Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Pocket Guide to Gastro Esophageal Reflux Disorder (GERD) Priti Chugh ... Anejo Health Communications // 3 © Anejo Health Communications E-mail: [email protected] www.anejo.eu First edition February 2014 All rights reserved Printed in February 2014 Although the information about medication given in this book has been carefully checked, the author and publisher accept no liability for the accuracy of this information. In every individual case the user must check such information by consulting the relevant literature. This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Table of Contents Useful Web Resources 11 GERD- Definition and Prevalence 13 GERD- Clinical Features . Pathophysiology of GERD . Functional Abnormalities at the Esophagogastric Junction . Clearance of Refluxate . Nature of Refluxate 17 18 18 20 21 GERD- Diagnosis . Response to PPI Therapy (Proton Pump Inhibitors) . Esophageal pH-Monitoring . Esophageal Impedance Monitoring and High-Resolution Manometry (HRM) . Radiological Findings - Barium Swallow Radiograph - Endoscopy 23 25 25 Treatment of GERD . Lifestyle Modifications . Antisecretory Drugs -H2-Receptor Blockers -Proton Pump Inhibitors (PPIs) 29 29 30 30 32 26 27 27 27 // 9 . Novel Pharmaceutical Approaches -Stereoisomers -Extended-Release PPIs -Newer PPIs -Potassium-Competitive Acid Blockers (PCABs) -Combinations of PPI with Other Agents -Agents in Pipeline . Alternative Treatments . Surgical Management -Surgical Technique -Restoration of Intra-Abdominal Esophagus -Reconstruction of Extrinsic Sphincter -Reinforcement of Intrinsic Sphincter -Special Precaution After the Surgery -Endoscopic Therapy 34 34 35 35 36 36 40 41 43 44 44 45 45 46 46 Complications of GERD . Benign Esophageal Stricture . Barrett’s Esophagus - Diagnosis of BE - Medical Management of BE - Endoscopic Treatment of BE . Extra Esophageal Syndromes 49 49 50 50 52 53 54 References 57 GERDDefinition and Prevalence Gastro esophageal reflux disorder (GERD) is a commonly occurring disorder in the modern world. It is primarily defined as "a condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications." The Montreal definition of the disorder was developed by an international consensus group of experts and family physicians over a period of 2 years. A series of statements was drafted based on evidence from systematic reviews of the literature in 3 databases (EMBASE, Cochrane Central Register of Controlled Trials, and MEDLINE). The group went through multiple sessions of voting to modify and approve the statements in order to incorporate all possible complications and broaden the definition of GERD. Gastro esophageal reflux occurring frequently (more than once a week) is designated gastrointestinal reflux disease and affects the quality of life significantly.(1) The main symptom of GERD in adults is frequent heartburn, also called acid indigestion—burning-type pain in the lower part of the mid-chest, behind the breast bone, and in the mid-abdomen. Most children under 12 years with GERD, and some adults, have GERD without heartburn. Instead, they may experience a dry cough, asthma symptoms, or trouble swallowing. Complications of GERD include erosive esophagitis, hemorrhage, ulcerative esophagitis, and esophageal strictures. GERD is a known risk factor for development of Barrett's esophagus (BE) and esophageal adenocarcinoma, the most rapidly rising incidence of cancer in the western world. GERD is described in subcategories for ease in // 13 diagnosis, non-erosive esophageal reflux disease NERD and additional pathologies that follow as result of GERD.(2) In a recent study of GI disorders in the United States, abdominal pain was the most common GI symptom that prompted a clinic visit (15.9 million visits). Gastro esophageal reflux was the most common GI diagnosis (8.9 million visits). About seven percent of US population is known to suffer from heartburn on a daily basis, of these about 2040% people are expected to be suffering from GERD. Reflux disease is associated with a huge economic burden in the western countries and significantly decreases the quality of life. It happens to be the most common diagnosis in gastrointestinal-related complaints during office visits and accounts for direct medical costs of over 10 billion dollars per year in the United States alone and the indirect costs amounting to additional burden of 75 billion dollars per year as a result of decreased work productivity. Reflux symptoms also account for the most common indication for upper endoscopy. Barrett's esophagus accounted for almost a half million visits in 2009. About 3.3 million Americans have been diagnosed with Barrett's esophagus. A large number of patients (90%) with Barrett's esophagus condition have non dysplastic disease. According to the guidelines the patients with non-dysplastic disease undergo endoscopic surveillance every 3 to 5 years. Given the large number of subjects with Barrett's, these examinations represent a substantial commitment of resources.(2,3,4) Earlier GERD was recognized mostly in the western world and was thought to be less prevalent in the developing countries. In a recent systematic review, 10-20% prevalence of GERD (at least weekly heartburn and/or regurgitation) was described in the western countries; while less than 5% incidence was noted in Asia. However there is an increasing trend in the prevalence of GERD over the last two decades in Asian countries and is more common than was previously recognized. Europe has an overall lower prevalence than North America, however there are studies reporting an overall increase in prevalence of GERD with time. Highest prevalence rates have been described for North America.(3) GERDClinical Features GERD can cause a variety of symptoms. Typical symptoms are heartburn, acid regurgitation, and dysphagia, which frequently occur in the absence of endoscopic change (nonerosive GERD) or histopathologic change; atypical symptoms reflect upper airway consequences of reflux (eg, nonproductive cough, belching, wheezing) and noncardiac chest pain. Heartburn the most common symptom is described as a burning sensation in the retrosternal area. Heartburn is produced by the contact of the refluxed material with inflamed esophageal mucosa. Regurgitation is defined as the perception of flow of refluxed gastric contents into the mouth or hypo pharynx. This aspiration of gastric juices into the esophagus can lead to chronic cough, recurrent pneumonitis, dental erosion or idiopathic pulmonary fibrosis. Epidemiological data suggests that 34-89% of asthmatics have GERD. GERD is also commonly associated with sleep disturbances and can also manifest as angina like radiating pain, hyper salivation, globus sensation, nausea, or dysphagia in some patients. Persistent dysphagia suggests development of peptic stricture; most patients with peptic stricture have a history of heartburn for several years preceding dysphagia. About one third of patients present with dysphagia as their first symptom. Sometimes rapidly progressive dysphagia and weight loss may indicate development of complications like adenocarcinoma in Barret’s esophagus. Bleeding could also occur due to erosion of mucosa or Barret’s ulcer. Laryngopharyngeal reflux is caused by reflux of gastric contents into the laryngopharynx and may result in coughing, choking, and hoarseness as a result of vocal cord edema or even ulceration. Patients may // 17 describe throat-clearing and globus pharyngeus more frequently than heartburn. Frequently occurring pulmonary aspiration could cause aspiration pneumonia, pulmonary fibrosis or chronic asthma. Some patients can remain asymptomatic over long periods of time. Histopathologic changes in erosive GERD can result in epithelial erosion, ulceration, and inflammation. Severe disease can cause severe epithelial injury or even mucosal destruction; mild disease can cause thickening of the basal zone and lengthening of the papillae. Esophageal pathology and severity of symptoms do not always correlate well: The majority of patients with symptoms of GERD have either no or only very minor histopathologic changes, and not all patients with histopathologic changes of GERD have symptoms. Healing of esophageal ulceration may sometimes result in strictures and scars. Barrett’s esophagus is a histopathologic consequence of chronic GERD in which normal esophageal epithelium is replaced by columnar epithelium; the presence of intestinal goblet cells is a marker for an increased risk for adenocarcinoma.(2,6,8) Pathophysiology of GERD GE reflux is a normal physiological phenomenon and several mechanisms exist to safeguard the esophageal mucosa from prolonged acid exposure. Anti- reflux barrier at the esophagogastric junction forms the first line of defense against acid reflux. Anomalous functioning of the junction components lead to flow of stomach contents into the esophagus. Caustic nature of refluxate and esophageal clearance mechanisms also play a role in GERD pathophysiology.(2,6) Functional Abnormalities at the Esophagogastric Junction Gastro esophageal reflux is expected to occur when the lower esophageal sphincter (LES) opens spontaneously for varying periods of time, or does not close properly and as a consequence the stomach contents rise up into the esophagus. The esophageal environment is normally maintained at a higher pH level than the stomach lining. When subjected to persistent // Gastro Esophageal Reflux Disorder (GERD) low pH acid, the esophageal lining is destroyed over long periods of time. Multiple mechanisms exist at the LES that support its action as a barrier to the acid reflux from the stomach. The sphincter is a physiological valve ranging 3 to 7 cm in length. It is controlled by coordination of various closing and opening mechanisms that contribute towards the proper function of the LES. The crux of the diaphragm creates a pinch cork action and functions to increase the pressure and the intra-abdominal portion of the esophagus is important as the anti-reflux barrier. The length of this portion is very important as it determines the functional valve-like effect. The angle between the stomach and the esophagus (the angle of His) is also of consequence in preventing reflux. Increased intraabdominal pressure arising from abnormalities like abdominal tumors, coughing, and constipation also increase the intra-gastric pressure and thus increases the risk of GERD.(5,6) Esophageal epithelium Epithelium of the stomach in esophageal area // 19 GERDDiagnosis Gastro esophageal reflux disease (GERD) can be diagnosed based on symptoms alone without additional diagnostic testing. The Montreal definition of GERD describes a symptom-based, patientcentered approach to diagnosis of GERD. (GERD review) Newer techniques for esophageal functional testing such as wireless pH capsule monitoring, duodeno-gastroesophageal (also referred to as alkaline or bile reflux) reflux detection, and esophageal impedance testing have been introduced over the past decade and are utilized in clinical practice when needed.(9) Clinical Presentation- According to the Montreal definition GERD can be diagnosed in primary care settings on the basis careful analysis of symptoms presented by the patient without additional diagnostic testing. This approach is appropriate for most patients and does not require additional resources. This approach to diagnosis relies on patient’s information regarding the effect of symptoms on their everyday lives. In cases where patients present with typical symptoms of heartburn, regurgitation and dysphagia without any complications the diagnosis of GERD is usually straightforward. However in the absence of classic symptoms, it requires more thorough examination of patients in order to eliminate other underlying illness. Among the atypical symptoms that may be caused by GERD are chest pain, hoarseness, nausea, cough, odynopia and asthma. In cases of chest pain it becomes // 23 important to rule out cardiac issues similarly in cases of dysphagia, odynophagia and weight loss it is important to rule out esophageal stricture or cancer. More extensive investigation is done before the diagnosis of GERD can be established. Different diagnostic tests are used when the diagnosis is complicated or less obvious. In infants suffering from GER, Orenstein’s infant GER questionnaire (i-GERQ) may help in distinguishing GER from GERD. Similarly, Rome III criteria can also be used to help diagnosing GER in infants. Orenstein, et al. have developed a symptom-based 11 points questionnaire (I-GERQ GERD) with maximum score of 25 to differentiate GER from GERD and have shown that a score of >7 has 74% sensitivity and 94% specificity in diagnosing GERD in infants.(12) pH monitoring catheter Reflux Meal B Monitoring device records pH in esophagus Supine 8 6 pH 4 2 10 AM C 8 2 AM 6 AM Meal Heartburn (H) 10 AM Supine H H 2 AM 6 AM 10 AM Post Pain 6 pH 4 2 10 AM 2 AM 6 AM 10 AM 2 AM 6 AM 10 AM // Gastro Esophageal Reflux Disorder (GERD) Response to PPI Therapy (Proton Pump Inhibitors) The role of proton pump inhibitor, omeprazole (Prilosec) in the diagnosis of GERD has been investigated and is widely recommended. It was found that the response to omeprazole (a dosage of 40 mg per day for 14 days) had similar accuracy and sensitivity to the results of 24-hour pH monitoring in context of GERD. Failure in relieving reflux symptoms subsequent to omeprazole intake often indicates a more detailed investigation of other possible causes for a patient's symptoms.(11) Esophageal pH-Monitoring Documentation and quantification of reflux becomes necessary when the reflux symptoms are complex. This can be accomplished by ambulatory 24 hr esophageal pH recording. 24 hours ambulatory pH-metry helps to establish the presence of acidic reflux (pH < 4) in a patient who does not have GER symptoms and it also helps to assess the efficacy of medical therapy. Esophageal pH monitoring is especially beneficial for measuring GER in patients not responding to anti reflux treatment and also in research. Esophageal pH-monitoring has several advantages; it can be done in any age (neonates to adults), it is relatively non-invasive, however the main disadvantage is that it does not measure non-acid or weakly acidic reflux (pH ≥4). PH monitoring has evolved to wireless pH capsule technology that has improved patient tolerability and allowed for prolonged recordings that allow for both detection of acid reflux and response to therapy. The sensitivity of pH monitoring might be enhanced by pH capsule positioning closer to the SCJ, but further validation is needed because of concerns for diminished diagnostic specificity. Ambulatory impedance-pH, catheter pH, or wireless pH monitoring (with PPI therapy withheld for 7 days) is suggested for evaluation of patients with a suspected esophageal GERD syndrome who have not responded to an empirical trial of PPI therapy, have normal findings on endoscopy, and have no major abnormality on manometry. Wireless pH monitoring has shown // 25 Treatment of GERD Interventions and Practices for initial treatment include lifestyle modifications and use of Antisecretory drugs such as proton pump inhibitors (PPIs), histamine receptor antagonists (H2RAs), metoclopramide. In complicated cases that are refractory to PPI therapy, diagnostic testing with Endoscopy (with or without biopsy), esophageal manometry, ambulatory impedance pH, catheter pH, or wireless pH monitoring is recommended. Chronic (long-term) management includes maintenance therapy with PPIs or H2RAs, endoscopy with or without mucosal biopsy, antireflux surgery in severe cases.(14,17) Lifestyle Modifications Lifestyle modifications are recommended for management of GERD and may include one or more of the following: • Raising the head of the bed is recommended for patients with nocturnal GERD, or erosive or complicated esophagitis, but is usually not helpful for patients suffering from daytime upright reflux. • Dietary changes could also be beneficial, lower intake of fatty foods, smaller portions instead of large meals or not lying down within approximately 3 hours after a meal. • Avoidance of food triggers that may precipitate attacks (eg, chocolate, caffeine, peppermint, spices, onions); these triggers need to identified for the individual patient. // 29 • Weight loss is recommended for GERD patients who have had recent weight gain or are overweight. Obesity is a risk factor for GERD. • Smoking is considered as one of the aggravating factors and should be avoided. • Avoiding clothing that is tight or constrictive around the abdomen or lower chest • Avoiding or reducing alcohol intake is also indicated in certain cases. A quasi-systematic review of 16 clinical trials evaluated the effect of lifestyle measures on changes in GERD symptoms, esophageal pH variables, and lower esophageal pressure. Although alcohol, tobacco, chocolate, and high-fat foods decrease lower esophageal pressure, no evidence was found to support efficacy of dietary measures. Similarly, stopping tobacco or alcohol led to improvement in esophageal pH profiles or symptoms, although elevating the head of the bed and lying on the left side improved the time that esophageal pH was less than 4.0. Weight loss improved pH and symptoms. These findings suggest that weight loss and raising the head of the bed may be effective modalities in treating GERD.(24) Antisecretory Drugs H2-Receptor Blockers H2-receptor blockers were the first agents of choice for treating reflux symptoms and healing esophagitis. Reflux treatment was revolutionized with the introduction of cimetidine (Tagamet) in mid 1970s. Cimetidine is of the first blockbuster drugs. They remain the mainstay of pharmacologic treatment. H2-receptor blockers act by inhibiting histamine stimulation of the gastric parietal cell, thereby suppressing gastric acid secretion. These agents are weak inhibitors of meal-stimulated acid secretion since they minimally inhibit parietal cell stimulation by gastrin and acetylcholine. They are known to effectively suppress the nocturnal acid secretion. They can be used to treat peptic ulcer disease in addition to relieving the symptoms of mild to moderate GERD. H2-receptor blockers are very successful in healing esophagitis because they are not able to inhibit acid secretion Complications of GERD Benign Esophageal Stricture Chronic reflux of acidic gastric contents can lead to ulceration, inflammation, and eventually stricture of the esophagus. An esophageal stricture is defined as any loss of lumen area within the esophagus. The normal esophagus measures 20 mm in diameter. The predominant clinical symptom of strictures is dysphagia, which is usually most prevalent when the luminal diameter is less than 15 mm. Even less severe strictures can cause intermittent dysphagia to large food pieces such as meat and bread. There are multiple intrinsic and extrinsic causes for esophageal strictures. Intrinsic strictures are most common, with acid or peptic causes accounting for the majority of cases (60% to 70%). Peptic strictures have become a less common due to the widespread use of PPIs. Dilation techniques with either through-thescope balloon or Savary-type dilators are effective in treating peptic stricture and relieving the associated dysphagia. In rare instances, peptic strictures can be refractory to simple dilation and are treated with endoscopic steroid injection, implanted stents, or anti-reflux surgery. Surgery may be necessary if medical treatment and dilatations are inadequate. There are two types of surgical repair, both of which are usually approached via a left thoracoabdominal incision. Gastroplasty after esophageal dilatation interposes the fundus of the stomach between esophageal mucosa and the acidic milieu of the stomach. The // 49 remaining fundus may be sewn to the lower esophagus to create a valve-like effect. The second type of repair is resection of the stricture and the creation of a thoracic end-to-side esophagogastrostomy. Vagotomy and antrectomy are performed to eliminate stomach acidity, and a Roux-en-Y gastric drainage procedure is performed to prevent alkaline intestinal reflux.(34) Barrett's Esophagus Abnormal Cells Normal Cells Gastric Reflux Stomach Barrett's esophagus results from development of an abnormal columnar epithelium that replaces the stratified squamous epithelium that normally lines the distal esophagus. An Australian surgeon named // Gastro Esophageal Reflux Disorder (GERD) for Norman Barrett, drew attention to the columnar-lined esophagus in 1950. Development of Barrett's esophagus is a risk factor for esophageal adenocarcinoma. Barrett's esophagus is a consequence of chronic gastroesophageal reflux disease (GERD). Metaplastic columnar epithelium, also known as intestinal metaplasia (IM) develops during healing of erosive esophagitis with continued acid reflux since columnar epithelium is more resistant to acid and pepsin damage than squamous epithelium. The metaplastic epithelium is a mosaic of different epithelial types including goblet cells and columnar cells that have features of both secretory and absorptive (incomplete or type 3 metaplasia). Barret’s epithelium progresses through a dyplastic stage before developing into adenocarcinoma. The columnar-lined esophagus causes no obvious symptoms; however the condition has clinical importance because it is a risk factor for esophageal adenocarcinoma, a tumor whose frequency has increased more than six-fold over the past several decades. The risk of developing esophageal cancer in BE patients is about 30 to 125 times the risk of general population. Conservative estimates suggest that 3% to 12% of patients with GERD will have BE, and this prevalence increases with age, with up to 25% of people older than 50 years with some degree of BE.(35,34) Diagnosis of BE Diagnosis of Barret’s esophagus can be made by endoscopic examination that fulfills the following two criteria. First, the examination should ascertain that columnar-appearing epithelium lines the distal esophagus. The second evidence is gathered by biopsy of the specimens and should show evidence of metaplasia (a change from one adult cell type to another). Endoscopically, columnar epithelium has a reddish color and velvet-like texture that can be distinguished readily from normal esophageal squamous epithelium, which is pale and glossy. There is a strong and probably causal relation between symptomatic prolonged and untreated GERD, Barrett’s esophagus, and esophageal adenocarcinoma. GI referral for upper endoscopy is needed when there are concerns about associated peptic ulcer disease, Barrett’s esophagus, or esophageal cancer. Patients with Barrett’s esophagus are recommended to undergo surveillance endoscopy with mucosal biopsy every 2 yr or less because the risk of developing adenocarcinoma of esophagus is at least 30 times greater than that of // 51 // Gastro Esophageal Reflux Disorder (GERD) References 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. Am J Gastroenterol. 2006 Aug;101(8):1900-20. 2. Patrick L. Gastroesophageal reflux disease (GERD): a review of conventional and alternative treatments. Altern Med Rev. 2011 Jun;16(2):116-33. 3. Webarticle Fact sheet: Heartburn and GERD http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0048152/ last accessed Sept16, 2013. 4. Pandolfino JE, The pathophysiologic basis for epidemiologic trends in gastroesophageal reflux disease Gastroenterol Clin North Am, 2008; 37(4); 827-843. 5. Sharma P, Wani S, Romero Y, Johnson D, Hamilton F. Racial and geographic issues in gastroesophageal reflux disease. Am J Gastroenterol. 2008 Nov;103(11):2669-80. 6. Peery AF, Dellon ES, Lund J, Crockett SD, McGowan CE, Bulsiewicz WJ, Gangarosa LM, Thiny MT, Stizenberg K, Morgan DR, Ringel Y, Kim HP, Dibonaventura MD, Carroll CF, Allen JK, Cook SF, Sandler RS, Kappelman MD, Shaheen NJ. Burden of gastrointestinal disease in the United States: 2012 update. Gastroenterology. 2012 Nov;143(5):1179-87. // 57 7. Liu XL, Wong KK. Gastroesophageal reflux disease in children. Hong Kong Med J. 2012 Oct;18(5):421-8. 8. Joel E. Richter and Frank K. Friedenberg Gastroesophageal Reflux Disease. Pg 705-726 Sleisenger and Fordtran's gastrointestinal and liver disease : pathophysiology, diagnosis, management / [edited by] Mark Feldman, Lawrence S. Friedman, Lawrence J. Brandt. -9th edHerbella. 9. FA, Patti MG.Gastroesophageal reflux disease: From pathophysiology to treatment. World J Gastroenterol. 2010 Aug 4;16(30):3745-9. 10. Orlando RC. The pathogenesis of gastroesophageal reflux disease: the relationship between epithelial defense, dysmotility, and acid exposure. Am J Gastroenterol. 1997;92(4 suppl):3S–5S. 11. Flook N, Jones R, Vakil N. Approach to gastroesophageal reflux disease in primary care: Putting the Montreal definition into practice. Can Fam Physician. 2008 May;54(5):701-5. 12. Poddar U. Diagnosis and management of gastroesophageal reflux disease (GERD): an Indian perspective. Indian Pediatr. 2013 Jan 8;50(1):119-26. 13. Gawron AJ, Hirano I. Advances in diagnostic testing for gastroesophageal reflux disease. World J Gastroenterol. 2010 Aug 14;16(30): 3750-6. 14. Federação Brasileira de Gastroenterologia; Sociedade Brasileira de Endoscopia Digestiva; Colégio Brasileiro de Cirurgia Digestiva; Sociedade Brasileira de Pneumologia e Tisiologia. Gastroesophageal reflux disease: diagnosis. Rev Assoc Med Bras. 2011 Sep-Oct;57(5): 499-507. 15. Kessing BF, Smout AJ, Bredenoord AJ. Clinical applications of esophageal impedance monitoring and high-resolution manometry.Curr Gastroenterol Rep. 2012 Jun;14(3):197-205. 16. Scott,M and Gelhot AR, Gastroesophageal Reflux Disease: Diagnosis and ManagementAm Fam Physician. 1999 Mar 1;59(5):1161-1169. // Gastro Esophageal Reflux Disorder (GERD) 17. Shaheen NJ. Highlights From the New ACG Guidelines for the Diagnosis and Management of GERD. Gastroenterol Hepatol (N Y). 2013 Jun;9(6):377-9. 18. Wang YK, Hsu WH, Wang SS, Lu CY, Kuo FC, Su YC, Yang SF, Chen CY, Wu DC, Kuo CH. Current pharmacological management of gastroesophageal reflux disease. Gastroenterol Res Pract. 2013; 2013:983653. 19. Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2013 Mar;108(3):308-28. 20. Madanick RD. Proton pump inhibitor side effects and drug interactions: much ado about nothing? Cleve Clin J Med. 2011 Jan;78(1):39-49. 21. WEbArticle , Proton-pump inhibitors, www.health.harvard.edu/newsletters/Harvard_Health_Letter/20 11/April/proton-pump-inhibitors, last accessed Sept16 2013. 22. Dutta U, Armstrong D. Novel pharmaceutical approaches to reflux disease. Gastroenterol Clin North Am. 2013 Mar;42(1):93-117. 23. Armstrong D New pharmacologic approaches in gastroesophageal reflux disease, Gastroenterol Clin North Am September, 2010; 39(3); 393-418. 24. Kumar AR, Katz PO. Functional esophageal disorders: a review of diagnosis and management. Expert Rev Gastroenterol Hepatol. 2013 Jul;7(5):453-61. 25. Yancy WS Jr, Provenzale D, Westman EC. Improvement of gastroesophageal reflux disease after initiation of a lowcarbohydrate diet: five brief case reports. Altern Ther Health Med 2001;7:120, 116-119. 26. Dickman R, Schiff E, Holland A, et al. Clinical trial: acupuncture vs. doubling the proton pump inhibitor dose in refractory heartburn. Aliment Pharmacol Ther 2007;26:1333-1344. 27. Madalinski MH. Does a melatonin supplement alter the course of gastro-esophageal reflux disease? World J Gastrointest Pharmacol Ther. 2011 Dec 6;2(6):50-1. // 59 28. Rice TW, Blackstone EH ,Surgical management of gastroesophageal reflux disease, Gastroenterol Clin North Am December, 2008; 37(4); 901-919. 29. Ramos Rf, Lustosa Sas, Almeida Cap, Silva Cp, Matos D. Surgical treatment of gastroesophageal reflux disease: total or partial fundoplication? Systematic review and meta-analysis Arq Gastroenterol. 2011 Oct-Dec; 48(4):252-60. 30. Dughera L, Navino M, Cassolino P, De Cento M, Cacciotella L, Cisarò F, Chiaverina M. Long-Term Results of Radiofrequency Energy Delivery for the Treatment of GERD: Results of a Prospective 48-Month Study. Diagn Ther Endosc. 2011;2011:507157. 31. Yew KC, Chuah SK. Antireflux e ndoluminal therapies: past and present. Gastroenterol Res Pract. 2013;2013:481417. doi: 10.1155/ 2013/481417. Epub 2013 Jul 9. 32. Davis CS, Baldea A, Johns JR, Joehl RJ, Fisichella PM. The evolution and long-term results of laparoscopic antireflux surgery for the treatment of gastroesophageal reflux disease. JSLS. 2010 Jul-Sep;14(3):332-41. 33. Bansal A, Kahrilas PJ. Treatment of GERD complications (Barrett's, peptic stricture) and extra-oesophageal syndromes. Best Pract Res Clin Gastroenterol. 2010 Dec;24(6):961-8. 34. De Palma GD. Management strategies of Barrett's esophagus. World J Gastroenterol. 2012 Nov 21;18(43):6216-25 . 35. Gaddam S Endoscopic therapy of Barrett esophagus.Gastrointest Endosc Clin N Am - 01-JAN-2013; 23(1): 1-16. 36. Heidelbaugh JJ, Atypical presentations of gastroesophageal reflux disease Am Fam Physician - 15-AUG-2008; 78(4): 483-8.