Textbook of Hepato-Gastroenterology Mahmud Hasan, Sheikh Mohammad Fazle Akbar, Mamun Al Mahtab
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Gastroesophageal Reflux DiseaseChapter 1

Sujay Ray
Kshaunish Das
GK Dhali
 
DEFINITION
Gastroesophageal reflux disease (GERD) is a disorder in which gastric contents reflux recurrently into esophagus, causing troublesome symptoms and/or complications This statement is similar to the Montreal definition.1 The term ‘troublesome’connotes impairment of quality of life .
 
EPIDEMIOLOGY
Gastroesophageal reflux disease is a major clinical problem in Western countries.
Several recent studies have suggested that the overall prevalence of reflux esophagitis (RE) in Western countries was around 10–20%.2 In contrast, GERD has traditionally been considered to be less common in Asian countries.3 But more recent studies suggest that the prevalence of GERD in Asia is increasing in Japan, and the overall prevalence of RE among the adult population is around 16%.4 While in Taiwan, the prevalence of RE in patients evaluated for upper gastrointestinal tract sympoms is 15%.5
These results are similar to the findinngs reported in the West. RE has been considered quite rare among Koreans. However, recent studies have revealed that the incidence is increasing in the Korean population. RE prevalence in subjects undergoing a routine check-up was reported to 2.36% in 19933 and 3.4% in 1997.6 In 1999, the prevalence of RE was found to be 5.3% in subjects with gastrointestinal symptoms. However in a recent study from Korea in 2009 the prevalence of RE in male was 14.6% and the in female was only 4.7%.7 According to univariate analysis, male sex, smoking history, total cholesterol >250 mg/dL, LDL cholesterol ≥160 mg/dL, triglyceride ≥150 mg/dL, high BP, and fasting glucose ≥110 mg/dL, were significant risk factors of RE.7 The prevalence rate of GERD in Qashgai migrating Nomads in sourthern Iran, defined as reflux occurring at least one time per week in the preceding year, was 33%.8 In a study from urban and rural population of southern Iran, the prevalence of refux symptoms occurring at least 3 times per week was 15.4%.9 Studies from china has revealed a wide range of variation in prevalence of GERD. Hu et al.10 demonstrated that only 4.8% of Chinese population had GERD. On the other hand, Wong et al.11 in a study by telephone contact, reported a prevalence of 29.8%. Thus Geographic differences in GERD prevalence are difficult to interpret, due to different patient selectionand questionnaires used.12 In a study in southern Iran, the prevalence of GERD was signifcantly higher in rural and illiterate persons.9 The relationship between lower educational status and the prevalence of GERD probably reflects the interaction of certain unhealthy lifestyle habits or poor ability to modify such habits. Meucci et al.13 found that patients with reflux-like and ulcer-like dyspepsia, the prevalence of migraine headache did not differ from that in controls, whereas a higher prevalence of migraine was noted in patients with dysmotility-like dyspepsia and in patients with nausea and vomiting alone. In the study by Aamodt et al.14 higher prevalence of headache was found in individuals with reflux, diarrhea, constipation, and nausea. They suggested that headache sufferers commonly are predisposed to gastrointestinal complaints. In a recent multicentric study from India study showed that 8% of Indians reported symptoms of GER frequent or severe enough to be diagnosed as GERD. The low prevalence could be attributed to genetic factors as Asians have a smaller parietal cell mass and a lower acid output compared with Caucasians. The lower prevalence of hiatus hernia and smaller body mass index in the Asian population might also have accounted for the lower prevalence of GERD similar to that reported from the rest of south Asian countries. H. pylori infection, common in Indian population, might also reduce the frequency of GERD by causing gastritis and reduced acid secretion. Subjects with GERD were older, more often female, frequently consulted doctors, and often had overlapping functional lower GI symptoms. Frequency of intake meat, fried food, fruit and spices was higher amongst subjects with GERD; also, meat, fried food, spice, aerated drink, tea, coffee, and smoking were often associated with induction of symptoms among subjects with GERD. On multivariate analysis, induction of symptoms of GERD following smoking 2and nonvegetarian foods was independently associated with GERD. Frequency of GERD was comparable in northern and southern Indian population. (ISG Task Force Report -In Press).
Assessment of health-related quality of life (HRQL) through the use of validated patient-completed questionnaires is likely to provide a good indication of how troublesome gastroesophageal reflux symptoms are. There are few studies assessing the relationship between HRQL and symptoms of GERD in the general population using validated questionnaires.15 A population-based study in Malmö, Sweden showed that even mild reflux symptoms on a weekly basis were associated with a clinically meaningful reduction in well-being,16 while another large survey of the Swedish population (the Kalixanda study) found that daily or weekly symptoms of heartburn and/or regurgitation substantially disrupted subjects’ everyday lives.17 Similar results were obtained in two recent studies in the USA.18, 19 These studies showed that the impact of GERD increased with symptom frequency and severity in the general population. There are few data on the impact of GERD on HRQL in Asia generally. One epidemiological study of GERD in Sanghai, East China, evaluated HRQL impairment in GERD subjects using a Chinese version of the SF-3620 (Figs 1 and 2).
 
Symptoms
Typical symptoms of reflux are heartburn (retrosternal burning sensation) and acid regurgitation. Heartburn, although an english term that has no equivalent in any of the Asian languages, is now thought to be increasingly understood by Asian patients.21, 22 Doctors may still have to describe in words in the local language what heartburn means, i.e. ‘a burning discomfort arising from the epigastrium and rising retrosternally’to clarify the term. Asian patients more easily understand acid regurgitation, meaning the experience of sour or acidic fluid in the mouth.
Other symptomatic presentations are chest pain, belching, nausea, dysphagia, early satiety, and epigastric pain, with or without typical reflux symptoms. There was much discussion that Asian patients may not complain of the cardinal symptoms of heartburn and acid regurgitation, but instead complain of other upper gastrointestinal symptoms which may be more prominent. Noncardiac chest pain, is a common condition among Asian patients.23, 24 and may be a presenting feature of GERD. GERD symptoms among Asian patients are more protean, and atypical symptoms may occur in the absence of
heartburn and acid regurgitation (Table 1).
 
Spectrum
Symptomatic GERD is endoscopically manifested in three spectrum—nonerosive reflux disease (NERD), consisting of majority of around 60%, erosive esophagitis of around 35%, and complicated GERD of 5%. Compliations of GERD are peptic stricture, bleeding ulcer, Barrett’s esophagus, and esophageal adenocarcinoma. NERD is defined as troublesome reflux symptoms in the absence of esophageal mucosal damage on endoscopy. Barrett’s esophagus is the presence of columnar lined epithelium suspected at endoscopy and proven by histology which requires the presence of intestinal metaplasia. The term Barrett’s esophagus has been loosely used, giving rise to undue alarm and concern among doctors and patients.
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Fig. 1: Health-related quality of life in subjects with and without GERD. Subjects with GERD, (black bars); subjects without GERD, (white bars). GERD, gastroesophageal reflux disease; QOLRAD, Quality of Life in Reflux and Dyspepsia. *P < 0.001;†P = 0.003. P-values were calculated by t-test. R. Wang et al. Digestive and Liver Disease. 2009;41:110-5
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Fig. 2: Health status and well-being in subjects with and without GERD. Subjects with GERD, (black bars); subjects without GERD, (white bars). BP, bodily pain; GERD, gastroesophageal reflux disease; GH, general health; MH, mental health; PF, physical functioning; RE, role-emotional;RP, role-physical; SF, social functioning; SF-36, 36-item short-form health survey; VT, vitality. *P < 0.001; †P = 0.019. P-values were calculated by t-test. R. Wang et al. Digestive and Liver Disease. 2009;41:110-5
Table 1   Symptoms of gastroesophageal reflux disease
Typical symptoms
Alarm symptoms
Heartburn (pyrosis)
Dysphagia
Acid regurgitation
Gastrointestinal hemorrhage
Iron deficiency anemia
Nausea and/or vomiting
Weight loss
Family history of cancer
Histological confirmation of columnar lined epithelium with intestinal metaplasia in the definition of Barrett’s esophagus, in addition to endoscopic diagnosis is important (Fig. 3).
Community-based studies identified older age and male sex as risk factors for GERD symptoms.25, 26 Endoscopy-based studies have also revealed age and male sex as risk factors for ERD.27, 28 Alcohol , smoking , BMI more than 25 and hiatus hernia are important risk factors.29 Three reports from Southeast Asia identified Indian race as being a risk factor for GERD.28, 30
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Fig 3: Spectrum of gastroesophageal disease
4The prevalence and incidence of GERD is increasing in asian countries as revealed in many studies.31, 32 Time trend studies have shown both an increase in symptoms of GERD33 in the community, as well as an increase in the prevalence of esophagitis.34-40
The prevalence of Barrett’s esophagus and adenocarcinoma of the esophagus, although lower than in the Western populations, is also increasing in Asia. The prevalence of Barrett’s esophagus is generally low in Asian patients and ranges from 0.9 to 2%.13, 35
An isolated study, however, showed prevalence rates of up to 6% of patients endoscoped, which was different from other studies from the same region. A study based at the Singapore Cancer Registry has shown a significant decrease in squamous cell carcinoma of the esophagus over 34 years and a numerical, but not statistically significant, increase in adenocarcinoma of the esophagus.41
 
PATHOGENESIS
 
Pathophysiology
 
Esophageal dysmotility and hiatus hernia
The GERD results from imbalance between aggressive and protective factors which interact at lower esophageal mucosa (Fig. 4). The protectve factors being lower esophageal sphincter which is supported by diaphragmatic crus, the esophageal clearance, and esophageal tissue resistance. The aggressive factors are the acid peptic secretion of stomach and bile which comes into contact of lower esophageal mucosa during reflux episodes. The pathophysiological mechanisms of GERD in Asian patients are similar to those in Western populations. Among the various motor dysfunction abnormalities of esophagus, transient lower esophageal sphincter relaxation (TLESR) with excessive acid reflux is the single most important mechanism.42 In patients with more severe GERD, hiatus hernia, impaired esophageal peristalsis and weak lower esophageal sphincter (LES) pressure play a more important role in the pathogenesis.42–44 However, it is intriguing to note that rates of TLESR tend to be lower in both Asian GERD patients and healthy volunteers compared to their Western counterparts.42 Furthermore, the reported prevalence of hiatus hernia in Asian populations is substantially lower than those reported in Western populations.45 Chang et al. reported that the prevalence of hiatus hernia was only 2.2% in the Taiwanese general population.21 In another study of patients with dyspepsia, the prevalence of hiatus hernia was 49% in English patients, but only 4% in Singaporeans, most of whom were Chinese, respectively. After adjusting for age and body mass index (BMI), race remains an independent risk factor for hiatus hernia.46 Furthermore, the prevalence of hiatus hernia has been reported as being lower in Asian GERD patients, ranging from 7 to 20% in NERD, and 20 to 30% in esophagitis.47, 48 Further studies are required to elucidate whether there are clear ethnic differences in TLESR dysfunction and hiatus hernia, but the apparent lower prevalence of these conditions could contribute to the lower prevalence of GERD and its complications in Asia.
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Fig. 4: Pathogenesis of gastroesophageal disease
 
Esophageal acid hypersensitivity
Esophageal acid hypersensitivity has been implicated in the pathogenesis of heartburn symptoms, especially in NERD patients.49 Psychological stress increases perception to low-intensity stimuli in the esophagus and is perceived as heartburn in NERD patients.50 It has been reported that NERD patients have higher positive rates of the acid perfusion test compared to those with erosive esophagitis, but results are conflicting.51, 52
 
Obesity
The strong association between GERD and abdominal obesity has been extensively reported in Western populations.53 Recent studies also support a similar ‘dose-response’ association between GERD and BMI in Asians. Patients with reflux esophagitis tend to have a higher BMI compared to NERD patients and non-reflux controls.54, 55 Recent studies have also reported a positive association between metabolic syndrome and GERD. Thus, hyperglycemia, hyperlipidemia, and high blood pressure have all been shown to be independent risk factors of esophagitis.56 The underlying mechanism(s) of 5obesity-related GERD is/are unclear. It has been reported that the prevalence of hiatus hernia increases with BMI, suggesting tthat hiatus hernia may play a role in the development of GERD-associated obesity.57 It has also been reported that BMI and waist circumference are significantly correlated with TLESR and gastroesophageal pressure gradient in both asymptomatic and GERD patients. This finding indicates that postprandial LES dysfunction plays an important role in the pathogenesis of obesity related GERD.58 The rising problem of obesity may be one of the major contributing factors for the increasing prevalence of GERD in Asia.
 
Role of H. pylori
The role of H. pylori in GERD has been a controversial subject and a major area of substantial discrepancies between Asian and Western studies. Most case-control and population-based studies tend to suggest a negative association between H. pylori infection and GERD in Asia. The prevalence of H. pylori infection in GERD patients ranges from 25 to 35%, which is 25–40% lower than that of the ‘non-reflux’ population in Asia.59, 60 The negative association is more prominent in the elderly,61 however, is only confined to patients with severe GERD in Western countries, especially for those infected by more virulent cytotoxin-associated gene A (CagA+) strains.62-64 The prevalence of H. pylori is also inversely related to the severity of GERD. The prevalence of H. pylori in patients ranges from 20 to 33% for esophagitis65, 66 and 0 to 37% for Barrett’s esophagus.67 Furthermore, patients with reflux esophagitis have lower rates of virulence for H. pylori infection compared to non-reflux controls.67, 68 Compared to cross-sectional prevalence studies, however, the results are less consistent in H. pylori eradication studies for peptic ulcer patients.69, 70 These conflicting observations may be attributed to different dominant patterns of H. pylori gastritis and acid secretion between peptic ulcer patients and nonulcer patients in the general population. Changes in patients with duodenal ulcer and nonulcer dyspepsia are characterized by antrum-predominant gastritis, hypergastrinemia, and relatively-preserved acid-secreting corpus mucosa. As a result, gastric acid hypersecretion is a common feature.71, 72 However, patients with gastric ulcer and gastric cancer are characterized by corpus-predominant gastritis or pangastritis, which is associated with profound destruction or even atrophy of acid-secreting mucosa. These patients are characterized by gastric acid hyposecretion, while eradication of H. pylori is followed by rebound gastric acid hypersecretion. It has been reported that recovery of gastric acid secretion and the emergence of reflux esophagitis occurs after H. pylori eradication in patients with corpus gastritis and atrophic gastritis.73, 74
 
DIAGNOSIS
Heartburn and regurgitation (or both) that occurs after meals are symptoms highly suggestive for GERD. Although the Montreal Consensus reported a high level of agreement on this issue, but the difinition of heartburn and the specificity of the term for GERD had been studied mostly in Caucasian populations, whereas the term ‘heartburn’ carries different meanings to different parts in Asia.1
There is lack of published data on the specificity and sensitivity of heartburn as a predictor of GERD in the Asia-Pacific region so the term heartburn must be clealy described and tested in different regions.
GERD symptoms do not predict the severity of esophagitis. However, there is some correlation between the severity of symptoms and the presence and grade of esophagitis.21, 75 Longer duration of symptoms, with increased frequency and presence of symptoms at night, as well as in the daytime, are features that are more likely to be associated with erosive esophagitis (figs 5 and 6). This correlation has been established in Caucasian GERD patients; about 30–40% of patients are found to have ERD, with the remainder having NERD. In Asian populations, the ratio of ERD to NERD is much lower and the correlation of symptoms with erosive disease in this population has not been tested sufficiently.
Endoscopy should be done in patients with alarm symptoms. But the sensitivity and specificity of alarm symptoms (like dysphagia, weight loss, and anemia) varies on the definitions, duration of symptoms, and the population studied. Clinical diagnosis made by a physician on the basis of alarm symptoms is very specific (range, 97–98%), but it lacks sensitivity.76 Urgent endoscopy in patients with alarm symptoms results in a significant yield of cancer (approximately 4% in one series) and of serious benign disease, such as peptic ulcer, stricture, and severe esophagitis (13%).77 There are no published regional data on the correlation between alarm symptoms and peptic stricture and esophagitis mainly because of the rarity of these in the Asia-Pacific region. In this region, patients with alarm features more likely to have gastric rather than esophageal pathology due to the higher prevalence of peptic ulcer disease and gastric cancer in the region. Nevertheless, alarm features suggest advanced malignancy.78 In clinical practice, expectation and anxiety of the patient is a major driver because any delay in the diagnosis of any pathologic condition will lead to patient dissatisfaction.
Patients with GERD symptoms for 5 years but no alarm features should also undergo endoscopy to exclude Barrett’s esophagus. But the statement is irrelevant to Asia as there is a very low prevalence of Barrett’s esophagus and adenocarcinoma of the esophagus at present in this region. Due to the overlap of upper gastrointestinal symptoms and the greater prevalence of peptic ulcer and gastric cancer in the region, the indication for endoscopy is more often to exclude gastric pathology.
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Figs 5A and B: (A) One (or more) mucosal break, no longer than 5 mm (Grade A); (B) One (or more) mucosal break, more than 5 mm that does not extend between the tops of mucosal folds (Grade B).
Source: Lundell et al. 1999, published with permission from professor G Tytga and professor J Dent
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Figs 6A and B: (A) One (or more) mucosal break that is continuous. Between the tops of two or more mucosal folds, but which involves less than 75% of the circumference. (Grade C); (B) One (or more) mucosal break that involves at least 75% of the esophageal circumference (Grade D).
Source: Lundell et al. 1999, published with permission from professor G Tytga and professor J Dent
Every patient with GERD symptoms should undergo endoscopy once in a lifetime.
The major reason to investigate a patient suffering from symptoms of GERD is to detect Barrett’s esophagus. The highest risk factor for development of Barrett’s esophagus is in white men with chronic symptoms of GERD.79 However, the criteria to select patients for screening of Barrett’s are not yet well defined and it is recognized that persons with Barrett’s esophagus may be asymptomatc. Even within the Western population, this a strategy of screening for Barrett’s esophagus is not uniformly accepted.80 Such a strategy is irrelevant to Asia at this time because of it’s low prevalence.31, 32 A recent direct comparative study also found a lower prevalence of esophagitis (6% vs 27%) and columnar-lined esophagus (1% vs 4%) in Asians compared to Western patients.81 In this region, the major reason for endoscopy is to diagnose or exclude gastric cancer or peptic ulcer. There is considerable debate regarding performance of endoscopy at least once in patients with chronic upper gut symptoms, recognizing the difficulty of clinical diagnosis between GERD and peptic ulcer and the ability of endoscopy to provide or exclude a diagnosis and aid in tailoring therapy. In one study, 18% of patients suffering from H. pylori-related peptic ulcers were misdiagnosed as GERD based on symptoms alone.82 As fear of gastric cancer is a major concern, endoscopy should be performed early rather than later. Empiric use of proton pump inhibitors (PPIs) is common prior to endoscopy resulted increased risk of a false-negative H. pylori biopsy test, so there is requirement to cease PPI prior to testing. Widespread availability of endoscopy in many parts of the region favored endoscopic approaches over a noninvasive test.
Symptomatic response to a trial of PPI is sufficient for a presumptive diagnosis of GERD in a patient with typical symptoms, in the absence of alarm symptoms. Although a symptomatic response to a trial of PPI therapy has been used to support a diagnosis of GERD in patients with typical symptoms, a meta-analysis revealed that the combined sensitivity and specificity of this is only modest.83 As there is overlap of GERD with the symptoms of peptic ulcer and the response of ulcer symptoms to PPI therapy, and the higher prevalence of ulcer in the region, such a strategy needs to be validated locally. However, there is support for an empirical trial of PPI in those with typical symptoms, particularly in the primary care setting.
Histopathology also plays an important role in diagnosis of GERD and its complication. Barrett’s esophagus is defined as presence of specialized intestinal metaplasia on histological examination of biopsies taken from suspected areas (if present) above gastroesophageal junction. Biopsies are taken from all four quadrants of distal 5 cm of the esophagus for histopathologic diagnosis of GERD which require presence of any of the following findings: (i) an increase in thickness of basal cell layer to more than 15% of the thickness of the epithelium, (ii)an increase in height of the papilla to greater than two third of thickness, (iii) presence of blood lakes at the top of papilla, (iv) presence balloon cells, or (v) presence of inflammatory cells in epithelium or lamina propia (Fig. 7).
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Fig. 7: Endoscopic biopsy: (A) Normal mucosa; (B) Reflux esophagitis; (C) Eosin­ophilic esophagitis
A negative ambulatory pH study off therapy helps exclude GERD, if a PPI test fails.
The test is considered positive if the total time for which pH is <4 is >4.5% (Fig. 8). However ambulatory pH testing is not widely available in Asia and is rarely done outside of major centers. Furthermore, there are few data on the test characteristics in Asian populations. For diagnostic purposes, the need to have patients off PPIs when performing pH studies was stressed. The likelihood of a positive test while on PPIs is low; the main role of the test with the patient on PPIs is for the assessment of the adequacy of acid suppression in patients with GERD who are not responding to therapy.
Other diagnostic modalities are barium swallow and fluoroscopy and radionuclide scintigraphy, which are not commonly used tests. In a recent study from Delhi, when all the individual tests were compared against the gold standard of three or more positive tests, then as a single test, 24-hour pH monitoring had the best combination of sensitivity and specificity.84
There is currently no established role for the use of narrow band imaging (NBI), capsule endoscopy, and wireless pH monitoring in the routine management of GERD in the Asia-Pacific region. However, these newer diagnostic modalities require validation as research tools and for clinical practice. It is recognized that they are not appropriate for routine clinical use in the region at present as the impact on diagnosis and management and the cost effectiveness of these new tests are yet to be determined. Nevertheless, NBI is considered a potentially valuable tool in diagnosing GERD, in particular in patients with Barrett’s esophagus. Wireless pH monitoring has been shown to increase the diagnostic yield of GERD by 20%,85 in Caucasian population.
Diagnostic strategies in the Asia-Pacific region must take consideration regarding the coexistence of GERD with other common conditions like gastric cancer and peptic ulcer. Gastric cancer still accounts for nearly one million deaths worldwide annually, with much of this occurring in the region.
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Fig. 8: Common pattern of24 hours esophageal pH monitoring. Upper panel showing physiologic pattern of gastroesophageal reflux (GER) seen in healthy subject. Reflux is noted after meals (M) but not while asleep(S). A reflux episode is defined when pH drops below 4. middle panel showing upright reflux pattern with extensive GER during the day but not at night. Lower panel showing combined pattern with GER during the day and night
There is immense difficulty in designing the management strategies in a large diverse region, where the prevalence and spectrum of GERD, peptic ulcer, and gastric cancer vary considerably. The strategy for management of upper gut symptoms must recognize that symptoms of GERD, peptic ulcer disease, and functional dyspepsia frequently overlap, causing difficulty in differentiating these conditions clinically.
H. pylori testing should be considered in patients presenting with GERD symptoms in regions with a high prevalence of gastric cancer or peptic ulcer disease. Symptoms were an imprecise way of distinguishing between upper gastrointestinal conditions in Asia and that GERD may coexist. Peptic ulcer and gastric cancer have greater impact than GERD on morbidity and mortality. There is evidence that benefits are gained by testing and treating H. pylori infection in the context of reducing symptoms, curing ulcer disease, and reducing the risk of gastric cancer.86H. pylori does not cause or prevent reflux disease and that eradication of this organism does not appreciably increase the risk of GERD occurring.87 Long-term PPI therapy for GERD increases the risk of progression of gastric atrophy and intestinal metaplasia in those infected with H. pylori. It is accepted to offer eradication therapy prior to long-term PPI therapy in this setting.88 The decision to test for and treat H. pylori infection in the context of reflux must be individualized based on patient factors including comorbidity, age, gastric histology, family history, and informed choice.
 
MANAGEMENT
 
Goals of Therapy
Resolution of symptoms (symptoms no longer bothersome)
Healing of esophagitis or ulcer, if present. Prevent long-term, etc. complications (ulcer, bleeding, Barrett’s esophagus, stricture, etc.). Weight loss and elevation of head of bed could improve symptoms in GERD patient. There is insufficient data to support other lifestyle modification recommendations.
Lifestyle modifications are commonly used as first line of therapy in patients presenting with GERD-related symptoms. They include weight loss, smoking cessation, avoidance of postprandial recumbency for a period of at least 3 hours, elevation of the head of the bed, avoidance of tight-fitting garments, and avoidance of large heavy meals as well as food 9and drink that exacerbate GERD symptoms (e.g. spicy foods, fatty meals, peppermint, chocolate, onions, citrus juices, and carbonated beverages).89 However, for many patients lifestyle modifications are difficult to follow, very restrictive, and may adversely affect the quality of life. In a recent systematic review that evaluated the value of the different lifestyle modifications in GERD, the authors demonstrated that only weight loss and elevation of the head of the bed are effective in improving symptoms of GERD.90 Elevation of the head of the bed and left lateral decubitus positioning improved the overall time pH <4.0, and weight loss improved pH profiles and GERD-related symptoms. There was no evidence that lifestyle interventions, such as dietary measures and tobacco or alcohol cessation were effective in reducing esophageal acid exposure or ameliorating GERD symptoms.90, 91
PPIs are the most effective medical intervention for GERD. Studies have shown repeatedly and consistently that PPIs are superior to histamine 2 receptor antagonists (H2RAs) in healing the esophageal mucosa and relieving GERD-related symptoms of patients with ERD.92–94
In a meta-analysis, the investigators demonstrated that after 12 weeks of treatment, healing rates were 83.6% with PPIs, 51.9% with H2RAs, 39.2% with sucralfate, and 28.2% with placebo.95 In addition, treatment with PPIs resulted in healing rates of esophageal inflammation and relief of GERD symptoms that were twofold higher than what was observed in patients receiving H2RAs. Similarly, PPIs demonstrate superiority in relieving heartburn symptoms in patients with NERD when compared to H2RAs.96-98
The superiority of PPIs over H2RAs in ERD is not limited to acute therapy but has also been demonstrated in maintenance studies over as long as 11 years.99 The symptoms response rate to once daily PPI in randomized controlled trials has been shown to be significantly higher in patients with ERD, as compared to those with NERD. In one meta-analysis, response rates at 4 weeks were significantly higher for patients with ERD as compared to those with NERD (56% vs 37%, P < 0.0001).98
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Fig. 9: Healing rates following up to 4 weeks of treatment with esomeprazole 40 mg (n = 1562) or pantoprazole 40 mg (n = 1589) by baseline Los Angeles (LA) grade of erosive esophagitis severity. Aliment Pharmacol Ther. 2005;21:739-46
All PPIs are equally efficacious. In GERD/NERD/esophagitis 6 good quality systematic reviews—no clinically important differences in standard doses PPIs. Comparisons showing some degree of difference involved non-equivalent comparisons (e.g. high dose vs. standard dose). However with higher grades of esophagitis esomeprazole is more effective (Fig. 9).
High or double-dose PPI, as initial therapy, is no better than standard daily dose therapy in the management of erosive esophagitis (Fig. 10). Double-dose PPIs: step-up therapy for nonresponders to standard dose PPI can be used.
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Fig. 10: Result of studies showing comparison between Standard vs double dose PPI—no difference in healing of esophagitis or symptom relief
10H2RAs and antacids are useful in treating episodic heartburn. 2RAs and antacids are commonly used for episodic heartburn, primarily for postprandial heartburn. The perception of heartburn serves as a trigger for medication use, and the expectation is an immediate symptom relief that PPIs are unlikely to provide. The onset of action of antacids on esophageal acid concentration is 30 min after dosing and inhibition persists for 1 hour.100 However, studies reported that effective heartburn relief can be achieved 19 min after consumption.101 In contrast, H2RAs have been shown to provide symptom relief within 30 min of dosing that can last up to 12 hours.102
When consumed 30 min prior to a meal, H2RAs are effective in completely or partially preventing postprandial heartburn.103 There is some evidence to suggest that simultaneous consumption of both an H2RA and an antacid provides better control of heartburn symptoms, when compared to the clinical effect of each one of these products alone.100 On-demand treatment with H2RAs has been shown to be safe and effective in GERD patients. In one study, ranitidine 75 mg daily was consumed on demand (up to three times daily) as compared to placebo in patients with uninvestigated GERD.104 The study revealed that 38–41% of those receiving H2RAs reported relief of at least 75% of heartburn episodes during the study period as compared to 28% on placebo.
The use of prokinetic agents either as monotherapy or adjunctive therapy to PPIs may have a role in the treatment of GERD in Asia. Several recent studies have demonstrated the value of prokinetic agents in GERD management. Itopride, a dopamine D2 antagonist with antiacetylcholinesterase effect, has been recently evaluated in patients with an abnormal pH test and mild ERD. After 30 days of treatment in an open label study design, itopride significantly reduced the extent of esophageal acid exposure and improved GERD-related symptoms as compared to baseline values.105 Mosapride, a newly developed 5-HT4 agonist, has been shown to increase the rate of complete esophageal bolus transit and enhances esophageal bolus transit in normal controls.106 In one study from India, 68 patients suffering from heartburn twice a week were randomized to either pantoprazole 40 mg twice daily or pantoprazole 40 mg twice daily plus mosapride 5 mg thrice daily for a period of 8 weeks.107 The investigators found that the PPI + mosapride regimen provided significantly better symptom control in patients with ERD as compared to the PPI alone. However, there was no difference between the two therapeutic arms in ERD healing rates or symptomatic response of subjects with NERD. Further studies using the new prokinetic agents are needed, but those that are currently available demonstrate little efficacy as sole therapy or in combination with a PPI in subsets of patients with GERD.
NERD patients will require a minimum of 4 weeks of initial continuous therapy with a PPI. Almost all therapeutic trials in NERD patients have lasted only 4 weeks. The studies were designed with the assumption that 4 weeks are sufficient to assess symptom improvement as opposed to esophageal mucosal healing, which requires more than 4 weeks of PPI therapy. This arbitrary time frame is unlikely to provide the full symptomatic response rate of patients with NERD undergoing PPI treatment. A systematic review of the literature, revealed a trend in increased therapeutic gain for NERD patients throughout the 4 weeks, suggesting that a 4-week follow-up evaluation alone may be insufficient to show the full therapeutic gain in this patient population.98 ERD patients will require a minimum of 4–8 weeks of initial continuous therapy with a PPI. Therapeutic studies in patients with ERD have almost always lasted 8 weeks. Healing rates in those receiving PPI once daily for 8 weeks ranged from 85–96%, regardless of the PPI that was used and the underlying severity or ERD.108-111
However, patients with severe grades of ERD demonstrated higher PPI failure rates as compared to those with mild-to-moderate disease after 8 weeks of treatment.107
In one study, patients were randomized to either omeprazole 20 mg once daily versus esomeprazole 40 mg once daily.112 The failure rate in those with Los Angeles grade A was 9.6% and 6.6%; grade B, 28.7% and 10.6%; grade C, 29.6% and 12.8%; and grade D 26.2% and 20%, respectively. Patients with lower grades of ERD are likely to heal earlier, and thus 4 weeks of treatment could be sufficient. This is particularly important in the Asian context where generally patients are less likely to develop severe ERD, specifically Los Angeles grades C and D, as compared to their Western counterparts.32 The rate of symptom resolution in patients with ERD is commonly 5–15% lower when compared to esophageal mucosal healing rate after 8 weeks of treatment.108-112 This clearly suggests that a small portion of the patients with ERD will continue to report GERD-related symptoms despite complete esophageal mucosal healing. In a meta-analysis of 43 therapeutic trials in ERD, the authors reported an overall 65% healing rate of esophageal mucosa after 4 weeks, 80% after 8 weeks, and 84% after 12 weeks of treatment with PPI once daily.
PPIs provided a healing rate of 11.7% per week and complete heartburn relief at a rate of 11.5% per week. The meta-analysis demonstrated that 12 weeks of treatment with PPI once a day provided only a modest increase in the healing rate as compared to 8 weeks of treatment in patients with ERD.
On-demand therapy is an appropriate ongoing management strategy in NERD patients. Several alternative therapeutic strategies have been proposed for patients with NERD. The one that has been studied the most is on-demand therapy defined as PPI consumption (up to once daily) when needed and for the duration desired. This patient-driven therapeutic strategy has been shown 11to be clinically efficacious and cost effective. On-demand therapy is attractive to patients because it provides their input into their own management, addresses concerns about chronic ingestion of PPIs, and offers personal cost savings. Studies have also demonstrated that patients are commonly consuming PPIs in an on-demand fashion despite instructions to take their medications on a daily basis.113 Many studies have assessed the value of on-demand PPI therapy as a maintenance strategy in patients with NERD.114-120 These studies commonly followed a similar design. Patients who responded to an acute treatment (4 weeks) with a daily PPI were then randomized to either placebo or PPI for a period of 6 months. Commonly used clinical endpoints included GERD symptom–load, days and nights without heartburn, discontinuation due to insufficient control of heartburn, and daily antacids consumption. All studies have shown that on-demand PPI therapy was superior to placebo in controlling GERD-related symptoms, antacids consumption, and patients’ satisfaction with therapy. Several cost effectiveness analyses have demonstrated that on-demand treatment with a PPI is cost effective compared with other therapeutic strategies for GERD (e.g. lifestyle therapy and antacids, H2RA therapy, step-up, step-down, as well as others).121, 122
It must be clarified that although the term ‘on-demand’ is used, it does not mean that patients take PPI whenever they like. The pharmacology of PPIs is such that to maximize gastric acid suppression, PPI should be taken 30–60 min before the first meal of the day and continued for 5–14 days on a daily basis when restarted.
 
Role of Surgery
For GERD patients who want to discontinue maintenance treatment, fundoplication could be offered when an experienced surgeon is available. Antireflux surgery is an effective therapeutic strategy for a subset of patients with GERD.123, 124 Long-term maintenance studies comparing medical therapy for GERD with antireflux surgery have demonstrated either similar clinical efficacy or significantly better control of symptoms post surgery.125-127 Patients’ satisfaction with antireflux surgery has been reported to be exceptionally high.128, 129 Long-term follow-up of patients who underwent antireflux surgery (up to 13 years post-surgery) demonstrated a high rate of symptoms relapse requiring continuing antireflux medications.122-124 This phenomenon can be seen soon after surgery and appears to increase in prevalence over the years, affecting up to 62% of patients more than 10 years post- surgery.128-130 This is also compounded by a postoperative mortality of up to 0.8% and a variety of complications after antireflux surgery, such as dysphagia, postvagotomy symptoms, gas-bloat syndrome and others.131-133 Furthermore, a surgeon’s experience in performing antireflux surgery is highly predictive of clinical success.132 In addition, several cost-effectiveness analyses have revealed that medical therapy is significantly less costly than antireflux surgery.134
Thus, only in GERD patients who wish to discontinue maintenance of medical treatment, surgery by a fully trained and highly experienced surgeon is recommended. Endoscopic treatment of GERD should not be offered outside well-designed clinical trials
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