Diagnosis and Treatment of Gastroesophageal Reflux Disease (Clinical Guidelines of the Russian Gastroenterological Association, Russian Scientific Medical Society of Internal Medicine, Russian Society for the Prevention of Noncommunicable Diseases, Scientific Community for Human Microbiome Research)

Aim. These recommendations are developed for practitioners in order to familiarize them with modern diagnostic methods, management features and pharmacotherapy of patients with gastroesophageal reflux disease (GERD).

General provisions. GERD is the most common reason for patients to visit clinics. There are esophageal and extraesophageal manifestations of GERD. Patients' complaints of heartburn and regurgitation remain the most sensitive and specific clinical manifestations of GERD. The diagnosis of GERD is established on the basis of anamnestic data, instrumental examination (detection of reflux esophagitis during upper gastrointestinal endoscopy, detection of pathological gastroesophageal reflux with 24-hour pH-metry or/and 24-hour pH-impedance monitoring). Patients with suspected GERD and the absence of erosive and ulcerative changes in the mucous membrane of the esophagus or the presence of erosive esophagitis of Grade A according to Los Angeles Classification of Gastroesophageal Reflux Disease are recommended to conduct 24-hour pH-metry on PPI off to exclude or confirm the diagnosis of GERD. Patients with extraesophageal manifestations of GERD without classic symptoms (heartburn, regurgitation) are recommended to undergo 24-hour pH-impedance monitoring with discontinuation of proton pump inhibitor therapy. When deciding on surgical treatment, all patients need to perform high-resolution esophageal manometry and 24-hour pH-impedance monitoring. Complications of GERD include bleeding, strictures, Barrett’s esophagus and esophageal adenocarcinoma. The main groups of medications used in the treatment of GERD are proton pump inhibitors (PPIs), potassium-competitive acid blockers (P-CABs), alginates, antacids, and prokinetics. PPIs are the drugs of choice in the treatment of both symptoms of gastroesophageal reflux disease and existing erosive esophagitis. Combination therapy Rebamipide with PPIs increases the effectiveness of relief of GERD symptoms, as well as reduces the frequency of relapses.

Conclusion. These clinical recommendations will improve the quality of medical care for patients with GERD.

1. Ivashkin V.T., Maev I.V., Trukhmanov A.S., Lapina T.L., Storonova O.A., Zayratyants O.V., et al. Recommendations of the Russian Gastroenterological Association in Diagnosis and Treatment of Gastroesophageal Reflux Disease. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2020;30(4):70–97. (In Russ). DOI: 10.22416/1382-43762020-30-4-70-97

2. Ivashkin V.T., Sheptulin A.A. Diseases of esophagus and stomach. Moscow: MEDpress-inform Publ., 2002. (In Russ.).

3. Katz P.O., Dunbar K.B., Schnoll-Sussman F.H., Greer K.B., Yadlapati R., Spechler S.J. ACG clinical guideline for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2022;117(1):27– 56. DOI: 10.14309/ajg.0000000000001538

4. Fitzgerald R.C., Onwuegbusi B.A., Bajaj-Elliott M., Saeed I.T., Burnham W.R., Farthing M.J. Diversi ty in the oesophageal phenotypic response to gastro-oesophageal reflux: Immunological determinants. Gut. 2002;50(4):451–9. DOI: 10.1136/gut.50.4.451

5. Yoshida N. Inflammation and oxidative stress in gastroesophageal reflux disease. J Clin Biochem Nutr. 2007;40(1):13–23. DOI: 10.3164/jcbn.40.13

6. Trukhmanov A.S., Rumyantseva D.E. Rebamipide and proton pump inhibitors: Benefits of combined use. Pediatric Nutrition. 2022;20(1):42–51. (In Russ).]. DOI: 10.20953/1727-5784-2022-1-42-51

7. Tobey N.A., Carson J.L., Alkiek R.A., Orlando R.C. Dilated intercellular spaces: A morphological feature of acid reflux-damaged human esophageal epithelium. Gastroenterology. 1996;111(5):1200–5. DOI: 10.1053/gast.1996.v111.pm8898633

8. Caviglia R., Ribolsi M., Gentile M., Rabitti C., Emerenziani S., Guarino M.P., et al. Dilated intercellular spac es and acid reflux at the distal and proximal oesophagus in patients with non-erosive gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2007;25(5):629–36. DOI: 10.1111/j.1365-2036.2006.03237.x

9. Antunes C., Aleem A., Curtis S.A. Gastroesophageal reflux disease. 2023 Jul 3. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publ.; 2024.

10. Clarrett D.M., Hachem C. Gastroesophageal Reflux Disease (GERD). Mo Med. 2018;115(3):214–8.

11. van Herwaarden M.A., Samsom M., Smout A.J. The role of hiatus hernia in gastro-oesophageal reflux disease. Eur J Gastroenterol Hepatol. 2004;16(9):831–5. DOI: 10.1097/00042737-200409000-00003

12. Storonova O.A., Trukhmanov A.S., Makushina A.A., Paraskevova A.V., Ivashkin V.T. New parameters for impedance-pH monitoring in diagnosing gastroesophageal reflux disease and predicting its severity. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2019;29(2):35–44. (In Russ.). DOI: 10.22416/1382-4376-2019-29-2-35-44

13. Eusebi L.H., Ratnakumaran R., Yuan Y., Solaymani-Dodaran M., Bazzoli F., Ford A.C. Global prevalence of, and risk factors for, gastro-oesophageal reflux symptoms: A meta-analysis. Gut. 2018;67(3):430–40. DOI: 10.1136/gutjnl-2016-313589

14. Hampel H., Abraham N.S., El-Serag H.B. Meta-analysis: Obesity and the risk for gastroesophageal reflux disease and its complications. Ann Intern Med. 2005;143(3):199–211. DOI: 10.7326/0003-4819-143-3-200508020-00006

15. Singh S., Sharma A.N., Murad M.H, Buttar N.S., El-Serag H.B., Katzka D.A., et al. Central adiposity is associated with increased risk of esophageal inflammation, metaplasia, and adenocarcinoma: A systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2013;11(11):1399–412.e7. DOI: 10.1016/j.cgh.2013.05.009

16. Nirwan J.S., Hasan S.S., Babar Z.U., Conway B.R., Ghori M.U. Global prevalence and risk factors of gastro-oesophageal reflux disease (GORD): Systematic review with meta-analysis. Sci Rep. 2020;10(1):5814. DOI: 10.1038/s41598-020-62795-1

17. Ness-Jensen E., Hveem K., El-Serag H., Lagergren J. Lifestyle intervention in gastroesophageal reflux disease. Clin Gastroenterol Hepatol. 2016;14(2):175–82.e1–3. DOI: 10.1016/j.cgh.2015.04.176

18. Peery A.F., Dellon E.S., Lund J., Crockett S.D., McGowan C.E., Bulsiewicz W.J., et al. Burden of gastrointestinal disease in the United States: 2012 update. Gastroenterology. 2012;143(5):1179–87.e3. DOI: 10.1053/j.gastro.2012.08.002

19. Isa kov V.A., Morozov S.V., Stavraki E.S., Komarov R.M. Analysis of the prevalence of heartburn: National epidemiological study of the adult urban population (ARIADNA). Experimental & Clinical Gastroenterology. 2008;1:20–30. (In Russ.).

20. Lazebnik L.B., Masharova A.A., Bordin D.S., Vasiliev Yu.V., Tkachenko E.I., Abdulhakov R.A., et al. Multicenter study “Epidemiology of GERD in Russia” (MEGRE): First results. Experimental & Clinical Gastroenterology. 2009;6:4–12. (In Russ.).

21. Bordin D.S., Abdulkhakov R.А., Osipenko M.F., Solovyeva A.V., Abdulkhakov S.R., Kirilenko N.P., et al. Multicenter study of gastroesophageal reflux disease symptoms prevalence in outpatients in Russia. Terapevticheskii arkhiv. 2022;94(1):48–56. (In Russ.). DOI: 10.26442/00403660.2022.01.201322

22. Eusebi L.H., Cirota G.G., Zagari R.M., Ford A.C. Global prevalence of Barrett’s oesophagus and oesophageal cancer in individuals with gastro-oesophageal reflux: A systematic review and meta-analysis. Gut. 2021;70(3):456–63. DOI: 10.1136/gutjnl-2020-321365

23. Shaheen N.J., Falk G.W., Iyer P.G., Gerson L.B.; American College of Gastroenterology. ACG clinical guideline: Diagnosis and management of Barrett’s esophagus. Am J Gastroenterol. 2016;111(1):30–50. DOI: 10.1038/ajg.2015.322

24. Healthcare in Russia. 2021: Statistical Digest. Moscow: Rosstat, 2021. (In Russ.). URL: https://rosstat.gov.ru/storage/mediabank/Zdravoohran2021.pdf

25. Kaprin A.D., Starinsky V.V., Shakhzadova A.O. (eds.). Malignant neoplasms in Russia in 2020 (morbidity and mortality). Moscow: P.A. Herzen Moscow Oncology Research Institute — Branch of the National Medical Research Center of Radiology, 2021. (In Russ.).

26. Vakil N., van Zanten S.V., 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;101(8):1900–20. DOI: 10.1111/j.15720241.2006.00630.x

27. Dent J., Vakil N., Jones R., Bytzer P., Schöning U., Halling K., et al. Accuracy of the diagnosis of GORD by questionnaire, physicians and a trial of proton pump inhibitor treatment: The Diamond study. Gut. 2010;59(6):714–21. DOI: 10.1136/gut.2009.200063

28. Numans M.E., Lau J., de Wit N.J., Bonis P.A. Short-term treatment with proton-pump inhibitors as a test for gastroesophageal reflux disease: A meta-analysis of diagnostic test characteristics. Ann Intern Med. 2004;140(7):518–27. DOI: 10.7326/0003-4819-140-7-200404060-00011

29. Gerson L.B., Fass R. A systematic review of the definitions, prevalence, and response to treatment of nocturnal gastroesophageal reflux disease. Clin Gastroenterol Hepatol. 2009;7(4):372–8. DOI: 10.1016/j.cgh.2008.11.021

30. Shaker R., Castell D.O., Schoenfeld P.S., Spechler S.J. Nighttime heartburn is an under-appreciated clinical problem that impacts sleep and daytime function: The results of a Gallup survey conducted on behalf of the American Gastroenterological Association. Am J Gastroenterol. 2003;98(7):1487–93. DOI: 10.1111/j.15720241.2003.07531.x

31. Dean B.B., Aguilar D., Johnson L.F., McGuigan J.E., Orr W.C., Fass R., et al. Night-time and daytime atypical manifestations of gastro-oesophageal reflux disease: Frequency, severity and impact on health-related quality of life. Aliment Pharmacol Ther. 2008;27(4):327–37. DOI: 10.1111/j.1365-2036.2007.03574.x

32. Ivashkin V.T., Mayev I.V., Trukhmanov A.S., Ba ranskaya Ye.K., Dronova O.B., Zayratyants O.V., et al. Diagnostics and treatment of gastroesophageal reflux disease: clinical guidelines of the Russian Gastroenterological Association. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2017;27(4):75–95. (In Russ.). DOI: 10.22416/1382-4376-2017-27-4-75-95

33. Dekel R., Pearson T., Wendel C., De Garmo P., Fennerty M.B., Fass R. Assessment of oesophageal motor function in patients with dysphagia or chest pain — the Clinical Outcomes Research Initiative experience. Aliment Pharmacol Ther. 2003;18(11–12):1083–9. DOI: 10.1046/j.1365-2036.2003.01772.x

34. Yanushevich O.O., Maev I.V., Krikheli N.I., Andreev D.N., Lyamina S.V., Sokolov F.S., et al. Prev alence and risk of dental erosion in patients with gastroesophageal reflux disease: A meta-analysis. Dent J (Basel). 2022;10(7):126. DOI: 10.3390/dj10070126

35. Zerbib F., Bredenoord A.J., Fass R., Kahrilas P.J., Roman S., Savarino E., et al. ESNM/ANMS consen sus paper: Diagnosis and management of refractory gastro-esophageal reflux disease. Neurogastroenterol Motil. 2021;33(4):e14075. DOI: 10.1111/nmo.14075

36. Liu C., Wang H., Liu K. Meta-analysis of the efficacy of proton pump inhibitors for the symptoms of laryngopharyngeal reflux. Braz J Med Biol Res. 2016;49(7):e5149. DOI: 10.1590/1414-431X20165149

37. Wong R.K., Hanson D.G., Waring P.J., Shaw G. ENT manifestations of gastroesophageal reflux. Am J Gastroenterol. 2000;95(8 Suppl):15–22. DOI: 10.1016/s00029270(00)01074-1

38. Vardar R., Varis A., Bayrakci B., Akyildiz S., Kirazli T., Bor S. Relationship between history, laryngoscopy and esophagogastroduodenoscopy for diagnosis of laryngopharyngeal reflux in patients with typical GERD. Eur Arch Otorhinolaryngol. 2012;269(1):187–91. DOI: 10.1007/s00405-011-1748-y

39. Higuchi D., Sugawa C., Shah S.H., Tokioka S., Lu cas C.E. Etiology, treatment, and outcome of esophageal ulcers: A 10-year experience in an urban emergency hospital. J Gastrointest Surg. 2003;7(7):836–42. DOI: 10.1007/s11605-003-0027-7

40. Tan M.C., Mansour N., White D.L., Sisson A., El-Serag H.B., Thrift A.P. Systematic review with meta-analysis: prevalence of prior and concurrent Barrett’s oesophagus in oesophageal adenocarcinoma patients. Aliment Pharmacol Ther. 2020;52(1):20–36. DOI: 10.1111/apt.15760

41. Yadlapati R., Gyawali C.P., Pandolfino J.E.; CGIT GERD Consensus Conference Participants. AGA clinical practice update on the personalized approach to the evaluation and management of GERD: Expert review. Clin Gastroenterol Hepatol. 2022;20(5):984–94.e1. DOI: 10.1016/j.cgh.2022.01.025

42. Vakil N.B., Halling K., Becher A., Rydén A. Systematic review of patient-reported outcome instruments for gastroesophageal reflux disease symptoms. Eur J Gastroenterol Hepatol. 2013;25(1):2–14. DOI: 10.1097/MEG.0b013e328358bf74

43. Dent J., El-Serag H.B., Wallander M.A., Johansson S. Epidemiology of gastro-oesophageal reflux disease: A systematic review. Gut. 2005;54(5):710–7. DOI: 10.1136/gut.2004.051821

44. El-Serag H.B., Sweet S., Winchester C.C., Dent J. Update on the epidemiology of gastro-oesophageal reflux disease: A systematic review. Gut. 2014;63(6):871–80. DOI: 10.1136/gutjnl-2012-304269

45. El-Serag H.B. Time trends of gastroesophageal reflux disease: A systematic review. Clin Gastroenterol Hepatol. 2007;5(1):17–26. DOI: 10.1016/j.cgh.2006.09.016

46. Lundell L.R., Dent J., Bennett J.R., Blum A.L., Armstrong D., Galmiche J.P., et al. Endoscopic assessment of oesophagitis: Clinical and functional correlates and further validation of the Los Angeles classification. Gut. 1999;45(2):172–80. DOI: 10.1136/gut.45.2.172

47. Poh C.H., Gasiorowska A., Navarro-Rodriguez T., Wil lis M.R., Hargadon D., Noelck N., et al. Upper GI tract findings in patients with heartburn in whom proton pump inhibitor treatment failed versus those not receiving antireflux treatment. Gastrointest Endosc. 2010;71(1):28–34. DOI: 10.1016/j.gie.2009.08.024

48. Roman S., Gyawali C.P., Savarino E., Yadlapati R., Zer bib F., Wu J., et al.; GERD consensus group. Ambulatory reflux monitoring for diagnosis of gastro-esophageal reflux disease: Update of the Porto consensus and recommendations from an international consensus group. Neurogastroenterol Motil. 2017;29(10):1–15. DOI: 10.1111/nmo.13067

49. Savarino, E., Zentilin, P., & Savarino, V. NERD: an umbrella term including heterogeneous subpopulations. Nature Reviews Gastroenterology & Hepatology. 2013;10(6):371–380. DOI: 10.1038/nrgastro.2013.50

50. Akdamar K., Ertan A., Agrawal N.M., McMahon F.G., Ryan J. Upper gastrointestinal endoscopy in normal asymptomatic volunteers. Gastrointest Endosc. 1986;32(2):78– 80. DOI: 10.1016/s0016-5107(86)71760-4

51. Takashima T., Iwakiri R., Sakata Y., Yamaguchi D., Tsuruoka N., Akutagawa K., et al. Endoscopic reflux esophagitis and Helicobacter pylori infection in young healthy Japanese volunteers. Digestion. 2012;86(1):55–8. DOI: 10.1159/000338849

52. Zagari R.M., Fuccio L., Wallander M.A., Johansson S., Fiocca R., Casanova S., et al. Gastro-oesophageal reflux symptoms, oesophagitis and Barrett’s oesophagus in the general population: The Loiano-Monghidoro study. Gut. 2008;57(10):1354–9. DOI: 10.1136/gut.2007.145177

53. Gyawali C.P., Kahrilas P.J., Savarino E., Zerbib F., Mion F., Smout AJPM, et al. Modern diagnosis of GERD: the Lyon Consensus. Gut. 2018;67(7):1351–62. DOI: 10.1136/gutjnl-2017-314722

54. Rank M.A., Sharaf R.N., Furuta G.T., Aceves S.S., Greenhawt M., Spergel J.M., et al.; AGA Institute. Electronic address: clinicalpractice@gastro.org; Joint Task Force on Allergy-Immunology Practice Parameters collaborators. Electronic address: drdanawallace@gmail.com; AGA Institute; Joint Task Force on Allergy-Immunology Practice Parameters collaborators. Technical review on the management of eosinophilic esophagitis: A report from the AGA Institute and the Joint Task Force on allergy-immunology practice parameters. Gastroenterology. 2020;158(6):1789–810.e15. DOI: 10.1053/j.gastro.2020.02.039

55. Gonçalves E.S., Assumpção M.S., Servidoni MFCP, Lomazi E.A., Ribeiro J.D. Multichannel intraluminal impedance-pH and psychometric properties in gastroesophageal reflux: Systematic review. J Pediatr (Rio J). 2020;96(6):673–85. DOI: 10.1016/j.jped.2020.01.005

56. Frazzoni M, de Bortoli N, Frazzoni L, et al. The added diagnostic value of postreflux swallow-induced peristaltic wave index and nocturnal baseline impedance in refractory reflux disease studied with on-therapy impedance-pH monitoring. Neurogastroenterol Motil 2017;29:e12947. DOI: 10.1111/nmo.12947

57. Saritas Yuksel E., Higginbotham T., Slaughter J.C., Mabary J., Kavitt R.T., Garrett C.G., et al. Use of direct, endoscopic-guided measurements of mucosal impedance in diagnosis of gastroesophageal reflux disease. Clin Gastroenterol Hepatol. 2012;10(10):1110–6. DOI: 10.1016/j.cgh.2012.05.018

58. Iluyomade A., Olowoyeye A., Fadahunsi O., Thomas L., Libend C.N., Ragunathan K., et al. Interference with dai ly activities and major adverse events during esophageal pH monitoring with bravo wireless capsule versus conventional intranasal catheter: A systematic review of randomized controlled trials. Dis Esophagus. 2017;30(3):1–9. DOI: 10.1111/dote.12464

59. Gyawali C.P., Rogers B., Frazzoni M., Savarino E., Roman S., Sifrim D. Inter-reviewer variability in interpretation of pH-impedance studies: The Wingate Consensus. Clin Gastroenterol Hepatol. 2021;19(9):1976–8.e1. DOI: 10.1016/j.cgh.2020.09.002

60. Woodland P., Shen Ooi J.L., Grassi F., Nikaki K.., Lee C, Evans J.A., et al. Superficial esophageal mucosal afferent nerves may contribute to reflux hypersensitivity in nonerosive reflux disease. Gastroenterology. 2017;153(5):1230–9. DOI: 10.1053/j.gastro.2017.07.017

61. Spechler S.J., Hunter J.G., Jones K.M., Lee R., Smith B.R., Mashimo H., et al. Randomized trial of medical versus surgical treatment for refractory heartburn. N Engl J Med. 2019;381(16):1513–23. DOI: 10.1056/NEJMoa1811424

62. Aziz Q., Fass R., Gyawali C.P., Miwa H., Pandolfino J.E., Zerbib F. Functional esophageal disorders. Gastroenterology. 2016;S0016-5085(16)00178-5. DOI: 10.1053/j.gastro.2016.02.012

63. Worrell S.G., DeMeester S.R., Greene C.L., Oh D.S., Hagen J.A. Pharyngeal pH monitoring better predicts a successful outcome for extraesophageal reflux symptoms after antireflux surgery. Surg Endosc. 2013;27(11):4113– 8. DOI: 10.1007/s00464-013-3076-3

64. Wiener G.J., Tsukashima R., Kelly C., Wolf E., Schmeltzer M., Bankert C., et al. Oropharyngeal pH monitoring for the detection of liquid and aerosolized supraesophageal gastric reflux. J Voice. 2009;23(4):498–504. DOI: 10.1016/j.jvoice.2007.12.005

65. Wang A.J., Liang M.J., Jiang A.Y., Lin J.K., Xiao Y.L., Peng S., et al. Gastroesophageal and laryngopharyngeal reflux detected by 24-hour combined impedance and pH monitoring in healthy Chinese volunteers. J Dig Dis. 2011;12(3):173–80. DOI: 10.1111/j.17512980.2011.00502.x

66. Patterson N., Mainie I., Rafferty G., McGarvey L., Heaney L., Tutuian R., et al. Nonacid reflux episodes reaching the pharynx are important factors associated with cough. J Clin Gastroenterol. 2009;43(5):414–9. DOI: 10.1097/MCG.0b013e31818859a3

67. Ivashkin V.T., Mayev I.V., Trukhmanov A.S., Storonova O.A., Abdulkhakov S.A., Andreev D.N., et al. Recommendations of the Russian Gastroenterological Association on clinical use of high-resolution manometry in diagnosis of esophageal disorders. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2020;30(3):61–88. (In Russ.). DOI: 10.22416/1382-4376-2020-30-3-61-88

68. Stoikes N., Drapekin J., Kushnir V., Shaker A., Brunt L.M., Gyawali C.P. The value of multiple rap id swallows during preoperative esophageal manometry before laparoscopic antireflux surgery. Surg Endosc. 2012;26(12):3401–7. DOI: 10.1007/s00464-012-2350-0

69. Alexander H.C., Hendler R.S., Seymour N.E., Shires G.T. 3rd. Laparoscopic treatment of gastroesophageal reflux disease. Am Surg. 1997;63(5):434–40.

70. Trudgill N.J., Sifrim D., Sweis R., Fullard M., Basu K., McCord M., et al. British Society of Gastroenterology guidelines for oesophageal manometry and oesophageal reflux monitoring. Gut. 2019;68(10):1731–50. DOI: 10.1136/gutjnl-2018-318115

71. Iwakiri K., Fujiwara Y., Manabe N., Ihara E., Kuri bayashi S., Akiyama J., et al. Evidence-based clinical practice guidelines for gastroesophageal reflux disease 2021. J Gastroenterol. 2022;57(4):267–85. DOI: 10.1007/s00535-022-01861-z

72. Zhang M., Hou Z.K., Huang Z.B., Chen X.L., Liu F.B. Dietary and lifestyle factors related to gastroesophageal reflux disease: A systematic review. Ther Clin Risk Manag. 2021;17:305–23. DOI: 10.2147/TCRM.S296680

73. Eherer A. Management of gastroesophageal reflux disease: Lifestyle modification and alternative approaches. Dig Dis. 2014;32(1–2):149–51. DOI: 10.1159/000357181

74. Singh M., Lee J., Gupta N., Gaddam S., Smith B.K., Wani S.B., et al. Weight loss can lead to resolution of gastroesophageal reflux disease symptoms: A prospective intervention trial. Obesity (Silver Spring). 2013;21(2):284–90. DOI: 10.1002/oby.20279

75. Cao H., Huang X., Zhi X., Han C., Li L., Li Y. Association between tea consumption and gastroesophageal reflux disease: A meta-analysis. Medicine (Baltimore). 2019;98(4):e14173. DOI: 10.1097/MD.0000000000014173

76. Kim J., Oh S.W., Myung S.K., Kwon H., Lee C., Yun J.M., et al.; Korean Meta-analysis (KORMA) Study Group. Association between coffee intake and gastroesophageal reflux disease: A meta-analysis. Dis Esophagus. 2014;27(4):311–7. DOI: 10.1111/dote.12099

77. Pan J., Cen L., Chen W., Yu C., Li Y., Shen Z. Alco hol consumption and the risk of gastroesophageal reflux disease: A systematic review and meta-analysis. Alcohol Alcohol. 2019;54(1):62–9. DOI: 10.1093/alcalc/agy063

78. Khan M., Santana J., Donnellan C., Preston C., Moayyedi P. Medical treatments in the short term management of reflux oesophagitis. Cochrane Database Syst Rev. 2007;(2):CD003244. DOI: 10.1002/14651858.CD003244.pub2

79. Tran T., Lowry A.M., El-Serag H.B. Meta-analysis: The efficacy of over-the-counter gastro-oesophageal reflux disease therapies. Aliment Pharmacol Ther. 2007;25(2):143–53. DOI: 10.1111/j.1365-2036.2006.03135.x

80. Carlsson R., Galmiche J.P., Dent J., Lundell L., Frison L. Prognostic factors influencing relapse of oesophagitis during maintenance therapy with antisecretory drugs: A meta-analysis of long-term omeprazole trials. Aliment Pharmacol Ther. 1997;11(3):473–82. DOI: 10.1046/j.1365-2036.1997.00167.x

81. Gralnek I.M., Dulai G.S., Fennerty M.B., Spiegel B.M. Esomeprazole versus other proton pump inhibitors in erosive esophagitis: A meta-analysis of randomized clinical trials. Clin Gastroenterol Hepatol. 2006;4(12):1452–8. DOI: 10.1016/j.cgh.2006.09.013

82. Gyawali C.P., Tutuian R., Zerbib F., Rogers B.D., Frazzoni M., Roman S., et al. Value of pH impedance monitoring while on twice-daily proton pump inhibitor therapy to identify need for escalation of reflux management. Gastroenterology. 2021;161(5):1412–22. DOI: 10.1053/j.gastro.2021.07.004

83. Miner P. Jr., Orr W., Filippone J., Jokubaitis L., Sloan S. Rabeprazole in nonerosive gastroesophageal reflux disease: A randomized placebo-controlled trial. Am J Gastroenterol. 2002;97(6):1332–9. DOI: 10.1111/j.15720241.2002.05769.x

84. Robinson M., Horn J. Clinical pharmacology of proton pump inhibitors: What the practising physi cian needs to know. Drugs. 2003;63(24):2739–54. DOI: 10.2165/00003495-200363240-00004

85. Besancon M., Simon A., Sachs G., Shin J.M. Sites of reaction of the gastric H,K-ATPase with extracytoplasmic thiol reagents. J Biol Chem. 1997;272(36):22438–46. DOI: 10.1074/jbc.272.36.22438

86. Kromer W. Relative efficacies of gastric proton-pump inhibitors on a milligram basis: Desired and undesired SH reactions. Impact of chirality. Scand J Gastroenterol Suppl. 2001;(234):3–9. DOI: 10.1080/003655201753265389

87. Kromer W., Krüger U., Huber R., Hartmann M., Steini jans V.W. Differences in pH-dependent activation rates of substituted benzimidazoles and biological in vitro correlates. Pharmacology. 1998;56(2):57–70. DOI: 10.1159/000028183

88. Pantoflickova D., Dorta G., Ravic M., Jornod P., Blum AL. Acid inhibition on the first day of dosing: Comparison of four proton pump inhibitors. Aliment Pharmacol Ther. 2003;17(12):1507–14. DOI: 10.1046/j.13652036.2003.01496.x

89. Horn J. Review article: Understanding the pharmacodynamic and pharmacokinetic differences between proton pump inhibitors — focus on pKa and metabolism. Alimentary Pharmacology & Therapeutics Symposium Series. 2006;2:340–50. DOI: 10.1111/j.1746-6342.2006.00065.x

90. Dekkers C.P., Beker J.A., Thjodleifsson B., Gabryelewicz A., Bell N.E., Humphries T.J. Double-blind comparison [correction of Double-blind, placebo-controlled comparison] of rabeprazole 20 mg vs. omeprazole 20 mg in the treatment of erosive or ulcerative gastro-oesophageal reflux disease. The European Rabeprazole Study Group. Aliment Pharmacol Ther. 1999;13(1):49–57. DOI: 10.1046/j.1365-2036.1999.00438.x

91. Katz P.O., Gerson L.B., Vela M.F. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2013;108(3):308–28. DOI: 10.1038/ ajg.2012.444

92. van Zanten S.J., Henderson C., Hughes N. Patient satisfaction with medication for gastroesophageal reflux disease: A systematic review. Can J Gastroenterol. 2012;26(4):196–204. DOI: 10.1155/2012/235476

93. Ghoneim S., Wang J., El Hage Chehade N., Ganocy S.J., Chitsaz E., Fass R. Diagnostic accuracy of the proton pump inhibitor test in gastroesophageal reflux disease and noncardiac chest pain: A systematic review and meta-analysis. J Clin Gastroenterol. 2023;57(4):380–8. DOI: 10.1097/MCG.0000000000001686

94. Boghossian T.A., Rashid F.J., Thompson W., Welch V., Moayyedi P., Rojas-Fernandez C., et al. Deprescribing versus continuation of chronic proton pump inhibitor use in adults. Cochrane Database Syst Rev. 2017;3(3):CD011969. DOI: 10.1002/14651858.CD011969.pub2

95. Ivashkin V.T., Maev I.V., Trukhmanov A.S., Sheptulin A.A., Simanenkov V.I., Lapina T.L., et al. Deprescribing and optimal selection of proton pump inhibitors (Contributions of the 26th United Russian Gastroenterology Week). Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2020;30(6):7–18. (In Russ.). DOI: 10.22416/1382-43762020-30-6-7-18

96. Moayyedi P., Eikelboom J.W., Bosch J., Connolly S.J., Dyal L., Shestakovska O., et al. Safety of proton pump inhibitors based on a large, multi-year, randomized trial of patients receiving rivaroxaban or aspirin. Gastroenterology. 2019;157(3):682–91. DOI: 10.1053/j.gastro.2019.05.056

97. Abdul-Hussein M., Freeman J., Castell D. Concomitant administration of a histamine2 receptor antagonist and proton pump inhibitor enhances gastric acid suppression. Pharmacotherapy. 2015;35(12):1124–9. DOI: 10.1002/phar.1665

98. Simanenkov V.I., Maev I.V., Tkacheva O.N., Alekseenko S.A., Andreev D.N., Bordin D.S., et al. Syndrome of increased epithelial permeability in clinical practice. Multidisciplinary national Consensus. Cardiovascular Therapy and Prevention. 2021;20(1):2758. (In Russ.). DOI: 10.15829/1728-8800-2021-2758

99. Li J., Chen X.L., Shaker A., Oshima T., Shan J., Miwa H., et al. Contribution of immunomodulators to gastroesophageal reflux disease and its complications: Stromal cells, interleukin 4, and adiponectin. Ann N Y Acad Sci. 2016;1380(1):183–94. DOI: 10.1111/nyas.13157

100. Yoon S.M., Ji J.W., Kim D.H., Kim H.W., Kim K.B., Choi S., et al. The effect of rebamipide in patients with gastroesophageal reflux disease, including non-erosive reflux disease: A multi-center, randomized, single-blind, placebo-controlled study. Gastroenterology. 2019;156(6):S-5. DOI: 10.1016/s0016-5085(19)36783-6

101. Yoshida N., Kamada K., Tomatsuri N., Suzuki T., Tak agi T., Ichikawa H., et al. Management of recurrence of symptoms of gastroesophageal reflux disease: Synergistic effect of rebamipide with 15 mg lansoprazole. Dig Dis Sci. 2010;55(12):3393–8. DOI: 10.1007/s10620-010-1166-9

102. Ivashkin V.T., Trukhmanov A.S., Gonik M.I. Rebamipide using in gastroesophageal reflux disease treatment. Terapevticheskii arkhiv. 2020;92(4):98–104. (In Russ.). DOI: 10.26442/00403660.2020.04.000568

103. Hong S.J., Park S.H., Moon J.S., Shin W.G., Kim J.G., Lee Y.C., et al. The benefits of combination therapy with esomeprazole and rebamipide in symptom improvement in reflux esophagitis: An international multicenter study. Gut Liver. 2016;10(6):910–6. DOI: 10.5009/gnl15537

104. Pauwels A., Altan E., Tack J. The gastric accommo dation response to meal intake determines the occurrence of transient lower esophageal sphincter relaxations and reflux events in patients with gastro-esophageal reflux disease. Neurogastroenterol Motil. 2014;26(4):581–8. DOI: 10.1111/nmo.12305

105. Ren L.H., Chen W.X., Qian L.J., Li S., Gu M., Shi R.H. Addition of prokinetics to PPI therapy in gastroesophageal reflux disease: A meta-analysis. World J Gastroenterol. 2014;20(9):2412–9. DOI: 10.3748/wjg. v20.i9.2412

106. Xi L., Zhu J., Zhang H., Muktiali M., Li Y., Wu A. The treatment efficacy of adding prokinetics to PPIs for gastroesophageal reflux disease: A meta-analysis. Esophagus. 2021;18(1):144–51. DOI: 10.1007/s10388-020-00753-6

107. Sheptulin A.A., Kurbatova A.A., Baranov S.A. Modern options of prokinetics in gastroesophageal reflux disease treatment. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2018;28(1):71–7. (In Russ.). DOI: 10.22416/1382-4376-2018-28-1-71-77

108. Jung D.H., Huh C.W., Lee S.K., Park J.C., Shin S.K., Lee Y.C. A systematic review and meta-analysis of randomized control trials: Combination treatment with proton pump inhibitor plus prokinetic for gastroesophageal reflux disease. J Neurogastroenterol Motil. 2021;27(2):165–75. DOI: 10.5056/jnm20161

109. Yamashita H., Okada A., Naora K., Hongoh M., Kinoshita Y. Adding acotiamide to gastric acid inhibitors is effective for treating refractory symptoms in patients with non-erosive reflux disease. Dig Dis Sci. 2019;64(3):823– 31. DOI: 10.1007/s10620-018-5377-9

110. Hoshino S., Takenouchi N., Hanada Y., Umeza wa M., Sano H., Kawami N., et al. Effect of acotiamide on esophageal motility in healthy subjects: A randomized, double-blind, placebo-controlled crossover study. Esophagus. 2017;14:146–52. DOI: 10.1007/s10388-016-0559-z

111. 111 Mayanagi S., Kishino M., Kitagawa Y., Sunamura M. Efficacy of acotiamide in combination with esomeprazole for functional dyspepsia refractory to proton-pump inhibitor monotherapy. Tohoku J Exp Med. 2014;234(3):237– 40. DOI: 10.1620/tjem.234.237

112. Takeuchi T., Takahashi Y., Kawaguchi S., Ota K., Harada S., Kojima Y., et al. Therapy of gastroesophage al reflux disease and functional dyspepsia overlaps with symptoms after usual-dose proton pump inhibitor: Acotiamide plus usual-dose proton pump inhibitor versus double-dose proton pump inhibitor. J Gastroenterol Hepatol. 2018;33(3):623–30. DOI: 10.1111/jgh.13970

113. Funaki Y., Ogasawara N., Kawamura Y., Yoshi mine T., Tamura Y., Izawa S., et al. Effects of acotiamide on functional dyspepsia patients with heartburn who failed proton pump inhibitor treatment in Japanese patients: A randomized, double-blind, placebo-controlled crossover study. Neurogastroenterol Motil. 2020;32(2):e13749. DOI: 10.1111/nmo.13749

114. Kim Y.S., Kim T.H., Choi C.S., Shon Y.W., Kim S.W., Seo G.S., et al. Effect of itopride, a new prokinetic, in patients with mild GERD: A pilot study. World J Gastroenterol. 2005;11(27):4210–4. DOI: 10.3748/wjg.v11.i27.4210

115. Ezzat W.F., Fawaz S.A., Fathey H., El Demerdash A. Virtue of adding prokinetics to proton pump inhibitors in the treatment of laryngopharyngeal reflux disease: Prospective study. J Otolaryngol Head Neck Surg. 2011;40(4):350–6.

116. Chun B.J., Lee D.S. The effect of itopride combined with lansoprazole in patients with laryngopharyngeal reflux disease. Eur Arch Otorhinolaryngol. 2013;270(4):1385–90. DOI: 10.1007/s00405-012-2341-8

117. Fedorchenko Yu.L. Comparative assessment of prokinetic therapy for gastroesophageal reflux disea se in patients with diabetes mellitus. Experimental and Clinical Gastroenterology. 2013;5:42–8. (In Russ.).

118. Maev I.V., Trukhmanov A.S., Sheptulin A.A., Simanenkov V.I., Abdulhakov S.R., Agafonova N.A., et al. The role of motility impairment in the pathogenesis of functional disorders of the gastrointestinal tract and modern possibilities for their treatment (Resolution of an Expert Council and literature review). Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2019;29(6):7–14. (In Russ.). DOI: 10.22416/1382-43762019-29-6-7-14

119. Babu S. Drug therapy of gastroesophageal reflux disease (GERD): Focus on itopride hydrochloride. Indian Practitioner. 2003;56(12):827–30.

120. Minushkin O.N., Loschinina Yu.N. Efficacy of Ganaton in GERD therapy. Effective Drug Therapy in Gastroenterology. 2008;3:20–4. (In Russ.).

121. Takeda N., Takemura M., Kanemitsu Y., Hijikata H., Fukumitsu K., Asano T., et al. Effect of anti-reflux treatment on gastroesophageal reflux-associated chronic cough: Implications of neurogenic and neutrophilic inflammation. J Asthma. 2020;57(11):1202–10. DOI: 10.1080/02770903.2019.1641204

122. Palmieri B., Merighi A., Corbascio D., Rottigni V., Fistetto G., Esposito A. Fixed combination of hyalu ronic acid and chondroitin-sulphate oral formulation in a randomized double blind, placebo controlled study for the treatment of symptoms in patients with non-erosive gastroesophageal reflux. Eur Rev Med Pharmacol Sci. 2013;17(24):3272–8.

123. Bordin D.S., Andreev D.N., Maev I.V. Efficacy of esophagus protection in complex treatment of erosive gastroesophageal reflux disease: A systematic review and meta-analysis of controlled trials. Terapevticheskii Arkhiv. 2022;94(12):1407–12. (In Russ.). DOI: 10.26442/00403660.2022.12.202011

124. Mandel K.G., Daggy B.P., Brodie D.A., Jacoby H.I. Review article: Alginate-raft formulations in the treatment of heartburn and acid reflux. Aliment Pharmacol Ther. 2000;14(6):669–90. DOI: 10.1046/j.13652036.2000.00759.x

125. Naik R.D., Meyers M.H., Vaezi M.F. Treatment of refractory gastroesophageal reflux disease. Gastroenterol Hepatol (N Y). 2020;16(4):196–205.

126. Otake K., Sakurai Y., Nishida H., Fukui H., Tagawa Y., Yamasaki H., et al. Characteristics of the novel potassium-competitive acid blocker vonoprazan fumarate (TAK-438). Adv Ther. 2016;33(7):1140–57. DOI: 10.1007/s12325-016-0345-2

127. Cheng Y., Liu J., Tan X., Dai Y., Xie C., Li X., et al. Direct comparison of the efficacy and safety of vonoprazan versus proton-pump inhibitors for gastroesophageal reflux disease: A systematic review and meta-analysis. Dig Dis Sci. 2021;66(1):19–28. DOI: 10.1007/s10620-020-06141-5

128. Quartarone G. Gastroesophageal reflux in pregnancy: A systematic review on the benefit of raft forming agents. Minerva Ginecol. 2013;65(5):541–9.

129. Du X., Hu Z., Yan C., Zhang C., Wang Z., Wu J. A meta-analysis of long follow-up outcomes of laparoscopic Nissen (total) versus Toupet (270°) fundoplication for gastro-esophageal reflux disease based on randomized controlled trials in adults. BMC Gastroenterol. 2016;16(1):88. DOI: 10.1186/s12876-016-0502-8

130. Galmiche J.P., Hatlebakk J., Attwood S., Ell C., Fiocca R., Eklund S., et al. Laparoscopic antireflux surgery vs esomeprazole treatment for chronic GERD. JAMA. 2011;305(19):1969–77. DOI: 10.1001/jama.2011.626

131. Wileman S.M., McCann S., Grant A.M., Krukowski Z.H., Bruce J. Medical versus surgical management for GERD in adults. Cochrane Database Syst Rev. 2010;(3):CD003243. DOI: 10.1002/14651858.CD003243.pub2