The Association between Smoking Exposure and Reflux Esophagitis: A Cross-sectional Study among Men Conducted as a Part of Health Screening

Abstract

Objective

Gastroesophageal reflux disease (GERD), including reflux esophagitis (RE), is recognized as a common gastrointestinal disease, and its prevalence is reported to be increasing. While current cigarette smoking has been established as a risk factor for RE in several cross-sectional studies, most of these studies did not include details concerning the smoking status in their analyses. Smoking-related conditions, such as chronic lung disease and cough, are reportedly also related to GERD.

Methods

To investigate the association between RE and detailed smoking habits, we performed a cross-sectional analysis of healthy men enrolled in a comprehensive health checkup program conducted in 2015 that included esophago-gastro-duodenoscopy. Smoking status was assessed using a self-reported questionnaire. Other smoking-related parameters, including the lung function, cough symptoms and presence of chronic lung disease, were also assessed. Unconditional logistic regression was applied to calculate the odds ratio (OR) with 95% confidence intervals (CIs) after adjusting for confounding factors.

Results

The study included 151 subjects with RE (RE group) and 814 without RE (control group). Compared with never-smokers, former smokers (OR, 1.5; 95% CI, 0.9-2.9) and current smokers (OR, 2.4; 95% CI, 1.5-3.9) showed an increased risk of RE. An increased risk of RE was also observed among subjects with current smoking for 10-20 PYs and more than 20 PYs (OR, 2.8; 95% CI, 1.4-5.8, OR, 3.1; 95% CI, 1.6-5.7 respectively). An elevated risk was observed in former smokers who reported more than 20 PYs (OR, 2.5; 95% CI, 1.3-4.8). When former smokers were stratified according to time since smoking cessation, a significant RE risk was observed in participants who had stopped smoking less than 10 years earlier compared with never smokers (OR, 1.9; 95% CI, 1.1-3.3). No significant associations were observed between chronic cough, FEV1.0%, and RE.

Conclusion

Cumulative lifetime exposure to smoking plays an important role in the risk of RE.

Introduction

Gastroesophageal reflux disease (GERD) is a troublesome condition in which there is a backward flow of acidic gastric contents into the esophagus, and it is recognized as a common gastrointestinal disease (1). Japan has recently experienced an increase in GERD prevalence rates, although the rates are still low compared with those in Western countries (2).

Many studies have evaluated the risk factors for GERD. Hiatal hernia is a well-established non-modifiable risk factor for GERD. However, a number of lifestyle factors, such as body weight, alcohol intake, and smoking, are modifiable risk factors of GERD (2-4). Being aware of modifiable risk factors for GERD aids in the development of possible preventive strategies.

Significant attention has been focused on the association between obesity and GERD. Numerous studies have reported that obesity raises the risk of developing GERD or reflux esophagitis (RE) (3,4). While smoking is an established risk factor for RE as per several studies conducted by Japan and Western countries (3,4), a full understanding of its mechanism as a risk for RE is unclear. Very few studies have examined the association between RE and the detailed smoking status of the patients. Little is known regarding the association of the duration, amount, and history of smoking with the risk of RE in most previous studies.

Cigarette smoking significantly increases the risk of developing chronic lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD), which are associated with GERD (5). COPD, chronic cough, and GERD are closely related, but most prior studies on GERD and chronic lung disease have used self-reported questionnaires or 24-hour pH monitoring (5). Very few published studies have assessed the relationship between endoscopically diagnosed RE and chronic lung disease (6).

The present cross-sectional study therefore further examined the association between the detailed smoking status and RE. Similarly, other smoking-related parameters, including the lung function and cough, were also assessed.

Materials and Methods

Study population

We conducted a cross-sectional study that focused on the impact of smoking on RE at the medical checkup unit of the Center for Preventive Medicine, Ebina Medical Center, Ebina City. The study subjects included men between 29 and 80 years old who underwent a comprehensive health checkup program, including esophagogastroduodenoscopy (EGD) and a workup for metabolic syndrome, at the clinic between January and June 2015. The study subjects were limited to men because there were not enough smokers among women. Fifty-one participants were excluded because of a history of gastric surgery (n=10), newly diagnosed gastric cancer (n=1), and proton pump inhibitor or H2 blocker use (n=40). In total, 965 participants were eligible and included in this study (Figure).

Figure.

Flow chart of study participants.

All participants had completed a simple self-administered questionnaire that inquired about symptoms related to RE, their medical history, and lifestyle factors, including smoking and alcohol consumption. The symptoms were assessed by the following questions: Do you get heart burn? and Do you have cough or sputum production? Answers were “yes” or “no.” Regarding the medical history, patients were asked whether or not they had been diagnosed with or received medications for bronchial asthma, hypertension, or COPD.

Weight (kg) and height (cm) were measured during the health checkup. From these measurements, the body mass index (BMI) (kg/m²), an indicator of obesity, was calculated.

Spirometry was performed in the 930 eventual participants, and the forced expiratory volume in one second (FEV1.0), forced vital capacity (FVC), and ratio of FEV1.0 to FVC (FEV1.0%) were similarly examined. An FEV1.0% above a cut-off level of 70 was considered a “normal lung condition,” so FEV1.0% was classified into ＜70 and ≥70.

This study was approved by the Ebina Medical Center Institutional Review Board (approval number: 286). Approval was based on the ethical guidelines of the Declaration of Helsinki.

Smoking assessments

As a part of the general health checkup, all participants completed a simple self-administered lifestyle questionnaire, recording their current and lifetime smoking status, the number of daily cigarettes smoked, and the age of cessation of smoking if relevant. The study participants were classified based on the smoking status into three groups: never smokers, former smokers, and current smokers. Current and former smokers reported how many cigarettes they smoked per day on average (CPD). Pack-years (PYs) were calculated as the CPD divided by 20 and multiplied by the number of years of smoking (smoking duration). The current and former smokers were categorized into three groups according to PYs and smoking duration (≤10, ＞10 to 20, ＞20).

EGD

EGD screening was performed by two experienced endoscopists and was conducted using a flexible endoscope (XQ290; Olympus Optical, Tokyo, Japan). Two board-certified gastroenterologists performed all EGD procedures while blinded to other study data. RE was diagnosed and graded according to the Los Angeles (LA) classification. All subjects with RE had Grade A or more severe changes. Minimal changes were classified as endoscopy-negative reflux disease in this study. Hiatal hernia was recorded if present according to the diagnostic Makuuchi criteria (7). According to the Makuuchi criteria, Grade A was defined as a sac-shaped portion covered with gastric mucosa seen ≥3 cm above the hiatus, Grade B was defined as gastric mucosa seen circularly ＜3 cm above the hiatus, and Grade C was defined as gastric mucosa seen partially above the hiatus. We defined hiatal hernia as Grade A or B. Grade C was not included as a hernia in this study.

If gastric mucosal atrophy was present, the endoscopic extent of atrophic mucosa was graded according to the Kimura-Takemoto classification (8). We defined C3, O1, O2 and O3 types as a positive for atrophic gastritis.

Statistical analyses

Student's unpaired t-test was used to compare the averages of continuous variables, and the chi-square test was used to compare the proportions of categorical variables between the control and RE groups. Unconditional logistic regression was performed to calculate the odds ratio (OR) and 95% confidence intervals (CIs) for the categorized smoking status with statistical significance set at 5%. ORs were adjusted for factors previously shown to be associated with RE (age, hiatal hernia, BMI, atrophic gastritis, and alcohol intake). Tests for a linear trend in the risk were based on continuous values. The association between the FEV, cough, and RE were analyzed. The OR of those with FEV ＜70 was calculated in comparison to those with an FEV ≥70.

All statistical analyses were performed using the SPSS software program, version 11 (SPSS, Chicago, USA).

Results

Of the 965 participants (mean age: 52±10 years old), 151 cases with RE were identified. RE was graded as per the LA classification as A in 65%, B in 23%, and C in 12% of the participants.

The baseline characteristics of participants in the non-RE (control) and RE groups are summarized in Table 1. Compared to controls, participants with RE had a higher BMI, larger prevalence of hiatal hernia and heartburn, and smaller proportion of atrophic gastritis (p＜0.01). The two groups were comparable with respect to alcohol consumption and receiving non-steroidal anti-inflammatory drugs (NSAIDs) or having hypertension.

Table 1.

Characteristics of the Study Population by RE.

	Control (n=814)	RE (n=151)	p
Age mean (s.d.)	51.9 (10.1)	51.7 (10.0)	0.8
BMI mean (s.d.)	23.2 (2.9)	24.2 (3.3)	<0.01
Alcohol n (%)	358 (44)	71 (47)	0.3
Hernia n (%)	203 (25)	98 (65)	<0.01
Atrophic gastritis n (%)	105 (13)	60 (4)	<0.01
HT n (%)	98 (12)	24 (16)	0.3
NSAID n (%)	2 (0.3)	1 (1)	0.2
Asthma or COPD n (%)	12 (1.5)	5 (3.3)	0.22
heart burn n (%)	49 (6)	21 (14)	<0.01
cough n (%)	90 (11)	18 (12)	0.8
FEV1.0* mean (s.d.)	76.7 (7.0)	75.4 (7.8)	0.07

*930 underwent a respiratory function test case (n=149) control (n=781)

BMI: body mass index, HT: hypertension, NSAID: non-steroidal anti-Inflammatory drugs, COPD: chronic obstructive pulmonary disease, FEV1.0: forced expiratory volume in one second

Table 2 presents the unadjusted and ORs for risk factors of RE. Never smokers, former smokers, and current smokers represented 37%, 42%, and 21% of the population, respectively. Compared with never smokers, the ORs for RE among former and current smokers were 1.5 (95% CI, 0.9-2.4; p=0.08) and 2.4 (95% CI, 1.5-3.9; p=0.01), respectively, after adjusting for covariates.

Table 2.

Results of Logistic Regression for the Association between Risk Factors and RE.

	Unadjusted			Adjusted*
	Case/control	OR (95%CI)	p	OR (95%CI)	p
Never smokers	42/312	ref		ref
Former smokers	62/342	1.4 (0.9-2.2)	0.09	1.5 (0.9-2.4)	0.08
Current smokers	47/160	2.1 (1.4-3.4)	<0.01	2.4 (1.5-3.9)	<0.01
BMI (>23)	100/484	2.2 (1.5-3.1)	<0.01	1.7 (1.2-2.6)	<0.01
Atrophic gastritis (positive)	6/110	0.3 (0.1-0.6)	<0.01	0.3 (0.1-0.8)	0.02
Hernia (positive)	98/305	5.4 (3.7-7.8)	<0.01	5.1 (3.5-7.6)	<0.01

*Adjusted for age, BMI, alcohol consumption, hiatal hernia and atrophic gastritis

BMI: body mass index

Table 3 shows the ORs for risk by smoking. A dose-dependent relationship was observed between PYs and RE risk among current smokers (p for trend ＜0.05). Among current smokers, an increased risk was observed for those who smoked between 10 to 20 PYs (OR, 2.8; 95% CI, 1.4-5.8), and the risk for those who smoked ＞20 PYs was 3 times that of never smokers (OR, 3.1; 95% CI, 1.6-5.7). Among former smokers, the risk for those with ≤10 PYs of smoking was comparable to that of never smokers, whereas an increased risk was observed for former smokers with ＞20 PYs (OR, 2.5; 95% CI, 1.3-4.8). When former smokers were stratified according to time since smoking cessation, a significant RE risk was observed in participants who had stopped smoking less than 10 years earlier compared with never smokers (OR, 1.9; 95% CI, 1.1-3.3).

Table 3.

Results of Logistic Regression for the Association between Smoking Exposures and RE.

		Unadjusted	p	Adjusted*	p
Current smoking
Pack years	Cases/control	OR (95%CI)		OR (95%CI)
PYs ≤ 10	3/28	0.8 (0.2-2.7)	0.7	0.5 (0.2-2.4)	0.5
10 <PYs ≤ 20	15/50	2.2 (1.1-4.3)	0.02	2.8 (1.4-5.8)	0.005
20 <	29/82	2.6 (1.5-4.5)	<0.01	3.1 (1.6-5.7)	<0.01
p for trend			<0.01		<0.01
Duration of smoking
≤ 20	9/36	1.9 (0.8-4.1)	0.1	1.7 (0.7-4.1)	0.2
20 < ≤ 30	20/63	2.4 (1.3-4.3)	<0.01	2.4 (1.3-4.9)	0.009
30 <	18/61	2.2 (1.2-4.1)	0.02	3.2 (1.5-6.8)	<0.01
p for trend			<0.01		<0.01
Former smoking
Pack years	Case/control	OR (95%CI)		OR (95%CI)
PYs ≤ 10	24/157	1.1 (0.7-1.9)	0.6	1.4 (0.8-2.4)	0.3
10 < PYs ≤ 20	13/84	1.2 (0.6-2.2)	0.7	1.0 (0.5-2.0)	0.9
20 <	25/101	1.8 (1.1-3.2)	0.03	2.5 (1.3-4.8)	<0.01
p for trend			0.05		0.08
Duration of smoking
≤ 10	18/122	1.1 (0.6-2.0)	0.8	1.2 (0.7-2.3)	0.5
10 < ≤ 20	31/165	1.4 (0.8-2.3)	0.2	1.5 (0.9-2.6)	0.1
20 <	13/55	1.8 (0.9-3.5)	0.1	1.9 (0.9-4.1)	0.1
p for trend			0.01		0.01
Smoking cessation
20 <	16/113	1.1 (0.6-1.9)	0.9	1.1 (0.6-2.2)	0.8
10 < ≤ 20	16/104	1.1 (0.6-2.2)	0.7	1.3 (0.7-2.5)	0.5
≤ 10	30/124	1.8 (1.1-3.0)	0.03	1.9 (1.1-3.3)	0.03

*Adjusted for age, BMI, alcohol consumption, hiatal hernia and atrophic gastritis

Table 4 shows the association between chronic cough and the FEV1.0% and RE. One hundred and fourteen participants developed cough or sputum production, accounting for 11% of this population. The adjusted OR among participants with these symptoms was 0.9 (95% CI, 0.5-1.8; p=0.98) compared to those without symptoms. Of the 970 participants who underwent spirometry, 75% had a normal lung function (FEV1.0% ＞70). In the univariate analysis, an increased OR for RE was observed for those with a low lung function (FEV1.0% ＜70) (OR, 1.6; 95% CI, 1.0-2.5; p=0.06). However, this association was attenuated after adjusting for confounders, including current smoking (OR, 1.4; 95% CI, 0.8-2.5; p=0.2).

Table 4.

Results of Logistic Regression for the Association between Chronic Cough, FEV1.0% and RE.

Cough	Case/control	Unadjusted OR (95%CI)	p	Adjusted OR (95%CI)	p
No	131/696	Ref		Ref
Yes	18/85	1.1 (0.7-1.9)	0.7	0.9 (0.5-1.8)	0.98
Adjusted for age, BMI, alcohol consumption, hiatal hernia and atrophic gastritis
FEV1.0%	Case/control	Unadjusted OR (95%CI)	p	Adjusted OR (95%CI)	p
70≤	123/689	Ref		Ref
<70	26/92	1.6 (1.0-2.5)	0.06	1.4 (0.8-2.5)	0.2

Adjusted for age, BMI, alcohol consumption, hiatal hernia, atrophic gastritis and current smoking, FEV1.0: forced expiratory volume in one second

Discussion

GERD is the most common gastrointestinal disease in Western countries. The prevalence of GERD is reportedly on the rise in Japan. This is possibly because of the recent change to a more westernized diet in Japan, leading to weight gain and a decrease in the rate of Helicobacter pylori infections (2).

The most common approach to the diagnosis of GERD is by inquiring about typical GERD symptoms and/or conducting EGD. When EGD is used as a diagnostic tool, GERD can be classified into two categories: erosive esophagitis (EE), which is diagnosed by detectable esophageal mucosal injury, and non-erosive reflux disease (NERD), wherein esophageal mucosal injury is absent despite the presence of GERD symptoms (9). EGD allows for an objective and direct evaluation of the presence of reflux esophagitis. When RE was defined as LA classification grade A or more, good intra-observer reproducibility was reportedly noted (10). Several cross-sectional studies in Japan have reported that the prevalence of RE varied considerably among study subjects (2). The reasons for this may be that various factors, such as obesity, atrophic gastritis, gender, and age, were associated with GERD or RE. Among the subjects who underwent health checkups, the mean prevalence of RE was reported to be 6.8% (3). In contrast, the prevalence of RE was 16% in our study, which is higher than that in a previous Japanese study (3). This may have partly been because the present study was limited to men.

Our study showed that RE had a positive correlation with the BMI and the presence of hiatal hernia. In contrast, a negative association was observed between RE and atrophic gastritis. These results were consistent with the findings of previous studies (3,4). Adiposity had been reported to be associated with an increased risk of RE in several Japanese and Western studies (2-4). The plausible mechanism underlying obesity as a cause of RE is that abdominal adiposity increases the intra-abdominal pressure and subsequently induces gastroesophageal reflux and acid exposure (4).

While several previous cross-sectional studies have reported current smoking as a significant independent risk factor (3,4), there has been uncertainty concerning causal links with the risk of RE because of inadequate information regarding the duration and amount of smoking, as well as the history of smoking. Most previous studies have used crude measures of smoking exposure, such as risk estimates for current versus never smoking (3,4).

In few Japanese cross-sectional studies, a dose-response relationship between current smoking and RE risk was reported (11,12). One study showed that a significantly increased OR of RE was observed for those who smoke less than 10, between 10 and 20, or more than 20 PYs compared with never smokers (OR 1.3, 1.5, 1.8; 95% CI 1.1-1.7, 1.3-2.0, 1.9-2.7 respectively) (11). Another study reported that those who smoked more than 20 PYs had a significantly increased RE risk (OR, 1.4; 95% CI, 1.2-1.6) (12). These analyses were performed without separating the former smokers from never smokers at risk of RE.

A cross-sectional analysis was conducted to examine the relationship between the different extent of smoking exposure and RE. In this study, former smokers, current smokers, and never smokers were separated before analyses based on detailed questionnaires. Similar to the results of other studies, the results confirmed that current smoking is an independent risk factor for RE (11,12). In the current and former smokers, a significant dose-dependent relationship was observed between PYs and RE risk. Our study showed that significantly increased ORs for RE were observed for those who currently smoked between 10-20 PYs (OR, 2.8; 95% CI, 1.4-5.8) and more than 20 PYs (OR, 3.1; 95% CI, 1.6-5.7) compared with those who never smoked. This result suggests that the magnitude of the association between smoking and RE is stronger than that observed in previous studies. Similarly, dose-response relationships were observed between former smokers and the risk of RE. The results showed that the OR for RE had significantly increased among former smokers with the greatest amount of smoking (＞20 PYs) compared with never smokers (OR, 2.5; 95% CI, 1.3-4.8); this was almost the same risk level as that observed in current smokers. This is a notable result, as it suggests that the risk for heavy smokers does not decrease and return to the level of never smokers even after cessation of smoking.

A positive relationship was observed between the smoking duration and RE risk. Among former smokers, those who had stopped smoking less than eight years earlier had a significant association with RE risk. Minimal to no increased risk of RE was noticed among those with ≤10 PYs of smoking. These results suggested that cumulative lifetime exposure to smoking plays an important role in the risk of developing RE. Early smoking cessation may reduce the risk of RE. Indeed, a recent prospective cohort study showed that smoking cessation reduced the prevalence of GERD and the severity of reflux symptoms (13).

However, the mechanism responsible for RE due to smoking remains unclear. One possible hypothesis involves the nicotine effect on the lower esophageal sphincter. Nicotine-induced relaxation of the lower esophageal sphincter increases the backward flow of acidic gastric contents and acid exposure in the lower esophagus (14).

Our study is the first, to our knowledge, to evaluate the association between former smoking and RE. The results showed that former heavy smokers had a significantly increased risk for RE compared to never smokers. This may be clinically plausible, as smoking cessation is generally accompanied by weight gain and abdominal obesity. A recent meta-analysis reported that smoking cessation was associated with a mean increase of 4 kg in body weight (15). Abdominal obesity itself is also a risk factor for RE. Another possible mechanism is that heavy smokers undergo thoraco-abdominal anatomical changes that could cause the development of reflux, including flattening of the diaphragm and increased intra-abdominal and negative intrathoracic pressure (16).

Chronic cough, which is a common symptom in smokers and those with chronic lung disease, may increase the intra-abdominal pressure and induce gastroesophageal reflux. There is a close relationship between cough, chronic lung disease, and GERD (17). A recent meta-analysis showed that GERD is a common comorbidity in those with COPD (5). Based on questionnaires, the prevalence of GERD in individuals with COPD was reported to range from 17% to 54%, and it has been suggested that the presence of GERD increases the risk of COPD exacerbations (5). However, in the present study, no significant associations were observed between chronic cough and RE, probably because the study subjects were selected from those undergoing EGD screening as part of routine health checkups, and only a few of them developed chronic lung disease. A few studies have examined the association between COPD and endoscopically diagnosed RE. One cross-sectional study in Korea showed that the prevalence of RE in patients with COPD was 30% (6). This study equally showed a significant association between RE and smoking exposure rather than FEV1.0%. Further studies on the correlation between chronic lung disease, the lung function, and RE may be necessary.

Several limitations associated with the present study warrant mention. First, participants in this study may have suffered from recall bias, particularly regarding the smoking status among former smokers. The study subjects were selected from those undergoing EGD screening as part of routine health checkups, and it should be considered that a selection bias may have been introduced. Furthermore, the study subjects were limited to men because only a few women smoked in this population. Several reports have demonstrated that the H. pylori serostatus and atrophic gastritis had an inverse association with GERD (2). We evaluated subjects for the presence of endoscopic atrophic gastritis; however, the serostatus of H. pylori infection could not be assessed in the study population. Since there has been a recent increase in the eradication of H. pylori, an endoscopic evaluation of gastric mucosal atrophy was expected to be more informative than that of the serostatus of H. pylori. Detailed questionnaires, such as the frequency scale for symptoms of gastroesophageal reflux disease (FSSG), were not utilized, and NERD was not evaluated. Many studies have demonstrated that RE and NERD have several different risk factors (2). Therefore, further studies are needed to investigate the association between NERD and smoking. Although the dose-response effect of smoking exposures on RE was fully studied, we did not examine the association between RE and other types of smoking products, such as heated cigarettes.

Conclusion

In summary, this study is the first, to our knowledge, to examine associations between current, past, and long-term smoking exposures and RE risk. This cross-sectional analysis adds to the body of evidence, concerning a dose-response relationship between cigarette smoking and the risk of RE, not only among current smokers but also among past smokers. This result is an important contribution to the literature, since evaluations of the detailed smoking status in relation to RE are limited. Cumulative lifetime exposure to smoking plays an important role in the risk of RE. Similarly, it should be noted that there is a risk of RE in heavy smokers even after smoking cessation. Thus, smoking cessation should be recommended early for RE prevention. Since the importance of smoking cessation has been emphasized worldwide, these study results do not suggest any changes to current public health policy. Our findings may contribute to the understanding of the relationship between GERD and chronic lung conditions.

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the 1964 Declaration of Helsinki and later versions. Informed consent or a substitute for it was obtained from all patients for inclusion in the study.

The authors state that they have no Conflict of Interest (COI).