1 LITHUANIAN UNIVERSITY OF HEALTH SCIENCES DEPARTMENT OF GASTROENTEROLOGY MEDICAL ACADEMY FACULTY OF MEDICINE

LITHUANIAN UNIVERSITY OF HEALTH SCIENCES DEPARTMENT OF GASTROENTEROLOGY

MEDICAL ACADEMY FACULTY OF MEDICINE

The Impact of Nutritional and Lifestyle Habits on the Development of GERD and the Influence of Antireflux Medications Use on the Development of Erosive Esophagitis.

Master’s thesis:

Or Shemesh Supervisor: Dr. Mindaugas Urba Consultant: Dr. Rūta Petereit, Phd

Table of Contents

1 SUMMARY ... 3

2 ACKNOWLEDGEMENTS ... 4

3 CONFLICT OF INTEREST ... 5

4 CLEARANCE ISSUED BY THE ETHICS COMMITTEE ... 6

5 LIST OF ABBREVIATIONS ... 7

6 INTRODUCTION ... 8

7 AIM AND OBJECTIVES ... 9

1 SUMMARY

The research was done by 6th_{-course medicine faculty-student Or Shemesh.}

1.1 Title: The impact of nutritional habits and lifestyle on the development of GERD, and the relationship between antireflux medications and the development of erosive esophagitis

7.1 Aim of the study:

Aim of the study: to evaluate the influence of diet and lifestyle on the development of GERD in the general population and to evaluate the prevalence of erosive esophagitis influence of medication use on the development of erosive esophagitis in patients who were diagnosed with GERD and underwent endoscopic examination.

1.2 Objectives:

1. To evaluate the prevalence of GERD among gender and age groups in the general population. 2. To evaluate the influence of diet on the development of GERD.

3. To evaluate the influence of lifestyle on the development of GERD. 4. To evaluate the prevalence of erosive esophagitis.

5. To evaluate the influence of antireflux medications use on the development of erosive esophagitis. 1.3 Methodology: a case-control study that evaluates the influence of diet and lifestyle on the development

of GERD. The first of the general population have filled in questionnaires about their diet habits and lifestyle. Diet habits included consumption of caffeine, alcohol, soft drinks, take away food (fatty and oily food), spicy food and chocolate. The lifestyle aspect focused on smoking, BMI and sleep regime (time of last meal before going to sleep). Another part of the study focused on the second group of subjects in whom GERD was previously diagnosed and endoscopic examination of the upper GI tract was done. This group was evaluated for the development of erosive esophagitis based on gender and antireflux medications use.

2 ACKNOWLEDGEMENTS

4 CLEARANCE ISSUED BY THE ETHICS COMMITTEE

Title: The impact of nutritional habits on the development of GERD and the probability of developing erosive esophagitis in the general population.

5 LIST OF ABBREVIATIONS

NERD- non-erosive reflux disease LES – lower esophageal sphincter. BMI – body mass index.

GI tract – gastrointestinal tract. PPI – proton pump inhibitors.

6 INTRODUCTION

Gastroesophageal reflux disease is a very common gastrointestinal disorder in western society, affecting as high as 50% of the population (1). Whilst symptoms are usually light or even not felt, a chronic disease may lead to structural changes in the esophagus that may lead to more severe esophageal and extraesophageal complications such as esophagitis, erosive esophagitis, Barrette's esophagus and esophageal strictures.

There is a very fine line between physiologic reflux and GERD. Physiological reflux of gastric contents into the esophagus can be normal in many individuals GERD is defined as symptoms and/or complications as a result of reflux of gastric content into the esophagus by The Montreal Definition and Classification Global Consensus Group (2).

Symptoms are usually heartburn and regurgitation. Heartburn is a burning sensation behind the sternum. Regurgitation is the passage of gastric contents into the mouth. Extraesophageal symptoms such as dental erosions, laryngitis, cough, and asthma may arise as well (2). According to the literature, the causes of GERD vary from the influence of diet to an infection with Helicobacter Pylori.

One of the chronic complications of GERD is erosive esophagitis. Erosive esophagitis appears due to reflux of gastric acid and pepsin which result in necrosis of esophageal surface mucosa. The presence of erosive esophagitis may be asymptomatic or accompanied by regurgitation, heartburn, dysphagia, and odynophagia. (3)

7 AIM AND OBJECTIVES

The study aims to evaluate the influence of diet and lifestyle on the development of GERD in the general population and to evaluate the prevalence of erosive esophagitis influence of medication use on the development of erosive esophagitis in patients who were diagnosed with GERD and was examined by endoscopic evaluation.

7.2 Objectives:

6. To evaluate the prevalence of GERD among gender and age groups in the general population. 7. To evaluate the influence of diet on the development of GERD.

8. To evaluate the influence of lifestyle on the development of GERD. 9. To evaluate the prevalence of erosive esophagitis.

8 LITERATURE REVIEW

Gastroesophageal reflux disease is a chronic condition in which gastric contents backflow occurs from the stomach into the esophagus. Mainly a clinical diagnosis based on symptoms when the main symptom is heartburn and acid regurgitation which is experienced in a lesser amount of people (2).

8.1 Epidemiology:

The exact prevalence of GERD is difficult to accomplish because many people even those with complications such as esophagitis or even Barrett’s esophagus are asymptomatic and exact testing such as endoscopy and esophageal PH monitoring are hard to establish (4). The worldwide prevalence of GERD according to a systematic review done in 2014 is: 19.8 % in North America, 15.2% in Europe, 14.4% in the Middle East and East Asia had the lowest prevalence with 5.2%. incidence in North America (5).

It is estimated that 20% - 40% of patients who complain of heartburn will be diagnosed with GERD at some point (6).

8.2 Classification:

Based on endoscopic examination GERD can be classified into erosive reflux disease where breaks in the esophageal mucosa are seen and non-erosive reflux disease (NERD) where symptoms are present but mucosal damage is not seen (7). Erosive esophagitis can be subclassified further into conditions that esophageal injury can cause (esophageal syndromes) which include, reflux esophagitis, reflux stricture, Barrett esophagus and esophageal adenocarcinoma and into conditions that have established relationship with GERD (extraesophageal syndromes) which include dental erosions, laryngitis, cough and asthma (8).

8.3 Causes and risk factors:

peppermint. Lastly medications such as SSRI anti-depressants, anticholinergics, inhaled bronchodilators and birth control pills (6)(10).

8.4 Pathophysiology:

Pathophysiology of GERD is multifactorial, except for LES dysfunction it can be attributed to esophageal dysmotility which delays refluxate clearance back into the stomach, increase abdominal pressure which exceeds the LES resting pressure (as seen in obesity) and decreased thoracic pressure due to increase respiratory effort in chronic pulmonary diseases. It is now attributed to failure of epithelial defense mechanisms as well (11).

8.5 Complications:

Esophagitis is the most common complication of GERD; this is an inflammation of the esophageal mucosa which cause erosions and is seen in 18%-25% of symptomatic GERD patient. Esophagitis might occur with typical symptoms or be asymptomatic. Diagnosis is made using an endoscopic examination of the upper GI tract. Esophagitis should be treated with long-term PPI but when effectiveness is proven dose should be adjusted to the lowest effective dose (12). In the current era of antisecretory medications, esophagitis (both erosive and peptic) becoming a rarer diagnosis (13).

Esophageal strictures are the result of the healing of ulcerative esophagitis, and usually, cause narrowing of the esophageal lumen (14).

Barrett’s esophagus is a more severe complication of GERD which is characterized by columnar metaplasia of the stratified squamous epithelium which normally lines the esophagus. Barrett’s esophagus is considered a precancerous condition (14).

8.6 Diagnosis:

to estimate the severity of the patient’s regurgitation, this procedure is indicated for patients who do not respond to treatment with PPI, patients with atypical presentation of GERD, patients who experience ADRs and patients being evaluated for surgical correction (6) Barium esophagogram is an available, non-invasive imagine technique (15). It is useful in diagnosing hiatal hernia but may be useful in the detection of peptic strictures. As well it is useful in the diagnosis of moderate to severe esophagitis with a sensitivity of 79%-100%. Reflux of barium into the esophagus is highly specific for GERD but sensitivity is not so high because many factors such as leg lifting, coughing, or Valsalva maneuver may elicit stress reflux (4). Esophageal manometry can now evaluate LES pressure and relaxation as well as peristaltic activity, yet manometry is not usually prescribed for evaluation of uncomplicated GERD because most patients will have a normal resting LES pressure (16). Manometry will usually be indicated before surgical correction of LES because if peristalsis disorders present, a complete fundoplication may be contraindicated (17).

8.7 Treatment:

Treatment goals are to provide symptomatic relief and to prevent complications in patients without esophagitis, in a patient with esophagitis the goal is to provide symptomatic relief and to treat esophagitis (7,18).

Lifestyle modifications are usually offered to patients to help and avoid symptoms. Modifications include avoiding provoking foods (commonly include fatty food, alcohol, coffee chocolate and mint), avoiding acidic food (including citrus and tomatoes), adapting behavior that minimizes reflux (13). Weight reduction in obese patients, smoking cessation and in case of nocturnal reflux sleeping in with head elevated are offered to the patients as well (12).

Patients presenting with typical symptoms and history should be given a trial of PPI once daily for a minimum of 4 weeks (19). Maintenance therapy with PPI is prescribed for patients in whom relapse occurs after discontinuation of PPI, relapse will be seen in 80% of patients in the first year usually in the first 3 months (7,20).

9 RESEARCH METHODOLOGY

This research is a retrospective study is divided into two parts:

- The first part checks the impact of lifestyle diet on the development of GERD in the general population using questionnaires. Using an 18-item questionnaire evaluation of the impact of diet habits and lifestyle on the development of heartburn as an individual symptom and GERD as diseas. The questionnaires evaluated: gender, age, weight and height of the subject alongside the diet habits and lifestyle such as take away food consumption (which includes oily fatty and food), spicy food consumption, chocolate consumption, caffeine consumption, soft sparkling drinks consumption, alcohol consumption, smoking and sleep regime (eating close to bedtime).

- The second part evaluates the influence of medication use on the development of erosive esophagitis in subjects previously diagnosed with GERD and who underwent endoscopy. The information known about the subjects that underwent endoscopy is gender, age, medication use and endoscopy results.

9.2 Statistical analysis

10 RESULTS

The research was conducted on two groups of subjects, the characteristic of both groups can be seen in Table 1.

The first group included 232 individuals from the general population on which the evaluation of lifestyle and diet habits were evaluated.

The second group included 82 individuals who were diagnosed with GERD and underwent endoscopic examination of the upper GI tract.

Table 1: Characterization of gender, age and BMI of the participants.

General population GERD confirmed by endoscopy

Subjects (N) (Female/Male) 232 (150/82) 82(48/34)

Age (mean (SD)) 35.27±16.24 47±18.01

BMI (mean (SD)) 23.8±5.26 -*

*data was not available due to technical issues due to Covid-19

This section (Figures 1-3, Tables 2-8) will discuss the results of the first group of subjects in which total of 232 questionnaires were filled by individuals from the general population which evaluated their lifestyle and nutritional habits, whether they suffer from heartburn and if they have or have not been diagnosed with GERD by a doctor. The results are shown in Figure 1 and Figure 2.

Figure 1. Subjects suffering from heartburn

Suffer from heartburn 16%

Do not suffer from heartburn

84%

Figure 2. Subjects diagnosed with GERD

In order to calculate prevalence, the subjects were divided into 3 age groups: young adults (20-35), middle-age (36-55) and older adults (older than 55) and 2 sex groups (female and male). A total of 16.4% (38 subjects) reported to be suffering from heartburn from which 11 males and 27 females. Out of the 38 subjects who reported to be suffering from heartburn 24 (63.15% of symptomatic subjects and 10.34% of total subjects) subjects were diagnosed with GERD. Further division into age groups can be seen in table 2 and table 3.

Table 3. description of GERD prevalence within sex and age group Male Female Young adults 20% 80% Middle age -* -* Older adults 55.55% 45.45% Total 3.44% 6.89%

*no subjects were diagnosed with GERD.

In a statistical chi-square test, no statistically significant difference was found between age groups nor gender for the development of heartburn or GERD.

The data collected regarding diet habits and lifestyle showed the following results: • Smoking: 204 subjects (87.6% do not smoke) and 29 subjects (12.4%) do smoke.

• Caffeine consumption: 156 subjects (67.2%) consume caffeinated beverages 1-3 times per day, 50 subjects (21.6%) do not consume caffeinated beverages at all, and 26 subjects (11.2%) consume caffeinated beverages more than 3 times per day.

• Alcoholic beverages: 122 subjects (52.4%) do not consume alcohol at all on a regular basis, 99 subjects (42.5%) consume alcohol 1-2 times per week, 6 subjects (2.6%) consume alcohol 3-5 times per week and another 6 subjects (2.6%) consume alcohol 6-7 times per week.

• Soft sparkling beverages: 107 subjects (46.1%) do not consume soft sparkling beverages at all, 80 subjects (34.5%) consume soft sparkling beverages 1-2 times per week, 23 subjects (9.9%) consume soft sparkling beverages 2-5 times per week and another 22 subjects (9.5%) consume soft sparkling beverages 6-7 times per week.

• Take away food: 123 subjects (52.8%) eat take away food 1-2 times per week, 90 subjects (38.6%) do not eat take away food at all, 19 subjects (8.2%) eat take away food 3-5 times per week and another 1 subject (0.4%) eat take away food 6-7 times per day.

• Chocolate - 101 subjects (43.5%) eat chocolate 1-2 times per week, 53 subjects (22.8) eat chocolate 3-5 times per week, 42 subjects (18.1%) eat chocolate 6-7 times per week and another 36 subjects (15.5%) do not eat chocolate at all.

Provocation of heartburn by certain products: out of the 233 subjects who participated in this questionnaire, 231 answered the question if they feel heartburn after consuming any of the products listed above. Out of 231 subjects, 187 subjects (81%) did not feel heartburn and 44 (19%) did feel heartburn after consuming any of the products above.

The products that mostly provoked heartburn can be seen in figure 3. Some subjects reported that more than 1 product but not all of them causing heartburn.

Figure 3. Provoking products

The Chi-Square statistic test was used for testing relationships between food and beverage types to the development of heartburn symptoms. The null hypothesis of the chi-square test is that there is no relationship between food and beverage consumption to the development of heartburn. in Table 4 the observed value represents the amount of people who complained of heart burn and consumed a specific product. caffeine 9% alcohol 13% sparkling drinks 9%

take away food 29% spicy food 18% chocolate 15% all 7%

Table 4. food products provoking heartburn

Observed (n) Expected (n) P-value Odds ratio

Caffeine 28 29.6 0.481 0.750

Alcohol 14 18.2 0.138 0.583

Soft drinks 23 22.1 0.749 1.123

Take away food 20 23.3 0.235 0.656

Spicy food 21 22.7 0.538 0.802

Chocolate 36 31.9 0.049 3.962

It can be concluded that only the variables with a P value less than 0.05 have a significant relationship between the considered variables. It is seen that the P-value of chocolate (0.049) is less than 0.05 thus, the null hypothesis is rejected, and it can be concluded that chocolate had a significant effect on the development of heartburn, that info is supported by an odds ratio of 3.962 which tells that there is a strong association between chocolate consumption and heartburn.

Another Chi-Square statistic test was used for testing relationships between a certain food and beverage types to the development of GERD. The null hypothesis of the chi-square test is that there is no relationship between food and beverage consumption to the development of GERD. Even though a statistically significant difference was not observed in the relationship between soft drinks consumption and heartburn (no P value was smaller than 0.05), an odds ratio of 1.123 shows that there is an association between the consumption of soft drinks and the sensation of heartburn. In Table 5 the observed value represents the amount of people who were diagnosed with GERD and consume certain product.

Table 5. Relationship between diet habits and GERD diagnosis

Observed (n) Expected (n) P-value Odds ratio

Caffeine 19 18.7 0.886 1.079

Alcohol 10 11.5 0.522 0.757

Soft drinks 13 14 0.673 0.833

Take away food 13 14.7 0.455 0.724

Spicy food 13 14.3 0.556 0.775

In this case, no P value was smaller than 0.05 thus, the null hypothesis is not rejected, and it is concluded that there is no strong relationship between the development of GERD and nutritional habits. Yet it is possible to see an association between subjects who were diagnosed with GERD and consumption of caffeine thanks to an odds ratio of 1.079.

One of the aims was to evaluate the subject’s lifestyle, this was done by questions about smoking, calculation of BMI (using height and weight data from the questionnaires) and sleeping regime (follows the finger rule that that ideally you should not eat 3 hours before sleep). The null hypothesis, in this case, was that obesity smoking and eating less than 3 hours before going to sleep are independent from heartburn and the development of GERD. The distribution of the lifestyle habits is as follows: out of the 232 subjects, 18 subjects are obese (BMI 30 or higher), 28 subjects are smoking, and 136 subjects sleep less than 3 hours before bedtime.

Table 6. Relationship between obesity and development of heartburn and GERD

Observed Expected P-value Odds ratio

Have heartburn (n) 6 3.3 0.120 2.357

Diagnosed with GERD (n)

4 2.1 0.187 2.350

In table 6 it is possible to see that that there is no statically significant difference in the relationship between obesity and heartburn development (P-value 0.120) and GERD (P-value 0.187). Yet, odds ratio for both subjects with heartburn and GERD diagnosed subjects was bigger than 1 so we can conclude that there is an association between obesity to heartburn and GERD.

Table 7. Relationship between smoking and development of heartburn and GERD

Observed (n) Expected (n) P-value Odds ratio

Have heartburn (n) 7 4.6 0.189 1.860

Diagnosed with GERD (n)

As seen in table 7 no P-value was lower than 0.05 thus null hypothesis is accepted, and we can conclude that there is no statically significant difference in the relationship between the development of heartburn and GERD. Yet again odds ratio of more than 1 shows an association between smoking and the development of heartburn and GERD.

Table 8. Evaluation of the relationship between heartburn GERD and sleep regime

Observed (n) Expected (n) P-value Odds ratio

Have heartburn 28 22.5 0.041 2.276

Diagnosed with GERD 19 13.4 0,009 4.601

In table 8 chi-square statistical test for the relationship between the last meal before going to sleep and the development of GERD and heartburn can be seen. Both P values (0.041 for heartburn and 0.009 for GERD) are smaller than 0.05 thus, the null hypothesis is rejected, and we can conclude that heartburn and sleep regime as well as GERD and sleep regime are directly related to each other. This is supported by odds ratio values (2.276 for heartburn and 4.601 for GERD) which are both bigger than 1.0.

This section (Tables 9-10) will discuss the results of the second group of subjects which included 82 individuals who were diagnosed with GERD and underwent endoscopic examination of the upper GI tract. In order to evaluate the prevalence of erosive esophagitis and the influence of medication use on the development of erosive esophagitis the second group of people was used. In this group, all subjects were previously diagnosed with GERD and underwent endoscopic examination for evaluation. The data regarding prevalence among the 82 subjects is presented in Table 9.

Table 9. Prevalence of erosive esophagitis

total Male female

Mean age 47±18.01 44.24±18.294 49.19±17.708

Erosive esophagitis 40.24% (n=33) 21.95% (n=18) 18.29% (n=15)

2.457 which suggests that the male gender is more likely to be related to the development of erosive esophagitis.

Out of the 82 subjects, data regarding the usage of medications was available only for 66 subjects. The data is presented in table 10.

Table 10. Use of antireflux medications

Taking medications (n) Not taking medications (n)

NERD 23 (34.84%) 11 (16.66%)

Erosive esophagitis 23 (34.84%) 9 (13.63%)

11 DISCUSSION

In this study, the aim was to evaluate the influence of diet and lifestyle on the development of GERD and to evaluate the influence of medication use on the development of erosive esophagitis in the general population.

11.1 The prevalence of GERD

This research has shown no statistically significant difference between men and women in symptomatic and previously diagnosed GERD patients. In a study done by Young Sun Kim (22), it was found that GERD affects women in a higher proportion than man however men tend to develop complications more often than women do. This may be attributed to the effect of estrogen and better mucosal protection of the esophagus in women. Another study by Sang Yoon Kim supported those findings by finding that while men will suffer more often from reflux esophagitis, women will more commonly have symptomatic GERD.

11.2 The influence of diet and lifestyle on the development of GERD

In an article written by Peter J Kahrilas, MD (21) in the database UpToDate it was stated that chocolate, peppermint, and fatty foods, as well as caffeine and alcohol, are related to the development of GERD. In this study, only chocolate showed a statistically significant in the development of GERD and heartburn, yet odds ratio calculation of the results showed that caffeine consumption does favor the development of GERD, this is supported as well by an article written by Teodora Surdea-Blaga (8), where it was stated that caffeine and chocolate induce gastroesophageal reflux. Also, in an article by Tang-Wei Chuang and co (23), it was stated that intake of fatty foods, spicy foods, alcohol, caffeine and carbonated drinks is associated with aggravation of GERD. In this study even though the largest number of subjects reported that take-out food (which includes oily and fatty food) is inducing heartburn, it was not found to be statistically significant different.

supported by an article written by Tetsuya Murao in Japan that did not find coffee can induce GERD symptoms (24).

A systematic review done by Tonya Kaltenbach (19) shown: inconclusive results whether alcohol consumption is related to GERD development, carbonated soft drinks have been related to GERD symptoms in multiple studies, caffeinated beverages have shown no increase in GERD, Which is supported by this study.

In this study, obesity did not show a statistically significant difference for GERD development. Yet calculation of odds ratio showed that obese individuals are more likely to have GERD. This finding is supported by a study done by Peter J. Kahrilas (17), which found a strong relationship between obesity and GERD.

However, this study found a very strong relationship between eating close to bedtime and symptomatic GERD. This fact is supported by a study done by Ling-Zhi Yuan and co (19), it was mentioned that GERD is not only attributed to what you eat but also to the way you eat, such as overeating, fast eating and eating before going to sleep.

11.3 Prevalence of erosive esophagitis and influence of antireflux medications use on the development of erosive esophagitis

This study found that the prevalence of erosive esophagitis is 40.24% among subjects with GERD. This is supported by the book, CONN’S CURRENT THERAPY 2021 (26), where it is stated that erosive esophagitis is observed in less than 50 percent of patients with GERD. On the other hand, in an article by Cesario Silvia et al from Italy (27), it was found that less than 30% of patients will develop erosive esophagitis.

11.4 Limitations

12 CONCLUSIONS

This study focused on the prevalence of GERD its provoking factors, the prevalence of erosive esophagitis among GERD patients and the relationship between antireflux medications and the development of erosive esophagitis. GERD is a condition with relatively high prevalence within the general population in western society.

1. There is no statistically significant difference between genders and age groups in the development of GERD and its symptoms.

2. In the aspect of diet, chocolate is the biggest contributor to GERD development, but caffeine and soft drinks do show some relation to the development of GERD and its symptoms.

3. In the aspect of lifestyle, eating close to bedtime was found to be the biggest contributor to the development of GERD and its symptoms. Obesity and smoking did show contribution as well but without statistically significant difference.

4. Almost half of the patients diagnosed with GERD will develop erosive esophagitis.

5. Statistically significant difference was not found between genders with erosive esophagitis, but odds ratio calculation did show that the male gender is more likely to develop erosive esophagitis. 6. There is no statistically significant relationship between the use of antireflux medications and the

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14 . ANNEX

Do you suffer from heartburn? • Yes

• No

Have you ever been diagnosed with gastroesophageal reflux disease? • Yes

• No • Maybe

• 0 • 1-3

• more than 3

How many times per week do you usually consume alcoholic beverages? • 0

• 1-2 • 3-5 • 6-7

How many times per week do you usually consume soft drinks (Coke, Sprite, Fanta etc.) ? • 0

• 1-2 • 3-5 • 6-7

How many times per week do you usually eat take away food? • 0

• 1-2 • 3-5 • 6-7

How many times per week do you usually eat spicy food? • 0

• 6-7

How many times per week do you usually eat chocolate? • 0

• 1-2 • 3-5 • 6-7

Do you feel heartburn more often after consuming any of the above mentioned food? • Yes

• No

If yes which one?

Your answer

Do you use any medication to relieve the heartburn? • Yes

• No

If yes which one?

Your answer