Peptic ulcer disease and mental illnesses

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General Hospital Psychiatry 36 (2014) 63–67

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Peptic ulcer disease and mental illnesses☆,☆☆ Wei-Yen Lim a, b,⁎, Mythily Subramaniam b, Edimansyah Abdin b, Janhavi Vaingankar b, Siow Ann Chong b a b

Saw Swee Hock School of Public Health, National University of Singapore & National University Health System, Singapore Research Division, Institute of Mental Health, Singapore

a r t i c l e

i n f o

Article history: Received 30 April 2013 Revised 16 August 2013 Accepted 11 September 2013 Keywords: Population survey Peptic ulcer disease Anxiety disorders Depression

a b s t r a c t Objective: We evaluated the association between self-reported doctor-diagnosed peptic ulcer disease (PUD) and mental disorders in a representative cross-sectional study conducted in 2010 in Singapore. Method: The sample comprised 6616 community-dwelling individuals. Participants were asked about a previous history of doctor-diagnosed PUD. Assessment of mental disorders was performed using the World Mental Health Composite International Diagnostic Interview version 3.0. Quality of life was assessed using the EuroQoL 5D. Results: The weighted prevalence of PUD was 1.58% (95% CI=1.13–2.02). In adjusted analyses, PUD was more common among people with anxiety disorders [obsessive compulsive disorders (OR 4.22, 95% CI 1.59–11.21), Generalized Anxiety Disorders (OR 9.25, 95% CI 2.43-35.17), any anxiety disorders (OR 4.41, 95% CI 1.8210.61)] and with any mood disorders (OR 2.66, 95% CI 1.08-6.53). PUD was associated with alcohol abuse and alcohol dependence, but not with smoking or nicotine dependence. Adjustment for nicotine and alcohol use attenuated the association of mood disorders with PUD, but not that of anxiety disorders. PUD was associated with reduced quality of life as measured on EuroQoL 5D, with further reduction in those with concomitant mental disorders. Conclusion: PUD was associated with anxiety disorders, and this association is not attenuated with adjustment for nicotine dependence or alcohol use disorder. © 2014 Elsevier Inc. All rights reserved.

In the mid-20th century, stress and anxiety were commonly implicated as etiologic factors for peptic ulcer disease (PUD) [1]. This hypothesis fell out of favor after the identification of Helicobacter pylori and the discovery of the relationship between Helicobacter pylori bacterial infection and peptic ulcer disease [2]. Other risk factors identified in the etiopathogenesis of PUD include the use of nonsteroidal anti-inflammatory drugs (NSAIDs) [3], cigarette smoking [4] and, possibly, alcohol consumption [4,5]. Cigarette constituents increase peptic ulcer risk through increasing gastric acid production and reducing mucus production in both the stomach and the duodenum and reducing gastric healing [6]. Alcohol consumption similarly stimulates gastric acid secretion, although it also has antimicrobial activity [7]. Recent mental health studies however suggest that there is a relationship between mental traits and illnesses and peptic ulcer ☆ Competing interests: The authors have no competing interests to declare. ☆☆ Contributor statement: Siow Ann Chong, Mythily Subramaniam and Janhavi Vaingankar designed and conducted the study. Edimansyah Abdin conducted the statistical analysis. Wei-Yen Lim and Mythily Subramaniam developed the analyses protocol. Wei-Yen Lim drafted the manuscript. All authors have contributed to and have approved the submission of this manuscript. ⁎ Corresponding author. Saw Swee Hock School of Public Health MD3, 16 Medical Drive S (117597), Singapore. E-mail addresses: [email protected], [email protected] (W.-Y. Lim). 0163-8343/$ – see front matter © 2014 Elsevier Inc. All rights reserved.

disease. People suffering from peptic ulcers are more likely to have anxiety disorder [8]. Other cross-sectional studies of communitydwelling individuals show that people with mental illnesses such as personality disorders [9], anxiety disorders [10,11] and panic disorders [11] are more likely to have had PUD compared to nonsufferers. People with neuroticism [12] or with a history of childhood physical abuse [13] are also more likely to suffer from PUD. It is not clear what the mechanisms for these associations might be. Goodwin et al. [14], using data from the National Epidemiologic Survey on Alcohol and Related Conditions, conducted in the United States, confirmed the association between mood and anxiety disorders with PUD, but also show substantial attenuation of risk associations after adjustment for nicotine and alcohol dependence, suggesting that comorbid dependence on nicotine and alcohol may partially explain these observations. Few studies have been conducted in Asian populations, where the underlying prevalence of H. pylori infection is much higher than in Western populations, and where the nature and prognosis of peptic ulcers also appear to be different [15]. In this study, we explore the association of PUD with mental health conditions using data obtained from a mental health survey of a multi-ethnic population in the Asian city-state of Singapore. We further evaluate the effect of PUD, with and without concomitant mental illnesses, on quality of life and workday loss.


W.-Y. Lim et al. / General Hospital Psychiatry 36 (2014) 63–67

1. Methods 1.1. Survey Data from the Singapore Mental Health Study (SMHS) were used. The design and conduct of this study have been previously described [16]. The SMHS is a representative cross-sectional survey of noninstitutionalized adult Singapore residents aged 18 years and above and able to speak English, Mandarin or Malay. The study was conducted from December 2009 to December 2010. Participants were randomly selected from a sampling frame of all residents. Exclusion criteria were foreigners residing in Singapore, persons younger than 18 years of age, persons unable to complete an interview due to severe physical or mental conditions or language barriers, persons who were institutionalized at the time of the survey, and persons who were uncontactable. A disproportionate stratified sampling was used with oversampling of older people, and equal proportion sampling of the three main ethnic groups of Chinese, Malays and Indians. Sampling weights were calculated, and post estimation weights were further calculated to adjust results based on the Department of Statistics, Singapore estimates of the Singapore resident population for the year 2007. Ethics approval was obtained from the relevant institutional review board prior to implementation of the study, and full informed consent was obtained from participants and parents / guardians of participants aged 18–20 years. The final study population was 6616 individuals (response rate 75.9%). The diagnoses of mental disorders were based on the World Mental Health Composite International Diagnostic Interview version 3.0 (CIDI 3.0), which assesses presence of mental disorders based on DSM-IV criteria [17]. Diagnostic modules for mood disorders, anxiety disorders (generalized anxiety disorder and obsessive compulsive disorder) and alcohol use disorders were included in the survey. Lifetime prevalence estimates were used for this study. Smoking practice was ascertained, where respondents were asked whether they were current smokers, ex-smokers or non-smokers (had never smoked before). For the analyses in this study, we divided participants into ever-smokers and never-smokers. Current smokers were administered the 6-item Modified Fagerstrom Test for Nicotine Dependence [18] to establish the diagnosis of nicotine dependence. Doctor-diagnosed ulcer disease was ascertained through the participant’s response to the question: “Has a doctor ever told you that you have stomach ulcer?” An index was created using health states defined by the Euro-Qol 5D instrument [19] to assess quality of life. Utilities of these EQ5D health states were elicited using the time trade-off method on a representative sample of the United Kingdom general population [20]. In addition, respondents’ response to the question using a Visual Analogue Scale (VAS) was also compared. Self-reported loss in work days was elicited from a question in the 30-day functioning and disability module of the CIDI 3.0 instrument that asked “Beginning yesterday, and going back 30 days, how many days out of the past 30 were you totally unable to work or carry out your normal activities because of problems with your physical health, your mental health or your use of alcohol or drugs?” 1.2. Statistical methods All data analyses were performed using weighted data. Mean and standard deviations were calculated for continuous variables, and frequencies and percentages for categorical variables. Multiple logistic regression was used to assess the association between PUD and sociodemographic variables and mental illnesses. Differences in EQ-5D Index, EQ-5D VAS scores and loss of workdays between three groups : (i) those with peptic ulcer only, (ii)those with peptic ulcer and any mental disorder, and (iii) those without peptic ulcer or any mental

disorder, were tested by simple linear regression, whilst differences in reported problems in EQ-5D domains (e.g., pain and discomfort, usual activities, etc) between these three groups were tested using simple logistic regression analyses. We also performed post-hoc pairwise comparisons amongst these 3 groups to identify differences in quality of life and loss of workdays. Standard errors and significance tests were estimated using the Taylor series linearization method. Multivariate significance was evaluated using the Wald test based on design corrected coefficient variance-covariance matrices. Adjustment variables were age, gender, ethnicity, marital status, education level, employment status and annual income, using listwise deletion method for missing values. Statistical significance was set at the conventional level of Pb.05, using 2-sided tests. Statistical analyses were carried out using the Statistical Analysis Software (SAS) system version 9.2 (Cary, NC, USA). 2. Results Participants in this study were almost equally divided between men and women. Malays (35,4%) and Indians (29.2%) were overrepresented in this study; this was intentional, to enable more stable and accurate ethnic-specific prevalence estimates of mental illnesses. About 6% of the population were 65 years and older, with a further 22.9% aged 50–64 years. The majority of participants (81.6%) had at least secondary level education. Overall, the weighted prevalence of self-reported doctor-diagnosed PUD was 1.6% (95% CI = 1.1-2.0). PUD was more common among males compared to females (2.3% prevalence in men, compared to 0.9% in women), and among older than younger agegroups (2.4% prevalence among those 65 years and older, compared to 0.7% among those 18–34 years). No associations were seen with other socio-demographic variables such as ethnicity, marital status, markers of socioeconomic status (household income and educational level) and employment status (Table 1). PUD was not significantly associated with lifetime major depressive disorder, dysthymia and bipolar disorder, but it was significantly associated with any mood disorder over the lifetime (OR 2.7, 95% CI 1.1-6.5). PUD was also significantly associated with lifetime Generalized Anxiety Disorder, and Obsessive Compulsive Disorder, and with any anxiety disorder over the lifetime ( OR 4.4, 95% CI 1.8-10.6). PUD was strongly associated with both alcohol abuse and alcohol dependence, but not with nicotine dependence (Table 2) or smoking behavior (not shown). Further adjustment for nicotine and alcohol use attenuated the association of any mood disorders with PUD. No attenuation was seen in terms of the association of PUD with anxiety disorders (Obsessive Compulsive Disorder, Generalized Anxiety Disorder, and any anxiety disorder) (Table 2). Compared to people without PUD or any mental disorder, those with PUD alone were more likely to report moderate or severe problems in the following domains of the EuroQoL-5D questionnaire: completing usual activities (6.5% vs. 2.1%), presence of pain and discomfort (31.8% vs. 13.9%), and anxiety and depression (16.3% vs. 6.0%). People with mental disorder in addition to PUD were even more likely to report difficulties in these domains compared to people without peptic ulcer or any mental disorder (10.2%, 46.2% and 39.1%for difficulty in completing usual activities, pain or discomfort, and anxiety and depression respectively, P at .04, .0002 and b.0001, respectively) (Table 3). People with PUD alone had a poorer quality of life as measured using the EuroQoL 5D health states index (0.906 vs. 0.958). The concomitant presence of any mental disorder in the lifetime lowered that further to 0.853 (P= .002). Similarly, on the VAS, there were substantial reductions in quality of life for those with PUD alone (80.1 vs. 83.9) compared to people without PUD or mental disorder, which was further compromised in the concomitant presence of a mental

W.-Y. Lim et al. / General Hospital Psychiatry 36 (2014) 63–67


Table 1 Demographic characteristics associated with ulcer prevalence in Singapore, 2010

Total Gender Age group (Years)


Marital status (2 missing)

Annual income (338 missing) Education level

Employment (187 missing) a


No ulcer (n=6519)

Ulcer (n=97)

Weighted Prevalence (S.E.%)

Men Women 18–34 35–49 50–64 65 and above Chinese Malay Indians Others Single Married Divorced/Separated Widowed Less than S$20,000 S$20,000–S$49,999 S$50,000 and above Completed primary school or lower Secondary School Pre–University/Junior College/Diploma/ Vocational certificates University Employed Economically inactivea Unemployed

3237 3282 2272 2332 1514 401 1976 2345 1938 260 1803 4221 258 235 3340 1901 943 1216 1945 2040

62 35 21 37 28 11 30 28 31 8 22 69 4 2 52 23 19 20 30 23

1.58 2.29 0.91 0.66 1.75 2.21 2.35 1.57 1.18 1.75 3.24 1.29 1.77 2.01 0.27 1.54 1.19 2.49 1.16 1.80 1.36

(95% CI 1.13–2.02) (0.41) (0.22) (0.20) (0.39) (0.55) (1.05) (0.29) (0.22) (0.33) (1.17) (0.37) (0.31) (1.24) (0.20) (0.33) (0.35) (0.69) (0.44) (0.48) (0.39)

1318 4531 1498 308

24 63 24 5

1.97 1.51 1.73 1.26

(0.52) (0.26) (0.53) (0.87)

P value

.0015 .043






Includes homemakers, students and retirees/pensioners.

disorder (to 73.6, P = 0.005) (Table 3). There were no significant differences in loss in workdays between the three groups. 3. Discussion In this study, we demonstrate that self-reported PUD was more common among people with anxiety disorders (obsessive compulsive disorders, generalized anxiety disorders and any anxiety disorders) and with any mood disorders, in a representative multiethnic Asian population. Self-reported PUD was also associated with alcohol abuse and alcohol dependence, but not with smoking or nicotine dependence. Adjustment for nicotine and alcohol use attenuated the association of any mood disorders with PUD. No attenuation was seen with anxiety disorders (obsessive compulsive disorder, generalized anxiety disorder and any anxiety disorder). H. pylori and NSAID use are now recognized as the major causes of PUD. Nevertheless, other factors are known to be important since not everyone infected with H. pylori or on long-term NSAIDs use develops PUD. Further, non- H. pylori non-NSAID peptic ulcer disease is wellrecognized, and comprises up to 40% of peptic ulcer disease cases in North America, but is much less common in Asian populations (studies have variously reported 1.3–4.1%, although a more recent Hong Kong study reported up to 19% of cases were non- H. pylori, nonNSAID peptic ulcer disease) [21]. The association of PUD with mental health conditions [9–13] may in part be explained by nicotine and alcohol use, which are both more prevalent among those with mental health conditions — many studies have reported that patients with mental health disorders have poorer health lifestyles and behaviors, including nicotine and alcohol use [22,23]. Smoking can increase the risk of PUD. Smokers have higher basal rates of pepsin and hydrocholoric acid production in the stomach [4]. Further, smoking affects mucosal integrity and defense through the production of free radicals, which can cause mucosal damage [4]. The increased production of vasoconstrictors such as vasopressin further limit mucosal repair and impair integrity of the stomach and duodenal mucosa [4]. Smoking and nicotine may also facilitate H. pylori

colonization after acute infection through its effects on gastric mucosa, which result in a more favorable environment for the bacterium [4]. The effect of alcohol use on PUD is slightly more complicated. Experimental studies in humans show that ethanol instillation causes direct gastric mucosa damage, although the effect of ethanol contained in alcoholic beverages was less damaging [7]. Ethanol is believed to also damage the gastric mucosal barrier, through the release of vasoactive and inflammatory molecules [7]. However, alcohol consumption appears to decrease the risk of H. pylori colonization in some epidemiologic studies, and other studies looking at alcohol consumption in general populations have not found an effect with PUD [7]. It should be noted that our study examined those with alcohol abuse and dependence and the results may not be generalizable to those with non-pathological alcohol consumption. Our present study did not detect an effect of smoking on PUD risk, although we did find an effect with alcohol. Further, the relationships we detected between mental illnesses (other than for any mood disorder) were not attenuated by alcohol dependence and abuse, or nicotine dependence, in contrast to the findings in Goodwin et al. These differences could be due to the relatively small proportion of smokers in our study (we had 736 ex-smokers and 1326 current smokers in our sample of 6616 participants), reducing our power to detect an independent effect of smoking, and to possible differences between these 2 study populations in terms of the duration and frequency of smoking. Further, the absence of attenuation suggests that in our study population, there is an independent association between mental disorders, especially anxiety disorders with peptic ulcer disease. Recent research has indicated a closer anatomic connection between the gut and the human brain than previously thought. In particular, the existence of an enteric nervous system able to function without central nervous input is now recognized [24]. This enteric nervous system has extensive connections with the brain, and comprises the third arm of the autonomic nervous system [24]. These central neural connections include the autonomic nervous system as well as the hypothalamus-pituitary-adrenal axis (HPA)


W.-Y. Lim et al. / General Hospital Psychiatry 36 (2014) 63–67

Table 2 Prevalence and odds of stomach ulcers among respondents with psychiatric disorders compared to those without, Singapore 2010 Mental disorder

Prevalence (%, SE) of ulcers among those with psychiatric disorder

Prevalence (%, SE) of ulcers among those without psychiatric disorder

Odds ratio (95% Confidence Interval), unadjusted

Odds ratio (95% Confidence Interval), adjusted for demographicsa

Major depressive disorder Dysthymia Bipolar disorder Any mood disorder Generalized Anxiety Disorder Obsessive Compulsive Disorder Any anxiety disorder Alcohol abuse Alcohol dependence Alcohol abuse or dependence (alcohol use disorder) Nicotine use Nicotine dependence

2.23, 1.86, 4.28, 2.60, 7.25, 4.77, 4.63, 6.00, 11.90, 6.76,

1.53, 1.57, 1.54, 1.50, 1.53, 1.48, 1.46, 1.43, 1.53, 1.38,

1.47 1.19 2.86 1.76 5.05 3.34 3.28 4.40 8.71 5.18

2.11 (0.77–5.80) 2.18 (0.24–19.44) 4.70 (0.90–24.51) 2.66 (1.08–6.53) 9.25 (2.43–35.17) 4.22 (1.59–11.21) 4.41 (1.83–10.61) 4.33 (1.68–11.17) 12.31 (2.24–67.54) 5.68 (2.46–13.11)


0.98 1.91 3.15 0.99 4.47 2.16 1.82 2.38 7.29 2.28

2.15, 0.62 2.32, 1.21

0.24 0.23 0.23 0.23 0.23 0.23 0.23 0.22 0.23 0.22

1.47, 0.24 1.54, 0.23

(0.58–3.73) (0.15–9.41) (0.62–13.25) (0.77–4.00) (1.33–19.21) (1.26–8.91) (1.38–7.80) (1.82–10.64) (2.16–35.10) (2.38–11.28)

1.48 (0.76–2.89) 1.52 (0.51–4.51)

Odds ratio (95% Confidence Interval), adjusted for demographics, nicotine dependence and alcohol use disordera

2.17 9.21 3.99 4.20

(0.82–5.78) (2.37–35.80) (1.44–11.04) (1.69–10.46)

1.66 (0.80–3.43) 1.50 (0.53–4.26)

Adjustments for demographics included age, gender, ethnicity, marital status, education level, employment status and annual income.

[25]. The intricate connections between the brain and the gut have been termed the brain-gut-axis. Anxiety disorders are known to be associated with dysfunction and derangement of both the autonomic nervous system [25] and the HPA axis [26]. These changes could potentially increase PUD risk. For example, increased basal corticotrophin-releasing hormone release ultimately results in higher cortisol secretion into the serum, and over time could predispose already susceptible persons to develop symptomatic PUD, through its effect on gastric acid production and mucosal integrity. It is also possible that the association between anxiety disorders and mental illnesses is due to higher levels of NSAID consumption among anxious patients. Although we have no evidence for this, other studies have shown that anxiety disorders are associated with prescription drug (such as opioid) misuse and abuse [27]. Finally, our data point to the relatively high impact on quality of life associated with peptic ulcer disease in an Asian general population, which is made worse in the presence of concomitant history of mental illness. Our study is consistent with other studies in showing an association of PUD with psychiatric conditions, especially anxiety, and suggests that this relationship holds in Asian populations as well.

Further, our study highlights the possibility that this relationship is independent of nicotine and alcohol dependence and abuse (incidentally, both conditions are relatively uncommon in our study population [28,29]), and suggest that further epidemiologic and biological research are needed to understand the mechanism for this association. From a clinical perspective, our results also suggest that gastroenterologists and primary care physicians may need to screen for mental disorders (especially anxiety disorders) among patients who are diagnosed with PUD. Diagnosis of the mental disorder and subsequent treatment may favorably influence the course of PUD, apart from the direct benefits on mental health. There are some limitations with this study that need to be considered. Our response rate of 75.9% is reasonable and consistent with response rates obtained in population-based surveys conducted elsewhere. However, differential non-response rates amongst people with mental illness and with or without PUD could affect estimates obtained in this analysis. We predict that people with mental illness and concomitant physical illnesses might be more likely to be noncontactable or refuse to participate compared to people with either condition alone. If so, the prevalence of PUD among people with mental illnesses could be higher than what we estimated.

Table 3 Quality of life and work-day loss among respondents with peptic ulcer disease and any mental disorder, Singapore, 2010

EuroQoL-5D domainsa Mobility Self-care Usual activities Pain/discomfort Anxiety/depression

EQ-5D UK index EQ-5D VAS Loss in workdays in the past 30 days a b c

Peptic ulcer only (A) (n=54)b

Peptic ulcer and any mental disorder (B) (n=24)b

No peptic ulcer or any mental disorder (C) (n=4832)b

Statistical significance

%, SE 4.06, 1.85 1.35, 1.03 6.48, 4.29 31.80, 9.57 16.32, 7.05

%, SE 0 0 10.19, 8.55 46.23, 13.47 39.14, 13.49

%, SE 3.64, 0.41 0.53, 0.17 2.13, 0.31 13.89, 0.73 5.99, 0.49

Mean, SE 0.906, 0.024 80.08, 1.85 0.934, 0.668

Mean 0.853,0.037 73.60,4.05 0.305, 0.174

SE 0.958, 0.002 83.92, 0.27 0.48, 0.06

Pairwise Comparisonc Peptic ulcer only vs. Peptic ulcer and any mental disorder (A vs B)

Peptic ulcer only vs. No peptic ulcer or any mental disorder (A vs C)

Peptic ulcer and any mental disorder vs. Without peptic ulcer and any mental disorder (B vs C)

P value N.05 N.05 .04 .0002 b.0001

P value . . .67 .38 .12

P value .82 .25 .11 .017 .033

P value . . .081 .0021 b.0001

P value .0017 .005 .50

.23 .15 .36

.031 .040 .50

.0044 .011 .34

Proportion of respondents reporting a problem (moderate or extreme) in each EuroQoL-5D domain. The EuroQoL 5D questionnaire was completed by only 5,594 respondents. Pairwise comparisons between 2 groups (A vs B, A vs C, B vs C); P values for significant pairwise comparison were derived using linear and logistic regression.

W.-Y. Lim et al. / General Hospital Psychiatry 36 (2014) 63–67

Secondly, the CIDI instrument that we used to diagnose mental illnesses has not been clinically validated in our population. However, CIDI has been validated in various populations around the world, including Asian ones [30,31], and it is likely that the sensitivity and specificity of this instrument would be reasonable. Thirdly, we did not obtain information about forms of nicotine use other than cigarette smoking, and so there could be residual confounding by nicotine consumption. However, we do not believe that this misclassification is significant. Data available online from Singapore Customs show that cigarettes represent about 95% of tobacco by weight that was brought legally into Singapore in 2011[32]. Finally, we depended on self-reported physician-diagnosed PUD rather than obtaining this information from medical or endoscopic records of the participants. It was not operationally feasible within our study setting to obtain medical records from participants. This reliance on self-reports could have led to misclassification with both under-estimates (if participants had not been informed or did not remember their condition), or over-estimates of the true prevalence (if participants considered other related gastrointestinal conditions such as gastritis and gastro-esophageal reflux disease as PUD) of PUD being possible. We think that the latter is not likely, as we specifically asked about a history of stomach ulcers, rather than about symptoms. This misclassification could also have affected the associations that we detected between mental illnesses and PUD. It is possible that people with mental illnesses are less likely to have sought professional medical help for PUD. If this is so, our findings of an association between mental illnesses and PUD would have been biased towards the null, and the true association would have been even greater. In conclusion, we show in this study an overall prevalence of selfreported PUD of 1.58%. We find an association of PUD with anxiety disorders that is not attenuated with adjustment for nicotine dependence or alcohol use disorder. PUD is associated with poorer quality of life as measured with the Euro-Qol instrument. Concomitant mental illness further increases this decline in quality of life. Acknowledgment The study was funded by the Singapore Millennium Foundation and the Ministry of Health, Singapore. References [1] Alp MH, Court JH, Grant KA. Personality pattern and emotional stress in the genesis of gastric ulcer. Gut 1970;11(9):773–7. [2] Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1984;1(8390):1311. [3] Sostres C, Gargallo CJ, Arroyo MT, Lanas A. Adverse effects of non-steroidal antiinflammatory drugs (NSAIDs, aspirin and coxibs) on upper gastrointestinal tract. Best Pract Res Clin Gastroenterol 2010;24(2):121–32. [4] Parasher G, Eastwood GL. Smoking and peptic ulcer in the Helicobacter pylori era. Eur J Gastroenterol Hepatol 2000;12(8):843–53. [5] Piper DW, Nasiry R, McIntosh J, Shy CM, Pierce J, Byth K. Smoking, alcohol, analgesics, and chronic duodenal ulcer. A controlled study of habits before first symptoms and before diagnosis. Scand J Gastroenterol 1984;19(8):1015–21. [6] Zhang L, Ren JW, Wong CCM, et al. Effects of cigarette smoke and its active components on ulcer formation and healing in the gastrointestinal mucosa. Curr Med Chem 2012;19(1):63–9. [7] Franke A, Teyssen S, Singer MV. Alcohol-related diseases of the esophagus and stomach. Dig Dis 2005;23(3–4):204–13.


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