Preface

Writing this book on gastroesophageal reflux disease is the result of a long journey of work. When I left the UK 27 years ago and after I received a fellowship from the Royal College of Surgeons of Edinburgh, I did my surgical training and joined the surgery department at Zliten University Hospital as young surgeon. At that time there were no surgeons performing endoscopy at the hospital and because I was encountering patients with upper gastrointestinal bleeding I had to perform elective and emergency upper gastrointestinal endoscopy. During this time in surgical endoscopy I faced many patients who came for diagnosis with symptoms typical of gastroesophageal reflux disease. Some of these patients were treated with medicine and others with surgery where reflux only, or reflux with hiatus hernia was diagnosed. From that day to this the idea of publishing a book on gastroesophageal reflux disease was born, and has now come to reality. Since gastroesophageal reflux disease is a common benign clinical problem in most countries and most practicing doctors will face patients who will need diagnosis and treatment. This book will be useful for resident upper gastrointestinal tract surgeons and gastroenterologists, as well as general practitioners. The book discusses the increase in gastric acid secretion and reactive oxygen species in the pathophysiology of reflux esophagitis, as well as the treatment and diagnosis of refractory gastroesophageal reflux disease. Gastroesophageal reflux disease can be seen in any age group and in the book there is a chapter that discusses the presentation, diagnosis and treatment of the disease in children. Finally, I would like to thank all authors for their contributions and for distributing their valuable knowledge to readers all over the world. Great thanks must go to Dolores Kuzelj who shared our long journey and put all her efforts into making this book a reality. My thanks also go to the IntechOpen publisher staff.

> **Ali Ibrahim Yahya** Director of Zliten University Hospital, Alsumaria University, Zliten, Libya

**1**

**Chapter 1**

*Ali I. Yahya*

**1. Introduction**

female, of 40 years old.

**2. History of GERD**

gastroesophageal reflux.

gastroesophageal reflux.

**3. Anatomy and Physiology**

these factors include the following:

Introductory Chapter:

Gastroesophageal Reflux Disease

Gastroesophageal reflux disease (GERD) occurs frequently in developed

1855—Bowditch Rokitansky reported that esophagitis was due to gastroesophageal reflux. Allison and Barrett found the association between hiatus hernia and

1828—Charles Millard in Paris noticed the first case of esophagitis in child. 1879—Heinrich Quincke reported that ulceration in the esophagus was due to

1920—Joseph Sheehan described the endoscopic findings of esophagitis. 1921—Porter Vinson noted the association between stricture and esophagitis.

1956—Rudolf Nissen performed a successful fundoplication for patient, who suffered from GERD, with hiatus hernia. Patient was cured from the complaint.

At the lower end of the esophagus is a sphincter which is formed by a change in the muscles of the esophagus. This sphincter controls the flow of esophageal contents to the stomach. Different factors related to the anatomy and physiology of the sphincter prevent the reflux of gastric contents into the esophagus. Among

1.High pressure zone: Pressure at the lower esophageal sphincter area is high than stomach pressure (gastric pressure is +4 to +6, at the lower esophageal sphincter is +24 mmgh, and in the thoracic esophagus is −6). Because of the high

1906—Tilston described the typical symptoms of esophagitis.

1934—Hampel introduced the term peptic esophagitis.

countries. The number of cases, in fact, is increasing in the Middle East countries. In western countries, its occurrence ranges from 10 to 20% of the population who may present with typical or atypical symptoms or with complications. Although GERD was described by Asher Winkelstein, an American gastroenterologist, in 1935, it had appeared among patients earlier than that time. Nowadays, cases of GERD are common among obese individuals, patients with gallbladder disease, and those individuals under stress. It has also become a common clinical problem that commonly affects young adults, both male and

#### **Chapter 1**

## Introductory Chapter: Gastroesophageal Reflux Disease

*Ali I. Yahya*

#### **1. Introduction**

Gastroesophageal reflux disease (GERD) occurs frequently in developed countries. The number of cases, in fact, is increasing in the Middle East countries. In western countries, its occurrence ranges from 10 to 20% of the population who may present with typical or atypical symptoms or with complications. Although GERD was described by Asher Winkelstein, an American gastroenterologist, in 1935, it had appeared among patients earlier than that time. Nowadays, cases of GERD are common among obese individuals, patients with gallbladder disease, and those individuals under stress. It has also become a common clinical problem that commonly affects young adults, both male and female, of 40 years old.

#### **2. History of GERD**

1855—Bowditch Rokitansky reported that esophagitis was due to gastroesophageal reflux. Allison and Barrett found the association between hiatus hernia and gastroesophageal reflux.

1828—Charles Millard in Paris noticed the first case of esophagitis in child.

1879—Heinrich Quincke reported that ulceration in the esophagus was due to gastroesophageal reflux.

1906—Tilston described the typical symptoms of esophagitis.

1920—Joseph Sheehan described the endoscopic findings of esophagitis.

1921—Porter Vinson noted the association between stricture and esophagitis.

1934—Hampel introduced the term peptic esophagitis.

1956—Rudolf Nissen performed a successful fundoplication for patient, who suffered from GERD, with hiatus hernia. Patient was cured from the complaint.

#### **3. Anatomy and Physiology**

At the lower end of the esophagus is a sphincter which is formed by a change in the muscles of the esophagus. This sphincter controls the flow of esophageal contents to the stomach. Different factors related to the anatomy and physiology of the sphincter prevent the reflux of gastric contents into the esophagus. Among these factors include the following:

1.High pressure zone: Pressure at the lower esophageal sphincter area is high than stomach pressure (gastric pressure is +4 to +6, at the lower esophageal sphincter is +24 mmgh, and in the thoracic esophagus is −6). Because of the high pressure at the sphincter, reflux is prevented. There are specific factors which will increase the tone of the sphincter, as well as factors like taking fatty meals, chocolate, smoking, and oral contraceptives that will reduce the tone of the sphincter.


### **4. Clinical presentation of gastroesophageal reflux disease**

GERD appears with typical symptoms or rarely by atypical symptoms, which resemble cardiac symptoms and have been called cardiac symptoms.

#### **4.1 Typical symptoms**

Typical symptoms which appear among 70% of patients include the following:


Some rare presenting complaints, with rate of occurrence among patients, are as follows:

**3**

**Figure 1.**

*Introductory Chapter: Gastroesophageal Reflux Disease DOI: http://dx.doi.org/10.5772/intechopen.84879*

Atypical symptoms are those where the patient will present with symptoms not related to gastrointestinal system: coughing, wheezing, recurrent pharyngitis, laryngitis, and chest pain. Its acute onset may resemble acute myocardial

**Patient may present with complicated gastroesophageal reflux disease** some symptoms include the following: stricture, Barrett esophagus, lung damage in

1. **Upper gastrointestinal endoscopy:** Upper gastrointestinal endoscopy is very

2.**Contrast barium study:** It is applied to detect hiatal hernia and esophageal stricture [8]. Barium contrast study can show hiatus hernia which can be small

3.**PH monitoring:** 24 pH monitoring is very important in atypical presentation of gastroesophageal reflux disease [9, 10]. It can confirm or exclude the disease, with a diagnostic rate of 70–90%. It is not indicated in patients with esophagitis.

important to exclude other serious disease which may mimic reflux, like tumors [7]. Upper gastrointestinal endoscopy can confirm hiatus hernia (**Figure 1**). Esophagitis will be experienced by 50% of patients with GERD. It can also diagnose Barrett

the form of pneumonia, and lung fibrosis if condition goes chronic.

esophagus and esophageal peptic stricture (**Figure 2**).

*The use of upper gastrointestinal endoscopy showing hiatus hernia in patient with GERD.*

**4.2 Atypical symptoms**

infarction.

**5. Investigations**

or large sac (**Figures 3–5**).


#### **4.2 Atypical symptoms**

*Gastroesophageal Reflux Disease - Theory and Research*

prevention of the gastroesophageal reflux.

which will reduce the effect of the acid refluxate.

symptom is seen among 50% of patients [1–6].

**4. Clinical presentation of gastroesophageal reflux disease**

resemble cardiac symptoms and have been called cardiac symptoms.

sphincter.

**4.1 Typical symptoms**

80% of patients.

reflux disease.

1.Abdominal pain: 30%

2.Belching: 30%

3.Coughing: 20%

4.Wheezing: 10%

pressure at the sphincter, reflux is prevented. There are specific factors which will increase the tone of the sphincter, as well as factors like taking fatty meals, chocolate, smoking, and oral contraceptives that will reduce the tone of the

2.The length of the lower esophageal sphincter is 3 cm which is divided into abdominal part and thoracic part. If the abdominal part is less than 2 cm, patient will get reflux. Other factors like change of mucosa, the muscular coat of the stomach which will have oblique muscles in addition to the other two types of circular and longitudinal, crural effect and angulation of the esophagus to the stomach which is called Angle of His are not important in the

3.Other factors that increase the effect of acid on the esophagus. Among these factors include the delayed gastric emptying. The increasing amount of the food in the stomach will lead to absorption of the sphincter and will increase the reflux. Reduced mucus and reduced saliva will lead to reduced bicarbonate

GERD appears with typical symptoms or rarely by atypical symptoms, which

Typical symptoms which appear among 70% of patients include the following:

1.Retrosternal pain (i.e., heart burn): It is the most common symptom which will be more manifested when patient is lying down or after meal and is seen among

2.Regurgitation: It is a symptom observed when gastric or esophageal content comes in the mouth effortlessly. Regurgitation of gastric content will reach tracheobronchial tree and will induce hoarseness of voice which is usually experienced in the morning. This hoarseness could be due to reflux of gastric content into the larynx or due to vagal irritation and will induce reflex spasm of the vocal cords. This

3.Dysphagia: This is observed among 20% of patients with gastroesophageal

Some rare presenting complaints, with rate of occurrence among patients, are as

**2**

follows:

Atypical symptoms are those where the patient will present with symptoms not related to gastrointestinal system: coughing, wheezing, recurrent pharyngitis, laryngitis, and chest pain. Its acute onset may resemble acute myocardial infarction.

**Patient may present with complicated gastroesophageal reflux disease** some symptoms include the following: stricture, Barrett esophagus, lung damage in the form of pneumonia, and lung fibrosis if condition goes chronic.

### **5. Investigations**


4.**Gastroesophageal scintigraphy:** Where drink like orange juice or milk is labeled with technetium and is used to study reflux, this test is rarely used for diagnosis of GERD. It is used in small children where we can study the reflexate to the lung, and the test is easy in small babies in comparison to other invasive tests. Gastroesophageal scintigraphy is used for patient who presents with atypical reflux symptoms like recurrent upper respiratory symptoms.

**Figure 2.** *The use of upper gastrointestinal endoscopy showing peptic stricture.*

**5**

**Figure 5.**

**Figure 4.**

*Barium metal showing child hiatus hernia.*

than usual pH monitoring.

*Hiatus hernia with esophageal spasm.*

5.**Multichannel impedance pH monitoring:** It is a gold standard technique for diagnosis of GERD; it is more superior and more sensitive in diagnosing GERD

*Introductory Chapter: Gastroesophageal Reflux Disease DOI: http://dx.doi.org/10.5772/intechopen.84879*

**Figure 3.** *Barium metal showing hiatus hernia.*

*Introductory Chapter: Gastroesophageal Reflux Disease DOI: http://dx.doi.org/10.5772/intechopen.84879*

*Gastroesophageal Reflux Disease - Theory and Research*

*The use of upper gastrointestinal endoscopy showing peptic stricture.*

symptoms.

**Figure 2.**

4.**Gastroesophageal scintigraphy:** Where drink like orange juice or milk is labeled with technetium and is used to study reflux, this test is rarely used for diagnosis of GERD. It is used in small children where we can study the reflexate to the lung, and the test is easy in small babies in comparison to other invasive tests. Gastroesophageal scintigraphy is used for patient who presents with atypical reflux symptoms like recurrent upper respiratory

**4**

**Figure 3.**

*Barium metal showing hiatus hernia.*

**Figure 4.** *Barium metal showing child hiatus hernia.*

5.**Multichannel impedance pH monitoring:** It is a gold standard technique for diagnosis of GERD; it is more superior and more sensitive in diagnosing GERD than usual pH monitoring.

6.**Manometry:** It is a very important investigation to exclude motility disorders like achalasia and is indicated in patient who presents with atypical symptoms of gastroesophageal reflux disease. High-resolution manometry is more sensitive and superior than ordinary manometry in diagnosing esophageal motility disorders.

### **6. Treatment**

Reasons for treating GERD:


#### **6.1 Nonsurgical treatment of gastroesophageal reflux disease**

	- a.Avoid having late meals, heavy meals, spicy or fatty meals, drinking alcohol, and smoking.
	- b.Reduce weight; avoid tight clothes around the waist.
	- c.Avoid drugs which reduce the tone of sphincter.

Medical treatment where drugs are used to neutralize the effect of the reflux on esophageal mucosa:


**7**

*Introductory Chapter: Gastroesophageal Reflux Disease DOI: http://dx.doi.org/10.5772/intechopen.84879*

2.Development of complications of the drugs.

4.Atypical presentation with positive 24 h pH records.

5.Patients do not like to take drug for long life to control the symptoms.

It can be done by lengthening the lower esophageal sphincter to create valve-like action to prevent refluxing of gastric contents in the esophagus. Procedure is done by wrapping the stomach around the lower esophagus [18–20], either full wrap of 360° (which is named after Nissen) or partial wrap of 270°, either done posteriorly or anteriorly.

Fundoplication was previously performed by open surgery. Nowadays, most operations are done laparoscopically (**Figures 6** and **7**), with excellent outcome on

Patient will stop taking the drugs. All patients should be seen by gastroenterologist, ENT specialist, and surgeons before surgery, especially for those patients who

It is also called incisionless surgery. Endoscopic treatment of GERD is still under

frequency application or injection of ethylene vinyl alcohol in the region of the

2.Endoscopic augmentation of lower esophageal sphincter, either by radio

It is a new technique where there is no need to make wrapping around the lower esophagus by the stomach. This is a magnet ring fixed around the lower esophagus [31, 32]. It is not widely used and still under trial where magnet ring is fixed laparoscopically around the esophageal sphincter. It moves out once food comes in, and it comes back when the food enters the stomach. It has benefit

For many years, open surgery has been used for hiatus hernia but was rarely applied for GERD without hernia. Many operations can be done, either abdominal approach or thoracic approach. The common operation is the Nissen fundoplication which has been used since 1950, with a success rate of 80–90%. Its complication rate ranges from 10 to 15% and includes difficulty in swallowing and flatulence

3.Association with large hiatal hernia.

**7. Surgery**

Indication of surgery:

**7.1 Surgery for GERD**

1.Failure of medical treatment.

short-term and long-term follow-ups.

come with atypical symptoms of GERD.

which may go for some time than ease off.

1.Natural orifices transendoscopic surgery [21–25]

lower esophageal sphincter [26–30].

**7.3 Esophageal magnet ring**

**7.2 Endoluminal surgery (NOTES)**

investigation:

*Introductory Chapter: Gastroesophageal Reflux Disease DOI: http://dx.doi.org/10.5772/intechopen.84879*

#### **7. Surgery**

*Gastroesophageal Reflux Disease - Theory and Research*

disorders.

Reasons for treating GERD:

1.Change of lifestyle

2.Medical

effect.

twice daily.

stopped [14–17].

esophageal mucosa:

and smoking.

**6. Treatment**

6.**Manometry:** It is a very important investigation to exclude motility disorders like achalasia and is indicated in patient who presents with atypical symptoms of gastroesophageal reflux disease. High-resolution manometry is more sensitive and superior than ordinary manometry in diagnosing esophageal motility

2.Complications of GERD may cause esophagitis which will result to bleeding. Predisposition to Barrett esophagus that may turn to malignancy is 40–60 times

a.Avoid having late meals, heavy meals, spicy or fatty meals, drinking alcohol,

Medical treatment where drugs are used to neutralize the effect of the reflux on

a.Antacids: Drugs that will neutralize the acid effect include the following—calcium, aluminum, and magnesium compounds. These are best taken after meals. Their effect is brief; and once they get emptied from the stomach, the symptoms may come back. These need to be given on an hour base to neutralize the acid

b.Histamine antagonists: There are receptors on the acid-producing cells which are stimulated by histamine to produce acid. These receptors are blocked by histamine-blocking drugs which act on H2 receptors. These drugs are best taken before meals. These include cimetidine which can be given 400–800 mg daily, ranitidine given 150 mg twice daily, and famotidine given 20–40 mg

c.Proton-pump inhibitors: These include omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole. Their dosages range from 20 to 40 mg daily. PPI will cure the esophagitis up to 90%; 80% will recur within 1 year if treatment is

1.Heart burn is a troubling symptom and affects patient life.

**6.1 Nonsurgical treatment of gastroesophageal reflux disease**

b.Reduce weight; avoid tight clothes around the waist.

c.Avoid drugs which reduce the tone of sphincter.

seen in patient with reflux esophagitis-induced Barrett [11–13].

**6**

Indication of surgery:


#### **7.1 Surgery for GERD**

It can be done by lengthening the lower esophageal sphincter to create valve-like action to prevent refluxing of gastric contents in the esophagus. Procedure is done by wrapping the stomach around the lower esophagus [18–20], either full wrap of 360° (which is named after Nissen) or partial wrap of 270°, either done posteriorly or anteriorly.

Fundoplication was previously performed by open surgery. Nowadays, most operations are done laparoscopically (**Figures 6** and **7**), with excellent outcome on short-term and long-term follow-ups.

Patient will stop taking the drugs. All patients should be seen by gastroenterologist, ENT specialist, and surgeons before surgery, especially for those patients who come with atypical symptoms of GERD.

For many years, open surgery has been used for hiatus hernia but was rarely applied for GERD without hernia. Many operations can be done, either abdominal approach or thoracic approach. The common operation is the Nissen fundoplication which has been used since 1950, with a success rate of 80–90%. Its complication rate ranges from 10 to 15% and includes difficulty in swallowing and flatulence which may go for some time than ease off.

#### **7.2 Endoluminal surgery (NOTES)**

It is also called incisionless surgery. Endoscopic treatment of GERD is still under investigation:


#### **7.3 Esophageal magnet ring**

It is a new technique where there is no need to make wrapping around the lower esophagus by the stomach. This is a magnet ring fixed around the lower esophagus [31, 32]. It is not widely used and still under trial where magnet ring is fixed laparoscopically around the esophageal sphincter. It moves out once food comes in, and it comes back when the food enters the stomach. It has benefit

over Nissen fundoplication. The patient can belch, vomit, and have no gas bloat syndrome, and it is reversible. The technique, however, is still under long-term trials.

**Figure 6.** *Laparoscopic view of big hiatus hernia in patient presented with GERD.*

**9**

**Author details**

Ali I. Yahya

provided the original work is properly cited.

*Introductory Chapter: Gastroesophageal Reflux Disease DOI: http://dx.doi.org/10.5772/intechopen.84879*

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Zliten University Hospital, Alasmaria University, Zliten, Libya

\*Address all correspondence to: aliyahyaz60@hotmail.com

**Figure 7.** *Laparoscopic view of hiatus hernia in patient came with GERD symptoms.*

*Introductory Chapter: Gastroesophageal Reflux Disease DOI: http://dx.doi.org/10.5772/intechopen.84879*

*Gastroesophageal Reflux Disease - Theory and Research*

trials.

**Figure 6.**

over Nissen fundoplication. The patient can belch, vomit, and have no gas bloat syndrome, and it is reversible. The technique, however, is still under long-term

**8**

**Figure 7.**

*Laparoscopic view of hiatus hernia in patient came with GERD symptoms.*

*Laparoscopic view of big hiatus hernia in patient presented with GERD.*

#### **Author details**

Ali I. Yahya Zliten University Hospital, Alasmaria University, Zliten, Libya

\*Address all correspondence to: aliyahyaz60@hotmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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for selecting a proton pump inhibitor. The American Journal of Medicine. 2004;**117**(Suppl. 5A):14s-22s

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[18] Papasavas PK, Keenan RJ, Yeaney WW, Caushaj PF, Gagne DJ, Landreneau RJ. Effectiveness of laparoscopic fundoplication in relieving the symptoms of gastroesophageal reflux disease (GERD) and eliminating antireflux medical therapy. Surgical Endoscopy. 2003;**17**(8):1200-1205

[19] Wetscher GJ, Glaser K, Gadenstaetter M, Profanter C, Hinder RA. The effect of medical therapy and antireflux surgery on dysphagia in patients with gastroesophageal reflux disease without esophageal stricture. American Journal of Surgery. 1999;**177**(3):189-192

[20] Shaw JM, Bornman PC, Callanan MD, Beckingham IJ, Metz DC. Long-term outcome of laparoscopic Nissen and laparoscopic Toupet fundoplication for gastroesophageal reflux disease: A prospective, randomized trial. Surgical Endoscopy. 2010;**24**(4):924-932

[21] Mayor MA, Fernando HC. Endoluminal approaches to gastroesophageal reflux disease. Thoracic Surgery Clinics. 2018;**28**(4):527-532

[22] Cadiere GB, Buset M, Muls V, Rajan A, Rosch T, Eckardt AJ, et al. Antireflux transoral incisionless fundoplication using Esophy X: 12-month results of a prospective multicenter study. World Journal of Surgery. 2008;**32**(8):1676-1688

[23] Testoni PA, Testoni S, Mazzoleni G, Vailati C, Passaretti S. Long-term efficacy of transoral incisionless

fundoplication with Esophyx (Tif 2.0) and factors affecting outcomes in GERD patients followed for up to 6 years: A prospective single-center study. Surgical Endoscopy. 2015;**29**(9):2770-2780

[24] Huang X, Chen S, Zhao H, Zeng X, Lian J, Tseng Y, et al. Efficacy of transoral incisionless fundoplication (TIF) for the treatment of GERD: A systematic review with metaanalysis. Surgical Endoscopy. 2017;**31**(3):1032-1044

[25] Richter JE, Kumar A, Lipka s, Miladinovic B, Velanovich V. Efficacy of laparoscopic Nissen fundoplication vs transoral incisionless fundoplication or proton pump inhibitors in patients with gastroesophageal reflux disease: A systematic review and network meta-analysis. Gastroenterology. 2018;**154**(5):1298.e7-1308.e7

[26] De Moura EGH et al. Endoscopic polymer injection and endoluminal plication in treatment of gastroesophageal reflux disease: Evaluation of long-term results. Endoscopy International Open. 2018;**6**(5):E630-E636

[27] Kinoshita Y et al. Gastroesophageal reflux after endoscopic injection sclerotherapy. The American Journal of Gastroenterology. 1992;**87**(3):282-286

[28] Deviere J et al. Endoscopic implantation of a biopolymer in the lower esophageal sphincter for gastroesophageal reflux: A pilot study. Gastrointestinal Endoscopy. 2002;**55**(3):335-341

[29] Deviere J et al. Nonresorbable copolymer implantation for gastroesophageal reflux disease: A randomized sham-controlled multicenter trial. Gastroenterology. 2005;**128**(3):532-540

[30] Yeh RW, Triadafilopoulos G. Endoscopic antireflux therapy: The Stretta

**10**

*Gastroesophageal Reflux Disease - Theory and Research*

pH monitoring with multichannel impedance, esophageal manometry, radiology and scintigraphy in gastroesophageal reflux disease? The Turkish Journal of Gastroenterology.

[10] Gokturk S et al. Gastroesophageal reflux in asymptomatic patients with diabetes: An impedance study diabetes, obesity and gastroesophageal reflux. Experimental and Clinical Endocrinology & Diabetes.

[11] Wetscher GJ, Gadenstaetter M, Klingler PJ, Weiss H, Obrist P, Wykypiel H, et al. Efficacy of medical therapy and antireflux surgery to prevent Barrett's metaplasia in patients with gastroesophageal reflux disease. Annals

of Surgery. 2001;**234**(5):627-632

adenocarcinoma in Barrett's esophagus? A meta-analysis. The American Journal of Gastroenterology.

[13] Lord RV. Does antireflux surgery prevent progression of Barrett's esophagus? Minerva Chirurgica. 2011;**66**(1):1-6

[14] Saifullah AM, Ahmed F, Shil BC, Banik RK, Saha SK, Chowdhury M, et al. Comparative study of Alginate and Omeprazole in symptomatic treatment of non-erosive gastroesophageal reflux disease. Mymensingh Medical Journal.

[15] Higuera-de-la-Tijera F. Efficacy of omeprazole/sodium bicarbonate treatment in gastroesophageal reflux disease: A systematic review. Medwave.

[16] Freston JW. Therapeutic choices in reflux disease: Defining the criteria

2003;**98**(11):2390-2394

2018;**27**(4):771-775

2018;**18**(2):e7179

[12] Corey KE, Schmitz SM, Shaheen NJ. Does a surgical antireflux procedure decrease the incidence of esophageal

2017;**28**(Suppl. 1):S16-S21

2018;**2018**:22

[1] Gao Y et al. A study of esophageal function and reflux characteristics of gastroesophageal reflux disease in patients presenting with chronic cough. Zhonghua Nei Ke Za Zhi.

[2] Gyawali CP, Fass R. Management of gastroesophageal reflux disease. Gastroenterology. 2018;**154**(2):302-318

[3] Broers C, Tack J, Pauwels A. Review article: Gastro-oesophageal reflux disease in asthma and chronic obstructive pulmonary disease. Alimentary Pharmacology & Therapeutics. 2018;**47**(2):176-191

[5] Iliaz S et al. Does gastroesophageal reflux increase chronic obstructive pulmonary disease exacerbations? Respiratory Medicine. 2016;**115**:20-25

[6] Chen Y, Xiong L, Zeng J, Wei YG, Tan Y. Gastroesophageal reflux disease is associated with high risk of obstructive sleep apnea syndrome. Zhonghua Nei Ke Za Zhi. 2018;**57**(11):824-829

[7] Gyawali CP, Kahrilas PJ, Savarino E, Zerbib F, Mion F, Smout A, et al. Modern diagnosis of GERD: the Lyon Consensus. Gut. 2018;**67**(7):1351-1362

[8] Khatami A et al. A comparison between gastroesophageal ultrasonography vs. barium swallow in determining the pattern of gastroesophageal reflux in a pediatric population. Medical Ultrasonography. 2015;**17**(1):22-27

[9] Vardar R, Keskin M. Indications of 24-h esophageal pH monitoring, capsule pH monitoring, combined

[4] Bor S et al. Prevalence of gastroesophageal reflux disease in patients with asthma and chronic obstructive pulmonary disease. Journal of Gastroenterology and Hepatology.

2010;**25**(2):309-313

2011;**50**(11):931-934

**References**

procedure. Thoracic Surgery Clinics. 2005;**15**(3):395-403

[31] Skubleny D, Switzer NJ, Dang J, Gill RS, Shi X, de Gara C, et al. LINX® magnetic esophageal sphincter augmentation versus Nissen fundoplication for gastroesophageal reflux disease: A systematic review and meta-analysis. Surgical Endoscopy. 2017;**31**(8):3078-3084

[32] Aiolfi A, Asti E, Bernardi D, Bonitta G, Rausa E, Siboni S, et al. Early results of magnetic sphincter augmentation versus fundoplication for gastroesophageal reflux disease: Systematic review and meta-analysis. International Journal of Surgery. 2018;**52**:82-88

**13**

**Chapter 2**

**Abstract**

inhibitors

**1. Introduction**

of GERD

*Shouji Shimoyama*

Challenges to Unravel Mechanisms

Gastroesophageal reflux disease (GERD) encompasses a spectrum of disorders

caused by a reflux of gastric contents into the esophagus or complications of gastroesophageal reflux. Although depending on the definition, the prevalence of GERD is higher in the West than in the East, and the prevalence has been slightly increasing, so that the clinicians, even though they are not gastroenterologists, must encounter GERD patients and treat them. However, the clinicians do feel difficulty in treating GERD patients, since prescription of acid neutralizing agents, such as proton pump inhibitors (PPIs), sometimes fail to resolve their complaints. This may be partly explained by the discrepancies between clinical complaint and endoscopic findings; some patients present endoscopic esophagitis while some do not, and be partly explained by the potentially wide spectrum of pathophysiological etiologies than has been thought. This chapter describes current knowledge on heterogeneous mechanisms of GERD development. Clarifying the mechanisms of GERD on the individual basis may realize conceptual shift from uniform prescription of acid

neutralizing agents to establishment of patient-oriented therapies.

**Keywords:** gastroesophageal reflux disease, nonerosive reflux disease, esophagitis, reflux hypersensitivity, functional heartburn, central sensitization, proton pump

Gastroesophageal reflux disease (GERD) is defined as a condition with at least weekly troublesome symptoms due to the abnormal reflux of stomach contents into the esophagus [1]. Heartburn and/or acid regurgitation are ranked 7th on the list prompting visits to doctors, and GERD is the most common diagnosis given in outpatient visits [2]. GERD appears worldwide with some geographic variation. Prevalence estimates are 18–28% in North and South America, 9–33% in the Middle East, 12% in Australia, but less than 10% in East Asia [3]. In addition, an analysis of temporal trends suggests a particular increase in GERD prevalence in North America and Europe [4], while such a trend in Asia is indeterminable [4–6], partly due to the regional variation of prevalence being much higher in Southwest and Western Asia than in Eastern Asia [6]. In Japan, the prevalence of GERD was below 10% in the 1980s but has shown a two- or three-fold increase in the twentyfirst century [7]. Although such time-trends or steady increases in the rise in the number of patients might be attributable to an increased awareness of the disease, and the prevalence of GERD varies between studies, the worldwide disease burden confirms that the numbers of patients suffering from GERD is substantial. Since

**Chapter 2**

*Gastroesophageal Reflux Disease - Theory and Research*

procedure. Thoracic Surgery Clinics.

[31] Skubleny D, Switzer NJ, Dang J, Gill RS, Shi X, de Gara C, et al. LINX® magnetic esophageal

sphincter augmentation versus Nissen fundoplication for gastroesophageal reflux disease: A systematic review and meta-analysis. Surgical Endoscopy.

[32] Aiolfi A, Asti E, Bernardi D, Bonitta G, Rausa E, Siboni S, et al. Early results of magnetic sphincter augmentation versus fundoplication for gastroesophageal reflux disease: Systematic review and meta-analysis. International Journal of

2005;**15**(3):395-403

2017;**31**(8):3078-3084

Surgery. 2018;**52**:82-88

**12**

## Challenges to Unravel Mechanisms of GERD

*Shouji Shimoyama*

#### **Abstract**

Gastroesophageal reflux disease (GERD) encompasses a spectrum of disorders caused by a reflux of gastric contents into the esophagus or complications of gastroesophageal reflux. Although depending on the definition, the prevalence of GERD is higher in the West than in the East, and the prevalence has been slightly increasing, so that the clinicians, even though they are not gastroenterologists, must encounter GERD patients and treat them. However, the clinicians do feel difficulty in treating GERD patients, since prescription of acid neutralizing agents, such as proton pump inhibitors (PPIs), sometimes fail to resolve their complaints. This may be partly explained by the discrepancies between clinical complaint and endoscopic findings; some patients present endoscopic esophagitis while some do not, and be partly explained by the potentially wide spectrum of pathophysiological etiologies than has been thought. This chapter describes current knowledge on heterogeneous mechanisms of GERD development. Clarifying the mechanisms of GERD on the individual basis may realize conceptual shift from uniform prescription of acid neutralizing agents to establishment of patient-oriented therapies.

**Keywords:** gastroesophageal reflux disease, nonerosive reflux disease, esophagitis, reflux hypersensitivity, functional heartburn, central sensitization, proton pump inhibitors

#### **1. Introduction**

Gastroesophageal reflux disease (GERD) is defined as a condition with at least weekly troublesome symptoms due to the abnormal reflux of stomach contents into the esophagus [1]. Heartburn and/or acid regurgitation are ranked 7th on the list prompting visits to doctors, and GERD is the most common diagnosis given in outpatient visits [2]. GERD appears worldwide with some geographic variation. Prevalence estimates are 18–28% in North and South America, 9–33% in the Middle East, 12% in Australia, but less than 10% in East Asia [3]. In addition, an analysis of temporal trends suggests a particular increase in GERD prevalence in North America and Europe [4], while such a trend in Asia is indeterminable [4–6], partly due to the regional variation of prevalence being much higher in Southwest and Western Asia than in Eastern Asia [6]. In Japan, the prevalence of GERD was below 10% in the 1980s but has shown a two- or three-fold increase in the twentyfirst century [7]. Although such time-trends or steady increases in the rise in the number of patients might be attributable to an increased awareness of the disease, and the prevalence of GERD varies between studies, the worldwide disease burden confirms that the numbers of patients suffering from GERD is substantial. Since

the symptoms do compromise patient quality of life (QOL) [8], clinicians, even if they are not gastroenterologists, may frequently encounter such patients and should treat them.

Acid-suppressing agents, such as proton pump inhibitors (PPIs), are a main choice of medication [9]; however, it is also true that while most patients do respond it, some do not. A recent study of PPI use has demonstrated that 20–26% of GERD patients showed persistent heartburn of any intensity for 2 or 3 days or more per week [10]. Recent systematic reviews found that 17–45% of GERD patients experienced persistent troublesome heartburn or regurgitation despite PPI therapy [11, 12]. That not all GERD patients can attain complete relief of GERD symptoms suggests that GERD is likely to be a heterogeneous disease entity which may explain the above unmet clinical needs. In light of the fact that patient QOL deteriorates by PPI refractoriness [13] as well as GERD symptoms *per se*, even if persistent symptoms are mild [14], clarifying the mechanisms of GERD or PPI refractoriness enables clinicians to prescribe medications according to the underlying mechanism on a patient-by-patient basis, which subsequently realizes clinical improvement.

This chapter discusses the current knowledge on the underlying mechanisms of PPI refractory GERD, and considers potential research directions attempting to resolve its symptoms, especially those among PPI refractory patients.

#### **2. Reflux symptoms do not necessarily coincide with endoscopic findings**

One of the complex phenomena that impedes the understanding of GERD is that reflux symptoms, endoscopic findings, and treatment results do not necessarily coincide with each other, despite the fact that GERD symptoms are by definition caused by the abnormal reflux of gastric contents into the esophagus. GERD is divided into reflux esophagitis and nonerosive reflux disease (NERD), which is a condition of reflux symptoms with no endoscopically apparent damage to the esophageal mucosa. A substantial proportion (50–70%) of GERD patients demonstrates endoscopically negative findings [15, 16], suggesting that NERD forms the main body of GERD. Curiously, endoscopic healing of erosive esophagitis does not necessarily result in symptom relief. In the same sense, a novel potassium-competitive acid blocker, vonoprazan, achieved improvement of heartburn in only approximately 20% of NERD patients [17]. These results suggest that the association of esophageal acid exposure with patient symptoms is tenuous in a certain fraction of GERD patients. On the other hand, some patients with endoscopically confirmed esophagitis are asymptomatic. Consequently, the prevalence and treatment success rate of GERD are greatly influenced by its definition, i.e., whether or not the study body includes NERD patients, whether or not it includes asymptomatic erosive reflux esophagitis patients, and whether or not treatment success includes only complete symptom relief or extends an even partial response.

#### **3. Mechanisms**

#### **3.1 Conventional theory: acid as a direct contributor**

Traditionally, reflux esophagitis is thought to be a condition resulting from a caustic, chemical injury inflicted by refluxate components such as hydrogen ions and pepsin. Hydrogen ions injure the superficial layer of the esophageal mucosa and cause esophagitis, and pepsin destroys the tight junction of the esophageal epithelium.

**15**

*Challenges to Unravel Mechanisms of GERD DOI: http://dx.doi.org/10.5772/intechopen.80793*

still exist as do symptomatic patients without esophagitis.

**3.2 New theory: GERD is an immune mediated injury**

those of asymptomatic healthy volunteers [21].

rat acute esophagitis [33].

These chemical injuries lead to dilatation of the intracellular spaces (DIS) and an increase in paracellular permeability, which eventually allows acid to penetrate into deep layers of the esophagus, followed by the attraction of inflammatory cells, and finally stimulates nocireceptors [18]. In this theory, the epithelial injury triggers the pathophysiological cascade of GERD, beginning at the luminal surface of the esophageal epithelium, and then proceeds to the deeper layer. This mechanism is readily plausible for GERD patients with esophagitis; however, acid penetration through DIS as a main causative mechanism of GERD cannot explain why PPI refractory patients

On the other hand, the literature contains some experimental data which cannot

Evidence has been accumulated that pro-inflammatory cytokine release from esophageal epithelium, mesenchymal cells, and endothelial cells is an initial event of GERD. The participants of pro-inflammatory cytokines are interleukin (IL)-8 [19, 22, 23], IL-1 beta [19, 23], monocyte chemoattractant protein 1 (MCP-1) [24], IL-6 [25], IL-33 [26], tumor necrosis factor (TNF)-alpha [27], prostaglandin E2 [28, 29], hypoxia inducible factor (HIF)-2alpha [30], and platelet activating factor (PAF) [31, 32]. These pro-inflammatory cytokines attract immune cells—lymphocytes and polymorphonuclear cells—into the esophageal mucosa and submucosa. Interestingly, antineutrophil serum was found to inhibit inflammatory markers in

Another source of pro-inflammatory cytokines is the proteinase-activated receptor 2 (PAR2) localized on the surface of epithelial cells. PAR2 is activated by trypsin and weak acid, then stimulates pro-inflammatory cytokine release such as IL-8 from the epithelial cells, induces a neuroinflammatory effect mediated by neurotransmitters such as substance P and calcitonin gene-related peptide (CGRP), and subsequently establishes visceral hypersensitivity [34]. Indeed, PAR2 expression increases in patients with erosive esophagitis as well as NERD [34]. PAR2 activation has been correlated with IL-8 expression and further with DIS, papillary hyperplasia, and intraepithelial lymphocyte density [34]. These mechanisms mediated by pro-inflammatory cytokines would partly explain why PPI solely cannot necessarily resolve GERD symptoms and why a protease inhibitor, i.e., camostat mesilate, is effective in patients in whom GERD symptoms are caused by weakly acidic episodes. Weak acid activates acid-sensing nocireceptors such as the transient receptor potential channel vanilloid subfamily receptor-1 (TRPV-1) [35, 36] and acidsensing ion channels (ASIC) [37]. TRPV-1 is also activated by pro-inflammatory cytokines. TRPV-1 is a detector of various noxious stimuli including heat, acid, and irritant pollutants [38, 39]; it thus has been recognized as an initial molecule of nociceptive transmission. Once activated, neurotransmitters such as substance P and CGRP are released, afferent neurons evoke a sensation of burning pain, and finally peripheral and central sensitization is established. The activation of TRPV-1

necessarily be explained by the conventional theory, namely, acid penetration through DIS as a cause of GERD. In a rat reflux esophagitis model, inflammatory cells appeared at the deep layer of the epithelium, and then infiltrated upward to the superficial layer of the esophagus [19]. Basal cell and papillary hyperplasia preceded the development of esophagitis [19]. Consistent results were demonstrated in a human study, where stopping the PPI therapy in successfully PPI treated patients was associated with T-lymphocyte infiltration in the deep layer of the esophagus as well as basal cell and papillary hyperplasia without apparent surface erosions [20]. Degrees of DIS in patients with reflux esophagitis or NERD did not differ from

#### *Challenges to Unravel Mechanisms of GERD DOI: http://dx.doi.org/10.5772/intechopen.80793*

*Gastroesophageal Reflux Disease - Theory and Research*

treat them.

**findings**

the symptoms do compromise patient quality of life (QOL) [8], clinicians, even if they are not gastroenterologists, may frequently encounter such patients and should

Acid-suppressing agents, such as proton pump inhibitors (PPIs), are a main choice of medication [9]; however, it is also true that while most patients do respond it, some do not. A recent study of PPI use has demonstrated that 20–26% of GERD patients showed persistent heartburn of any intensity for 2 or 3 days or more per week [10]. Recent systematic reviews found that 17–45% of GERD patients experienced persistent troublesome heartburn or regurgitation despite PPI therapy [11, 12]. That not all GERD patients can attain complete relief of GERD symptoms suggests that GERD is likely to be a heterogeneous disease entity which may explain the above unmet clinical needs. In light of the fact that patient QOL deteriorates by PPI refractoriness [13] as well as GERD symptoms *per se*, even if persistent symptoms are mild [14], clarifying the mechanisms of GERD or PPI refractoriness enables clinicians to prescribe medications according to the underlying mechanism on a patient-by-patient basis, which subsequently realizes clinical improvement.

This chapter discusses the current knowledge on the underlying mechanisms of PPI refractory GERD, and considers potential research directions attempting to

One of the complex phenomena that impedes the understanding of GERD is that reflux symptoms, endoscopic findings, and treatment results do not necessarily coincide with each other, despite the fact that GERD symptoms are by definition caused by the abnormal reflux of gastric contents into the esophagus. GERD is divided into reflux esophagitis and nonerosive reflux disease (NERD), which is a condition of reflux symptoms with no endoscopically apparent damage to the esophageal mucosa. A substantial proportion (50–70%) of GERD patients demonstrates endoscopically negative findings [15, 16], suggesting that NERD forms the main body of GERD. Curiously, endoscopic healing of erosive esophagitis does not necessarily result in symptom relief. In the same sense, a novel potassium-competitive acid blocker, vonoprazan, achieved improvement of heartburn in only approximately 20% of NERD patients [17]. These results suggest that the association of esophageal acid exposure with patient symptoms is tenuous in a certain fraction of GERD patients. On the other hand, some patients with endoscopically confirmed esophagitis are asymptomatic. Consequently, the prevalence and treatment success rate of GERD are greatly influenced by its definition, i.e., whether or not the study body includes NERD patients, whether or not it includes asymptomatic erosive reflux esophagitis patients, and whether or not treatment success includes only complete

resolve its symptoms, especially those among PPI refractory patients.

symptom relief or extends an even partial response.

**3.1 Conventional theory: acid as a direct contributor**

Traditionally, reflux esophagitis is thought to be a condition resulting from a caustic, chemical injury inflicted by refluxate components such as hydrogen ions and pepsin. Hydrogen ions injure the superficial layer of the esophageal mucosa and cause esophagitis, and pepsin destroys the tight junction of the esophageal epithelium.

**2. Reflux symptoms do not necessarily coincide with endoscopic** 

**14**

**3. Mechanisms**

These chemical injuries lead to dilatation of the intracellular spaces (DIS) and an increase in paracellular permeability, which eventually allows acid to penetrate into deep layers of the esophagus, followed by the attraction of inflammatory cells, and finally stimulates nocireceptors [18]. In this theory, the epithelial injury triggers the pathophysiological cascade of GERD, beginning at the luminal surface of the esophageal epithelium, and then proceeds to the deeper layer. This mechanism is readily plausible for GERD patients with esophagitis; however, acid penetration through DIS as a main causative mechanism of GERD cannot explain why PPI refractory patients still exist as do symptomatic patients without esophagitis.

#### **3.2 New theory: GERD is an immune mediated injury**

On the other hand, the literature contains some experimental data which cannot necessarily be explained by the conventional theory, namely, acid penetration through DIS as a cause of GERD. In a rat reflux esophagitis model, inflammatory cells appeared at the deep layer of the epithelium, and then infiltrated upward to the superficial layer of the esophagus [19]. Basal cell and papillary hyperplasia preceded the development of esophagitis [19]. Consistent results were demonstrated in a human study, where stopping the PPI therapy in successfully PPI treated patients was associated with T-lymphocyte infiltration in the deep layer of the esophagus as well as basal cell and papillary hyperplasia without apparent surface erosions [20]. Degrees of DIS in patients with reflux esophagitis or NERD did not differ from those of asymptomatic healthy volunteers [21].

Evidence has been accumulated that pro-inflammatory cytokine release from esophageal epithelium, mesenchymal cells, and endothelial cells is an initial event of GERD. The participants of pro-inflammatory cytokines are interleukin (IL)-8 [19, 22, 23], IL-1 beta [19, 23], monocyte chemoattractant protein 1 (MCP-1) [24], IL-6 [25], IL-33 [26], tumor necrosis factor (TNF)-alpha [27], prostaglandin E2 [28, 29], hypoxia inducible factor (HIF)-2alpha [30], and platelet activating factor (PAF) [31, 32]. These pro-inflammatory cytokines attract immune cells—lymphocytes and polymorphonuclear cells—into the esophageal mucosa and submucosa. Interestingly, antineutrophil serum was found to inhibit inflammatory markers in rat acute esophagitis [33].

Another source of pro-inflammatory cytokines is the proteinase-activated receptor 2 (PAR2) localized on the surface of epithelial cells. PAR2 is activated by trypsin and weak acid, then stimulates pro-inflammatory cytokine release such as IL-8 from the epithelial cells, induces a neuroinflammatory effect mediated by neurotransmitters such as substance P and calcitonin gene-related peptide (CGRP), and subsequently establishes visceral hypersensitivity [34]. Indeed, PAR2 expression increases in patients with erosive esophagitis as well as NERD [34]. PAR2 activation has been correlated with IL-8 expression and further with DIS, papillary hyperplasia, and intraepithelial lymphocyte density [34]. These mechanisms mediated by pro-inflammatory cytokines would partly explain why PPI solely cannot necessarily resolve GERD symptoms and why a protease inhibitor, i.e., camostat mesilate, is effective in patients in whom GERD symptoms are caused by weakly acidic episodes.

Weak acid activates acid-sensing nocireceptors such as the transient receptor potential channel vanilloid subfamily receptor-1 (TRPV-1) [35, 36] and acidsensing ion channels (ASIC) [37]. TRPV-1 is also activated by pro-inflammatory cytokines. TRPV-1 is a detector of various noxious stimuli including heat, acid, and irritant pollutants [38, 39]; it thus has been recognized as an initial molecule of nociceptive transmission. Once activated, neurotransmitters such as substance P and CGRP are released, afferent neurons evoke a sensation of burning pain, and finally peripheral and central sensitization is established. The activation of TRPV-1 also produces PAF [31] and adenosine triphosphate (ATP) [40], the former acting as a chemoattractant of inflammatory cells [41], while the latter stimulates both substance P and CGRP release from esophageal submucosal neurons [40] as well as the secretion of pro-inflammatory cytokines at the esophageal epithelium [35]. ATP *per se* is also a neurotransmitter [42] involved in the sensation of pain. Interestingly, an increased expression of TRPV-1 was observed not only in erosive esophagitis but also in NERD patients without correlation with acid exposure [43].

Taking all these processes into account, while not fully elucidated, it is conceivable that the secretion of pro-inflammatory cytokines, decreased mucosal integrity, exposure of subepithelial nerves to acid, and neuropeptide release to transmit nociceptive stimuli through the peripheral nerve to the brain may interplay to manifest GERD symptoms. Once such a network operates, patients have a lower threshold for pain perception by chemical or mechanical stimulation. The above findings support the hypothesis that an immune mediated neuroinflammatory cascade may underlie the development of GERD symptoms, and that GERD is an immune mediated injury rather than a chemical burn. This hypothesis considers that the secretion of pro-inflammatory cytokines is an initial event, the release of a variety of mediators is the second, and then the transmission of pain through the peripheral nerve to the central nervous system is the last step of the cascade. This cascade contrasts sharply with the conventional theory in which caustic acid-induced direct epithelial injury is an initial event of GERD; it could explain why not all GERD symptoms can be regulated solely by acid suppression. This is an essential background to the clinically reiterating and troublesome claim that there is a distinction between endoscopically-based and symptom-based GERD diagnosis.

#### **4. PPI-refractory GERD comprises heterogeneous pathophysiological conditions**

Under the above new theory, the primary focus should be on which factors switch on the cascade. The advent of multichannel intraluminal impedance-pH monitoring enables us to count the number of reflux events, to measure acidity of reflux content, and to differentiate between liquid and air in a refluxate. This technique clarifies that the initial event that triggers the cascade at the esophagus is not only acid exposure but also weak acid or weak alkaline conditions, temperature, electrical stimuli, and mechanical stimuli [44–48]. More detailed analyses of content and pH in the refluxate as well as degrees of symptom-reflux association create challenges to classify PPI-refractory GERD into three subcategories: (1) true GERD, in which symptoms are associated with acid reflux but acid neutralization is incomplete; (2) reflux hypersensitivity, where symptoms are associated with nonacid reflux; and (3) functional heartburn, where symptoms are exerted by nonacid and nonreflux events. The second and third subcategories could be putative factors that are responsible for PPI refractoriness or symptomatic NERD (**Figure 1**). Recently, the Rome IV classification [49] involves these mechanisms as underlying mechanisms of PPI-refractory GERD that allows a paradigm change for understanding this condition.

Reflux hypersensitivity is a heightened perception of physiological reflux which results in persistent GERD symptoms despite PPI therapy [44]. This is characterized by normal acid exposure in the distal esophagus but symptoms are attributable to reflux. On the other hand, functional heartburn is distinct from reflux hypersensitivity, in that functional heartburn is characterized by normal acid exposure in the distal esophagus without any apparent symptom-reflux association. That baseline impedance was reduced in erosive gastritis and acid-associated GERD but not in functional heartburn suggests that functional heartburn is caused by factors other than acid [50].

**17**

**Figure 1.**

*Challenges to Unravel Mechanisms of GERD DOI: http://dx.doi.org/10.5772/intechopen.80793*

In this regard, peripheral and central sensitization has recently provided insight into mechanisms establishing of esophageal perception and symptom exacerbation unrelated to acid reflux. Peripheral neuron stimuli triggers repeated neurotransmitter release, and repetitive peripheral firing causes increased excitability of afferent nerves that could establish central sensitization [51]. The upregulated nociceptive pathways could lower resting esophageal pain thresholds, resulting in amplified responses to painful stimuli (hyperalgesia), or resulting in pain perception to nonpainful stimuli (allodynia). In this condition, minor physiological noxious stimuli or even innocuous stimuli can be interpreted by the patient as a major symptom, and once hypersensitivity is established, it could continue to potentiate pain even after the stimuli is discontinued, thus "acid" would no longer be a major cause. In this context, psychiatric comorbidity or psychological stressors could be causes of, or amplifying factors of peripheral and central sensitization. Psychological distress [52], anxiety [53], depression [53], poor sleep quality [54–57], decreased general well-being [58–60], and environmental stress [61] are associated with PPI-refractory GERD. The improvement of reflux symptoms by interventions aimed at reducing stress suggests that the brain-gut interaction and cerebral processing [62] might be responsible for this condition. These psychological factors may compromise esophageal motor function by affecting the enteric nervous system and can modulate esophageal perception, making patients pay excessive attention to intraesophageal events, and consequently cause perception and interpretation of these esophageal events as painful (hypervigilance). By contrast, however, several studies have failed to demonstrate such interaction. Psychological distress was not associated with treatment failure [63]. The relative risk of anxiety or depression in PPI failure was minimal, with the odds ratio being 1.15 [64]. The plausible explanations for these inconsistent results are that the degrees of influence on the enteric nervous system are different between patients

*The acidity of refluxate is associated with probability of PPI response. The higher probability of PPI refractoriness is ascribed to the conditions that factors other than acid are more predominant. The possibilities of reflux hypersensitivity and functional heartburn are more increased according to the less roles of acid.*

#### **Figure 1.**

*Gastroesophageal Reflux Disease - Theory and Research*

also produces PAF [31] and adenosine triphosphate (ATP) [40], the former acting as a chemoattractant of inflammatory cells [41], while the latter stimulates both substance P and CGRP release from esophageal submucosal neurons [40] as well as the secretion of pro-inflammatory cytokines at the esophageal epithelium [35]. ATP *per se* is also a neurotransmitter [42] involved in the sensation of pain. Interestingly, an increased expression of TRPV-1 was observed not only in erosive esophagitis but

Taking all these processes into account, while not fully elucidated, it is conceivable that the secretion of pro-inflammatory cytokines, decreased mucosal integrity, exposure of subepithelial nerves to acid, and neuropeptide release to transmit nociceptive stimuli through the peripheral nerve to the brain may interplay to manifest GERD symptoms. Once such a network operates, patients have a lower threshold for pain perception by chemical or mechanical stimulation. The above findings support the hypothesis that an immune mediated neuroinflammatory cascade may underlie the development of GERD symptoms, and that GERD is an immune mediated injury rather than a chemical burn. This hypothesis considers that the secretion of pro-inflammatory cytokines is an initial event, the release of a variety of mediators is the second, and then the transmission of pain through the peripheral nerve to the central nervous system is the last step of the cascade. This cascade contrasts sharply with the conventional theory in which caustic acid-induced direct epithelial injury is an initial event of GERD; it could explain why not all GERD symptoms can be regulated solely by acid suppression. This is an essential background to the clinically reiterating and troublesome claim that there is a distinction between

also in NERD patients without correlation with acid exposure [43].

endoscopically-based and symptom-based GERD diagnosis.

**4. PPI-refractory GERD comprises heterogeneous pathophysiological** 

GERD that allows a paradigm change for understanding this condition.

Reflux hypersensitivity is a heightened perception of physiological reflux which results in persistent GERD symptoms despite PPI therapy [44]. This is characterized by normal acid exposure in the distal esophagus but symptoms are attributable to reflux. On the other hand, functional heartburn is distinct from reflux hypersensitivity, in that functional heartburn is characterized by normal acid exposure in the distal esophagus without any apparent symptom-reflux association. That baseline impedance was reduced in erosive gastritis and acid-associated GERD but not in functional heartburn suggests that functional heartburn is caused by factors other than acid [50].

Under the above new theory, the primary focus should be on which factors switch on the cascade. The advent of multichannel intraluminal impedance-pH monitoring enables us to count the number of reflux events, to measure acidity of reflux content, and to differentiate between liquid and air in a refluxate. This technique clarifies that the initial event that triggers the cascade at the esophagus is not only acid exposure but also weak acid or weak alkaline conditions, temperature, electrical stimuli, and mechanical stimuli [44–48]. More detailed analyses of content and pH in the refluxate as well as degrees of symptom-reflux association create challenges to classify PPI-refractory GERD into three subcategories: (1) true GERD, in which symptoms are associated with acid reflux but acid neutralization is incomplete; (2) reflux hypersensitivity, where symptoms are associated with nonacid reflux; and (3) functional heartburn, where symptoms are exerted by nonacid and nonreflux events. The second and third subcategories could be putative factors that are responsible for PPI refractoriness or symptomatic NERD (**Figure 1**). Recently, the Rome IV classification [49] involves these mechanisms as underlying mechanisms of PPI-refractory

**16**

**conditions**

*The acidity of refluxate is associated with probability of PPI response. The higher probability of PPI refractoriness is ascribed to the conditions that factors other than acid are more predominant. The possibilities of reflux hypersensitivity and functional heartburn are more increased according to the less roles of acid.*

In this regard, peripheral and central sensitization has recently provided insight into mechanisms establishing of esophageal perception and symptom exacerbation unrelated to acid reflux. Peripheral neuron stimuli triggers repeated neurotransmitter release, and repetitive peripheral firing causes increased excitability of afferent nerves that could establish central sensitization [51]. The upregulated nociceptive pathways could lower resting esophageal pain thresholds, resulting in amplified responses to painful stimuli (hyperalgesia), or resulting in pain perception to nonpainful stimuli (allodynia). In this condition, minor physiological noxious stimuli or even innocuous stimuli can be interpreted by the patient as a major symptom, and once hypersensitivity is established, it could continue to potentiate pain even after the stimuli is discontinued, thus "acid" would no longer be a major cause.

In this context, psychiatric comorbidity or psychological stressors could be causes of, or amplifying factors of peripheral and central sensitization. Psychological distress [52], anxiety [53], depression [53], poor sleep quality [54–57], decreased general well-being [58–60], and environmental stress [61] are associated with PPI-refractory GERD. The improvement of reflux symptoms by interventions aimed at reducing stress suggests that the brain-gut interaction and cerebral processing [62] might be responsible for this condition. These psychological factors may compromise esophageal motor function by affecting the enteric nervous system and can modulate esophageal perception, making patients pay excessive attention to intraesophageal events, and consequently cause perception and interpretation of these esophageal events as painful (hypervigilance). By contrast, however, several studies have failed to demonstrate such interaction. Psychological distress was not associated with treatment failure [63]. The relative risk of anxiety or depression in PPI failure was minimal, with the odds ratio being 1.15 [64]. The plausible explanations for these inconsistent results are that the degrees of influence on the enteric nervous system are different between patients

even under the same psychiatric stress. Alternatively, the difference in psychiatric medication given to each patient may play a role. Undoubtedly, the manifestation of GERD symptoms due to a greater psychiatric background should be more likely to be approached by psychotherapy.

This subclassification is clinically important in that true GERD is expected to respond to enhanced or double dose PPI therapy or be a candidate for antireflux surgery, while reflux hypersensitivity and functional heartburn are assumed to show scant response to it. Therefore, it is important to clarify the weight of each component and dominancy in the PPI refractory patients. In a study of 329 NERD patients, 40% showed abnormal acid exposure (true GERD), 36% had reflux hypersensitivity, and 24% had functional heartburn [65]. Another study demonstrated that 40% of 171 symptoms in the PPI refractory GERD patients were considered reflux hypersensitivity, while acid related GERD was only 4.7% [66]. A recent study to explore the composition of 4296 reflux events in 78 PPI refractory patients elucidated that reflux contents are heterogeneous: 24% of reflux events were caused by gas, and 55% of patients were nonacid and reflux unrelated [67]. Finally, as many as 58% of GERD symptoms or 52% of PPI-refractory GERD patients fall into the functional heartburn category [68, 69].

Perhaps background causative factors are mixed, and the extent to which each factor contributes to PPI-refractory GERD is different between patients. Those who are currently categorized as PPI refractory GERD with their manifestations deemed uniform may in fact have heterogeneous etiologies, and therefore a more tailored treatment on the basis of each multifaceted pathway is anticipated to resolve their symptoms better.

#### **5. Therapeutics**

By gaining increasing recognition of these mechanisms, therapeutic possibilities could be widened by understanding which individual element is dominant in eliciting GERD symptoms and by diminishing the sensory threshold of what is perceived as painful. Several drugs targeting one of these mechanisms are already in phase III trials, while others are in a developmental stage.

Since the prostaglandin (PG) E2 receptor, EP1, mediates pain perception [70], attempts have been made to reduce PGE2 production or to block EP1 for the treatment of GERD symptoms. There are several randomized, placebo-controlled crossover studies using diclofenac (reduce PGE2 production), ONO8539, and ZD6416 (both EP1 antagonists). Acid induced heartburn was attenuated by diclofenac [71], ONO8539 [72], and ZD6416 [73] as compared with a placebo. As discussed earlier, TRPV-1 activation in primary afferent neurons evokes the sensation of burning pain and induces neurogenic inflammation. Thus the TRPV-1 antagonist, AZD1386, is expected to reduce responses to noxious stimuli; however, the effect has been limited. It was able to increase the pain threshold to heat in healthy men [74] but failed to change the threshold in patients with GERD and partial PPI responders [75].

Several randomized trials focusing on modulating neurotransmitters or the downstream central nervous system have been reported. Pregabalin, a pain modulator including substance P, was able to inhibit the development of acid-induced esophageal hypersensitivity [76]. In order to alleviate the central hypersensitivity, antidepressant nortriptyline was investigated in 20 NERD patients [77]. Functional brain imaging by magnetic resonance revealed that nortriptyline was found to reduce more significantly brain response to esophageal acid perfusion than did placebo. However, this reduction could not improve mental outcome. A

**19**

*Challenges to Unravel Mechanisms of GERD DOI: http://dx.doi.org/10.5772/intechopen.80793*

substance P and CGRP expression [78].

[NCT01753128].

**6. Future perspectives**

current therapeutic gaps.

patient basis could help realize tailored treatment.

**7. Conclusions**

randomized controlled trial to investigate the efficacy of antidepressant imipramine in patients with esophageal hypersensitivity or functional heartburn is underway

In an animal study, rikkunshito, a mixture of eight herbal ingredients, was able to reduce neuronal activation and peripheral sensitization through the inhibition of

The mechanisms that exert GERD symptoms in patients lacking esophageal mucosal injury and/or apparent reflux events remain an area of intense research because these patients often show resistance to PPI therapy, and such refractoriness compromises patient QOL. There is increasing evidence that multifactorial determinants including the number of reflux episodes, the acidity of the refluxate, reflux volume, liquid/gas composition, esophageal hypersensitivity, and cognitive hypervigilance form a fine network to generate GERD symptoms. Although acid is corrosive, the less the roles of acid or mucosal injuries are, the more peripheral and central sensitization become important. The advancement of novel diagnostic tools focusing on impedance, neuropathophysiology, and psychometrics could help identify GERD phenotypes more precisely and practically. These novel metrics could also facilitate an understanding that underlying backgrounds of GERD are diverse, response to treatment is variable, and mechanistic phenotypes are heterogeneous, including hypersensitivity and hypervigilance. Therefore, the traditional single approach of focusing solely on acid suppression makes treatment results unsatisfactory and problematic. Otherwise, an expanded consideration of such multifactorial determinants deserves merit. Each determinant could be a potential therapeutic target, and given the wide array of potential therapeutic targets, the development of drugs to control each target could therefore increase treatment possibilities. Therefore, determining which factors are responsible for GERD symptoms on a patient basis can establish more effective and individualized treatments, leading to the treatment concept that there is no longer a "one size fits all." This conceptual shift will realize the prescription of tailored, more effective drugs as well as the performance of behavioral intervention, and ultimately, fill the

The underlying mechanisms of GERD, especially PPI refractory GERD, are multifactorial. Evidence has been accumulated which supports the concept that GERD is established by a cascade starting from cytokine release to central sensitization. Since each component could be a therapeutic target, it is important to develop novel metrics to quantify the weight of each component and to develop drugs to control each component. Clarifying which component is predominant on the patient-by-

#### *Challenges to Unravel Mechanisms of GERD DOI: http://dx.doi.org/10.5772/intechopen.80793*

randomized controlled trial to investigate the efficacy of antidepressant imipramine in patients with esophageal hypersensitivity or functional heartburn is underway [NCT01753128].

In an animal study, rikkunshito, a mixture of eight herbal ingredients, was able to reduce neuronal activation and peripheral sensitization through the inhibition of substance P and CGRP expression [78].

#### **6. Future perspectives**

*Gastroesophageal Reflux Disease - Theory and Research*

the functional heartburn category [68, 69].

trials, while others are in a developmental stage.

symptoms better.

**5. Therapeutics**

partial PPI responders [75].

be approached by psychotherapy.

even under the same psychiatric stress. Alternatively, the difference in psychiatric medication given to each patient may play a role. Undoubtedly, the manifestation of GERD symptoms due to a greater psychiatric background should be more likely to

This subclassification is clinically important in that true GERD is expected to respond to enhanced or double dose PPI therapy or be a candidate for antireflux surgery, while reflux hypersensitivity and functional heartburn are assumed to show scant response to it. Therefore, it is important to clarify the weight of each component and dominancy in the PPI refractory patients. In a study of 329 NERD patients, 40% showed abnormal acid exposure (true GERD), 36% had reflux hypersensitivity, and 24% had functional heartburn [65]. Another study demonstrated that 40% of 171 symptoms in the PPI refractory GERD patients were considered reflux hypersensitivity, while acid related GERD was only 4.7% [66]. A recent study to explore the composition of 4296 reflux events in 78 PPI refractory patients elucidated that reflux contents are heterogeneous: 24% of reflux events were caused by gas, and 55% of patients were nonacid and reflux unrelated [67]. Finally, as many as 58% of GERD symptoms or 52% of PPI-refractory GERD patients fall into

Perhaps background causative factors are mixed, and the extent to which each factor contributes to PPI-refractory GERD is different between patients. Those who are currently categorized as PPI refractory GERD with their manifestations deemed uniform may in fact have heterogeneous etiologies, and therefore a more tailored treatment on the basis of each multifaceted pathway is anticipated to resolve their

By gaining increasing recognition of these mechanisms, therapeutic possibilities could be widened by understanding which individual element is dominant in eliciting GERD symptoms and by diminishing the sensory threshold of what is perceived as painful. Several drugs targeting one of these mechanisms are already in phase III

Since the prostaglandin (PG) E2 receptor, EP1, mediates pain perception [70], attempts have been made to reduce PGE2 production or to block EP1 for the treatment of GERD symptoms. There are several randomized, placebo-controlled crossover studies using diclofenac (reduce PGE2 production), ONO8539, and ZD6416 (both EP1 antagonists). Acid induced heartburn was attenuated by diclofenac [71], ONO8539 [72], and ZD6416 [73] as compared with a placebo. As discussed earlier, TRPV-1 activation in primary afferent neurons evokes the sensation of burning pain and induces neurogenic inflammation. Thus the TRPV-1 antagonist, AZD1386, is expected to reduce responses to noxious stimuli; however, the effect has been limited. It was able to increase the pain threshold to heat in healthy men [74] but failed to change the threshold in patients with GERD and

Several randomized trials focusing on modulating neurotransmitters or the downstream central nervous system have been reported. Pregabalin, a pain modulator including substance P, was able to inhibit the development of acid-induced esophageal hypersensitivity [76]. In order to alleviate the central hypersensitivity, antidepressant nortriptyline was investigated in 20 NERD patients [77]. Functional brain imaging by magnetic resonance revealed that nortriptyline was found to reduce more significantly brain response to esophageal acid perfusion than did placebo. However, this reduction could not improve mental outcome. A

**18**

The mechanisms that exert GERD symptoms in patients lacking esophageal mucosal injury and/or apparent reflux events remain an area of intense research because these patients often show resistance to PPI therapy, and such refractoriness compromises patient QOL. There is increasing evidence that multifactorial determinants including the number of reflux episodes, the acidity of the refluxate, reflux volume, liquid/gas composition, esophageal hypersensitivity, and cognitive hypervigilance form a fine network to generate GERD symptoms. Although acid is corrosive, the less the roles of acid or mucosal injuries are, the more peripheral and central sensitization become important. The advancement of novel diagnostic tools focusing on impedance, neuropathophysiology, and psychometrics could help identify GERD phenotypes more precisely and practically. These novel metrics could also facilitate an understanding that underlying backgrounds of GERD are diverse, response to treatment is variable, and mechanistic phenotypes are heterogeneous, including hypersensitivity and hypervigilance. Therefore, the traditional single approach of focusing solely on acid suppression makes treatment results unsatisfactory and problematic. Otherwise, an expanded consideration of such multifactorial determinants deserves merit. Each determinant could be a potential therapeutic target, and given the wide array of potential therapeutic targets, the development of drugs to control each target could therefore increase treatment possibilities. Therefore, determining which factors are responsible for GERD symptoms on a patient basis can establish more effective and individualized treatments, leading to the treatment concept that there is no longer a "one size fits all." This conceptual shift will realize the prescription of tailored, more effective drugs as well as the performance of behavioral intervention, and ultimately, fill the current therapeutic gaps.

#### **7. Conclusions**

The underlying mechanisms of GERD, especially PPI refractory GERD, are multifactorial. Evidence has been accumulated which supports the concept that GERD is established by a cascade starting from cytokine release to central sensitization. Since each component could be a therapeutic target, it is important to develop novel metrics to quantify the weight of each component and to develop drugs to control each component. Clarifying which component is predominant on the patient-bypatient basis could help realize tailored treatment.

*Gastroesophageal Reflux Disease - Theory and Research*

#### **Author details**

Shouji Shimoyama Gastrointestinal Unit, Settlement Clinic, Tokyo, Japan

\*Address all correspondence to: shimoyama@apost.plala.or.jp

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**21**

*Challenges to Unravel Mechanisms of GERD DOI: http://dx.doi.org/10.5772/intechopen.80793*

[1] Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R, Global Consensus Group. The Montreal definition and classification of gastroesophageal reflux disease: A global evidence-based consensus. The American Journal of Gastroenterology. 2006;**101**:1900-1920

M. Psychometric validation of the Japanese translation of the quality of life in reflux and dyspepsia questionnaire in patients with heartburn. Journal of Gastroenterology. 2007;**42**:807-815. DOI: 10.1007/s00535-007-2098-9

[9] Sigterman KE, van Pinxteren B, Bonis PA, Lau J, Numans ME. Shortterm treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastro-oesophageal reflux disease-like symptoms and endoscopy negative reflux disease. Cochrane Database of Systematic Reviews. 2013;**5**:CD002095. DOI: 10.1002/14651858.CD002095.pub5

[10] Bytzer P, van Zanten SV, Mattsson H, Wernersson B. Partial symptomresponse to proton pump inhibitors in patients with non-erosive reflux disease or reflux oesophagitis—A post hoc analysis of 5796 patients. Alimentary Pharmacology & Therapeutics.

2012;**36**:635-643. DOI: 10.1111/apt.12007

[12] Scarpellini E, Ang D, Pauwels A, De Santis A, Vanuytsel T, Tack J. Management of refractory typical GERD symptoms. Nature Reviews. Gastroenterology & Hepatology. 2016;**13**:281-294. DOI:

[13] Becher A, El-Serag H. Systematic review: The association between symptomatic response to proton pump inhibitors and health-related quality of life in patients with gastro-oesophageal reflux disease. Alimentary Pharmacology & Therapeutics. 2011;**34**:618-627. DOI: 10.1111/j.1365-2036.2011.04774.x

10.1038/nrgastro.2016.50

[11] El-Serag H, Becher A, Jones R. Systematic review: Persistent reflux symptoms on proton pump inhibitor therapy in primary care and community studies. Alimentary Pharmacology & Therapeutics. 2010;**32**:720-737. DOI: 10.1111/j.1365-2036.2010.04406.x

[2] Shaheen NJ, Hansen RA, Morgan DR, Gangarosa LM, Ringel Y, Thiny MT, et al. The burden of gastrointestinal and liver diseases, 2006. The American Journal of

Gastroenterology. 2006;**101**:2128-2138. DOI: 10.1111/j.1572-0241.2006.00723.x

[3] El-Serag HB, Sweet S, Winchester CC, Dent J. Update on the epidemiology of gastro-oesophageal reflux disease: A systematic review. Gut. 2014;**63**:871- 880. DOI: 10.1136/gutjnl-2012-304269

[4] El-Serag HB. Time trends of gastroesophageal reflux disease: A systematic review. Clinical Gastroenterology and Hepatology. 2007;**5**:17-26. DOI: 10.1016/j.

[5] Wong BC, Kinoshita Y. Systematic

review on epidemiology of gastroesophageal reflux disease in Asia. Clinical Gastroenterology and Hepatology. 2006;**4**:398-407. DOI:

10.1016/j.cgh.2005.10.011

[6] Jung HK. Epidemiology of gastroesophageal reflux disease in Asia: A systematic review. Journal of Neurogastroenterology and Motility. 2011;**17**:14-27. DOI: 10.5056/

[7] Fujiwara Y, Arakawa T. Epidemiology and clinical characteristics of GERD in the Japanese population. Journal of Gastroenterology. 2009;**44**:518-534. DOI: 10.1007/s00535-009-0047-5

[8] Hongo M, Kinoshita Y, Shimozuma

K, Kumagai Y, Sawada M, Nii

cgh.2006.09.016

jnm.2011.17.1.14

**References**

*Challenges to Unravel Mechanisms of GERD DOI: http://dx.doi.org/10.5772/intechopen.80793*

#### **References**

*Gastroesophageal Reflux Disease - Theory and Research*

**20**

**Author details**

Shouji Shimoyama

provided the original work is properly cited.

Gastrointestinal Unit, Settlement Clinic, Tokyo, Japan

\*Address all correspondence to: shimoyama@apost.plala.or.jp

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

[1] Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R, Global Consensus Group. The Montreal definition and classification of gastroesophageal reflux disease: A global evidence-based consensus. The American Journal of Gastroenterology. 2006;**101**:1900-1920

[2] Shaheen NJ, Hansen RA, Morgan DR, Gangarosa LM, Ringel Y, Thiny MT, et al. The burden of gastrointestinal and liver diseases, 2006. The American Journal of Gastroenterology. 2006;**101**:2128-2138. DOI: 10.1111/j.1572-0241.2006.00723.x

[3] El-Serag HB, Sweet S, Winchester CC, Dent J. Update on the epidemiology of gastro-oesophageal reflux disease: A systematic review. Gut. 2014;**63**:871- 880. DOI: 10.1136/gutjnl-2012-304269

[4] El-Serag HB. Time trends of gastroesophageal reflux disease: A systematic review. Clinical Gastroenterology and Hepatology. 2007;**5**:17-26. DOI: 10.1016/j. cgh.2006.09.016

[5] Wong BC, Kinoshita Y. Systematic review on epidemiology of gastroesophageal reflux disease in Asia. Clinical Gastroenterology and Hepatology. 2006;**4**:398-407. DOI: 10.1016/j.cgh.2005.10.011

[6] Jung HK. Epidemiology of gastroesophageal reflux disease in Asia: A systematic review. Journal of Neurogastroenterology and Motility. 2011;**17**:14-27. DOI: 10.5056/ jnm.2011.17.1.14

[7] Fujiwara Y, Arakawa T. Epidemiology and clinical characteristics of GERD in the Japanese population. Journal of Gastroenterology. 2009;**44**:518-534. DOI: 10.1007/s00535-009-0047-5

[8] Hongo M, Kinoshita Y, Shimozuma K, Kumagai Y, Sawada M, Nii

M. Psychometric validation of the Japanese translation of the quality of life in reflux and dyspepsia questionnaire in patients with heartburn. Journal of Gastroenterology. 2007;**42**:807-815. DOI: 10.1007/s00535-007-2098-9

[9] Sigterman KE, van Pinxteren B, Bonis PA, Lau J, Numans ME. Shortterm treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastro-oesophageal reflux disease-like symptoms and endoscopy negative reflux disease. Cochrane Database of Systematic Reviews. 2013;**5**:CD002095. DOI: 10.1002/14651858.CD002095.pub5

[10] Bytzer P, van Zanten SV, Mattsson H, Wernersson B. Partial symptomresponse to proton pump inhibitors in patients with non-erosive reflux disease or reflux oesophagitis—A post hoc analysis of 5796 patients. Alimentary Pharmacology & Therapeutics. 2012;**36**:635-643. DOI: 10.1111/apt.12007

[11] El-Serag H, Becher A, Jones R. Systematic review: Persistent reflux symptoms on proton pump inhibitor therapy in primary care and community studies. Alimentary Pharmacology & Therapeutics. 2010;**32**:720-737. DOI: 10.1111/j.1365-2036.2010.04406.x

[12] Scarpellini E, Ang D, Pauwels A, De Santis A, Vanuytsel T, Tack J. Management of refractory typical GERD symptoms. Nature Reviews. Gastroenterology & Hepatology. 2016;**13**:281-294. DOI: 10.1038/nrgastro.2016.50

[13] Becher A, El-Serag H. Systematic review: The association between symptomatic response to proton pump inhibitors and health-related quality of life in patients with gastro-oesophageal reflux disease. Alimentary Pharmacology & Therapeutics. 2011;**34**:618-627. DOI: 10.1111/j.1365-2036.2011.04774.x

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[23] Mönkemüller K, Wex T, Kuester D, Fry LC, Peitz U, Beyer M, et al. Interleukin-1beta and interleukin-8 expression correlate with the histomorphological changes in esophageal mucosa of patients with erosive and non-erosive reflux disease. Digestion. 2009;**79**:186-195. DOI: 10.1159/000211714

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*Challenges to Unravel Mechanisms of GERD DOI: http://dx.doi.org/10.5772/intechopen.80793*

*Gastroesophageal Reflux Disease - Theory and Research*

reflux disease with esophageal histologic changes. Journal of the American Medical Association. 2016;**315**:2104- 2112. DOI: 10.1001/jama.2016.5657

[21] Azumi T, Adachi K, Furuta K, Nakata S, Ohara S, Koshino K, et al. Esophageal epithelial surface in patients with gastroesophageal reflux disease: An electron microscopic study. World Journal of Gastroenterology. 2008;**14**:5712-5716. DOI: 10.3748/

[22] Isomoto H, Saenko VA, Kanazawa Y, Nishi Y, Ohtsuru A, Inoue K, et al. Enhanced expression of interleukin-8 and activation of nuclear factor kappa-B in endoscopy-negative gastroesophageal reflux disease. The American Journal of Gastroenterology. 2004;**99**:589-597. DOI: 10.1111/j.1572-0241.2004.04110.x

[23] Mönkemüller K, Wex T, Kuester D, Fry LC, Peitz U, Beyer M, et al. Interleukin-1beta and interleukin-8 expression correlate with the histomorphological changes in esophageal mucosa of patients with erosive and non-erosive reflux disease. Digestion. 2009;**79**:186-195. DOI:

[24] Isomoto H, Wang A, Mizuta Y, Akazawa Y, Ohba K, Omagari K, et al. Elevated levels of chemokines in esophageal mucosa of patients with reflux esophagitis. The American Journal of Gastroenterology. 2003;**98**:551-556. DOI:

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*Gastroesophageal Reflux Disease - Theory and Research*

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S0140-6736(00)02758-6

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[49] Schmulson MJ, Drossman DA. What is new in Rome IV. Journal of Neurogastroenterology and Motility. 2017;**23**:151-163. DOI: 10.5056/jnm16214

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cgh.2014.11.033

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Pharmacological Reviews.

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**24**

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[58] Avidan B, Sonnenberg A, Giblovich H, Sontag SJ. Reflux symptoms are associated with psychiatric disease. Alimentary Pharmacology &

Therapeutics. 2001;**15**:1907-1912. DOI: 10.1046/j.1365-2036.2001.01131.x

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[66] Iwakiri K, Kawami N, Sano H, Tanaka Y, Umezawa M, Kotoyori M, et al. Acid and non-acid reflux in Japanese patients with non-erosive reflux disease with persistent reflux symptoms, despite taking a double-dose of proton pump inhibitor: A study using combined pH-impedance monitoring.

Journal of Gastroenterology. 2009;**44**:708-712. DOI: 10.1007/

[67] Roman S, Keefer L, Imam H, Korrapati P, Mogni B, Eident K, et al. Majority of symptoms in esophageal reflux PPI non-responders are not related to reflux. Neurogastroenterology and Motility. 2015;**27**:1667-1674. DOI:

[68] Mainie I, Tutuian R, Shay S, Vela M, Zhang X, Sifrim D, et al. Acid and nonacid reflux in patients with persistent symptoms despite acid suppressive therapy: A multicentre study using combined ambulatory impedance-pH monitoring. Gut. 2006;**55**:1398-1402. DOI: 10.1136/gut.2005.087668

[69] Sharma N, Agrawal A, Freeman J, Vela MF, Castell D. An analysis of persistent symptoms in acid-suppressed patients undergoing impedance-pH monitoring. Clinical Gastroenterology and Hepatology. 2008;**6**:521-524. DOI:

[70] Stock JL, Shinjo K, Burkhardt J, Roach M, Taniguchi K, Ishikawa T, et al. The prostaglandin E2 EP1 receptor mediates pain perception and regulates blood pressure. The Journal of Clinical Investigation. 2001;**107**:325-331. DOI:

10.1016/j.cgh.2008.01.006

s00535-009-0070-6

10.1111/nmo.12666

s00535-011-0480-0

**26**

10.1172/JCI6749

the development of acid-induced oesophageal hypersensitivity in healthy volunteers—A placebo-controlled study. Alimentary Pharmacology & Therapeutics. 2012;**35**:319-326. DOI: 10.1111/j.1365-2036.2011.04955.x

[77] Forcelini CM, Tomiozzo JC Jr, Farré R, Van Oudenhove L, Callegari-Jacques SM, Ribeiro M, et al. Effect of nortriptyline on brain responses to painful esophageal acid infusion in patients with non-erosive reflux disease. Neurogastroenterology and Motility. 2014;**26**:187-195. DOI: 10.1111/ nmo.12251

[78] Kondo T, Oshima T, Koseki J, Hattori T, Kase Y, Tomita T, et al. Effect of rikkunshito on the expression of substance P and CGRP in dorsal root ganglion neurons and voluntary movement in rats with experimental reflux esophagitis. Neurogastroenterology and Motility. 2014;**26**:913-921. DOI: 10.1111/ nmo.12342

**29**

**Chapter 3**

**Abstract**

*Xia Chen and Fei Wang*

monitoring, refractory reflux symptoms

**1. Introduction**

mucosal healing, is expected.

Refractory Gastroesophageal

Reflux Disease (GERD) Symptoms

Gastroesophageal reflux disease (GERD) is a chronic condition in which patients

suffer troublesome symptoms and/or complications as the reflux of stomach contents occurs. GERD is a common disease worldwide with the range of estimated prevalence 18.1–27.8% in North America, 8.8–25.9% in Europe, 2.5–7.8% in East Asia, 8.7–33.1% in the Middle East, 11.6% in Australia and 23.0% in South America. It causes significant morbidity, considerable decrease of quality of life and high costs of exams and treatment derived from repeated visit doctor. The patients with GERD suffer from typical symptoms such as heartburn and regurgitation, as well as other atypical symptoms including chest pain, cough, asthma, and hoarseness. With the usage of pump inhibitors (PPIs) in clinic, a dramatic improvement in symptom resolution and life quality, as well as in mucosal healing is expected. However, the treatment of GERD fails in a proportion of patients despite the high efficacy of PPIs. This situation is getting more and more common in clinical practices. In this chapter, we will discuss about this difficult situation, emphasizing diagnosis and treatment, combined with suggested management of these patients.

**Keywords:** gastroesophageal reflux disease (GERD), refractory proton pump inhibitor (PPI) symptoms, high-resolution manometry (HRM), impedance-pH

costs of exams and treatment derived from repeated visits to the doctor.

Gastroesophageal reflux disease (GERD) is a chronic condition in which patients suffer troublesome symptoms and/or complications as the reflux of stomach contents occurs. GERD is a common disease worldwide with the range of an estimated prevalence of 18.1–27.8% in North America, 8.8–25.9% in Europe, 2.5–7.8% in East Asia, 8.7–33.1% in the Middle East, 11.6% in Australia, and 23.0% in South America [1]. It causes significant morbidity, considerable decrease of quality of life, and high

The patients with GERD suffer from typical symptoms, such as heartburn and regurgitation, as well as other atypical symptoms including chest pain, cough, asthma, and hoarseness. With the usage of proton pump inhibitors (PPIs) in the clinic, a dramatic improvement in symptom resolution and life quality, as well as in

However, the treatment of GERD fails in a proportion of patients despite the high efficacy of PPIs. This situation is referred as to refractory GERD symptoms. What is worse, it is getting more and more common in clinical practices. In this

#### **Chapter 3**

## Refractory Gastroesophageal Reflux Disease (GERD) Symptoms

*Xia Chen and Fei Wang*

#### **Abstract**

Gastroesophageal reflux disease (GERD) is a chronic condition in which patients suffer troublesome symptoms and/or complications as the reflux of stomach contents occurs. GERD is a common disease worldwide with the range of estimated prevalence 18.1–27.8% in North America, 8.8–25.9% in Europe, 2.5–7.8% in East Asia, 8.7–33.1% in the Middle East, 11.6% in Australia and 23.0% in South America. It causes significant morbidity, considerable decrease of quality of life and high costs of exams and treatment derived from repeated visit doctor. The patients with GERD suffer from typical symptoms such as heartburn and regurgitation, as well as other atypical symptoms including chest pain, cough, asthma, and hoarseness. With the usage of pump inhibitors (PPIs) in clinic, a dramatic improvement in symptom resolution and life quality, as well as in mucosal healing is expected. However, the treatment of GERD fails in a proportion of patients despite the high efficacy of PPIs. This situation is getting more and more common in clinical practices. In this chapter, we will discuss about this difficult situation, emphasizing diagnosis and treatment, combined with suggested management of these patients.

**Keywords:** gastroesophageal reflux disease (GERD), refractory proton pump inhibitor (PPI) symptoms, high-resolution manometry (HRM), impedance-pH monitoring, refractory reflux symptoms

#### **1. Introduction**

Gastroesophageal reflux disease (GERD) is a chronic condition in which patients suffer troublesome symptoms and/or complications as the reflux of stomach contents occurs. GERD is a common disease worldwide with the range of an estimated prevalence of 18.1–27.8% in North America, 8.8–25.9% in Europe, 2.5–7.8% in East Asia, 8.7–33.1% in the Middle East, 11.6% in Australia, and 23.0% in South America [1]. It causes significant morbidity, considerable decrease of quality of life, and high costs of exams and treatment derived from repeated visits to the doctor.

The patients with GERD suffer from typical symptoms, such as heartburn and regurgitation, as well as other atypical symptoms including chest pain, cough, asthma, and hoarseness. With the usage of proton pump inhibitors (PPIs) in the clinic, a dramatic improvement in symptom resolution and life quality, as well as in mucosal healing, is expected.

However, the treatment of GERD fails in a proportion of patients despite the high efficacy of PPIs. This situation is referred as to refractory GERD symptoms. What is worse, it is getting more and more common in clinical practices. In this

chapter, we will discuss about this difficult situation, emphasizing on diagnosis and treatment, combined with suggested management of these patients.

#### **2. Definition of refractory GERD symptom**

The definition of "refractory GERD" has traditionally been described as a group of varying symptom presentations related to GERD, which persists even though the patients accepted the standard daily PPI therapy for at least 12 weeks. Some researchers referred to a failure to achieve satisfactory symptomatic response, for example, less than 50% improvement of relief of symptoms and life quality, to once-daily PPI to be classified as "refractory GERD" or "refractory reflux symptoms" [2]. The continued symptoms must be to a degree that impairs quality of life, and symptoms must be "reflux-related," which are supposed to be influenced by sex, age, ethnicity, social status, comorbidity, and cultural background. However, there is a controversy of the PPI dose for the definition of "refractory GERD." Some investigators prefer that inadequate response to twice-daily PPI treatment as refractory disease [3]. Moreover, the patient's remaining symptoms are subjective to and dependent on the patient's expectations of the therapy. It needs more clinical practice and further researches to supplement the definition in the future.

#### **3. Causes of refractory GERD symptom**

There are some underlying causes of refractory GERD. Firstly, poor compliance and adherence should be excluded before further evaluation is pursued. There are some key points of medication administration for patients, such as taking PPIs at the optimal 30–60 minutes prior to meal; avoiding discontinued PPIs without doctors' instruction even though the symptoms are relieved; receiving enough information about PPIs therapy. These points are initial important considerations for resolving the refractory GERD. Then, other disorders with GERD-like symptoms, such as esophageal disorders and functional gastrointestinal disorders, should be considered in the differential diagnosis of patients with persistent symptoms (**Figure 1**).

**31**

*Refractory Gastroesophageal Reflux Disease (GERD) Symptoms*

PPI failure in patients initially diagnosed with GERD.

**4. Diagnosis of refractory GERD symptom**

Additionally, obesity and overeating are other common factors associated with

The first important step is to identify the actual nature of the persisting symptoms. It can help a physician to choose the correct equipment for the next step of diagnosis. The typical symptoms of GERD are heartburn and regurgitation, which can be recognized by the GerdQ questionnaire. It is a revision of the Reflux Disease Questionnaire (RDQ ) with positive predictor questions about heartburn and regurgitation as well as negative predictors about epigastric pain and nausea. It is reported that there is a sensitivity of 65% and specificity of 71% with GerdQ, which is close to the efficiency done by the clinical judgment of gastroenterologists [4]. However, presenting regurgitation should also be differentiated to gastroparesis or rumination syndrome. Except that, the physician should be aware of the proportion of patients with the atypical symptoms, such as retrosternal discomfort and pain, cough, asthma, hoarseness, throat discomfort, foreign body sensation in throat, globus sensation,

A recent study shows that there is about half of patients with atypical symptom, combined or uncombined with typical symptom [5]. In short, it is essential to figure out which symptoms respond and which do not respond to PPI therapy. More detailed questioning about symptom often help clarify the cause for a patient's persistent symptoms. Especially, the patients with atypical symptom might have poor response to PPI therapy because there are probably other causes or diseases that overlapped GERD.

Upper endoscopy should be taken principally to exclude non-reflux esophageal disorders and other gastric diseases and to check whether erosive esophagitis exists, which can provide evidence of ongoing acid reflux. However, endoscopy is of limited value for diagnosis of refractory GERD symptom. It is because that most patients have normal endoscopy. The potential reasons are that most patients with refractory GERD symptom have other esophageal motility problem; they have nonerosive reflux disease (NERD); or PPIs they taken has healed the mucosal injury.

All patients with refractory GERD symptom are strongly recommended to undergo esophageal manometry. The purpose mainly is to find esophageal motor disorders, for example, achalasia, weak peristalsis, hypertensive esophageal dysmotility, diffuse esophageal spasm (DES), hiatus hernias (HH), high UES pressure, and abnormal lower esophageal sphincter (LES) pressure. Secondly, but more important, esophageal manometry is applied for identifying the accurate location

There are two methods for esophageal reflux monitoring, called as On-PPI and Off-PPI. In off-PPI (7 days after cessation of PPI), the presence of abnormal acid reflux and/or positive symptom-reflux relationship can be confirmed. The relevant

of LES in order to place reflux monitoring pH sensors.

**4.4 Ambulatory monitoring for reflux**

belching, dysphagia, and epigastric pain and epigastric discomfort.

*DOI: http://dx.doi.org/10.5772/intechopen.80792*

**4.1 Symptom evaluation**

**4.2 Endoscopy**

**4.3 Esophageal manometry**

**Figure 1.** *Causes of refractory GERD symptom.*

Additionally, obesity and overeating are other common factors associated with PPI failure in patients initially diagnosed with GERD.

#### **4. Diagnosis of refractory GERD symptom**

#### **4.1 Symptom evaluation**

*Gastroesophageal Reflux Disease - Theory and Research*

**2. Definition of refractory GERD symptom**

**3. Causes of refractory GERD symptom**

chapter, we will discuss about this difficult situation, emphasizing on diagnosis and

The definition of "refractory GERD" has traditionally been described as a group of varying symptom presentations related to GERD, which persists even though the patients accepted the standard daily PPI therapy for at least 12 weeks. Some researchers referred to a failure to achieve satisfactory symptomatic response, for example, less than 50% improvement of relief of symptoms and life quality, to once-daily PPI to be classified as "refractory GERD" or "refractory reflux symptoms" [2]. The continued symptoms must be to a degree that impairs quality of life, and symptoms must be "reflux-related," which are supposed to be influenced by sex, age, ethnicity, social status, comorbidity, and cultural background. However, there is a controversy of the PPI dose for the definition of "refractory GERD." Some investigators prefer that inadequate response to twice-daily PPI treatment as refractory disease [3]. Moreover, the patient's remaining symptoms are subjective to and dependent on the patient's expectations of the therapy. It needs more clinical practice and further researches to supplement the definition in the future.

There are some underlying causes of refractory GERD. Firstly, poor compliance and adherence should be excluded before further evaluation is pursued. There are some key points of medication administration for patients, such as taking PPIs at the optimal 30–60 minutes prior to meal; avoiding discontinued PPIs without doctors' instruction even though the symptoms are relieved; receiving enough information about PPIs therapy. These points are initial important considerations for resolving the refractory GERD. Then, other disorders with GERD-like symptoms, such as esophageal disorders and functional gastrointestinal disorders, should be considered

in the differential diagnosis of patients with persistent symptoms (**Figure 1**).

treatment, combined with suggested management of these patients.

**30**

**Figure 1.**

*Causes of refractory GERD symptom.*

The first important step is to identify the actual nature of the persisting symptoms. It can help a physician to choose the correct equipment for the next step of diagnosis. The typical symptoms of GERD are heartburn and regurgitation, which can be recognized by the GerdQ questionnaire. It is a revision of the Reflux Disease Questionnaire (RDQ ) with positive predictor questions about heartburn and regurgitation as well as negative predictors about epigastric pain and nausea. It is reported that there is a sensitivity of 65% and specificity of 71% with GerdQ, which is close to the efficiency done by the clinical judgment of gastroenterologists [4]. However, presenting regurgitation should also be differentiated to gastroparesis or rumination syndrome. Except that, the physician should be aware of the proportion of patients with the atypical symptoms, such as retrosternal discomfort and pain, cough, asthma, hoarseness, throat discomfort, foreign body sensation in throat, globus sensation, belching, dysphagia, and epigastric pain and epigastric discomfort.

A recent study shows that there is about half of patients with atypical symptom, combined or uncombined with typical symptom [5]. In short, it is essential to figure out which symptoms respond and which do not respond to PPI therapy. More detailed questioning about symptom often help clarify the cause for a patient's persistent symptoms. Especially, the patients with atypical symptom might have poor response to PPI therapy because there are probably other causes or diseases that overlapped GERD.

#### **4.2 Endoscopy**

Upper endoscopy should be taken principally to exclude non-reflux esophageal disorders and other gastric diseases and to check whether erosive esophagitis exists, which can provide evidence of ongoing acid reflux. However, endoscopy is of limited value for diagnosis of refractory GERD symptom. It is because that most patients have normal endoscopy. The potential reasons are that most patients with refractory GERD symptom have other esophageal motility problem; they have nonerosive reflux disease (NERD); or PPIs they taken has healed the mucosal injury.

#### **4.3 Esophageal manometry**

All patients with refractory GERD symptom are strongly recommended to undergo esophageal manometry. The purpose mainly is to find esophageal motor disorders, for example, achalasia, weak peristalsis, hypertensive esophageal dysmotility, diffuse esophageal spasm (DES), hiatus hernias (HH), high UES pressure, and abnormal lower esophageal sphincter (LES) pressure. Secondly, but more important, esophageal manometry is applied for identifying the accurate location of LES in order to place reflux monitoring pH sensors.

#### **4.4 Ambulatory monitoring for reflux**

There are two methods for esophageal reflux monitoring, called as On-PPI and Off-PPI. In off-PPI (7 days after cessation of PPI), the presence of abnormal acid reflux and/or positive symptom-reflux relationship can be confirmed. The relevant


**Table 1.**

*Diagnosis based on endoscopy, esophageal manometry, and ambulatory monitoring for reflux.*

parameter to be observed is esophageal acid exposure, which is the proportion of time (in minutes or percentage of time) spent below pH 4, as well as correlation between symptoms and reflux events (symptom index (SI) and/or symptom association probability (SAP)). Positive symptom association with normal esophageal acid exposure is considered hypersensitive esophagus (HE), reflecting an underlying visceral hypersensitivity. For on-PPI reflux monitoring, impedance-pH monitoring should reasonably be proposed as the preferred investigation. It can detect nonacid reflux during the PPI therapy period, which is one of causes for persistent GERD symptom. It also can figure out whether acid reflux is controlled or not by the treatment (**Table 1**).

#### **4.5 Assessment and evaluation for psychological status**

Psychological disorders such as hysteria, anxiety, and distress should also be evaluated in patients with refractory symptoms. Weak correlation of symptoms with acid reflux events might indicate a high level of anxiety and hysteria as compared with patients who demonstrate a close correlation between symptoms and acid reflux event [6]. Anxiety and depression have been shown to increase reflux symptoms reported in population-based studies. A study has reported that patients who did not respond to PPI treatment were suffered from more psychosocial problem [7].

#### **5. Management of refractory GERD symptom**

#### **5.1 Lifestyle modifications**

Weight loss, head of bed elevation, and avoiding late-night meals, which have been shown as effective interventions for GERD, have not been demonstrated yet equally useful in patients with refractory reflux symptoms. The value of lifestyle modifications in patients with refractory symptoms lies in avoidance of specific lifestyle activities that have been identified by patients or physicians to trigger symptoms. A low-bulk and low-fat diet along with small but more frequent meals should surely be recommended.

#### **5.2 Medicine**

Increasing the PPI dose or to change to an alternative PPI improved the symptom in some patients [8]. However, this dosing strategy should be used for a short time period (2–3 months) and should be tapered if it does not result in improvement of symptoms. The addition of an H2RA at bedtime was shown to significantly reduce the duration of nocturnal acid breakthrough (NAB) pain modulators. Transient lower esophageal sphincter relaxation (TLESR) reducers can be considered for patients with abnormal frequency of nonacid reflux. The drugs that can reduce the number of reflux events regardless of their acidity are theoretically desirable

**33**

**Figure 2.**

*Refractory Gastroesophageal Reflux Disease (GERD) Symptoms*

which still needs further studies to demonstrate its efficiency.

*Diagnostic and treatment algorithm for patients with refractory GERD symptom.*

because of the potential for weakly acidic or bile reflux to cause symptoms.

Nevertheless, high-quality controlled trials are needed to demonstrate its efficacy in

Visceral pain modulator therapy has been another option for patients with an acid-hypersensitive esophagus or functional heartburn. A randomized, placebo-controlled trial has demonstrated citalopram 20 mg/day to be of symptomatic benefit in patients with acid-hypersensitive esophagus and refractory GERD symptoms [9].

Stretta procedure and EsophyX transoral incisionless fundoplication are two antireflux endoscopic devices which are clinically available. The Stretta procedure showed clinical improvement of esophageal symptoms and a decrease in PPI use but no significant effect on esophageal acid exposure [10]. EsophyX offers a less invasive alternative to laparoscopic fundoplication for PPI-dependent GERD patients,

Comparing with patients with adequate PPI symptom control, antireflux surgery might have a less favorable clinical outcome for the patients with refractory GERD symptom. Normal acid exposure and the presence of atypical reflux symptoms and persisting symptoms despite PPI therapy are predictors of a poor postoperative outcome. It is important to confirm pathological reflux before considering antireflux surgery if there is no proven esophagitis. Summarily, surgery can be a valuable option in patients with typical reflux symptoms with inadequate response to PPIs, provided abnormal esophageal acid exposure and/or positive symptom

According to a recent research, perceptions of reflux symptoms are associated with psychosocial distress in these patients with refractory GERD symptom who

*DOI: http://dx.doi.org/10.5772/intechopen.80792*

patients with refractory symptoms.

**5.3 Endoscopic therapy**

**5.4 Antireflux surgery**

association analysis in off-PPI test [11].

**5.5 Psychological treatment**

*Refractory Gastroesophageal Reflux Disease (GERD) Symptoms DOI: http://dx.doi.org/10.5772/intechopen.80792*

because of the potential for weakly acidic or bile reflux to cause symptoms. Nevertheless, high-quality controlled trials are needed to demonstrate its efficacy in patients with refractory symptoms.

Visceral pain modulator therapy has been another option for patients with an acid-hypersensitive esophagus or functional heartburn. A randomized, placebo-controlled trial has demonstrated citalopram 20 mg/day to be of symptomatic benefit in patients with acid-hypersensitive esophagus and refractory GERD symptoms [9].

#### **5.3 Endoscopic therapy**

*Gastroesophageal Reflux Disease - Theory and Research*

Nonerosive reflux disease (NERD) No mucosal break

Hypersensitive esophagus (HE) No mucosal break

Functional heartburn (FH) Heartburn refractory to PPIs,

*Diagnosis based on endoscopy, esophageal manometry, and ambulatory monitoring for reflux.*

parameter to be observed is esophageal acid exposure, which is the proportion of time (in minutes or percentage of time) spent below pH 4, as well as correlation between symptoms and reflux events (symptom index (SI) and/or symptom association probability (SAP)). Positive symptom association with normal esophageal acid exposure is considered hypersensitive esophagus (HE), reflecting an underlying visceral hypersensitivity. For on-PPI reflux monitoring, impedance-pH monitoring should reasonably be proposed as the preferred investigation. It can detect nonacid reflux during the PPI therapy period, which is one of causes for persistent GERD symptom. It also can figure out whether acid reflux is controlled or not by the treatment (**Table 1**).

no mucosal break,

Normal esophageal acid exposure

Normal esophageal acid exposure SI > 50%, SAP > 95%

normal esophageal acid exposure SI < 50%, SAP < 95%

Psychological disorders such as hysteria, anxiety, and distress should also be evaluated in patients with refractory symptoms. Weak correlation of symptoms with acid reflux events might indicate a high level of anxiety and hysteria as compared with patients who demonstrate a close correlation between symptoms and acid reflux event [6]. Anxiety and depression have been shown to increase reflux symptoms reported in population-based studies. A study has reported that patients who did not respond to PPI treatment were suffered from more psychosocial problem [7].

Weight loss, head of bed elevation, and avoiding late-night meals, which have been shown as effective interventions for GERD, have not been demonstrated yet equally useful in patients with refractory reflux symptoms. The value of lifestyle modifications in patients with refractory symptoms lies in avoidance of specific lifestyle activities that have been identified by patients or physicians to trigger symptoms. A low-bulk and low-fat diet along with small but more frequent meals should surely be recommended.

Increasing the PPI dose or to change to an alternative PPI improved the symptom in some patients [8]. However, this dosing strategy should be used for a short time period (2–3 months) and should be tapered if it does not result in improvement of symptoms. The addition of an H2RA at bedtime was shown to significantly reduce the duration of nocturnal acid breakthrough (NAB) pain modulators. Transient lower esophageal sphincter relaxation (TLESR) reducers can be considered for patients with abnormal frequency of nonacid reflux. The drugs that can reduce the number of reflux events regardless of their acidity are theoretically desirable

**4.5 Assessment and evaluation for psychological status**

**5. Management of refractory GERD symptom**

**5.1 Lifestyle modifications**

**32**

**5.2 Medicine**

**Table 1.**

Stretta procedure and EsophyX transoral incisionless fundoplication are two antireflux endoscopic devices which are clinically available. The Stretta procedure showed clinical improvement of esophageal symptoms and a decrease in PPI use but no significant effect on esophageal acid exposure [10]. EsophyX offers a less invasive alternative to laparoscopic fundoplication for PPI-dependent GERD patients, which still needs further studies to demonstrate its efficiency.

#### **5.4 Antireflux surgery**

Comparing with patients with adequate PPI symptom control, antireflux surgery might have a less favorable clinical outcome for the patients with refractory GERD symptom. Normal acid exposure and the presence of atypical reflux symptoms and persisting symptoms despite PPI therapy are predictors of a poor postoperative outcome. It is important to confirm pathological reflux before considering antireflux surgery if there is no proven esophagitis. Summarily, surgery can be a valuable option in patients with typical reflux symptoms with inadequate response to PPIs, provided abnormal esophageal acid exposure and/or positive symptom association analysis in off-PPI test [11].

#### **5.5 Psychological treatment**

According to a recent research, perceptions of reflux symptoms are associated with psychosocial distress in these patients with refractory GERD symptom who

#### **Figure 2.**

*Diagnostic and treatment algorithm for patients with refractory GERD symptom.*

have normal impedance-pH results. Furthermore, patient-reported symptom severity is associated with physiological differences, as opposed to psychosocial factors [11]. In these patients with psychological disorders, treatment-targeted psychosocial abnormality may improve patient response to PPI therapy [2]. Psychological treatment should be a potential consideration in the case of the patients without other identifiable causes. In many clinical experiences, psychological disorders may be an underlying etiology in many patients with refractory symptoms (**Figure 2**).

### **Author details**

Xia Chen\* and Fei Wang Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China

\*Address all correspondence to: xiac6686@gmail.com

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**35**

*Refractory Gastroesophageal Reflux Disease (GERD) Symptoms*

[8] Fass R, Sontag SJ, Traxler B, Sostek M. Treatment of patients with persistent heartburn symptoms: A double-blind, randomized trial. Clinical Gastroenterology and Hepatology.

[9] Viazis N, Keyoglou A, Kanellopoulos AK, Karamanolis G, Vlachogiannakos J, Triantafyllou K, et al. Selective serotonin reuptake inhibitors for the treatment of hypersensitive esophagus: A randomized, doubleblind, placebo-controlled study. The American Journal of Gastroenterology.

2006;**4**:50-56

2012;**107**:1662-1667

[10] Arts J, Sifrim D, Rutgeerts P, Lerut A, Janssens J, Tack J. Influence of radiofrequency energy delivery at the gastroesophageal junction (the Stretta procedure) on symptoms, acid exposure, and esophageal sensitivity to acid perfusion in gastroesophageal reflux disease. Digestive Diseases and

Sciences. 2007;**52**:2170-2177

are associated with symptom severity in PPI non-responders with normal impedance-pH profiles. The American Journal of Gastroenterology.

2018;**113**:31-38

[11] Yadlapati R, Tye M, Keefer L, Kahrilas PJ, Pandolfino JE. Psychosocial distress and quality of life impairment

*DOI: http://dx.doi.org/10.5772/intechopen.80792*

[1] El-Serag HB, Sweet S, Winchester CC, Dent J. Update on the epidemiology of gastro-oesophageal reflux disease: A systematic review. Gut. 2014;**63**:871-880

[2] Sifrim D, Zerbib F. Diagnosis and management of patients with reflux symptoms refractory to proton pump inhibitors. Gut. 2012;**61**:1340-1354

[3] Martinez SD, Malagon IB, Garewal HS, Cui H, Fass R. Nonerosive reflux disease (NERD)—Acid reflux and symptom patterns. Alimentary Pharmacology & Therapeutics.

[4] Jones R, Junghard O, Dent J, Vakil N,

[5] Wang F, Li P, Ji GZ, Miao L, Fan Z, You S, et al. An analysis of 342 patients with refractory gastroesophageal reflux disease symptoms using questionnaires, high-resolution manometry, and impedance-pH monitoring. Medicine.

[6] Becher A, El-Serag H. Systematic review: The association between symptomatic response to proton pump inhibitors and health-related quality of life in patients with gastrooesophageal reflux disease. Alimentary

Pharmacology & Therapeutics.

[7] Chen X, Li P, Wang F, Ji G, Miao L, You S. Psychological results of 438 patients with persisting gastroesophageal reflux disease symptoms by symptom checklist 90-revised questionnaire. Euroasian Journal of Hepato-Gastroenterology. 2017;**7**:117-121

Halling K, Wernersson B, et al. Development of the GerdQ, a tool for the diagnosis and management of gastro-oesophageal reflux disease in primary care. Alimentary Pharmacology & Therapeutics. 2009;**30**:1030-1038

**References**

2003;**17**:537-545

2017;**96**(5):e5906

2011;**34**:618-627

*Refractory Gastroesophageal Reflux Disease (GERD) Symptoms DOI: http://dx.doi.org/10.5772/intechopen.80792*

#### **References**

*Gastroesophageal Reflux Disease - Theory and Research*

have normal impedance-pH results. Furthermore, patient-reported symptom severity is associated with physiological differences, as opposed to psychosocial factors [11]. In these patients with psychological disorders, treatment-targeted psychosocial abnormality may improve patient response to PPI therapy [2]. Psychological treatment should be a potential consideration in the case of the patients without other identifiable causes. In many clinical experiences, psychological disorders may be an underlying etiology in many patients with refractory symptoms (**Figure 2**).

**34**

**Author details**

Xia Chen\* and Fei Wang

Medical University, Nanjing, China

provided the original work is properly cited.

\*Address all correspondence to: xiac6686@gmail.com

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing

[1] El-Serag HB, Sweet S, Winchester CC, Dent J. Update on the epidemiology of gastro-oesophageal reflux disease: A systematic review. Gut. 2014;**63**:871-880

[2] Sifrim D, Zerbib F. Diagnosis and management of patients with reflux symptoms refractory to proton pump inhibitors. Gut. 2012;**61**:1340-1354

[3] Martinez SD, Malagon IB, Garewal HS, Cui H, Fass R. Nonerosive reflux disease (NERD)—Acid reflux and symptom patterns. Alimentary Pharmacology & Therapeutics. 2003;**17**:537-545

[4] Jones R, Junghard O, Dent J, Vakil N, Halling K, Wernersson B, et al. Development of the GerdQ, a tool for the diagnosis and management of gastro-oesophageal reflux disease in primary care. Alimentary Pharmacology & Therapeutics. 2009;**30**:1030-1038

[5] Wang F, Li P, Ji GZ, Miao L, Fan Z, You S, et al. An analysis of 342 patients with refractory gastroesophageal reflux disease symptoms using questionnaires, high-resolution manometry, and impedance-pH monitoring. Medicine. 2017;**96**(5):e5906

[6] Becher A, El-Serag H. Systematic review: The association between symptomatic response to proton pump inhibitors and health-related quality of life in patients with gastrooesophageal reflux disease. Alimentary Pharmacology & Therapeutics. 2011;**34**:618-627

[7] Chen X, Li P, Wang F, Ji G, Miao L, You S. Psychological results of 438 patients with persisting gastroesophageal reflux disease symptoms by symptom checklist 90-revised questionnaire. Euroasian Journal of Hepato-Gastroenterology. 2017;**7**:117-121

[8] Fass R, Sontag SJ, Traxler B, Sostek M. Treatment of patients with persistent heartburn symptoms: A double-blind, randomized trial. Clinical Gastroenterology and Hepatology. 2006;**4**:50-56

[9] Viazis N, Keyoglou A, Kanellopoulos AK, Karamanolis G, Vlachogiannakos J, Triantafyllou K, et al. Selective serotonin reuptake inhibitors for the treatment of hypersensitive esophagus: A randomized, doubleblind, placebo-controlled study. The American Journal of Gastroenterology. 2012;**107**:1662-1667

[10] Arts J, Sifrim D, Rutgeerts P, Lerut A, Janssens J, Tack J. Influence of radiofrequency energy delivery at the gastroesophageal junction (the Stretta procedure) on symptoms, acid exposure, and esophageal sensitivity to acid perfusion in gastroesophageal reflux disease. Digestive Diseases and Sciences. 2007;**52**:2170-2177

[11] Yadlapati R, Tye M, Keefer L, Kahrilas PJ, Pandolfino JE. Psychosocial distress and quality of life impairment are associated with symptom severity in PPI non-responders with normal impedance-pH profiles. The American Journal of Gastroenterology. 2018;**113**:31-38

**37**

**1. Introduction**

**Chapter 4**

**Abstract**

Clinical Picture of Gastroesophageal

Gastroesophageal reflux (GER), defined as the passage of gastric contents into the esophagus, is a normal physiologic process occurring several times per day in healthy infants, children, and adults. The majority of GER episodes occur in the postprandial period, last in <3 min, and cause few or no symptoms. Conversely, when the reflux of gastric contents into the esophagus causes troublesome symptoms and/or complications, we talk about "gastroesophageal reflux disease (GERD)." Distinguishing physiologic GER from GERD may often be tricky for clinicians, especially in infants. The typical presentation of GERD includes the following symptoms: recurrent regurgitation, vomiting, weight loss or poor weight gain, excessive crying and irritability in infants, heartburn or chest pain, ruminative behavior, hematemesis, and dysphagia. Besides these esophageal symptoms, there is a set of extra-esophageal symptoms, mainly respiratory, which may occur along with typical symptoms or may represent the only clinical picture of GERD: odynophagia, wheezing, stridor, cough, hoarseness, dental erosions, and apnea/apparent life-threatening events (ALTEs). While infantile GER tends to resolve spontaneously and does not deserve pharmacological treatment, GERD management includes lifestyle changes, pharmacologic therapy, and surgery. Therefore, a proper diagnosis of these two conditions, besides other possible conditions mimicking reflux, is crucial in order to target the treatment, avoiding the overuse of antacid drugs that currently represents a major source of concern.

**Keywords:** gastroesophageal reflux, gastroesophageal reflux disease, vomiting,

times per day in healthy infants, children, and adults. Most episodes of GER in healthy individuals occur in the postprandial period, last in <3 min, and cause few or no symptoms [1]. In contrast, according to the clinical practice guidelines for the diagnosis and management of reflux in the pediatric population, published by the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN), gastroesophageal reflux disease (GERD) is present when the reflux of gastric contents into the esophagus causes troublesome symptoms and/or complications [2]. Reflux symptoms may vary widely according to age. Therefore, distinguishing physiologic GER from GERD may often be tricky, especially in infants. A proper diagnosis of these two conditions, besides other

Gastroesophageal reflux (GER) is a normal physiologic process occurring several

regurgitation, heartburn, irritability, chest pain, respiratory symptoms,

typical GERD presentation, atypical GERD presentation

Reflux Disease in Children

*Paolo Quitadamo and Annamaria Staiano*

## Clinical Picture of Gastroesophageal Reflux Disease in Children

*Paolo Quitadamo and Annamaria Staiano*

#### **Abstract**

Gastroesophageal reflux (GER), defined as the passage of gastric contents into the esophagus, is a normal physiologic process occurring several times per day in healthy infants, children, and adults. The majority of GER episodes occur in the postprandial period, last in <3 min, and cause few or no symptoms. Conversely, when the reflux of gastric contents into the esophagus causes troublesome symptoms and/or complications, we talk about "gastroesophageal reflux disease (GERD)." Distinguishing physiologic GER from GERD may often be tricky for clinicians, especially in infants. The typical presentation of GERD includes the following symptoms: recurrent regurgitation, vomiting, weight loss or poor weight gain, excessive crying and irritability in infants, heartburn or chest pain, ruminative behavior, hematemesis, and dysphagia. Besides these esophageal symptoms, there is a set of extra-esophageal symptoms, mainly respiratory, which may occur along with typical symptoms or may represent the only clinical picture of GERD: odynophagia, wheezing, stridor, cough, hoarseness, dental erosions, and apnea/apparent life-threatening events (ALTEs). While infantile GER tends to resolve spontaneously and does not deserve pharmacological treatment, GERD management includes lifestyle changes, pharmacologic therapy, and surgery. Therefore, a proper diagnosis of these two conditions, besides other possible conditions mimicking reflux, is crucial in order to target the treatment, avoiding the overuse of antacid drugs that currently represents a major source of concern.

**Keywords:** gastroesophageal reflux, gastroesophageal reflux disease, vomiting, regurgitation, heartburn, irritability, chest pain, respiratory symptoms, typical GERD presentation, atypical GERD presentation

#### **1. Introduction**

Gastroesophageal reflux (GER) is a normal physiologic process occurring several times per day in healthy infants, children, and adults. Most episodes of GER in healthy individuals occur in the postprandial period, last in <3 min, and cause few or no symptoms [1]. In contrast, according to the clinical practice guidelines for the diagnosis and management of reflux in the pediatric population, published by the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN), gastroesophageal reflux disease (GERD) is present when the reflux of gastric contents into the esophagus causes troublesome symptoms and/or complications [2]. Reflux symptoms may vary widely according to age. Therefore, distinguishing physiologic GER from GERD may often be tricky, especially in infants. A proper diagnosis of these two conditions, besides other

possible conditions mimicking reflux, is crucial in order to target the treatment, avoiding the overuse of antacid drugs which currently represents a major source of concern. The clinical picture alone is frequently nonspecific and does not allow, except in older children and adolescents, to detect the actual need for acid suppressive medications. Therefore, instrumental diagnostic testing, such as esophageal combined multiple intraluminal impedance and pH monitoring and upper gastrointestinal endoscopy, are often requested [3].

The typical presentation of GERD includes the following symptoms: recurrent regurgitation, vomiting, weight loss or poor weight gain, excessive crying and irritability in infants, heartburn or chest pain, ruminative behavior, hematemesis, and dysphagia. Besides these esophageal symptoms, there is a set of extra-esophageal symptoms, mainly respiratory, which may occur along with typical symptoms or may represent the only clinical picture of GERD: odynophagia, wheezing, stridor, cough, hoarseness, dental erosions, and apnea/apparent life-threatening events (ALTEs). Moreover, GERD may underlie other signs or conditions, such as impaired quality of life, food refusal, persisting hiccups, abnormal posturing/Sandifer's syndrome, anemia, and bradycardia. Finally, esophagitis, Barrett's esophagus, and esophageal adenocarcinoma are possible acknowledged and worrisome long-term outcomes, especially when GERD is undiagnosed or untreated [3].

As already reported, all the above-mentioned signs and symptoms are variously prevalent and relevant in the different pediatric age groups. Therefore, GERD clinical pictures of infants, children, and adolescents will be treated in separate paragraphs.

#### **2. Clinical picture of physiologic GER and GERD in infants**

Regurgitation and vomiting are very frequent in healthy infants, mostly during the first months of life. About 70% of healthy infants physiologically regurgitate several times per day, and in about 95% of them, symptoms disappear without intervention by 12–14 months of age [4, 5]. The term "happy spitter" has been used to identify these patients, in order to highlight the benignity of such condition. Infants regurgitate more frequently than adults due to the large liquid volume intake, the prolonged horizontal position of infants, and the limited capacity of both the stomach and esophagus [6]. Irritability and excessive crying are also very frequent in infants and may present along with regurgitation and vomiting. Therefore, neither regurgitation and vomiting nor irritability and excessive crying, regardless of their severity extent and their extent, are sufficient to diagnose GERD. GERD should be suspected in infants with these symptoms, but none of the symptoms are specific to GERD alone. The major role of history and physical examination in the evaluation of purported GERD is to rule out other more worrisome disorders that present with similar symptoms (especially vomiting) and to identify possible complications of GERD. The vast majority of spitting and crying infants suffer from physiologic GER (also called infant regurgitation), a benign condition with an excellent prognosis, needing no intervention except for parental education and anticipatory guidance, and possible changes on feeding composition. Overfeeding exacerbates recurrent regurgitation [6]. Thickened or anti-regurgitation formulas decrease overt regurgitation [7].

Although reflux does occur physiologically in most infants, clinicians should be aware that there is a continuum between physiologic GER and GERD leading to significant symptoms, signs, and complications. Therefore, a small proportion of symptomatic infants may deserve an instrumental diagnostic assessment for GERD or other GERD-mimicking diseases. To help identify this subgroup of infants, the latest international GER guidelines drafted a list of warning signals requiring investigations in infants with regurgitation or vomiting (**Table 1**).

**39**

*Clinical Picture of Gastroesophageal Reflux Disease in Children*

**3. Clinical picture of GERD in young children**

*Warning signals requiring investigation in infants with regurgitation or vomiting.*

Documented or suspected genetic/metabolic syndrome

Whether persisting from infancy or of new onset, regurgitation and vomiting are less common in children older than 18 months of age and deserve an instrumental evaluation to diagnose possible GERD or to rule out alternative diagnosis [2]. Besides regurgitation and vomiting, GERD may present in children with many

*DOI: http://dx.doi.org/10.5772/intechopen.82453*

Gastrointestinal bleeding

Consistently forceful vomiting

Onset of vomiting after 6 months of life

Hematemesis Hematochezia Bilious vomiting

Failure to thrive Diarrhea Constipation Fever Lethargy

Hepatosplenomegaly Bulging fontanelle

Macro/microcephaly

Abdominal tenderness or distension

**Gastrointestinal obstruction**

Malrotation with intermittent volvulus

**Other gastrointestinal disorders**

Eosinophilic esophagitis/gastroenteritis

Inflammatory bowel disease

Pyloric stenosis

Achalasia Gastroparesis Gastroenteritis Peptic ulcer

Food allergy

Pancreatitis Appendicitis

Intestinal duplication Hirschsprung disease Antral/duodenal web Foreign body Incarcerated hernia

Seizures

**Table 1.**


**Table 1.**

*Gastroesophageal Reflux Disease - Theory and Research*

intestinal endoscopy, are often requested [3].

possible conditions mimicking reflux, is crucial in order to target the treatment, avoiding the overuse of antacid drugs which currently represents a major source of concern. The clinical picture alone is frequently nonspecific and does not allow, except in older children and adolescents, to detect the actual need for acid suppressive medications. Therefore, instrumental diagnostic testing, such as esophageal combined multiple intraluminal impedance and pH monitoring and upper gastro-

The typical presentation of GERD includes the following symptoms: recurrent regurgitation, vomiting, weight loss or poor weight gain, excessive crying and irritability in infants, heartburn or chest pain, ruminative behavior, hematemesis, and dysphagia. Besides these esophageal symptoms, there is a set of extra-esophageal symptoms, mainly respiratory, which may occur along with typical symptoms or may represent the only clinical picture of GERD: odynophagia, wheezing, stridor, cough, hoarseness, dental erosions, and apnea/apparent life-threatening events (ALTEs). Moreover, GERD may underlie other signs or conditions, such as impaired quality of life, food refusal, persisting hiccups, abnormal posturing/Sandifer's syndrome, anemia, and bradycardia. Finally, esophagitis, Barrett's esophagus, and esophageal adenocarcinoma are possible acknowledged and worrisome long-term

As already reported, all the above-mentioned signs and symptoms are variously prevalent and relevant in the different pediatric age groups. Therefore, GERD clinical pictures of infants, children, and adolescents will be treated in separate paragraphs.

Regurgitation and vomiting are very frequent in healthy infants, mostly during the first months of life. About 70% of healthy infants physiologically regurgitate several times per day, and in about 95% of them, symptoms disappear without intervention by 12–14 months of age [4, 5]. The term "happy spitter" has been used to identify these patients, in order to highlight the benignity of such condition. Infants regurgitate more frequently than adults due to the large liquid volume intake, the prolonged horizontal position of infants, and the limited capacity of both the stomach and esophagus [6]. Irritability and excessive crying are also very frequent in infants and may present along with regurgitation and vomiting. Therefore, neither regurgitation and vomiting nor irritability and excessive crying, regardless of their severity extent and their extent, are sufficient to diagnose GERD. GERD should be suspected in infants with these symptoms, but none of the symptoms are specific to GERD alone. The major role of history and physical examination in the evaluation of purported GERD is to rule out other more worrisome disorders that present with similar symptoms (especially vomiting) and to identify possible complications of GERD. The vast majority of spitting and crying infants suffer from physiologic GER (also called infant regurgitation), a benign condition with an excellent prognosis, needing no intervention except for parental education and anticipatory guidance, and possible changes on feeding composition. Overfeeding exacerbates recurrent regurgitation [6]. Thickened or anti-regurgitation formulas decrease overt regurgitation [7]. Although reflux does occur physiologically in most infants, clinicians should be aware that there is a continuum between physiologic GER and GERD leading to significant symptoms, signs, and complications. Therefore, a small proportion of symptomatic infants may deserve an instrumental diagnostic assessment for GERD or other GERD-mimicking diseases. To help identify this subgroup of infants, the latest international GER guidelines drafted a list of warning signals requiring

outcomes, especially when GERD is undiagnosed or untreated [3].

**2. Clinical picture of physiologic GER and GERD in infants**

investigations in infants with regurgitation or vomiting (**Table 1**).

**38**

*Warning signals requiring investigation in infants with regurgitation or vomiting.*

### **3. Clinical picture of GERD in young children**

Whether persisting from infancy or of new onset, regurgitation and vomiting are less common in children older than 18 months of age and deserve an instrumental evaluation to diagnose possible GERD or to rule out alternative diagnosis [2]. Besides regurgitation and vomiting, GERD may present in children with many



#### **Table 2.**

*Differential diagnosis of vomiting in infants and children.*

other signs or symptoms, the most frequent of which are heartburn, food refusal, dysphagia, feeding or sleeping disturbances, failure to thrive, persisting hiccups, impaired quality of life, and dental erosions. Respiratory symptoms, such as chronic cough, wheezing, hoarseness, laryngitis, chronic asthma, aspiration pneumonia, ear problems, and sinusitis, are atypical symptoms possibly associated with GERD. Nevertheless, the paucity of clinical studies, varying disease definitions, and small sample sizes do not allow to draw firm conclusions about their association with reflux [8].

According to the latest international pediatric guidelines, subjective reflux symptom description is unreliable in children younger than 8 to 12 years of age, and many of the purported symptoms of GERD in children are nonspecific [9–11].

**41**

*Clinical Picture of Gastroesophageal Reflux Disease in Children*

Therefore, a clinical diagnosis based on a history of heartburn cannot be inferred since these individuals cannot reliably communicate the quality and quantity of their symptoms [12–16]. GERD testing mainly include esophageal pH/MII, upper GI endoscopy, and barium upper GI series. The diagnosis of GERD has to be inferred when tests show excessive frequency or duration of reflux episodes, esophagitis, or a clear association of symptoms and signs with reflux episodes in the

In older children and adolescents' heartburn, regurgitation and chest pain are the specific symptoms of GERD. According to experts' opinions, in this age group, the description and localization of these symptoms are a reliable indicator for GERD, and an acid suppressive trial may be empirically started, regardless of an objective evaluation of reflux. This approach is mainly driven from adult studies [17, 18]. Along with heartburn and chest pain, other symptoms and signs may occur in older children and adolescents, such as regurgitation, epigastric pain, food refusal, dysphagia, impaired quality of life, sleeping disturbances, anorexia, and dental erosions. Moreover, likewise infants and younger children, even older children and adolescents, may experience respiratory symptoms as the only manifestation of GERD [3].

Several studies report a significant degree of overlap between GERD and functional dyspepsia (FD) [19, 20]. According to the Rome diagnostic criteria for pediatric functional gastrointestinal disorders, FD is defined as a "persistent or recurrent pain or discomfort in the upper abdomen, most often aggravated by meal ingestion, not relieved by defecation or associated with the onset of a change in stool frequency or stool form (i.e., not irritable bowel syndrome) when no physical or organic cause for the symptom is identified with conventional testing" [21]. Clinicians should careful approach upper GI symptoms, being aware that the current literature on the overlap between GERD and FD is affected by considerable heterogeneity in terms of the criteria and diagnostic procedures used to assess both conditions. To exclude GERD, patients must undergo upper digestive endoscopy, pH monitoring, and/or an empiric acid-suppressive trial. A lack of correspondence between symptoms and reflux episodes, together with normal acid exposure in the distal esophagus, would suggest a diagnosis of FD. Finally, clinicians should also be aware that other causes of heartburn-like chest pain including respiratory, cardiac, musculoskeletal, medication-

induced, or infectious etiologies should be considered besides GERD.

As abovementioned, GERD may also underlie respiratory symptoms, such as chronic cough, wheezing, stridor, odynophagia, and hoarseness. Although the role of GERD in the pathogenesis of respiratory symptoms in adults is widely accepted [22], in children there is less evidence to support this relationship [23, 24]. Several pathogenetic mechanisms have been proposed to explain the link between GERD and respiratory symptoms, including aspiration of acid gastric contents into the upper airways, vagal reflex induced by the presence of acid in the esophageal

Recent advances in the pathogenesis of reflux-induced respiratory symptoms have followed the introduction in clinical practice of MII-pH, which is available for pediatric use since 2002 [26]. Combined esophageal pH and impedance monitoring offer several advantages over a standard pH assessment, including the ability

**5. Overview on GERD and respiratory symptoms**

lumen, and sensitization of the central cough reflex [2, 25].

**4. Clinical picture of GERD in older children and adolescents**

*DOI: http://dx.doi.org/10.5772/intechopen.82453*

absence of alternative diagnose (**Table 2**).

*Clinical Picture of Gastroesophageal Reflux Disease in Children DOI: http://dx.doi.org/10.5772/intechopen.82453*

*Gastroesophageal Reflux Disease - Theory and Research*

**Infectious** Sepsis Meningitis

Pneumonia Otitis media Hepatitis

Galactosemia

**Renal**

**Toxic** Lead Iron

**Cardiac**

**Table 2.**

Vascular ring **Others**

Urea cycle defects

Obstructive uropathy Renal insufficiency

Vitamins A and D

Congestive heart failure

Child neglect or abuse Self-induced vomiting Cyclic vomiting syndrome Autonomic dysfunction

Medications—ipecac, digoxin, theophylline, etc.

*Differential diagnosis of vomiting in infants and children.*

Pediatric falsification disorder (Munchausen syndrome by proxy)

Urinary tract infection

**Metabolic/endocrine**

Hereditary fructose intolerance

Amino and organic acidemias Congenital adrenal hyperplasia

other signs or symptoms, the most frequent of which are heartburn, food refusal, dysphagia, feeding or sleeping disturbances, failure to thrive, persisting hiccups, impaired quality of life, and dental erosions. Respiratory symptoms, such as chronic cough, wheezing, hoarseness, laryngitis, chronic asthma, aspiration pneumonia, ear problems, and sinusitis, are atypical symptoms possibly associated with GERD. Nevertheless, the paucity of clinical studies, varying disease definitions, and small sample sizes do not allow to draw firm conclusions about their association

According to the latest international pediatric guidelines, subjective reflux symptom description is unreliable in children younger than 8 to 12 years of age, and many of the purported symptoms of GERD in children are nonspecific [9–11].

**40**

with reflux [8].

Therefore, a clinical diagnosis based on a history of heartburn cannot be inferred since these individuals cannot reliably communicate the quality and quantity of their symptoms [12–16]. GERD testing mainly include esophageal pH/MII, upper GI endoscopy, and barium upper GI series. The diagnosis of GERD has to be inferred when tests show excessive frequency or duration of reflux episodes, esophagitis, or a clear association of symptoms and signs with reflux episodes in the absence of alternative diagnose (**Table 2**).

#### **4. Clinical picture of GERD in older children and adolescents**

In older children and adolescents' heartburn, regurgitation and chest pain are the specific symptoms of GERD. According to experts' opinions, in this age group, the description and localization of these symptoms are a reliable indicator for GERD, and an acid suppressive trial may be empirically started, regardless of an objective evaluation of reflux. This approach is mainly driven from adult studies [17, 18]. Along with heartburn and chest pain, other symptoms and signs may occur in older children and adolescents, such as regurgitation, epigastric pain, food refusal, dysphagia, impaired quality of life, sleeping disturbances, anorexia, and dental erosions. Moreover, likewise infants and younger children, even older children and adolescents, may experience respiratory symptoms as the only manifestation of GERD [3].

Several studies report a significant degree of overlap between GERD and functional dyspepsia (FD) [19, 20]. According to the Rome diagnostic criteria for pediatric functional gastrointestinal disorders, FD is defined as a "persistent or recurrent pain or discomfort in the upper abdomen, most often aggravated by meal ingestion, not relieved by defecation or associated with the onset of a change in stool frequency or stool form (i.e., not irritable bowel syndrome) when no physical or organic cause for the symptom is identified with conventional testing" [21].

Clinicians should careful approach upper GI symptoms, being aware that the current literature on the overlap between GERD and FD is affected by considerable heterogeneity in terms of the criteria and diagnostic procedures used to assess both conditions. To exclude GERD, patients must undergo upper digestive endoscopy, pH monitoring, and/or an empiric acid-suppressive trial. A lack of correspondence between symptoms and reflux episodes, together with normal acid exposure in the distal esophagus, would suggest a diagnosis of FD. Finally, clinicians should also be aware that other causes of heartburn-like chest pain including respiratory, cardiac, musculoskeletal, medicationinduced, or infectious etiologies should be considered besides GERD.

#### **5. Overview on GERD and respiratory symptoms**

As abovementioned, GERD may also underlie respiratory symptoms, such as chronic cough, wheezing, stridor, odynophagia, and hoarseness. Although the role of GERD in the pathogenesis of respiratory symptoms in adults is widely accepted [22], in children there is less evidence to support this relationship [23, 24]. Several pathogenetic mechanisms have been proposed to explain the link between GERD and respiratory symptoms, including aspiration of acid gastric contents into the upper airways, vagal reflex induced by the presence of acid in the esophageal lumen, and sensitization of the central cough reflex [2, 25].

Recent advances in the pathogenesis of reflux-induced respiratory symptoms have followed the introduction in clinical practice of MII-pH, which is available for pediatric use since 2002 [26]. Combined esophageal pH and impedance monitoring offer several advantages over a standard pH assessment, including the ability

of detecting non-acid reflux events, determining the height and composition of the refluxate (liquid, gas, or mixed), recognizing swallows from authentic reflux episodes, assessing the bolus clearance time, and measuring symptom association with reflux (symptom association probability, SAP) even while the patient is assuming acid-suppressive medications [27]. Thanks to pH-impedance studies, several authors have recently highlighted the role of weakly acid and non-acid reflux [28–35]. Furthermore, a recent review reported that a significant percentage of patients with GERD-related respiratory symptoms do not improve despite an aggressive acid-suppressive therapy [36], thus supporting the hypothesis that respiratory symptoms are less related to acidity than GI symptoms.

In conclusion, the analysis of the medical literature concerning the relationship between GERD and respiratory symptoms highlights a large body of evidence often discordant or conflicting, rarely allowing to draw firm conclusions to be used in clinical practice. Over the next years, the use of pH-impedance, combined with manometry or with cardiorespiratory monitoring, in longitudinal, placebocontrolled, double-blind clinical trials, will help in clarifying the main pathophysiological aspects that link GER and respiratory system, providing the clinician with fundamental scientific basis for diagnostic and therapeutic choices.

#### **6. Management of physiologic GER**

In newborns and infants, TLESRs are physiological events. Further considering the physiologic poorer tone of the lower esophageal sphincter, the frequency of GER events is commonly much higher compared to the other ages of life. Thus, uncomplicated GER in otherwise healthy infants is classified as physiologic or functional GER. This condition tends to resolve spontaneously in 95% of infants within 12–14 months of life [37, 38]. According to the current international guidelines, infants with functional GER should not receive pharmacological treatment, despite symptoms may cause significant distress to both infants and parents [2]. The most common symptoms associated with GER in the first year of life are regurgitation, vomiting, irritability, cough, and food refusal [39–42]. When physiologic GER is clinically suspected in healthy, thriving infants, parental education, reassurance, and anticipatory guidance are always required and usually sufficient [2].

#### **6.1 Feeding changes in infants**

Cow's milk allergy: Infants with cow's milk protein allergy may present with vomiting and regurgitation as well as infants with GER. In order to avoid possible misdiagnoses, formula-fed infants with regurgitation and vomiting could benefit of a 4-week trial with hydrolyzed milk or amino acid formula [43, 44]. Breast-fed infants as well may be affected by cow's milk protein allergy since a few proteins pass into the human breast milk. Therefore, an exclusion of cow's milk proteins from maternal diet should be considered [45–47].

**Overfeeding:** Although exact numbers are unknown, overfeeding has recently been thought to be a prominent cause of GER because the ingested volume is relatively large compared to the size of the stomach in infants. Large-volume feeds can promote regurgitation in infants due to gastric distention and increase in TLESR frequency [48]. Restricting volume, however, can result in insufficient energy intake. Thus, increasing the caloric concentration of the feedings while decreasing the total volume of the feedings may decrease GER [2].

**Thickening feeds:** Several studies have demonstrated the efficacy of thickened formula in reduction of reflux events in infants with GER. A thickened formula

**43**

*Clinical Picture of Gastroesophageal Reflux Disease in Children*

was recently tested in premature neonates with apnea. The primary outcome was assessed through multichannel intraluminal impedance, reporting a significant decrease of only acid reflux episodes, while apneic episodes and non-acid GER indexes were not significantly altered [49–51]. The efficacy of thickened formula was demonstrated both on typical and atypical reflux symptoms [52–55]. Despite thickened feeds are currently increasingly being used to treat infants with GER [56], it has been debated that thickened formula increases the caloric intake, thus predisposing infants to later obesity [51, 53, 56–58]. Conversely, infants fed with formula thickened with carob bean gum were reported having a comparable weight increase to the control group [54]. Similar results were with a soy fiber-thickened formula [58]. Furthermore, the fermentation of thickening agents has been reported to cause side effects such as abdominal pain and diarrhea [42]. Further, well-designed clinical trial on these possible side effects are needed in order to

Positioning of the body may have an impact on the incidence of GER episodes. Therefore, among the conservative measures to manage infantile GER, the current NASPGHAN-ESPGHAN guidelines include positioning strategies. Different positionings have been so far evaluated: semisupine, prone, supine and flat, supine with head elevated, and left-side down and right-side down position [59–66]. Infants with GER were shown having a longer exposure to gastroesophageal reflux in semisupine position, with an infant seat, than in prone position. Therefore, semisupine position is strongly discouraged, especially for infants younger than 6 months of age. The prone position reduces the reflux episodes significantly more than the other positions. However, the increased risk of a sudden infant death syndrome (SIDS) shifts the prone position in a negative cost/benefit ratio. Currently, the prone position is advisable only in infants with demonstrated airway disorders, in which the risk of death from GERD is higher than that from SIDS. Conversely, the prone position may be suggested for all infants in the early postprandial period when they are still awake or in children

The number of PPI prescriptions for infants has increased manifold over the last years, despite the absence of evidence for acid-related disorders in the majority [66, 67]. This dramatic increase in PPIs' prescribing patterns has raised concerns related to their appropriate use and associated costs [68]. Although irritable infants are frequently empirically treated with PPIs as the reflux esophagitis is believed to be the cause of crying, there is no evidence supporting the usefulness of PPIs, neither as a diagnostic test nor as a treatment strategy in this age group. Double-blind randomized placebo-controlled trials of PPI efficacy in infants with GER symptoms showed that PPIs and placebo produced similar improvement in crying, despite the finding that acid suppression occurred only in the PPI group [6, 69]. In the largest double-blind randomized placebo-controlled trial of PPIs in infants with symptoms purported to be GERD-related, response rates in those treated with lansoprazole or placebo for 4 weeks were identical (54%) [70]. Therefore, no placebo-controlled treatment trial, in which enrollment was based on "typical" GERD symptoms, has demonstrated symptom improvement in infants. Thus, in accordance to the ESPGHAN-NASPGHAN international guidelines, we believe that a serious effort to

*DOI: http://dx.doi.org/10.5772/intechopen.82453*

evaluate their true relevance.

older than 1 year of age [2].

curtail PPI empiric use in infant is firmly required.

**6.3 PPI abuse in infants**

**6.2 Positioning therapy for infants**

*Clinical Picture of Gastroesophageal Reflux Disease in Children DOI: http://dx.doi.org/10.5772/intechopen.82453*

*Gastroesophageal Reflux Disease - Theory and Research*

of detecting non-acid reflux events, determining the height and composition of the refluxate (liquid, gas, or mixed), recognizing swallows from authentic reflux episodes, assessing the bolus clearance time, and measuring symptom association with reflux (symptom association probability, SAP) even while the patient is assuming acid-suppressive medications [27]. Thanks to pH-impedance studies, several authors have recently highlighted the role of weakly acid and non-acid reflux [28–35]. Furthermore, a recent review reported that a significant percentage of patients with GERD-related respiratory symptoms do not improve despite an aggressive acid-suppressive therapy [36], thus supporting the hypothesis that

In conclusion, the analysis of the medical literature concerning the relationship between GERD and respiratory symptoms highlights a large body of evidence often discordant or conflicting, rarely allowing to draw firm conclusions to be used in clinical practice. Over the next years, the use of pH-impedance, combined with manometry or with cardiorespiratory monitoring, in longitudinal, placebocontrolled, double-blind clinical trials, will help in clarifying the main pathophysiological aspects that link GER and respiratory system, providing the clinician with

In newborns and infants, TLESRs are physiological events. Further considering the physiologic poorer tone of the lower esophageal sphincter, the frequency of GER events is commonly much higher compared to the other ages of life. Thus, uncomplicated GER in otherwise healthy infants is classified as physiologic or functional GER. This condition tends to resolve spontaneously in 95% of infants within 12–14 months of life [37, 38]. According to the current international guidelines, infants with functional GER should not receive pharmacological treatment, despite symptoms may cause significant distress to both infants and parents [2]. The most common symptoms associated with GER in the first year of life are regurgitation, vomiting, irritability, cough, and food refusal [39–42]. When physiologic GER is clinically suspected in healthy, thriving infants, parental education, reassurance,

respiratory symptoms are less related to acidity than GI symptoms.

fundamental scientific basis for diagnostic and therapeutic choices.

and anticipatory guidance are always required and usually sufficient [2].

Cow's milk allergy: Infants with cow's milk protein allergy may present with vomiting and regurgitation as well as infants with GER. In order to avoid possible misdiagnoses, formula-fed infants with regurgitation and vomiting could benefit of a 4-week trial with hydrolyzed milk or amino acid formula [43, 44]. Breast-fed infants as well may be affected by cow's milk protein allergy since a few proteins pass into the human breast milk. Therefore, an exclusion of cow's milk proteins

**Overfeeding:** Although exact numbers are unknown, overfeeding has recently been thought to be a prominent cause of GER because the ingested volume is relatively large compared to the size of the stomach in infants. Large-volume feeds can promote regurgitation in infants due to gastric distention and increase in TLESR frequency [48]. Restricting volume, however, can result in insufficient energy intake. Thus, increasing the caloric concentration of the feedings while decreasing

**Thickening feeds:** Several studies have demonstrated the efficacy of thickened formula in reduction of reflux events in infants with GER. A thickened formula

**6. Management of physiologic GER**

**6.1 Feeding changes in infants**

from maternal diet should be considered [45–47].

the total volume of the feedings may decrease GER [2].

**42**

was recently tested in premature neonates with apnea. The primary outcome was assessed through multichannel intraluminal impedance, reporting a significant decrease of only acid reflux episodes, while apneic episodes and non-acid GER indexes were not significantly altered [49–51]. The efficacy of thickened formula was demonstrated both on typical and atypical reflux symptoms [52–55]. Despite thickened feeds are currently increasingly being used to treat infants with GER [56], it has been debated that thickened formula increases the caloric intake, thus predisposing infants to later obesity [51, 53, 56–58]. Conversely, infants fed with formula thickened with carob bean gum were reported having a comparable weight increase to the control group [54]. Similar results were with a soy fiber-thickened formula [58]. Furthermore, the fermentation of thickening agents has been reported to cause side effects such as abdominal pain and diarrhea [42]. Further, well-designed clinical trial on these possible side effects are needed in order to evaluate their true relevance.

#### **6.2 Positioning therapy for infants**

Positioning of the body may have an impact on the incidence of GER episodes. Therefore, among the conservative measures to manage infantile GER, the current NASPGHAN-ESPGHAN guidelines include positioning strategies. Different positionings have been so far evaluated: semisupine, prone, supine and flat, supine with head elevated, and left-side down and right-side down position [59–66]. Infants with GER were shown having a longer exposure to gastroesophageal reflux in semisupine position, with an infant seat, than in prone position. Therefore, semisupine position is strongly discouraged, especially for infants younger than 6 months of age. The prone position reduces the reflux episodes significantly more than the other positions. However, the increased risk of a sudden infant death syndrome (SIDS) shifts the prone position in a negative cost/benefit ratio. Currently, the prone position is advisable only in infants with demonstrated airway disorders, in which the risk of death from GERD is higher than that from SIDS. Conversely, the prone position may be suggested for all infants in the early postprandial period when they are still awake or in children older than 1 year of age [2].

#### **6.3 PPI abuse in infants**

The number of PPI prescriptions for infants has increased manifold over the last years, despite the absence of evidence for acid-related disorders in the majority [66, 67]. This dramatic increase in PPIs' prescribing patterns has raised concerns related to their appropriate use and associated costs [68]. Although irritable infants are frequently empirically treated with PPIs as the reflux esophagitis is believed to be the cause of crying, there is no evidence supporting the usefulness of PPIs, neither as a diagnostic test nor as a treatment strategy in this age group. Double-blind randomized placebo-controlled trials of PPI efficacy in infants with GER symptoms showed that PPIs and placebo produced similar improvement in crying, despite the finding that acid suppression occurred only in the PPI group [6, 69]. In the largest double-blind randomized placebo-controlled trial of PPIs in infants with symptoms purported to be GERD-related, response rates in those treated with lansoprazole or placebo for 4 weeks were identical (54%) [70]. Therefore, no placebo-controlled treatment trial, in which enrollment was based on "typical" GERD symptoms, has demonstrated symptom improvement in infants. Thus, in accordance to the ESPGHAN-NASPGHAN international guidelines, we believe that a serious effort to curtail PPI empiric use in infant is firmly required.

#### **7. Treatment options for GERD**

GERD management in children includes lifestyle changes, pharmacologic therapy, and surgery. Lifestyle changes which may contribute to prevent and improve reflux symptoms in infants have already been discussed in the previous sections. In children and adolescents, lifestyle changes include modification of diet and sleeping position, weight reduction, and smoking cessation [2, 71]. Although usually sufficient to manage physiologic GER, lifestyle changes alone are not effective in the treatment of GERD, which must include pharmacologic therapies and possible surgical intervention for severe, unresponsive cases.

The major pharmacologic agents currently used for treating GERD in children are gastric acid-buffering agents, mucosal surface barriers, and gastric antisecretory agents. Since the withdrawal of cisapride from commercial availability in most countries, prokinetic agents have been less frequently used, although domperidone is commercially available in Canada and Europe. Pediatric studies comparing pharmacologic agents for GERD have been impaired by small sample size, absence of controls, and use of unreliable endpoints. Therefore, most studies investigating effectiveness and safety of GERD drugs have been performed in adults, and their applicability to children of all ages is uncertain.

#### **7.1 Histamine-2 receptor antagonists**

Histamine-2 receptor antagonists (H2 RAs) inhibit histamine-2 receptors on gastric parietal cells, thus decreasing acid secretion. H2 RAs currently available in most countries are cimetidine, ranitidine, famotidine, and nizatidine. These four drugs have similar spectra of activity, side effects, and clinical indications and are extremely well tolerated by patients [72–79]. However, the efficacy of H2 RAs in achieving mucosal healing is much greater in mild than in severe esophagitis [80]. Extrapolation of the results of a large number of adult studies to older children and adolescents suggests that H2 RAs may be used in these patients for the treatment of GERD symptoms and for healing esophagitis, although H2 RAs are less effective than PPIs for both symptom relief and healing of esophagitis [77, 81, 82]. The fairly rapid tachyphylaxis that develops with H2 RAs is a major drawback to their chronic use. The occurrence of tachyphylaxis, or a decrease of the response, to intravenous ranitidine and the escape from its acid-suppressive effect have been observed after 6 weeks [83], and tolerance to oral H2 RAs in adults is well recognized [84, 85]. In some infants, H2 RA therapy causes irritability, head banging, headache, somnolence, and other side effects that, if interpreted as persistent symptoms of GERD, could result in an inappropriate increase in dosage [79]. H2 RAs, particularly cimetidine, are associated with an increased risk of liver disease [86, 87] and cimetidine with gynecomastia [88].

#### **7.2 Proton pump inhibitors**

PPIs act by blocking Na+–K+**-**ATPase, the final common pathway of parietal cell acid secretion, often called the proton pump, thus inhibiting acid secretion. Studies in adults have shown that PPIs produce higher and faster healing rates for erosive esophagitis than H2 Ras, largely because of their ability to maintain intragastric pH at or above 4 for longer periods and to inhibit meal-induced acid secretion [89]. Moreover, the strong suppression of acid secretion by PPIs also results in decrease of 24-h intragastric volumes, thereby facilitating gastric emptying and decreasing volume reflux [90]. To date, PPIs approved for use in children in North America are omeprazole, lansoprazole, esomeprazole, pantoprazole, and rabeprazole. No

**45**

*Clinical Picture of Gastroesophageal Reflux Disease in Children*

erosive disease. PPIs have greater efficacy than H2

metoclopramide, domperidone, or baclofen for GERD.

PPI has been approved for use in infants younger than 1 year of age. Most studies of PPIs in children are open-label and uncontrolled [91, 92]. In children, as in adults, PPIs are highly efficacious for the treatment of GERD symptoms and the healing of

Although the role of delayed gastric emptying in the pathogenesis of GERD has never been clarified and remains controversial, prokinetic agents have been used as first-choice treatment for reflux symptoms in children for many years. The most well-known prokinetic drug is cisapride, widely prescribed until 2000, when it was withdrawn due to cardiac toxicity which increased the risk of sudden death [97]. Currently, other prokinetics such as domperidone and metoclopramide are still commonly prescribed. Nevertheless, neither have robust evidence to support their use in children with GERD [98–100]. Baclofen is a gamma-amino-butyric-acid (GABA) receptor agonist which has been shown to reduce both acid and non-acid refluxes in adults, probably by inhibiting the transient relaxations of the lower esophageal sphincters (TLESRs) [101]. In children, baclofen was shown to accelerate gastric emptying for 2 h after administration, decreasing the frequency of emesis [102, 103]. Despite its promising effects, many side effects, such as dyspeptic symptoms, drowsiness, dizziness, and seizures, preclude its routine use [104]. In conclusion, there is insufficient evidence to justify the routine use of cisapride,

Alginates and antacids are commonly combined in the same product and are widely used by adult patients to treat reflux symptoms. Antacids act by directly buffering gastric contents, thereby reducing heartburn. There is little evidence for the use of antacids in pediatric age [105, 106]. Conversely, alginates have been studied to a greater extent in children. Alginates precipitate in the stomach to form a low-density but viscous gel that forms a foam that floats on the surface of gastric content and can preferentially enter the esophagus instead of gastric content during reflux episodes [107]. Studies performed both in infants and children showed a significant reduction in the height of reflux episodes, along with an improvement of symptomatic scores [108–113]. On-demand use of antacids and alginates may provide prompt relief from reflux symptoms in children and adolescents [114]. Nevertheless, although alginates seem to have a good safety profile, antacids have possible adverse effects, such as increased serum levels of aluminum, magnesium, or calcium, which represent a major drawback to their long-term use [113, 115, 116].

Surgical treatment represents the last option for GERD management. When and which children could likely benefit from anti-reflux surgery (ARS) has never yet been elucidated. Currently, surgery should be considered for children with confirmed GERD who have failed optimal medical therapy, who are dependent on medical therapy over a long period of time, who are significantly nonadherent with medical therapy, or who have life-threatening complications [2]. Medical literature on surgical therapy in children with GERD mainly consists of retrospective case series in which details on GERD diagnosis and on previous medical therapy are partially lacking, making it difficult to evaluate the indications for and the outcomes of

higher per kilogram doses to obtain the same acid-blocking effect [93–96].

RAs. Young children may require

*DOI: http://dx.doi.org/10.5772/intechopen.82453*

**7.3 Prokinetic agents**

**7.4 Alginates and antacids**

**7.5 Surgical therapy**

PPI has been approved for use in infants younger than 1 year of age. Most studies of PPIs in children are open-label and uncontrolled [91, 92]. In children, as in adults, PPIs are highly efficacious for the treatment of GERD symptoms and the healing of erosive disease. PPIs have greater efficacy than H2 RAs. Young children may require higher per kilogram doses to obtain the same acid-blocking effect [93–96].

#### **7.3 Prokinetic agents**

*Gastroesophageal Reflux Disease - Theory and Research*

GERD management in children includes lifestyle changes, pharmacologic therapy, and surgery. Lifestyle changes which may contribute to prevent and improve reflux symptoms in infants have already been discussed in the previous sections. In children and adolescents, lifestyle changes include modification of diet and sleeping position, weight reduction, and smoking cessation [2, 71]. Although usually sufficient to manage physiologic GER, lifestyle changes alone are not effective in the treatment of GERD, which must include pharmacologic therapies and

The major pharmacologic agents currently used for treating GERD in children are gastric acid-buffering agents, mucosal surface barriers, and gastric antisecretory agents. Since the withdrawal of cisapride from commercial availability in most countries, prokinetic agents have been less frequently used, although domperidone is commercially available in Canada and Europe. Pediatric studies comparing pharmacologic agents for GERD have been impaired by small sample size, absence of controls, and use of unreliable endpoints. Therefore, most studies investigating effectiveness and safety of GERD drugs have been performed in adults, and their

most countries are cimetidine, ranitidine, famotidine, and nizatidine. These four drugs have similar spectra of activity, side effects, and clinical indications and are

achieving mucosal healing is much greater in mild than in severe esophagitis [80]. Extrapolation of the results of a large number of adult studies to older children and

than PPIs for both symptom relief and healing of esophagitis [77, 81, 82]. The fairly

use. The occurrence of tachyphylaxis, or a decrease of the response, to intravenous ranitidine and the escape from its acid-suppressive effect have been observed after

lence, and other side effects that, if interpreted as persistent symptoms of GERD,

dine, are associated with an increased risk of liver disease [86, 87] and cimetidine

PPIs act by blocking Na+–K+**-**ATPase, the final common pathway of parietal cell acid secretion, often called the proton pump, thus inhibiting acid secretion. Studies in adults have shown that PPIs produce higher and faster healing rates for erosive

at or above 4 for longer periods and to inhibit meal-induced acid secretion [89]. Moreover, the strong suppression of acid secretion by PPIs also results in decrease of 24-h intragastric volumes, thereby facilitating gastric emptying and decreasing volume reflux [90]. To date, PPIs approved for use in children in North America are omeprazole, lansoprazole, esomeprazole, pantoprazole, and rabeprazole. No

RA therapy causes irritability, head banging, headache, somno-

Ras, largely because of their ability to maintain intragastric pH

extremely well tolerated by patients [72–79]. However, the efficacy of H2

RAs) inhibit histamine-2 receptors on

RAs is a major drawback to their chronic

RAs in adults is well recognized [84, 85]. In

RAs may be used in these patients for the treatment

RAs currently available in

RAs in

RAs are less effective

RAs, particularly cimeti-

possible surgical intervention for severe, unresponsive cases.

applicability to children of all ages is uncertain.

Histamine-2 receptor antagonists (H2

rapid tachyphylaxis that develops with H2

6 weeks [83], and tolerance to oral H2

gastric parietal cells, thus decreasing acid secretion. H2

of GERD symptoms and for healing esophagitis, although H2

could result in an inappropriate increase in dosage [79]. H2

**7.1 Histamine-2 receptor antagonists**

adolescents suggests that H2

some infants, H2

with gynecomastia [88].

esophagitis than H2

**7.2 Proton pump inhibitors**

**7. Treatment options for GERD**

**44**

Although the role of delayed gastric emptying in the pathogenesis of GERD has never been clarified and remains controversial, prokinetic agents have been used as first-choice treatment for reflux symptoms in children for many years. The most well-known prokinetic drug is cisapride, widely prescribed until 2000, when it was withdrawn due to cardiac toxicity which increased the risk of sudden death [97]. Currently, other prokinetics such as domperidone and metoclopramide are still commonly prescribed. Nevertheless, neither have robust evidence to support their use in children with GERD [98–100]. Baclofen is a gamma-amino-butyric-acid (GABA) receptor agonist which has been shown to reduce both acid and non-acid refluxes in adults, probably by inhibiting the transient relaxations of the lower esophageal sphincters (TLESRs) [101]. In children, baclofen was shown to accelerate gastric emptying for 2 h after administration, decreasing the frequency of emesis [102, 103]. Despite its promising effects, many side effects, such as dyspeptic symptoms, drowsiness, dizziness, and seizures, preclude its routine use [104]. In conclusion, there is insufficient evidence to justify the routine use of cisapride, metoclopramide, domperidone, or baclofen for GERD.

#### **7.4 Alginates and antacids**

Alginates and antacids are commonly combined in the same product and are widely used by adult patients to treat reflux symptoms. Antacids act by directly buffering gastric contents, thereby reducing heartburn. There is little evidence for the use of antacids in pediatric age [105, 106]. Conversely, alginates have been studied to a greater extent in children. Alginates precipitate in the stomach to form a low-density but viscous gel that forms a foam that floats on the surface of gastric content and can preferentially enter the esophagus instead of gastric content during reflux episodes [107]. Studies performed both in infants and children showed a significant reduction in the height of reflux episodes, along with an improvement of symptomatic scores [108–113]. On-demand use of antacids and alginates may provide prompt relief from reflux symptoms in children and adolescents [114]. Nevertheless, although alginates seem to have a good safety profile, antacids have possible adverse effects, such as increased serum levels of aluminum, magnesium, or calcium, which represent a major drawback to their long-term use [113, 115, 116].

#### **7.5 Surgical therapy**

Surgical treatment represents the last option for GERD management. When and which children could likely benefit from anti-reflux surgery (ARS) has never yet been elucidated. Currently, surgery should be considered for children with confirmed GERD who have failed optimal medical therapy, who are dependent on medical therapy over a long period of time, who are significantly nonadherent with medical therapy, or who have life-threatening complications [2]. Medical literature on surgical therapy in children with GERD mainly consists of retrospective case series in which details on GERD diagnosis and on previous medical therapy are partially lacking, making it difficult to evaluate the indications for and the outcomes of surgery [117–119]. Moreover, most surgical series include children with underlying conditions predisposing to the most severe GERD, such as neurological impairment, thereby confounding efforts to determine the benefits versus risks of surgical antireflux procedures in specific patient populations. Nevertheless, according to the available data, ARS in children shows a good overall success rate (median 86%) in terms of complete relief of symptoms, and its outcome does not seem to be significantly influenced by different surgical techniques [120]. Gastric fundoplication is the most commonly performed intervention. Different types of fundoplication have been developed, according to Nissen (360° fundic wrap around the esophagus) and Thal and Toupet (both partial wraps). Traditionally, these procedures were performed open, whereas in most centers, laparoscopic fundoplications are now preferred. Nevertheless, a recent pediatric trial showed that open and laparoscopic fundoplications provide similar control of reflux and quality of life at follow-up, although the latter is associated with reduced incidence of retching persisting over a 4-year period [120–122].

#### **Author details**

Paolo Quitadamo1,2 and Annamaria Staiano1 \*

1 Department of Translational Medical Science, Section of Pediatrics, "Federico II" University of Naples, Italy

2 Department of Pediatrics, AORN Santobono-Pausilipon, Naples, Italy

\*Address all correspondence to: staiano@unina.it

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**47**

*Clinical Picture of Gastroesophageal Reflux Disease in Children*

reflux disease in children: Association

monitoring. Scandinavian Journal of Gastroenterology. 2005;**40**:636-640

[9] Deal L, Gold BD, Gremse DA, et al. Age-specific questionnaires distinguish

[10] Tolia V, Bishop PR, Tsou VM, et al. Multicenter, randomized, double-blind study comparing 10, 20 and 40mg pantoprazole in children (5-11 years) with symptomatic gastroesophageal reflux disease. Journal of Pediatric Gastroenterology and Nutrition.

GERD symptom frequency and severity in infants and young children: Development and initial validation. Journal of Pediatric Gastroenterology and Nutrition. 2005;**41**:178-185

2006;**42**:384-391

2006;**120**:16-23

1990;**5**:350-356

2003;**29**:281-290

[11] von Baeyer CL, Spagrud LJ. Systematic review of observational (behavioral) measures of pain for children and adolescents aged 3 to 18

years. Pain. 2007;**127**:140-150

[13] Stanford EA, Chambers CT, Craig KD. A normative analysis of the development of pain-related vocabulary in children. Pain. 2005;**114**:278-284

[14] Beyer JE, McGrath PJ, Berde CB. Discordance between self-report and behavioral pain measures in children aged 3-7 years after surgery. Journal of Pain and Symptom Management.

[15] Shields BJ, Palermo TM, Powers JD, et al. Predictors of a child's ability to use a visual analogue scale. Child: Care, Health and Development.

[12] Stanford EA, Chambers CT, Craig KD. The role of developmental factors in predicting young children's use of a self-report scale for pain. Pain.

between symptoms and pH

*DOI: http://dx.doi.org/10.5772/intechopen.82453*

[1] Sherman P, Hassall E, Fagundes-Neto U, et al. A global evidence-based

consensus on the definition of gastroesophageal reflux disease in children. The American Journal of Gastroenterology. 2009;**104**:1278-1295

[2] Vandenplas Y, Rudolph CD, Di Lorenzo C, et al. Pediatric

gastroesophageal reflux clinical practice guidelines: Joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). North American Society for Pediatric Gastroenterology Hepatology and Nutrition, European Society for Pediatric Gastroenterology Hepatology and Nutrition. Journal of Pediatric Gastroenterology and Nutrition. 2009;**49**(4):498-547

[3] Paolo Quitadamo and Annamaria Staiano. Gastroesophageal Reflux in Children. Prof. Yvan Vandenplas-Print

[4] Hegar B, Dewanti NR, Kadim M, et al. Natural evolution of

regurgitation in healthy infants. Acta

Gastroenterology Reports. 2013;**15**:353

[6] Moore DJ, Tao BS, Lines DR, et al. Double-blind placebo-controlled trial of omeprazole in irritable infants with gastroesophageal reflux. The Journal of

[7] Tolia V, Vandenplas Y. Systematic review: The extra-oesophageal symptoms of gastro-oesophageal reflux disease in children. Alimentary Pharmacology &

ISBN: 978-3-319-60677-4

Paediatrica;**98**:1189-1193

[5] Orenstein SR. Current

Pediatrics. 2003;**143**:219-237

Therapeutics. 2009;**29**:258-272

[8] Stordal K, Johannesdottir GB, Bentsen BS, et al. Gastroesophageal

**References**

*Clinical Picture of Gastroesophageal Reflux Disease in Children DOI: http://dx.doi.org/10.5772/intechopen.82453*

#### **References**

*Gastroesophageal Reflux Disease - Theory and Research*

4-year period [120–122].

**Author details**

University of Naples, Italy

surgery [117–119]. Moreover, most surgical series include children with underlying conditions predisposing to the most severe GERD, such as neurological impairment, thereby confounding efforts to determine the benefits versus risks of surgical antireflux procedures in specific patient populations. Nevertheless, according to the available data, ARS in children shows a good overall success rate (median 86%) in terms of complete relief of symptoms, and its outcome does not seem to be significantly influenced by different surgical techniques [120]. Gastric fundoplication is the most commonly performed intervention. Different types of fundoplication have been developed, according to Nissen (360° fundic wrap around the esophagus) and Thal and Toupet (both partial wraps). Traditionally, these procedures were performed open, whereas in most centers, laparoscopic fundoplications are now preferred. Nevertheless, a recent pediatric trial showed that open and laparoscopic fundoplications provide similar control of reflux and quality of life at follow-up, although the latter is associated with reduced incidence of retching persisting over a

**46**

provided the original work is properly cited.

Paolo Quitadamo1,2 and Annamaria Staiano1

\*Address all correspondence to: staiano@unina.it

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*

1 Department of Translational Medical Science, Section of Pediatrics, "Federico II"

2 Department of Pediatrics, AORN Santobono-Pausilipon, Naples, Italy

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[5] Orenstein SR. Current Gastroenterology Reports. 2013;**15**:353

[6] Moore DJ, Tao BS, Lines DR, et al. Double-blind placebo-controlled trial of omeprazole in irritable infants with gastroesophageal reflux. The Journal of Pediatrics. 2003;**143**:219-237

[7] Tolia V, Vandenplas Y. Systematic review: The extra-oesophageal symptoms of gastro-oesophageal reflux disease in children. Alimentary Pharmacology & Therapeutics. 2009;**29**:258-272

[8] Stordal K, Johannesdottir GB, Bentsen BS, et al. Gastroesophageal reflux disease in children: Association between symptoms and pH monitoring. Scandinavian Journal of Gastroenterology. 2005;**40**:636-640

[9] Deal L, Gold BD, Gremse DA, et al. Age-specific questionnaires distinguish GERD symptom frequency and severity in infants and young children: Development and initial validation. Journal of Pediatric Gastroenterology and Nutrition. 2005;**41**:178-185

[10] Tolia V, Bishop PR, Tsou VM, et al. Multicenter, randomized, double-blind study comparing 10, 20 and 40mg pantoprazole in children (5-11 years) with symptomatic gastroesophageal reflux disease. Journal of Pediatric Gastroenterology and Nutrition. 2006;**42**:384-391

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[95] Zhao J, Li J, Hamer-Maansson JE, Fulmer R, Illueca M, Lundborg P. Pharmacokinetic properties of esomeprazole in children aged 1 to 11 years with symptoms of gastroesophageal reflux disease: A randomized, open-label study. Clinical Therapeutics. 2006;**28**:1868-1867

[96] Gremse D, Winter H, Tolia V, Gunasekaran T, Pan WJ, Karol M. Pharmacokinetics and pharmacodynamics of lansoprazole in children with gastroesophageal reflux disease. Journal of Pediatric Gastroenterology and Nutrition. 2002;**35**(Suppl. 4):S319-S326

[97] Perrio M, Voss S, Shakir SA. Application of the Bradford hill criteria to assess the causality of cisapride-induced arrhythmia: A model for assessing causal association in pharmacovigilance. Drug Safety. 2007;**30**:333-346

[98] Pritchard DS, Baber N, Stephenson T. Should domperidone be used for the treatment of gastro-oesophageal reflux in children? Systematic review of randomized controlled trials in children aged 1 month to 11 years old. British Journal of Clinical Pharmacology. 2005;**59**(6):725-729

[99] van Noord C, Dieleman JP, van Herpen G, Verhamme K, Sturkenboom MC. Domperidone and ventricular arrhythmia or sudden cardiac death: A population-based case-control study in the Netherlands. Drug Safety. 2010;**33**(11):1003-1001

[100] Djeddi D, Kongolo G, Lefaix C, Mounard J, Léké A. Effect of domperidone on QT interval in neonates. The Journal of Pediatrics. 2008;**153**:663-666

[101] Vela MF, Tutuian R, Katz PO, Castell DO. Baclofen decreases acid and non-acid post-prandial gastrooesophageal reflux measured by combined multichannel intraluminal impedance and pH. Alimentary Pharmacology & Therapeutics. 2003;**17**:243-251

[102] Omari TI, Benninga MA, Sansom L, Butler RN, Dent J, Davidson GP. Effect of baclofen on esophagogastric motility and gastroesophageal reflux in children with gastroesophageal reflux disease: A randomized controlled trial. The Journal of Pediatrics. 2006;**149**:468-474

[103] Kawai M, Kawahara H, Hirayama S, Yoshimura N, Ida S. Effect of baclofen on emesis and 24-hour esophageal pH in neurologically impaired children with gastroesophageal reflux disease. Journal of Pediatric Gastroenterology and Nutrition. 2004;**38**:317-323

[104] Di Lorenzo C. Gastroesophageal reflux: Not a time to "relax". The Journal of Pediatrics. 2006;**149**:436-438

[105] Carroccio A, Iacono G, Montalto G, Cavataio F, Soresi M, Notarbartolo A. Domperidone plus magnesium hydroxide and aluminum hydroxide: A valid therapy in children with gastroesophageal reflux. A doubleblind randomized study versus placebo. Scandinavian Journal of Gastroenterology. 1994;**29**(4):300-304

[106] Cucchiara S, Staiano A, Romaniello G, Capobianco S, Auricchio S. Antacids and cimetidine treatment for gastrooesophageal reflux and peptic oesophagitis. Archives of Disease in Childhood. 1984;**59**(9):842-847

[107] Mandel KG, Daggy BP, Brodie DA, Jacoby HI. Review article: Alginateraft formulations in the treatment of heartburn and acid reflux. Alimentary Pharmacology & Therapeutics. 2000;**14**:669-690

[108] Del Buono R, Wenzl TG, Ball G, Keady S. Thomson effect of Gaviscon infant on gastro-oesophageal reflux in infants assessed by combined intraluminal impedance/ pH. Archives of Disease in Childhood. 2005;**90**(5):460-463

[109] Greally P, Hampton FJ, MacFadyen UM, Simpson H. Gaviscon and Carobel compared with cisapride in gastrooesophageal reflux. Archives of Disease in Childhood. 1992;**67**:618-621

[110] Forbes D, Hodgson M, Hill R. The effects of gaviscon and metoclopramide in gastroesophageal reflux in children. Journal of Pediatric Gastroenterology and Nutrition. 1986;**5**:556-559

[111] Le Luyer B, Mougenot JF, Mashako L, Chapoy P, Olives JP, Morali A, et al. Multicenter study of sodium alginate in the treatment of regurgitation in infants. Annales de Pédiatrie (Paris). 1992;**39**:635-640

[112] Buts JP, Barudi C, Otte JB. Doubleblind controlled study on the efficacy of sodium alginate (Gaviscon) in reducing gastroesophageal reflux assessed by 24 h continuous pH monitoring in infants and children. European Journal of Pediatrics. 1987;**146**:156-158

[113] Miller S. Comparison of the efficacy and safety of a new aluminiumfree paediatric alginate preparation and placebo in infants with recurrent gastrooesophageal reflux. Current Medical Research and Opinion. 1999;**15**:160-168

[114] Tran TT, Quandalle P. Long term results of treatment by simple surgical closure of perforated gastroduodenal ulcer followed by eradication of

*Helicobacter pylori*. Annales de Chirurgie. 2006;**131**:502-503

[115] Beall DP, Henslee HB, Webb HR, Scofield RH. Milk-alkali syndrome: A historical review and description of the modern version of the syndrome. The American Journal of the Medical Sciences. 2006;**331**:233-242

[116] Erdeve O, Atasay B, Arsan S, Türmen T. Efficacy and safety of sodium alginate for GERD in preterm infants. Alimentary Pharmacology & Therapeutics. 2011

[117] Gilger MA, Yeh C, Chiang J, Dietrich C, Brandt ML, El-Serag HB. Outcomes of surgical fundoplication in children. Clinical Gastroenterology and Hepatology. 2004;**2**:978-984

[118] Fonkalsrud EW, Ashcraft KW, Coran AG, Ellis DG, Grosfeld JL, Tunell WP, et al. Surgical treatment of gastroesophageal reflux in children: A combined hospital study of 7467 patients. Pediatrics. 1998;**101**:419-422

[119] Mathei J, Coosemans W, Nafteux P, Decker G, De Leyn P, Van Raemdonck D, et al. Laparoscopic Nissen fundoplication in infants and children: Analysis of 106 consecutive patients with special emphasis in neurologically impaired vs. neurologically normal patients. Surgical Endoscopy. 2008;**22**:1054-1059

[120] Mauritz FA, van Herwaarden-Lindeboom MYA, Stomp W, Zwaveling S, Fischer K, Houwen RHJ, et al. The effects and efficacy of antireflux surgery in children with gastroesophageal reflux disease: A systematic review. Journal of Gastrointestinal Surgery. 2011;**15**(10):1872-1878

[121] Kubiak R, Böhm-Sturm E, Svoboda D, Wessel LM. Comparison of longterm outcomes between open and laparoscopic Thal fundoplication in children. Journal of Pediatric Surgery. 2014;**49**(7):1069-1074

**55**

*Clinical Picture of Gastroesophageal Reflux Disease in Children*

*DOI: http://dx.doi.org/10.5772/intechopen.82453*

[122] Pacilli M, Eaton S, McHoney M, Kiely EM, Drake DP, Curry JI, et al. Four year follow-up of a randomised controlled trial comparing open and laparoscopic Nissen fundoplication in children. Archives of Disease in Childhood. 2014;**99**(6):516-512

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[122] Pacilli M, Eaton S, McHoney M, Kiely EM, Drake DP, Curry JI, et al. Four year follow-up of a randomised controlled trial comparing open and laparoscopic Nissen fundoplication in children. Archives of Disease in Childhood. 2014;**99**(6):516-512

*Gastroesophageal Reflux Disease - Theory and Research*

*Helicobacter pylori*. Annales de Chirurgie. 2006;**131**:502-503

Sciences. 2006;**331**:233-242

Therapeutics. 2011

[116] Erdeve O, Atasay B, Arsan S, Türmen T. Efficacy and safety of sodium alginate for GERD in preterm infants. Alimentary Pharmacology &

[117] Gilger MA, Yeh C, Chiang J, Dietrich C, Brandt ML, El-Serag HB. Outcomes of surgical fundoplication in children. Clinical Gastroenterology and

[118] Fonkalsrud EW, Ashcraft KW, Coran AG, Ellis DG, Grosfeld JL, Tunell WP, et al. Surgical treatment of gastroesophageal reflux in children: A combined hospital study of 7467 patients. Pediatrics. 1998;**101**:419-422

[119] Mathei J, Coosemans W, Nafteux P, Decker G, De Leyn P, Van Raemdonck D, et al. Laparoscopic Nissen fundoplication in infants and children: Analysis of 106 consecutive patients with special emphasis in neurologically impaired vs. neurologically normal patients. Surgical

Endoscopy. 2008;**22**:1054-1059

2011;**15**(10):1872-1878

2014;**49**(7):1069-1074

[120] Mauritz FA, van Herwaarden-Lindeboom MYA, Stomp W, Zwaveling S, Fischer K, Houwen RHJ, et al. The effects and efficacy of antireflux surgery in children with gastroesophageal reflux disease: A systematic review. Journal of Gastrointestinal Surgery.

[121] Kubiak R, Böhm-Sturm E, Svoboda D,

Wessel LM. Comparison of longterm outcomes between open and laparoscopic Thal fundoplication in children. Journal of Pediatric Surgery.

Hepatology. 2004;**2**:978-984

[115] Beall DP, Henslee HB, Webb HR, Scofield RH. Milk-alkali syndrome: A historical review and description of the modern version of the syndrome. The American Journal of the Medical

[107] Mandel KG, Daggy BP, Brodie DA, Jacoby HI. Review article: Alginateraft formulations in the treatment of heartburn and acid reflux. Alimentary Pharmacology & Therapeutics.

[108] Del Buono R, Wenzl TG, Ball G, Keady S. Thomson effect of Gaviscon

[109] Greally P, Hampton FJ, MacFadyen UM, Simpson H. Gaviscon and Carobel compared with cisapride in gastrooesophageal reflux. Archives of Disease

[110] Forbes D, Hodgson M, Hill R. The effects of gaviscon and metoclopramide in gastroesophageal reflux in children. Journal of Pediatric Gastroenterology

[111] Le Luyer B, Mougenot JF, Mashako L, Chapoy P, Olives JP, Morali A, et al. Multicenter study of sodium alginate in the treatment of regurgitation in infants. Annales de Pédiatrie (Paris).

[112] Buts JP, Barudi C, Otte JB. Doubleblind controlled study on the efficacy of sodium alginate (Gaviscon) in reducing gastroesophageal reflux assessed by 24 h continuous pH monitoring in infants and children. European Journal of Pediatrics. 1987;**146**:156-158

[113] Miller S. Comparison of the efficacy and safety of a new aluminiumfree paediatric alginate preparation and placebo in infants with recurrent gastrooesophageal reflux. Current Medical Research and Opinion. 1999;**15**:160-168

[114] Tran TT, Quandalle P. Long term results of treatment by simple surgical closure of perforated gastroduodenal ulcer followed by eradication of

infant on gastro-oesophageal reflux in infants assessed by combined intraluminal impedance/ pH. Archives of Disease in Childhood.

in Childhood. 1992;**67**:618-621

and Nutrition. 1986;**5**:556-559

1992;**39**:635-640

2000;**14**:669-690

2005;**90**(5):460-463

**54**

**57**

**Chapter 5**

**Abstract**

of GER.

**1. Introduction**

The Role of Increased Gastric Acid

Species in the Pathophysiology of

Gastroesophageal reflux (GER) disease is a chronic disease characterized by the recurrent ascension of some of the gastric contents in the esophagus. Indeed, gastric acid secreted by parietal cells and the gastric pepsin activity, but not the intestinal alkaline content, are the most important pathogenic factors of GER. Several pathophysiological mechanisms are involved, the most important of which is the imbalance of the redox state of the esophageal tissue. Indeed, several studies have shown that reflux esophagitis is mediated by oxygen-derived free radicals. In this chapter, we describe the pathophysiology and important pathways, especially acid gastric contents and reactive oxygen species involved in pathology

**Keywords:** esophagus, parietal cells, pepsin activity, reactive oxygen species

as reactive oxygen species (ROS) in the pathophysiology of reflux esophagitis.

Gastroesophageal reflux (GER) is defined as the passage through the cardia of the contents of the stomach into the esophagus, without any effort of vomiting [1]. The intermittent ascent of the gastric contents, particularly the acid in the esophagus, is the main determinant of the esophageal mucosa lesions [2, 3]. The alteration of gastric or esophageal motility, the aggressiveness of the refluxing fluid, and the alteration of esophageal mucosal resistance are also important factors in the genesis of esophagitis lesions [4]. Disturbances of the inflammatory and immune response reported during reflux esophagitis are numerous [5]. It is well established that oxidative stress, by excessive production of oxidizing mediators or by a deficiency of certain nutrients essential to the maintenance of a suitable antioxidant defense, contributes to cellular dysfunctions and to the esophagus tissue destruction [5, 6]. This chapter gives a detailed insight about the role of acidic gastric secretions and the involvement of oxidative stress as well

Secretion and Reactive Oxygen

Reflux Esophagitis

*Mohamed-Amine Jabri and Hichem Sebai*

#### **Chapter 5**

## The Role of Increased Gastric Acid Secretion and Reactive Oxygen Species in the Pathophysiology of Reflux Esophagitis

*Mohamed-Amine Jabri and Hichem Sebai*

#### **Abstract**

Gastroesophageal reflux (GER) disease is a chronic disease characterized by the recurrent ascension of some of the gastric contents in the esophagus. Indeed, gastric acid secreted by parietal cells and the gastric pepsin activity, but not the intestinal alkaline content, are the most important pathogenic factors of GER. Several pathophysiological mechanisms are involved, the most important of which is the imbalance of the redox state of the esophageal tissue. Indeed, several studies have shown that reflux esophagitis is mediated by oxygen-derived free radicals. In this chapter, we describe the pathophysiology and important pathways, especially acid gastric contents and reactive oxygen species involved in pathology of GER.

**Keywords:** esophagus, parietal cells, pepsin activity, reactive oxygen species

#### **1. Introduction**

Gastroesophageal reflux (GER) is defined as the passage through the cardia of the contents of the stomach into the esophagus, without any effort of vomiting [1]. The intermittent ascent of the gastric contents, particularly the acid in the esophagus, is the main determinant of the esophageal mucosa lesions [2, 3]. The alteration of gastric or esophageal motility, the aggressiveness of the refluxing fluid, and the alteration of esophageal mucosal resistance are also important factors in the genesis of esophagitis lesions [4]. Disturbances of the inflammatory and immune response reported during reflux esophagitis are numerous [5]. It is well established that oxidative stress, by excessive production of oxidizing mediators or by a deficiency of certain nutrients essential to the maintenance of a suitable antioxidant defense, contributes to cellular dysfunctions and to the esophagus tissue destruction [5, 6]. This chapter gives a detailed insight about the role of acidic gastric secretions and the involvement of oxidative stress as well as reactive oxygen species (ROS) in the pathophysiology of reflux esophagitis.

**Figure 1.** *Mechanism of acidic gastric secretion and production of reactive oxygen species in the esophageal mucosa.*

#### **2. Mechanism of acidic gastric secretion**

Gastric secretion is essentially characterized by its high concentration of hydrochloric acid. This acidity makes it possible to sterilize the food bowl and initiate digestion, especially food proteins. Gastric acid secretion is permanently modulated by the endocrine (gastrin), paracrine (histamine and somatostatin), as well as nerve (acetylcholine) pathways (**Figure 1**). Gastrin is secreted at the basal pole of the G cells of the pyloric glands of the antrum into the bloodstream. It acts by binding membrane receptors of enterochromaffin-like cells (ELC) by stimulating the secretion of histamine and on the membrane receptors of parietal cells by stimulating the secretion of hydrochloric acid [7, 8].

Histamine is secreted by ELC, in the vicinity of parietal cells, in response to stimulation by gastrin and parasympathetic activation. This secretion is inhibited by somatostatin. Histamine stimulates the HCl secretion by action on the histamine H2-type receptors of parietal cells [9].

Acetylcholine, released by postganglionic neurons from the parasympathetic system, stimulates the parietal cells, gastrin, and histamine secretions. Somatostatin is the main inhibitor of gastric acid secretion: its secretion by D cells is stimulated by increasing the concentration of H+ ions in the gastric cavity [8].

#### **3. Physiopathology of gastroesophageal reflux**

#### **3.1 Failure of the anti-reflux barrier**

Generally, GER is related to a failure of the anti-reflux barrier. This anti-reflux barrier is composed of the lower esophageal sphincter (LES), which plays the role of an internal sphincter, and the diaphragmatic muscle that plays the role of an external sphincter. The LES is a zone of high pressure, 2–4 cm long, with no individualized thickening of the circular layer of the muscularis. This area of high pressure separates the thoracic esophagus subjected to negative pressure from the stomach that supports the positive pressure prevailing in the enclosure of the abdominal cavity [1, 10]. The pressure of the LES is influenced by several dietary factors, certain drugs, and circulating hormones. Chocolate, fats, alcohol, and caffeine reduce the pressure of the LES

**59**

*The Role of Increased Gastric Acid Secretion and Reactive Oxygen Species in the Pathophysiology…*

[4, 10]. Tobacco also lowers the pressure of the LES, and in smokers, the periods of smoking are marked by an increased GER frequency. Many medications affect also the LES pressure. Indeed, anticholinergics, nitrates, theophylline, and anticalcics

The reflux that reaches the esophagus may be of variable acidity, may be depending on the case of a pure liquid or a mixture of gas and liquid [11]. The role of pepsin in the occurrence of esophageal lesions during GER is uncertain. Animal studies have shown that the toxicity to the esophageal mucosa of an HCl-pepsin mixture is higher than that of a pure acid solution [4, 12]. The reflux of duodenal contents into the stomach is a postprandial physiological phenomenon. It is therefore not unusual for GER to contain duodenal, pancreatic, and bile secretions. In experimental models, conjugated bile acids are toxic to the esophagus at acidic pH, whereas nonconjugated bile acids have a toxicity that is observed mainly at neutral pH. But the human bile acid concentrations in the reflux liquid never reached the

Studies in humans have shown that the frequency of duodeno-gastroesophageal

reflux is particularly high in patients with severe esophagitis and especially an endobrachy-esophagus, notably in those who respond to treatment with proton

**4. Involvement of oxidative stress in the pathophysiology of reflux** 

**4.1 Oxidative stress and production of oxygenated free radicals**

Several recent studies have shown that esophagitis induced by gastroesophageal reflux is mediated by reactive oxygen species (ROS) [13–16]. The role of ROS has been extensively studied in gastric and esophageal mucosal lesions induced by the administration of NSAIDs such as aspirin [17] or ethanol [18] as well as by ischemia [6].

Oxidative stress is defined as an excessive intracellular oxidation due to an imbalance between the production of oxidizing species or reactive oxygen species (ROS) and that of antioxidant systems [16, 19]. The equilibrium or redox homeostasis is then disrupted, and the cells become vulnerable to free radical attacks, resulting in oxidative damage to cellular components [20, 21]. Indeed, ROS are responsible for denaturation and degradation of biomolecules and are involved in tissue lesions observed during inflammatory processes [22]. They are produced during various biological processes by a large number of cells, particularly phagocytic cells [23].

According to recent studies on animal models [14, 24, 25], it has been shown that

**4.2 Free oxygen derivatives and caustic injuries of esophagus during GER**

gastroesophageal reflux promotes the production of ROS, which leads to lesions of the esophageal mucosa. Reactive oxygen species appear to be a major cause of esophageal lesion during GER. In point of fact, it has been shown that the administration of a free radical scavenger effectively inhibits esophagitis in rats [6]. The increased production of free radicals derived from oxygen has been accompanied by increased lipid peroxidation of the esophageal mucosa, which is a sensitive marker of membrane damage caused by free radicals [24]. In addition, several previous

lower it, while cisapride and metoclopramide increase it [4, 10].

concentrations used in these experimental models [11, 12].

*DOI: http://dx.doi.org/10.5772/intechopen.81021*

**3.2 The reflux material composition**

pump inhibitors [12].

**esophagitis**

*The Role of Increased Gastric Acid Secretion and Reactive Oxygen Species in the Pathophysiology… DOI: http://dx.doi.org/10.5772/intechopen.81021*

[4, 10]. Tobacco also lowers the pressure of the LES, and in smokers, the periods of smoking are marked by an increased GER frequency. Many medications affect also the LES pressure. Indeed, anticholinergics, nitrates, theophylline, and anticalcics lower it, while cisapride and metoclopramide increase it [4, 10].

#### **3.2 The reflux material composition**

*Gastroesophageal Reflux Disease - Theory and Research*

**2. Mechanism of acidic gastric secretion**

**Figure 1.**

ing the secretion of hydrochloric acid [7, 8].

H2-type receptors of parietal cells [9].

by increasing the concentration of H+

**3.1 Failure of the anti-reflux barrier**

**3. Physiopathology of gastroesophageal reflux**

Gastric secretion is essentially characterized by its high concentration of hydrochloric acid. This acidity makes it possible to sterilize the food bowl and initiate digestion, especially food proteins. Gastric acid secretion is permanently modulated by the endocrine (gastrin), paracrine (histamine and somatostatin), as well as nerve (acetylcholine) pathways (**Figure 1**). Gastrin is secreted at the basal pole of the G cells of the pyloric glands of the antrum into the bloodstream. It acts by binding membrane receptors of enterochromaffin-like cells (ELC) by stimulating the secretion of histamine and on the membrane receptors of parietal cells by stimulat-

*Mechanism of acidic gastric secretion and production of reactive oxygen species in the esophageal mucosa.*

Histamine is secreted by ELC, in the vicinity of parietal cells, in response to stimulation by gastrin and parasympathetic activation. This secretion is inhibited by somatostatin. Histamine stimulates the HCl secretion by action on the histamine

Acetylcholine, released by postganglionic neurons from the parasympathetic system, stimulates the parietal cells, gastrin, and histamine secretions. Somatostatin is the main inhibitor of gastric acid secretion: its secretion by D cells is stimulated

Generally, GER is related to a failure of the anti-reflux barrier. This anti-reflux barrier is composed of the lower esophageal sphincter (LES), which plays the role of an internal sphincter, and the diaphragmatic muscle that plays the role of an external sphincter. The LES is a zone of high pressure, 2–4 cm long, with no individualized thickening of the circular layer of the muscularis. This area of high pressure separates the thoracic esophagus subjected to negative pressure from the stomach that supports the positive pressure prevailing in the enclosure of the abdominal cavity [1, 10]. The pressure of the LES is influenced by several dietary factors, certain drugs, and circulating hormones. Chocolate, fats, alcohol, and caffeine reduce the pressure of the LES

ions in the gastric cavity [8].

**58**

The reflux that reaches the esophagus may be of variable acidity, may be depending on the case of a pure liquid or a mixture of gas and liquid [11]. The role of pepsin in the occurrence of esophageal lesions during GER is uncertain. Animal studies have shown that the toxicity to the esophageal mucosa of an HCl-pepsin mixture is higher than that of a pure acid solution [4, 12]. The reflux of duodenal contents into the stomach is a postprandial physiological phenomenon. It is therefore not unusual for GER to contain duodenal, pancreatic, and bile secretions. In experimental models, conjugated bile acids are toxic to the esophagus at acidic pH, whereas nonconjugated bile acids have a toxicity that is observed mainly at neutral pH. But the human bile acid concentrations in the reflux liquid never reached the concentrations used in these experimental models [11, 12].

Studies in humans have shown that the frequency of duodeno-gastroesophageal reflux is particularly high in patients with severe esophagitis and especially an endobrachy-esophagus, notably in those who respond to treatment with proton pump inhibitors [12].

#### **4. Involvement of oxidative stress in the pathophysiology of reflux esophagitis**

Several recent studies have shown that esophagitis induced by gastroesophageal reflux is mediated by reactive oxygen species (ROS) [13–16]. The role of ROS has been extensively studied in gastric and esophageal mucosal lesions induced by the administration of NSAIDs such as aspirin [17] or ethanol [18] as well as by ischemia [6].

#### **4.1 Oxidative stress and production of oxygenated free radicals**

Oxidative stress is defined as an excessive intracellular oxidation due to an imbalance between the production of oxidizing species or reactive oxygen species (ROS) and that of antioxidant systems [16, 19]. The equilibrium or redox homeostasis is then disrupted, and the cells become vulnerable to free radical attacks, resulting in oxidative damage to cellular components [20, 21]. Indeed, ROS are responsible for denaturation and degradation of biomolecules and are involved in tissue lesions observed during inflammatory processes [22]. They are produced during various biological processes by a large number of cells, particularly phagocytic cells [23].

#### **4.2 Free oxygen derivatives and caustic injuries of esophagus during GER**

According to recent studies on animal models [14, 24, 25], it has been shown that gastroesophageal reflux promotes the production of ROS, which leads to lesions of the esophageal mucosa. Reactive oxygen species appear to be a major cause of esophageal lesion during GER. In point of fact, it has been shown that the administration of a free radical scavenger effectively inhibits esophagitis in rats [6]. The increased production of free radicals derived from oxygen has been accompanied by increased lipid peroxidation of the esophageal mucosa, which is a sensitive marker of membrane damage caused by free radicals [24]. In addition, several previous

studies have shown that GER induced experimentally in rats caused an increase in the level of malondialdehyde, a final product of lipid peroxidation, as well as a decrease in the activity of antioxidant enzymes such as catalase, glutathione peroxidase, and superoxide dismutase in the esophageal mucosa tissues [5, 13, 14]. GER has also induced the decrease of reduced glutathione and thiol group levels as well as plasma scavenging activity, an indicator of free radical generation in tissues [13]. Other studies have shown that blocking acid secretion or administering an antioxidant compound effectively reduced the severity of reflux esophagitis. Indeed, the administration of the various free radical scavengers prevented the esophageal mucosa damage, by stimulating the activity of antioxidant enzymes and inhibiting lipid peroxidation [5, 14].

### **5. Conclusion**

Several mechanisms are involved in the occurrence of GER and in its severity, especially the gastric secretion of acid and pepsin as well as the role of reactive oxygen species. Therefore, the ROS-scavenging compounds should be considered in the prevention and treatment of reflux esophagitis, in accordance with the current antisecretory treatment.

### **Author details**

Mohamed-Amine Jabri\* and Hichem Sebai Laboratoire de Physiologie Fonctionnelle et Valorisation des Bio-Ressources - Institut Supérieur de Biotechnologie de Béja, Université de Jendouba, Béja, Tunisia

\*Address all correspondence to: jabri.amino@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**61**

pp. 845-863

*The Role of Increased Gastric Acid Secretion and Reactive Oxygen Species in the Pathophysiology…*

in gastric mucosa. In: Progress in gastroenterology. New York, Grune and

Stratton; 1977. pp. 203-240

[10] Ducrotté P. Traitement du reflux gastro-oesophagien: Règles hygiéno-diététiques et topiques. Gastroentérologie Clinique et Biologique. 1999;**23**:570-577

[11] Sifrim D, Holloway R, Silny J, Xin Z, Tack J, Lerut A, et al. Acid, nonacid, and gas reflux in patients with gastroesophageal reflux disease during ambulatory 24-hour pH-impedance recordings. Gastroenterology.

[12] Sifrim D, Holloway R, Silny J, Tack J, Lerut A, Janssens J. Composition of the postprandial refluxate in patients with gastroesophageal reflux disease. American Journal of Gastroenterology.

[13] Tack J, Koek G, Demedts I, Sifrim D, Janssens J. Gastroesophageal reflux disease poorly responsive to single-dose proton pump inhibitors in patients without Barrett's esophagus: acid reflux, bile reflux, or both? American Journal of Gastroenterology. 2004;**99**:981-988

[14] Jabri MA, Tounsi H, Rtibi K, Marzouki L, Sakly M, Sebai H.

extract during reflux-induced esophagitis in rats. Pharmaceutical

Biology. 2016;**54**:1575-1585

2018;**25**:63-69

Ameliorative and antioxidant effects of myrtle berries seeds (*Myrtus communis*)

[15] Jabri MA, Tounsi H, Abdellaoui A, Marzouki L, Sebai H. Protective effects of Artemisia campestris extract against gastric acid reflux-induced esophageal mucosa injuries. Pathophysiology.

[16] Aiyer HS, Li Y, Liu QH, Reuter N, Martin RC. Dietary freeze-dried black raspberry's effect on cellular antioxidant

2001;**120**:1588-1598

2001;**96**:647-655

*DOI: http://dx.doi.org/10.5772/intechopen.81021*

[1] Meining A, Classen M. The role of diet and lifestyle measures in the pathogenesis and treatment of gastroesophageal reflux disease. American Journal of Gastroenterology.

[2] Ferreira CT, Ed C, Sdepanian VL, Morais MB, Vieira MC, Silva LR. Gastroesophageal reflux disease: exaggerations, evidence and

clinical practice. Jornal de Pediatria.

[3] Weijenborg PW, Bredenoord AJ. How reflux causes symptoms: Reflux perception in gastroesophageal

reflux disease. Best Practice & Research. Clinical Gastroenterology.

Pathophysiology of gastro-oesophageal reflux. EMC-Hepato-Gastroenterology.

[5] Ozel SK, Dagli TE, Yuksel M, Kiyan G, Kotiloglu E. The roles of free oxygen radicals, nitric oxide, and endothelin in caustic injury of rat esophagus. Journal of Pediatric Surgery. 2004;**39**:1381-1385

[6] Wetscher GJ, Hinder RA, Bagchi D, Perdikis G, Redmond EJ, Glaser K, et al. Free radical scavengers prevent reflux esophagitis in rats. Digestive Diseases and Sciences. 1995;**40**:1292-1296

[7] Feldman M, Richardson CT. Gastric acid secretion in humans. In: Physiology of the Gastrointestinal Tract. New York:

[8] Grossman MI. Neural and hormonal stimulation of gastric secretion of acid. In: Handbook of Physiology. Section 6: Alimentary Canal. Washington: American Physiological Society; 1987.

[9] Lewin MJ, Soumarmon A, Bonfils S. Gastrin and histamine receptors

Raven Press; 1981. pp. 693-807

[4] Ducrotté P, Chaput U.

**References**

2000;**95**:2692-2697

2014;**90**:105-118

2013;**27**:353-364

2005;**2**:362-369

*The Role of Increased Gastric Acid Secretion and Reactive Oxygen Species in the Pathophysiology… DOI: http://dx.doi.org/10.5772/intechopen.81021*

#### **References**

*Gastroesophageal Reflux Disease - Theory and Research*

lipid peroxidation [5, 14].

antisecretory treatment.

**5. Conclusion**

studies have shown that GER induced experimentally in rats caused an increase in the level of malondialdehyde, a final product of lipid peroxidation, as well as a decrease in the activity of antioxidant enzymes such as catalase, glutathione peroxidase, and superoxide dismutase in the esophageal mucosa tissues [5, 13, 14]. GER has also induced the decrease of reduced glutathione and thiol group levels as well as plasma scavenging activity, an indicator of free radical generation in tissues [13]. Other studies have shown that blocking acid secretion or administering an antioxidant compound effectively reduced the severity of reflux esophagitis. Indeed, the administration of the various free radical scavengers prevented the esophageal mucosa damage, by stimulating the activity of antioxidant enzymes and inhibiting

Several mechanisms are involved in the occurrence of GER and in its severity, especially the gastric secretion of acid and pepsin as well as the role of reactive oxygen species. Therefore, the ROS-scavenging compounds should be considered in the prevention and treatment of reflux esophagitis, in accordance with the current

**60**

**Author details**

provided the original work is properly cited.

Mohamed-Amine Jabri\* and Hichem Sebai

\*Address all correspondence to: jabri.amino@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Laboratoire de Physiologie Fonctionnelle et Valorisation des Bio-Ressources - Institut Supérieur de Biotechnologie de Béja, Université de Jendouba, Béja, Tunisia [1] Meining A, Classen M. The role of diet and lifestyle measures in the pathogenesis and treatment of gastroesophageal reflux disease. American Journal of Gastroenterology. 2000;**95**:2692-2697

[2] Ferreira CT, Ed C, Sdepanian VL, Morais MB, Vieira MC, Silva LR. Gastroesophageal reflux disease: exaggerations, evidence and clinical practice. Jornal de Pediatria. 2014;**90**:105-118

[3] Weijenborg PW, Bredenoord AJ. How reflux causes symptoms: Reflux perception in gastroesophageal reflux disease. Best Practice & Research. Clinical Gastroenterology. 2013;**27**:353-364

[4] Ducrotté P, Chaput U. Pathophysiology of gastro-oesophageal reflux. EMC-Hepato-Gastroenterology. 2005;**2**:362-369

[5] Ozel SK, Dagli TE, Yuksel M, Kiyan G, Kotiloglu E. The roles of free oxygen radicals, nitric oxide, and endothelin in caustic injury of rat esophagus. Journal of Pediatric Surgery. 2004;**39**:1381-1385

[6] Wetscher GJ, Hinder RA, Bagchi D, Perdikis G, Redmond EJ, Glaser K, et al. Free radical scavengers prevent reflux esophagitis in rats. Digestive Diseases and Sciences. 1995;**40**:1292-1296

[7] Feldman M, Richardson CT. Gastric acid secretion in humans. In: Physiology of the Gastrointestinal Tract. New York: Raven Press; 1981. pp. 693-807

[8] Grossman MI. Neural and hormonal stimulation of gastric secretion of acid. In: Handbook of Physiology. Section 6: Alimentary Canal. Washington: American Physiological Society; 1987. pp. 845-863

[9] Lewin MJ, Soumarmon A, Bonfils S. Gastrin and histamine receptors

in gastric mucosa. In: Progress in gastroenterology. New York, Grune and Stratton; 1977. pp. 203-240

[10] Ducrotté P. Traitement du reflux gastro-oesophagien: Règles hygiéno-diététiques et topiques. Gastroentérologie Clinique et Biologique. 1999;**23**:570-577

[11] Sifrim D, Holloway R, Silny J, Xin Z, Tack J, Lerut A, et al. Acid, nonacid, and gas reflux in patients with gastroesophageal reflux disease during ambulatory 24-hour pH-impedance recordings. Gastroenterology. 2001;**120**:1588-1598

[12] Sifrim D, Holloway R, Silny J, Tack J, Lerut A, Janssens J. Composition of the postprandial refluxate in patients with gastroesophageal reflux disease. American Journal of Gastroenterology. 2001;**96**:647-655

[13] Tack J, Koek G, Demedts I, Sifrim D, Janssens J. Gastroesophageal reflux disease poorly responsive to single-dose proton pump inhibitors in patients without Barrett's esophagus: acid reflux, bile reflux, or both? American Journal of Gastroenterology. 2004;**99**:981-988

[14] Jabri MA, Tounsi H, Rtibi K, Marzouki L, Sakly M, Sebai H. Ameliorative and antioxidant effects of myrtle berries seeds (*Myrtus communis*) extract during reflux-induced esophagitis in rats. Pharmaceutical Biology. 2016;**54**:1575-1585

[15] Jabri MA, Tounsi H, Abdellaoui A, Marzouki L, Sebai H. Protective effects of Artemisia campestris extract against gastric acid reflux-induced esophageal mucosa injuries. Pathophysiology. 2018;**25**:63-69

[16] Aiyer HS, Li Y, Liu QH, Reuter N, Martin RC. Dietary freeze-dried black raspberry's effect on cellular antioxidant status during reflux-induced esophagitis in rats. Nutrition. 2011;**27**:182-187

[17] Halliwell B, Gutteridge JM, Cross CE. Free radicals, antioxidants, and human disease: Where are we now? The Journal of Laboratory and Clinical Medicine. 1992;**119**:598-620

[18] Masuda T, Yano F, Omura N, Tsuboi K, Hoshino M, Yamamoto SR, et al. Effect of low-dose aspirin on chronic acid reflux esophagitis in rats. Digestive Diseases and Sciences. 2018;**63**:72-80

[19] Roh SS, Shin MR, Shin SH, Lee JY, Song YO, Woo M, et al. Low-molecular-weight oligonol, a polyphenol derived from lychee fruit, attenuates experimental reflux esophagitis and HCl/ethanol-induced gastric ulcer. Journal of Medicinal Food. 2017;**20**:1214-1221

[20] Bloomer RJ, Goldfarb AH. Anaerobic exercise and oxidative stress: A review. Canadian Journal of Applied Physiology. 2004;**29**:245-263

[21] Chen X, Ding YW, Yang GY, Bondoc F, Lee MJ, Yang CS. Oxidative damage in an esophageal adenocarcinoma model with rats. Carcinogenesis. 2000;**21**:257-263

[22] Landriscina M, Maddalena F, Laudiero G, Esposito F. Adaptation to oxidative stress, chemoresistance, and cell survival. Antioxidants & Redox Signaling. 2009;**11**:2701-2716

[23] Hurtado-Nedeleca M, Dang PM-C, Monteiroa RC, El-Benna J, Gougerot-Pocidaloa M-A. Physiologie des polynucléaires neutrophiles humains. French Medical Magazines. 2014;**462**:25-38

[24] Franceschelli S, Gatta DMP, Pesce M, Ferrone A, Di Martino G, Di Nicola M, et al. Modulation of the oxidative plasmatic state in gastroesophageal reflux disease with the addition of

rich water molecular hydrogen: A new biological vision. Journal of Cellular and Molecular Medicine. 2018;**22**:2750-2759

[25] Kauppi J, Räsänen J, Sihvo E, Nieminen U, Arkkila P, Ahotupa M, et al. Increased oxidative stress in the proximal stomach of patients with Barrett's esophagus and adenocarcinoma of the esophagus and esophagogastric junction. Translational Oncology. 2016;**9**:336-339

**62**

*Gastroesophageal Reflux Disease - Theory and Research*

rich water molecular hydrogen: A new biological vision. Journal of Cellular and Molecular Medicine. 2018;**22**:2750-2759

[25] Kauppi J, Räsänen J, Sihvo E, Nieminen U, Arkkila P, Ahotupa M, et al. Increased oxidative stress in the proximal stomach of patients with Barrett's esophagus and adenocarcinoma of the esophagus and esophagogastric junction. Translational Oncology.

2016;**9**:336-339

status during reflux-induced esophagitis in rats. Nutrition. 2011;**27**:182-187

[17] Halliwell B, Gutteridge JM, Cross CE. Free radicals, antioxidants, and human disease: Where are we now? The Journal of Laboratory and Clinical

[18] Masuda T, Yano F, Omura N, Tsuboi K, Hoshino M, Yamamoto SR, et al. Effect of low-dose aspirin on chronic acid reflux esophagitis in rats. Digestive Diseases and Sciences. 2018;**63**:72-80

Medicine. 1992;**119**:598-620

[19] Roh SS, Shin MR, Shin SH, Lee JY, Song YO, Woo M, et al. Low-molecular-weight oligonol, a polyphenol derived from lychee fruit, attenuates experimental reflux esophagitis and HCl/ethanol-induced gastric ulcer. Journal of Medicinal Food.

[20] Bloomer RJ, Goldfarb AH.

Physiology. 2004;**29**:245-263

damage in an esophageal

[21] Chen X, Ding YW, Yang GY, Bondoc F, Lee MJ, Yang CS. Oxidative

adenocarcinoma model with rats. Carcinogenesis. 2000;**21**:257-263

[22] Landriscina M, Maddalena F, Laudiero G, Esposito F. Adaptation to oxidative stress, chemoresistance, and cell survival. Antioxidants & Redox Signaling. 2009;**11**:2701-2716

[23] Hurtado-Nedeleca M, Dang PM-C, Monteiroa RC, El-Benna J, Gougerot-Pocidaloa M-A. Physiologie des polynucléaires neutrophiles humains. French Medical Magazines.

[24] Franceschelli S, Gatta DMP, Pesce M, Ferrone A, Di Martino G, Di Nicola M, et al. Modulation of the oxidative plasmatic state in gastroesophageal reflux disease with the addition of

2014;**462**:25-38

Anaerobic exercise and oxidative stress: A review. Canadian Journal of Applied

2017;**20**:1214-1221

### *Edited by Ali Ibrahim Yahya*

Gastroesophageal reflux disease (GERD) is a very common, global clinical problem. It affects any age group, both males and females, and is seen mainly in developed countries, especially among obese individuals. GERD needs to be treated to prevent nuisance symptoms and long-term complications. The book deals with the diagnosis of GERD, including clinical presentations and diagnostic investigations, and describes the different available conservative, medical, surgical and endoscopic treatments. The book also covers gastroesophageal disease in children, its presentation and treatment. It also deals with the refractory type of gastroesophageal disease including different theories. It is very useful for gastroenterologists and upper gastrointestinal surgeons.

Published in London, UK © 2019 IntechOpen © dzika\_mrowka / iStock

Gastroesophageal Reflux Disease - Theory and Research

Gastroesophageal

Reflux Disease

Theory and Research

*Edited by Ali Ibrahim Yahya*