Associations of duration, intensity, and quantity of smoking with risk of gastric intestinal metaplasia

Abstract

Goal:

Determine whether various dimensions of smoking increase risk for gastric intestinal metaplasia.

Background:

Cigarette smoking has been implicated in the etiology of gastric cancer, but it is not clear if smoking is a risk factor for gastric intestinal metaplasia, a precursor lesion of gastric cancer.

Methods:

We compared data from 385 gastric intestinal metaplasia cases and 1577 controls without gastric intestinal metaplasia recruited into a cross-sectional study at the Michael E. DeBakey VA Medical Center in Houston, Texas. All participants completed standardized questionnaires and underwent a study endoscopy with gastric mapping biopsies. Gastric intestinal metaplasia cases included participants with intestinal metaplasia on any non-cardia gastric biopsy. We calculated odds ratios (OR) and associated 95% confidence intervals (95% CI) using multivariable logistic regression models.

Results:

Compared to never smokers, current smokers had 2-fold increased risk for gastric intestinal metaplasia (OR, 2.05; 95% CI, 1.47–2.85). Among ever smokers, increasing duration and total dose were significantly associated with increased risk for gastric intestinal metaplasia (p-trend, 0.004 and 0.01, respectively). Among former smokers, risk for gastric intestinal metaplasia decreased over time and was no different to never smokers after 15 years smoking cessation. Cases with gastric intestinal metaplasia were more likely than controls to have H. pylori infection (53.2% vs. 21.7%); however, smoking effect on gastric intestinal metaplasia was not different by H. pylori infection status.

Conclusions:

Cigarette smoking is a risk factor for gastric intestinal metaplasia. Risk of gastric intestinal metaplasia among former smokers remained significantly elevated until 15 years post cessation.

INTRODUCTION

Gastric intestinal metaplasia is a precancerous change that precedes the development of non-cardia gastric cancer.¹ Persons with gastric intestinal metaplasia have 6–9 fold higher risk of non-cardia gastric cancer compared to the general adult population.^2,3 Helicobacter pylori is a known strong risk factor for gastric intestinal metaplasia;⁴ however, few studies, particularly among Western populations, have examined other potentially modifiable risk factors for gastric intestinal metaplasia.⁵

Tobacco smoking is an established risk factor for gastric cancer arising both in the cardia as well non-cardia.^6,7 Whether this is because smoking is a risk factor for early events in the carcinogenic pathway (i.e., promoting the development of gastric intestinal metaplasia) or for later events, such as the transformation of gastric intestinal metaplasia to cancer, is unclear. While some studies have found a positive association between smoking and gastric intestinal metaplasia risk,^5,8 other studies did not find an association.⁹ In a meta-analysis of 19 studies published through 2014, there was no overall association between cigarette smoking status (ever/current use) and risk of gastric intestinal metaplasia.¹⁰ However, few of these studies were conducted among Western populations, and there was considerable heterogeneity between studies. In addition to smoking status, exposure to tobacco smoke is measured across dimensions such as duration, intensity, total dose, and, for former smokers, time since quitting, and each can be assessed independently as a risk factor. To our knowledge, no studies have comprehensively assessed simultaneously the independent contribution of each dimension of smoking to determine which are associated with gastric intestinal metaplasia risk.

We therefore examined the associations of multiple dimensions of smoking exposure on risk of gastric intestinal metaplasia. Specifically, we sought to quantify the independent associations between dimensions of smoking and their dose patterns and the risk of gastric intestinal metaplasia and to explore potential effect modifiers of these associations.

MATERIAL AND METHODS

We have previously described in detail the study population and methods.^11,12 Briefly, data for the current analysis came from a cross-sectional study conducted at the Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC) in Houston, Texas. The study was approved by the Institutional Review Boards for MEDVAMC and the Baylor College of Medicine (H-27828).

Study Population

We recruited study participants from among (i) consecutive eligible patients undergoing an elective esophagogastroduodenoscopy (EGD) for non-urgent upper GI symptoms and indications; and (ii) consecutive patients attending one of seven selected primary care clinics. The primary care patients were eligible for a routine (i.e., average risk) screening colonoscopy and invited to participate in our study, which required having a study EGD. None of the primary care patients were primarily referred for EGD and none were approached during a time of a pre-scheduled colonoscopy. Patients recruited from primary care underwent the study EGD at the same time as their colonoscopy. These two groups represent the source population for gastric intestinal metaplasia cases at the MEDVAMC. The eligibility criteria were: (1) age 50–80 years (40–80 years for the elective EGD group); (2) no previous gastroesophageal surgery; (3) no previous gastroesophageal cancer; (4) no active lung, liver, colon, breast or stomach cancer; (5) no anticoagulants; (6) no significant liver disease indicated by platelet count below 70,000 ascites, or known gastroesophageal varices; and (7) no history of major stroke or mental condition.

All study participants underwent a study EGD with at least 10 biopsies (2 biopsies each from 5–7 biopsy sites according to adoption of the Sydney System¹³ at the time of study EGD) from the antrum (both greater and lesser curvature), corpus (proximal greater curvature, proximal lesser curvature, with optional additional biopsies at distal greater curvature and distal lesser curvature), and cardia. Endoscopic findings from the upper endoscopy were systematically recorded. Biopsy specimens were embedded in paraffin, oriented on edge, sectioned in 5-sections, and stained with hematoxylin and eosin, alcian blue at pH 2.5; and in case of negative staining for H. pylori, a modified silver stain; and alcian blue–periodic acid Schiff stain. The presence and severity of gastric intestinal metaplasia was independently determined by two gastrointestinal pathologists, blinded to endoscopic findings and patient questionnaires. Disagreements in pathology reads were determined by a third pathologist. Gastric intestinal metaplasia cases were patients with evidence of intestinal metaplasia on ≥1 non-cardia gastric biopsy. We compared cases to controls without gastric intestinal metaplasia on any of their gastric biopsies. Pathologists graded gastric intestinal metaplasia using the Operative Link for Gastric Intestinal Metaplasia (OLGIM) Assessment criteria.¹⁴ Among eligible patients in the elective EGD group, 70% underwent the study EGD and completed the study survey. In the primary care group, 43% of eligible patients underwent the study EGD and completed the study survey.

Data Collection

Prior to the study EGD, participants completed the study survey with assistance from trained research staff. The survey ascertained information about age, sex, race/ethnicity, use of alcohol and smoking, medical history, and use of medications. Height and weight were measured prior to the study EGD and were used to calculate body mass index (BMI). A flexible tape measure was used to measure waist and hip circumference. Waist-to-hip ratio (WHR) was calculated as the ratio of waist circumference divided by hip circumference, and categorized as high if it was ≥0.9 for males or ≥0.85 for females.

To process cultures for H. pylori, frozen tissue specimens were thawed, homogenized, and inoculated onto two types of selective media: (1) Brain Heart Infusion (nutrient rich agar ideal for culturing fastidious microorganisms) and (2) H. pylori Special Peptone Agar plates with 7% horse blood. The plates were incubated at 37°C under micro-aerophilic conditions (5% O2, 10% CO2, and 85% N2) in an Anoxomat jar for up to two weeks. Positive growth was transferred to a fresh, nonselective Brain Heart Infusion blood agar plate and incubated for 48–72 hours. H. pylori were identified when the oxidase, catalase, and urease reactions were positive with a compatible Gram stain. To obtain a pure culture, we selected and subcultured several small round colonies from each patient’s plate 1 or 2 times. Isolated strains were then stored at 80°C in cysteine storage medium containing 20% glycerol. Patients were considered to have H. pylori infection if H. pylori organisms were isolated on gastric tissue culture or found on histopathology of ≥1 gastric biopsy site (using hematoxylin and eosin, alcian blue at pH 2.5, a modified silver stain, or alcian blue–periodic acid Schiff stain).⁵

We asked participants whether, in their lifetime, they had smoked more than 100 cigarettes (including hand-rolled cigarettes), cigars, or pipes. Participants that responded positively to this question were subsequently asked to complete further questions about the age at which they started smoking, if and age at which they stopped smoking, and the total number of years they had smoked. Additionally, we asked participants to report whether they smoked during each decade of life (10–19, 20–29, 30–39, 40–49, 50–59, 60–69, and 70–79 years old) and the amount they smoked in a typical day during these decades.

Ever smokers were defined as those participants who reported having smoked >100 cigarettes, cigars or pipes in their lifetime. The group of participants classified as ever smokers included current smokers and former smokers who quit smoking ≥1 year prior to study enrollment. We defined smoking duration as the difference between starting age and either permanent quitting age (former smokers) or reference age (current smokers). Smoking intensity was defined as the average number of cigarettes smoked in a typical day. We estimated each participant’s lifetime cumulative quantity of tobacco smoked (dose) in pack-years as the sum of decade-specific smoking doses, where each decade-specific smoking dose was the product of the smoking intensity during that decade, the number of days of smoking per week, and smoking duration within that decade. Time since quitting was calculated as the difference between the age at which former smokers had permanently stopped smoking and their age 1 year prior to their study enrollment date. Among 423 cases and 1796 controls in the cross-sectional study, we excluded 38 cases and 219 controls from the current analysis due to missing or incomplete data on smoking exposure.

Statistical analysis

In all analyses, never smokers were used as the reference group. We compared the characteristics of cases and controls using chi-square tests for categorical variables and Student’s t-test for continuous variables. We estimated odds ratios (OR) and corresponding 95% confidence intervals (95% CI) for associations between cigarette smoking measures and risk of gastric intestinal metaplasia using unconditional logistic regression. The multivariable models were adjusted for potential confounders including age, sex, race/ethnicity, and H. pylori infection status. We performed tests for trend by assigning the median value to each category of the main exposure (found in controls only) and modeling this value as a continuous variable in the logistic regression model. We performed subgroup analyses to examine whether the associations with smoking varied across strata of age, sex, race/ethnicity, BMI and H. pylori infection status. Tests for interaction were performed by the Wald test, using interaction terms in the model. Finally, we assessed potential biological interaction between smoking and H. pylori infection by creating an additional variable that reclassified participants according to their combined exposure to smoking and H. pylori (reference group was those that were never smokers and without H. pylori) and tested for departure from additivity using the Synergy Index (SI). A SI >1 indicates that the joint effect of two risk factors on the risk of gastric intestinal metaplasia is greater than the sum of their independent effects and suggests the presence of biological interaction.

All analyses were conducted using Stata 13.0 (StataCorp LP, College Station, TX) and all tests for statistical significance two-sided at α = 0.05.

RESULTS

This study included data from 385 cases with gastric intestinal metaplasia and 1577 controls. The distributions of study participant characteristics are shown in Table 1. Ninety-two percent of participants were male; however, cases were still significantly more likely to be male than controls (97.1 vs. 90.8%). Cases were older on average than controls but had a lower proportion of Whites (41.3% vs. 61.6%). The distributions of BMI and WHR were no different between cases and controls. As expected, cases with gastric intestinal metaplasia were more likely than controls to have H. pylori infection (53.2% vs. 21.7%). More cases with gastric intestinal metaplasia were current or former smokers than controls (80.8% vs. 71.0%).

Table 1.

Characteristics of controls and gastric intestinal metaplasia cases

		Controls N=1,577	Cases N=385
		N (%)	N (%)	P
Age group, years				<0.001
	<60	667 (42.3)	126 (32.7)
	60–69	737 (46.7)	196 (50.9)
	≥70	173 (11.0)	63 (16.4)
Sex				<0.001
	Male	1432 (90.8)	374 (97.1)
	Female	145 (9.2)	11 (2.9)
Race/Ethnicity				<0.001
	White	971 (61.6)	159 (41.3)
	Black	450 (28.5)	164 (42.6)
	Other	156 (9.9)	62 (16.1)
BMI, kg/m2				0.12
	<25	286 (18.1)	82 (21.3)
	25–29.9	564 (35.8)	147 (38.2)
	≥30	726 (46.1)	156 (40.5)
	Missing	1	0
WHR				0.96
	Low	225 (14.6)	55 (14.7)
	High	1321 (85.4)	320 (85.3)
	Missing	31	10
H. pylori infection				<0.001
	No	1217 (78.3)	178 (46.8)
	Yes	338 (21.7)	202 (53.2)
	Missing	22	5
Alcohol use				0.14
	Never	143 (9.1)	24 (6.2)
	Former	600 (38.1)	160 (41.7)
	Current	831 (52.8)	200 (52.1)
	Missing	3	1
Smoking status				<0.001
	Never	457 (29.0)	74 (19.2)
	Former	639 (40.5)	167 (43.4)
	Current	481 (30.5)	144 (37.4)

BMI, body mass index; WHR, waist-to-hip ratio.

WHR was categorized as high if it was ≥0.9 for males or ≥0.85 for females.

Missing category was excluded from statistical tests for differences between controls and cases.

Table 2 shows the associations between dimension of smoking and risk of gastric intestinal metaplasia. In the multivariable model, compared with never smokers, current smokers had a two-fold elevation in risk for gastric intestinal metaplasia (adjusted OR, 2.05; 95% CI, 1.47–2.85). In the same model, former smokers had 40% higher risk for gastric intestinal metaplasia (adjusted OR, 1.40; 95% CI, 1.02–1.93).

Table 2.

Unadjusted and adjusted odds ratios for associations between smoking-related variables and risk of gastric intestinal metaplasia

		Controls	Cases
		N	N	Unadjusted OR (95% CI)	Adjusted ORa (95% CI)
Smoking status
	Neverb	457	74	1.00 (ref)	1.00 (ref)
	Former	639	167	1.61 (1.20–2.18)	1.40 (1.02–1.93)
	Current	481	144	1.85 (1.36–2.52)	2.05 (1.47–2.85)
Age at smoking initiation (years)
	≤15	364	107	1.82 (1.31–2.52)	1.89 (1.33–2.68)
	16–18	430	115	1.65 (1.20–2.28)	1.66 (1.18–2.33)
	>18	325	89	1.69 (1.20–2.37)	1.43 (1.00–2.05)
	p-trendc			0.65	0.07
Smoking duration (years)
	≤25	390	80	1.27 (0.90–1.79)	1.16 (0.80–1.67)
	25.01–40	420	133	1.96 (1.43–2.68)	2.00 (1.43–2.80)
	>40	310	98	1.95 (1.40–2.73)	1.86 (1.30–2.67)
	p-trendc			0.005	0.004
Smoking intensity (cigarettes/day)
	≤15	431	123	1.76 (1.28–2.42)	1.46 (1.04–2.04)
	15.01–20	348	109	1.93 (1.40–2.68)	2.06 (1.45–2.92)
	>20	338	79	1.44 (1.02–2.04)	1.57 (1.08–2.28)
	p-trendc			0.25	0.38
Pack-years of smoking
	≤15	352	86	1.51 (1.07–2.12)	1.26 (0.88–1.81)
	15.01–40	420	127	1.87 (1.36–2.56)	1.86 (1.32–2.60)
	>40	345	98	1.75 (1.26–2.45)	1.93 (1.34–2.77)
	p-trendc			0.43	0.01
Smoking cessation (years)
	≤15	244	70	1.77 (1.23–2.54)	1.65 (1.12–2.43)
	15.01–30	235	62	1.63 (1.12–2.36)	1.34 (0.90–2.00)
	>30	158	33	1.29 (0.82–2.02)	0.97 (0.59–1.59)
	p-trendc			0.19	0.07

CI, confidence interval; OR, odds ratio.

^aAdjusted for age, sex, race/ethnicity, and H. pylori infection.

^bReference group for all analyses is never smokers.

^cp for trend excludes never smokers.

We found some evidence for greater risk with earlier age at starting smoking (p-trend among ever smokers, 0.07), although we had limited age range. A longer duration of smoking was more strongly associated with the risk of gastric intestinal metaplasia than a shorter duration (p-trend among ever smokers, 0.004); significantly increased risks were observed for smoking durations of 25.01–40 years (adjusted OR, 2.00; 95% CI, 1.43–2.80) and >40 years (adjusted OR, 1.86; 95% CI, 1.30–2.67) but not for a duration of 25 years or less (adjusted OR, 1.16; 95% CI, 0.80–1.67). While there was no significant linear trend in the risk of gastric intestinal metaplasia with increasing smoking intensity (cigarettes/day; p-trend among ever smokers, 0.38), risk of gastric intestinal metaplasia increased with increasing total cumulative dose among ever smokers (p-trend, 0.01) (Table 2).

We assessed the effect of smoking cessation by comparing the risks of gastric intestinal metaplasia between former and never smokers. In this analysis, risk of gastric intestinal metaplasia among former smokers remained significantly elevated until 15 years post cessation. Among those that quit smoking 15.01–30 years (adjusted OR, 1.34; 95% CI, 0.90–2.00) and >30 years (adjusted OR, 0.97; 95% CI, 0.59–1.59) prior to the study EGD, there was no elevated risk for gastric intestinal metaplasia compared with never smokers.

We found no evidence for effect modification when we stratified the analyses for smoking status by age group, sex, BMI, or WHR (Table 3). Likewise, the smoking effect on gastric intestinal metaplasia was not different for those with (current vs. never smokers; adjusted OR, 1.93; 95% CI, 1.16–3.21) and without (adjusted OR, 2.21; 95% CI, 1.40–3.46) H. pylori infection. There was also no evidence of biological interaction between smoking and H. pylori infection (SI, 1.62; 95% CI, 0.93–2.81). However, the risk associated with current smoking was stronger in Blacks (adjusted OR, 3.99; 95% CI, 2.30–6.94) compared with other races/ethnicities (p-interaction, 0.01).

Table 3.

Associations between smoking status and risk of gastric intestinal metaplasia, stratified by age group, sex, race/ethnicity, body mass index, and H. pylori infection status

		Adjusted OR (95% CI)
		Never smokers	Former smokers	Current smokers
Age group, years
	<60	1.00 (ref)	1.75 (0.96–3.19)	2.54 (1.48–4.36)
	60–69	1.00 (ref)	1.22 (0.79–1.89)	1.77 (1.10–2.85)
	≥70	1.00 (ref)	1.42 (0.64–3.16)	2.02 (0.69–5.86)
Sex
	Males	1.00 (ref)	1.43 (1.03–1.98)	1.99 (1.42–2.80)
	Females	1.00 (ref)	0.67 (0.09–4.88)	2.67 (0.51–14.0)
Race/Ethnicity
	White	1.00 (ref)	1.10 (0.68–1.78)	1.57 (0.96–2.56)
	Black	1.00 (ref)	2.32 (1.35–4.00)	3.99 (2.30–6.94)
	Other	1.00 (ref)	0.89 (0.43–1.84)	0.67 (0.27–1.68)
Body mass index, kg/m2
	<25	1.00 (ref)	0.95 (0.38–2.41)	2.12 (0.92–4.89)
	25–29.9	1.00 (ref)	2.34 (1.34–4.08)	2.24 (1.25–4.02)
	≥30	1.00 (ref)	1.04 (0.67–1.63)	1.97 (1.16–3.32)
H. pylori infection
	No	1.00 (ref)	1.52 (0.96–2.38)	2.21 (1.40–3.46)
	Yes	1.00 (ref)	1.30 (0.81–2.07)	1.93 (1.16–3.21)
Alcohol use
	Never	1.00 (ref)	1.78 (0.02–1.57)	2.77 (0.93–8.25)
	Former	1.00 (ref)	1.45 (0.87–2.43)	1.46 (0.81–2.66)
	Current	1.00 (ref)	1.41 (0.87–2.27)	2.41 (1.52–3.81)

DISCUSSION

In this large cross-sectional study, we confirmed that smoking is a significant risk factor for gastric intestinal metaplasia. The risk of gastric intestinal metaplasia increased with increasing duration of smoking and pack-years of smoking exposure. We also found tentative evidence that the relationship between cigarette smoking and gastric intestinal metaplasia may be stronger in Blacks. Finally, the current analysis found that risks of gastric intestinal metaplasia among former smokers remained significantly elevated until 15 years post cessation.

Tobacco smoking is an established risk factor for gastric cancer. In 2002, the International Agency for Research on Cancer (IARC) concluded that there was sufficient evidence that tobacco smoking causes gastric cancer.¹⁵ A meta-analysis of 40 studies found that smoking was associated with approximately 1.5-fold higher risk of gastric cancer, and that 11% of all gastric cancer cases worldwide were attributable to tobacco smoking.¹⁶ The risk of smoking on gastric cancer may be higher for males than females, although the reasons remain unclear.⁷ Few studies have evaluated Western populations, particularly in the U.S. In the multiethnic cohort study among participants from Hawaii and California, current smokers had approximately two-fold higher risk for gastric cancer compared to never smokers, and risk increased linearly with increasing intensity and duration of smoking among current smokers.¹⁷ The association with smoking was consistent across all five ethnicities (African Americans, Japanese Americans, Latino Americans, Native Hawaiians, and Whites).¹⁷ While the accumulated dose of cigarette smoke may be a significant factor in the risk for gastric cancer, evidence indicates that the duration since quitting smoking may demonstrate an inverse association with the development of gastric cancer. Nomura et al. revealed that previous smokers who quit smoking over 21 years prior to evaluation had an excess risk for the development of gastric cancer significantly less compared to participants who quit within 10 years prior to evaluation.¹⁷ Therefore, evidence indicates a plausible biological association between varying magnitudes of tobacco smoke accumulation and risk of gastric cancer.

Whether smoking promotes the development of gastric intestinal metaplasia or later events, such as progression from gastric intestinal metaplasia to cancer, has been unclear. Prior studies examining the association between smoking and gastric intestinal metaplasia have reported conflicting results. While some studies suggest smoking as a risk factor,^8,18,19 other studies did not find an association.⁹ A meta-analysis of 19 studies found a trend though non-significant among ever smokers (adjusted OR 1.26, 95% CI 0.98–1.61; 7 studies) and current smokers (adjusted OR 1.49, 95% CI 0.99–2.25; 2 studies) with gastric intestinal metaplasia risk.¹⁰ In the current study, we found strong evidence that smoking is associated with increased risk for gastric intestinal metaplasia. Compared to never smokers, current smokers had two-fold increased risk for gastric intestinal metaplasia. However, binary categorization as smokers and non-smokers includes a wide range of smoking patterns, which may not all be associated with gastric intestinal metaplasia. To our knowledge, few studies have examined detailed smoking history and the risk of gastric intestinal metaplasia.^8,20 An Italian study found 4-fold increased risk of gastric intestinal metaplasia in participants currently smoking >20 cigarettes per day relative to the 2-fold elevated risk in participants smoking <20 cigarettes per day or former smokers.⁸ Although our study did not find an association with intensity of smoking, we found that risk of gastric intestinal metaplasia increased with increased duration of smoking and increasing pack-years of smoking history.

There is pathophysiologic evidence for how cigarette smoking may contribute to intestinal metaplasia and gastric carcinogenesis. Tobacco smoke reduces gastric defense mechanisms through decreasing concentrations of vitamin C²¹ and mucus²² content in gastric secretions while also increasing bile reflux.²³ Elevated bile acid concentrations in gastric contents²⁴ and impaired gastric defense mechanisms may be implicated in the development and progression of gastric cancer precursor lesions.²⁰ While smoking may alter normal gastroenterological physiology, tobacco additionally introduces known gastric carcinogens into the digestive tract²⁵ and smokers generally present with an elevated concentration of DNA adducts in the gastric mucosa.²⁶

In our analyses stratified by race/ethnicity, there was evidence that cigarette smoking may be a stronger risk factor for gastric intestinal metaplasia among Blacks than among Whites and other races/ethnicities. Relative to Whites, Blacks generally smoke fewer cigarettes yet inhale more deeply and achieve higher net indices of smoke exposure. Perez-Stable et al. identified higher cotinine, a metabolite of nicotine, levels in Blacks, which was attributed to a slower clearance of cotinine and higher intake of nicotine per cigarette among Blacks.²⁷ Additionally, Blacks are more inclined to smoke menthol cigarettes and cigarettes with higher tar yields and may have an elevated vulnerability to physical dependence and exposure to smoke toxins.^28–30 Thus, Blacks may be exposed to an elevated concentration and duration of nicotine and tobacco smoke carcinogens per cigarette, which may explain the higher magnitude of risk for gastric intestinal metaplasia associated with smoking among Blacks compared with Whites in the current study.

Most prior studies of smoking and gastric intestinal metaplasia were conducted among predominantly H. pylori infected individuals. In our study, we found that the effect of smoking on gastric intestinal metaplasia was not different by H. pylori infection status and did not identify evidence in support of a synergistic effect of smoking and H. pylori infection on risk of gastric intestinal metaplasia. Furthermore, we found no evidence for effect modification by age, sex, and BMI.

There were several strengths of this analysis, including the large sample size, well-defined groups of cases and controls, the collection of information on a wide range of potential confounders and the systematic collection of detailed measures of smoking exposure. We used comprehensive measures of lifetime exposure to smoking to ensure that changes in use were captured and integrated into measures of overall exposure. Our results are unlikely to be explained by differential reporting as we ascertained questionnaire data prior to the study EGD (before case and control status was defined) to minimize the possibility of biased recall.

This study has a few limitations. Because most participants in our VA-based study were White men and the characteristics of VA and non-VA populations may differ, our findings may not be generalizable to women or non-White men from the general non-VA population. While we captured extensive data on clinical and lifestyle factors through the study survey and via chart review, residual confounding by poorly measured or unmeasured factors could have influenced our results. Nonetheless, it is unlikely that residual confounding explains fully the observed two-fold higher risk associated with smoking. The study was also limited by cross-sectional design, which prevents us from making causal inferences but should not reduce the importance of the observed associations. We were unable to collect information from those invited patients who refused participation in the study since they did not consent to be in a research study. However, the sex and racial distribution in our cohort was representative of the racial distribution overall in the MEDVAMC population, which suggests minimal selection bias.

In conclusion, cigarette smoking is a strong risk factor for gastric intestinal metaplasia. We found that duration of smoking was a strong determinant of risk, but risk of gastric intestinal metaplasia among smokers was not influenced by intensity of use or H. pylori infection. Importantly, time since quitting was an independent risk factor, with evidence that risk among formers smokers was no different to never smokers after 15 years smoking cessation.