancer and several important suspected carcinogens, salt, H pylori, N-methyl-N-nitro-N- nitrosoguanidine (MNNG), and 4-nitroquinoline-1-oxide (NQO). In general, salt alone has no apparent effect on the development of gastric carcinogenesis, but administration of salt in rats induced a concentration-dependent damage of surface mucous cell layer, and also increased replicative DNA synthesis[89]. Interestingly, a synergistic effect was observed when salt and other risk factors (H pylori, MNNG, NQO) were analyzed simultaneously. This conclusion was derived in animal experiments addressing gastric carcinogenesis from both the molecular level and tumor progression. At the molecular level, a high salt diet was associated with an elevation of anti-H pylori antibody titers, serum gastrin levels, and inflammatory cell infiltration in a dose dependent model in Mongolian gerbils infected with H pylori[87]. Similarly, in H pylori infected gerbils, a high-salt diet significantly up-regulated the expression of cyclooxygenase-2 (COX-2), and nitric oxide synthase (iNOS)[93]; the number of colony-forming units was also significantly higher. Dietary sodium chloride also produced a reduction in cell yield, and an increase in S-phase cell numbers that are the most susceptible to mutagenesis, which may possibly increase tumor incidence[90]. Several studies examined gastric tumor progression in mice infected with H pylori and administered with a high-salt diet, and all of these studies consistently demonstrate that a high-salt diet enhances the effects of H pylori infection, and consequently promotes the development of stomach cancers[889495]. Additionally, a high-salt diet significantly increased gastric tumor incidence in those mice pre-treated with MNNG[14] or MNU[96], suggesting that salt and chemical carcinogens also exert a synergistic effect in the development of gastric carcinogenesis.

CONCLUSION

Most published epidemiological studies provide positive evidence for an association between salt or salted food consumption and stomach cancer risk, which was also supported by experimental studies[14879497]. The limitations of salt assessment in epidemiological studies may have attenuated the true effect of salt intake on stomach cancer risk, or even biased the results away from the null, in the reviewed ecological, case-control, and cohort studies. Ideally, dietary modification of salt intake, as well as eradication of H pylori infection, is a promising strategy for gastric cancer prevention throughout the world, especially in developing counties. However, the former strategy is more practical than the latter according to previous epidemiological studies. Future studies that address the association with salt and other dietary factors and the interactions between these factors in different aspects, e.g. molecular level, may help to shed light on the etiology of stomach cancer.