Laryngopharyngeal reflux disease (LPRD) –Review article-
Main Article Content
Abstract
Laryngopharyngeal reflux disease (LPRD) is caused by the back-flow of stomach contents and/or gastric acid into the laryngopharynx. Symptoms of laryngopharyngeal reflux (LPR) include hoarseness, sore throat, throat-clearing, chronic cough, globus sensation, dysphagia, and postnasal drip. LPRD is diagnosed in approximately 10% of patients presenting to outpatient otolaryngology clinics and in more than 50% of patients presenting with voice complaints. Gastroesophageal reflux disease (GERD) and LPRD may be associated with periodontitis, sleep disorders, and otolaryngology disease.Gastric acid reflux with LPRD is thought to cause laryngeal granulomas.The most useful endolaryngeal signs for diagnosing LPRD are erythema, edema, and interarytenoid hypertrophy. Ambulatory 24-h dual-probe pH monitoring can be misleading; false-positive outcomes may occur due to artifacts in the upper probe, and false-negative outcomes can occur as a result of the intermittent character of reflux episodes. In patients with LPRD, proton pump inhibitors (PPIs) have been shown to significantly improve reflux laryngitis. However, some patients are resistant to antacid therapy. Nocturnal acid breakthrough (NAB) on PPI has been suggested as one reason for resistance to PPI therapy. Administration of a PPI with the additional bedtime administration of a histamine-2 receptor antagonist has been shown to be an effective treatment of LPRD with NAB. Recently, potassium-competitive acid blockers have been proposed as an effective treatment of antacid-resistant disease.
Article Details
How to Cite
CHIBA, Toshimi.
Laryngopharyngeal reflux disease (LPRD) –Review article-.
Medical Research Archives, [S.l.], v. 5, n. 2, feb. 2017.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/1014>. Date accessed: 17 nov. 2024.
Keywords
LPRD; GERD; acid-related disease; 24-h esophageal pH monitoring; periodontitis; sleep disorder; otolaryngology disease; treatment; PPI; PCAB
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
References
1. Koufman JA, Amin MR, Panetti M. Prevalence of reflux in 113 consecutive patients with laryngeal and voice disorders. Otolaryngol Head Neck Surg 2000;123:385-388.
2. Richer JE. Typical and atypical manifestations of gastroesophageal reflux disease. Gastroenterol Clin North Am 1996;25:75-102.
3. Koufman JA. The otolaryngologic manifestations of gastroesophageal reflux disease. Laryngoscope 1991;101(Suppl 53):1-78.
4. Poelmans J, Tack J, Feenstra L. Prospective study on the incidence of chronic ear complains related to gastroesophageal reflux and on the outcome of antireflux therapy. Ann Otol Rhinol Laryngol 2004;99:1419-1426.
5. Chiba T, Kudara N, Abiko Y, et al. Effects of proton pump inhibitors in patients with laryngopharyngeal reflux disease. Hepatogastroenterology 2011;58:1580-1582.
6. Ahmed TF, Khandwala F, Abelson T, et al. Chronic Laryngitis associated with gastroesophageal reflux: prospective assessment of differences in practice patterns between gastroenterologists and ENT physicians. Am J Gastroenterol 2006;101:470-478.
7. Lenderking WR, Hillson E, Crawley JA, et al. The clinical characteristics and impact of laryngopharyngeal reflux disease on health-related quality of life. Value in Health 2003; 6:560-565.
8. Hopwood D. Oesophageal damage and defence in reflux oesophaggitis: pathophysiological and cell biological mechanisms. Prog Histochem Cytochem 1997;32:1-42.
9. Vaesi MF, Hicks DM, Abelson TI, Richter JE. Laryngeal signs and symptoms and gastroesophageal reflux disease (GERD): a critical assessment of cause and effect association. Clin Gastroenterol Hepatol 2003;1:333-344.
10. Monini S, Di Stadio A, Vestri A, Barbara M. Silent reflux: ex juvantibus criteria for diagnosis and treatment of laryngeal disorders. Acta Otolaryngol. 2006;126:866-871.
11. Mesallam TA, Stemple JG, Sobeih TM, Elluru RG. Reflux symptom index versus reflux finding score. Ann Otol Rhinol Laryngol 2007;116:436-440.
12. Fraser AG. Review article: gastro-oesophageal reflux and laryngeal symptoms. Aliment Pharmacol Ther 1994;8:265-272.
13. Becker V, Bajbouj M, Waller K, et al. Clinical trial: persistent gastro-oesophageal reflux symptoms despite standard therapy with proton pump inhibitors - a follow-up study of intraluminal-impedance guided therapy. Aliment Pharmacol Ther 2007;26:1355-1360.
14. Sifrim D, Castell D, Dent J, Kahrilas PJ. Gastro-oesophageal reflux monitoring: review and consensus report on detection and definitions of acid, non-acid, and gas reflux. Gut 2004;53:1024-1031.
15. Locke GR 3rd, Tally NJ, Fett SL, et al. Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmsted County, Minnesota. Gastroenterology 1997;112:1448-1456.
16. Tauber S, Gross M, Issing WJ. Association of laryngopharyngeal symptoms with gastroesophageal reflux disease. Laryngoscope 2002;112:879-886.
17. Shimazu R, Kuratomi Y, Aoki S, Inokuchi A. Laryngeal granuloma in experimental rats with gastroesophageal reflux disease and mechanically injured vocal cord mucosa. Ann Otol Rhinol Laryngol. 2014;123:247-251.
18. Tokashiki R, Nakamura K, Watanabe Y, et al. The relationship between esophagoscopic findings and total acid reflux time below pH 4 and pH 5 in the upper esophagus in patients with laryngopharyngeal reflux disease (LPRD). Auris Nasus Larynx 2005;32:265-268.
19. Sato K. Laryngopharyngeal reflux disease with nocturnal gastric acid breakthrough while on proton pump inhibitor therapy. Eur Arch Otorhinolaryngol 2006;263:1121-1126.
20. Merati AL, Lim HJ, Ulualp SO, et al. Meta-analysis of upper probe measurements in normal subjects and patients with laryngopharyngeal reflux. Ann Otol Rhinol Laryngol 2005;114:177-182.
21. Ford CN. Evaluation and management of laryngopharyngeal reflux. JAMA 2005;294:1534-1540.
22. Book DT, Rhee JS, Toohill RJ, Smith TL. Perspectives in laryngopharyngeal reflux: an international survey. Laryngoscope 2002;112:1399-1406.
23. Branski RC, Bhattacharyya N, Shapiro J. The reliability of the assessment of endoscopic laryngeal findings associated with laryngopharyngeal reflux disease. Laryngoscope 2002;112:1019-1024.
24. Dippold S, Nusseck M, Richter B, Echternach M. The use of narrow band imaging for the detection of benign lesions of the larynx. Eur Arch Otorhinolaryngol 2016: DOI 10.1007/s00405-016-4300-2.
25. Mahieu HF. Review article: the laryngological manifestations of reflux disease: why the skepticism? Aliment Pharmacol Ther 2007;26 (Suppl 2):17-24.
26. Jacob P, Kahrilas PJ, Herzon G. Proximal esophageal pHmetry in patients with ‘reflux laryngitis’. Gastroenterology 1999;100:305-310.
27. Shaker R, Milbrath M, Ren J, et al. Esophagopharyngeal distribution of refluxed gastric acid in patients with reflux laryngitis. Gastroenterology 1995;109:1575-1582.
28. Ylitalo R, Lindestad PA, Remal S. Symptoms, laryngeal findings, and 24-hour pH monitoring in patients with suspected gastroesophago-pharyngeal reflux. Laryngoscope 2001;111:1735-1741.
29. Vaezi MF, Schroeder PL, Richter JE. Reproducibility of proximal probe pH parameters in 24-hour ambulatory esophageal pH monitoring. Am J Gastroenterol 1997;92:825-829.
30. Shaker R, Bardan E,GuC, et al. Intrapharyngeal distribution of gastric acid refluxate. Laryngoscope 2003;113:1182-1191.
31. Park W, Hicks DM, Khandwala F, et al. Laryngopharyngeal reflux (LPR): Prospective cohort study evaluating optimal dose of PPI therapy and pre-therapy predictors of response. Laryngoscope 2005;115:1230-1238.
32. Ulualp SO, Toohill RJ, Shaker R. Outcomes of acid suppressive therapy in patients with posterior laryngitis. Otolaryngol Head Neck Surg 2001;124:16-22.
33. Ross JA, Noordzji JP, Woo P. Voice disorders in patients with suspected laryngo-pharyngeal reflux disease. J Voice 1998;12:84-88.
34. Beaver ME, Stasney CR, Weitzel E, et al. Diagnosis of laryngopharyngeal reflux disease with digital imaging. Otolaryngol Head Neck Surg 2003;128:103-108.
35. Song JY, Kim HH, Cho EJ, Kim TY. The relationship between gastroesophageal reflux disease and chronic periodontitis. Gut liver 2014;8:35-40.
36. Adibi P, Keshteli AH, Saneei M, et al. Relationship between Tooth Loss, Functional Dyspepsia and Gastro-Esophageal Reflux Disorder among Isfahani Adults. Arch Iran Med 2016;19:123-130.
37. Zee PC, Turek FW. Sleep and health: Everywhere and in both directions. Archives of internal medicine. 2006;166:1686-1688.
38. Suzuki M, Saigusa H, Kurogi R, et al. Arousals in obstructive sleep apnea patients with laryngopharyngeal and gastroesophageal reflux. Sleep Med 2010;11:356-360.
39. Górecka-Tuteja A, Jastrzębska I, Składzień J, Fyderek K. Laryngopharyngeal reflux in children with chronic otitis media with effusion. J Neurogastroenterol Motil. 2016;22:452-458.
40. Ozmen S, Yücel OT, Sinici I, et al. Nasal pepsin assay and pH monitoring in chronic rhinosinusitis. Laryngoscope. 2008;118:890-894.
41. Harding SM, Richter JE, Guzzo MR, et al. Asthma and gastroesophageal reflux: acid suppressive therapy improves asthma outcome. Am J Med 1996;100:395-405.
42. Shaw GY, Searl JP, Young JL, et al. Subjective, laryngoscopic, and acoustic measurements of laryngeal reflex before and after treatment with omeprazole. J Voice 1996;10:410-418.
43. Shaw GY, Searl JP. Laryngeal manifestation of gastroesophageal reflux before and after treatment with omeprazole. South Med J 1997;11:1115-1122.
44. Hanson DG, Conley D, Jitang J, et al. Role of esophageal pH recording in management of chronic laryngitis: an overview. Ann Otol Rinol Laryngol Suppl 2000;184:4-9.
45. El-Serag HB, Lee P, Buchner A, et al. Lansoprazole treatment of patients with chronic idiopathic laryngitis: a placebo-controlled trial. Am J Gastroenterol 2001;96:979-983.
46. Noordzij JP, Khidr A, Evans BA, et al. Evaluation of omeprazole in the treatment of reflux laryngitis: a prospective, placebo-controlled, randomized, double-blind study. Laryngoscope 2001;111:2147-2151.
47. Karkos PD, Wilson JA. Empiric treatment of laryngopharyngeal reflux with proton pump inhibitors: a systematic review. Laryngoscope 2006;116:144-148.
48. Hopkins C, Yousaf U, Pedersen M. Acid reflux treatment for hoarseness. Cochrane Database Syst Rev. 2006;25:CD005054.
49. Sen P, Georgalas C, Bhattacharyya AK. A systematic review of the role of proton pump inhibitors for symptoms of laryngopharyngeal reflux. Clin Otolaryngol 2006;31:20-24.
50. Lindstrom DR, Wallace J, Loehrl TA, et al. Nissen fundoplication surgery for extraesophageal manifestations of gastroesophageal reflux (EER). Laryngoscope 2002;112:1762-1765.
51. Bough IDJr, Sataloff RT, Castell DO, et al. Gastroesophageal reflux laryngitis resistant to omeprazole therapy. J Voice 1995;9:205-211.
52. Adachi K, Katsube T, Kawamura A, et al. CYP2C19 genotype status and intragastric pH during dosing with lansoprazole or rabeprazole. Alim Pharmacol Ther 2000;14:1259-1266.
53. Ishizaki T, Horai Y. Review article: cytochrome P450 and the metabolism of proton pump inhibitors--emphasis on rabeprazole. Alim Pharmacol Ther 1999;13 (Suppl 3):27-36.
54. Shirai N, Furuta T, Moriyama Y, et al. Effects of CYP2C19 genotypic differences in the metabolism of omeprazole and rabeprazole on intragastric pH. Alim Pharmacol Ther 2001;15:1929-1937.
55. Inatomi N, Matsukawa J, Sakurai Y, Otake K. Potassium-competitive acid blockers: Advanced therapeutic option for acid-related diseases. Pharmacol Ther 2016;168:12-22.
56. Fackler WK, Ours TM, Vaezi MF, Richter JE. Long term effect of H2RA therapy on nocturnal gastric acid breakthrough. Gastroenterology 2002;122:625-632.
57. Adachi K, Komazawa Y, Fujishiro H, et al. Nocturnal gastric acid breakthrough during the administration of rabeprazole and ranitidine in Helicobacter pylori-negative subjects: effects of different regimens. J Gastroenterol 2003;38:830-835.
58. Altman KW, Waltonen JD, Hammer ND, et al. Proton pump (H+/K+-ATPase) expression in human laryngeal seromucinous glands.Otolaryngol Head Neck Surg 2005;133:718-724.
1. Koufman JA, Amin MR, Panetti M. Prevalence of reflux in 113 consecutive patients with laryngeal and voice disorders. Otolaryngol Head Neck Surg 2000;123:385-388.
2. Richer JE. Typical and atypical manifestations of gastroesophageal reflux disease. Gastroenterol Clin North Am 1996;25:75-102.
3. Koufman JA. The otolaryngologic manifestations of gastroesophageal reflux disease. Laryngoscope 1991;101(Suppl 53):1-78.
4. Poelmans J, Tack J, Feenstra L. Prospective study on the incidence of chronic ear complains related to gastroesophageal reflux and on the outcome of antireflux therapy. Ann Otol Rhinol Laryngol 2004;99:1419-1426.
5. Chiba T, Kudara N, Abiko Y, et al. Effects of proton pump inhibitors in patients with laryngopharyngeal reflux disease. Hepatogastroenterology 2011;58:1580-1582.
6. Ahmed TF, Khandwala F, Abelson T, et al. Chronic Laryngitis associated with gastroesophageal reflux: prospective assessment of differences in practice patterns between gastroenterologists and ENT physicians. Am J Gastroenterol 2006;101:470-478.
7. Lenderking WR, Hillson E, Crawley JA, et al. The clinical characteristics and impact of laryngopharyngeal reflux disease on health-related quality of life. Value in Health 2003; 6:560-565.
8. Hopwood D. Oesophageal damage and defence in reflux oesophaggitis: pathophysiological and cell biological mechanisms. Prog Histochem Cytochem 1997;32:1-42.
9. Vaesi MF, Hicks DM, Abelson TI, Richter JE. Laryngeal signs and symptoms and gastroesophageal reflux disease (GERD): a critical assessment of cause and effect association. Clin Gastroenterol Hepatol 2003;1:333-344.
10. Monini S, Di Stadio A, Vestri A, Barbara M. Silent reflux: ex juvantibus criteria for diagnosis and treatment of laryngeal disorders. Acta Otolaryngol. 2006;126:866-871.
11. Mesallam TA, Stemple JG, Sobeih TM, Elluru RG. Reflux symptom index versus reflux finding score. Ann Otol Rhinol Laryngol 2007;116:436-440.
12. Fraser AG. Review article: gastro-oesophageal reflux and laryngeal symptoms. Aliment Pharmacol Ther 1994;8:265-272.
13. Becker V, Bajbouj M, Waller K, et al. Clinical trial: persistent gastro-oesophageal reflux symptoms despite standard therapy with proton pump inhibitors - a follow-up study of intraluminal-impedance guided therapy. Aliment Pharmacol Ther 2007;26:1355-1360.
14. Sifrim D, Castell D, Dent J, Kahrilas PJ. Gastro-oesophageal reflux monitoring: review and consensus report on detection and definitions of acid, non-acid, and gas reflux. Gut 2004;53:1024-1031.
15. Locke GR 3rd, Tally NJ, Fett SL, et al. Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmsted County, Minnesota. Gastroenterology 1997;112:1448-1456.
16. Tauber S, Gross M, Issing WJ. Association of laryngopharyngeal symptoms with gastroesophageal reflux disease. Laryngoscope 2002;112:879-886.
17. Shimazu R, Kuratomi Y, Aoki S, Inokuchi A. Laryngeal granuloma in experimental rats with gastroesophageal reflux disease and mechanically injured vocal cord mucosa. Ann Otol Rhinol Laryngol. 2014;123:247-251.
18. Tokashiki R, Nakamura K, Watanabe Y, et al. The relationship between esophagoscopic findings and total acid reflux time below pH 4 and pH 5 in the upper esophagus in patients with laryngopharyngeal reflux disease (LPRD). Auris Nasus Larynx 2005;32:265-268.
19. Sato K. Laryngopharyngeal reflux disease with nocturnal gastric acid breakthrough while on proton pump inhibitor therapy. Eur Arch Otorhinolaryngol 2006;263:1121-1126.
20. Merati AL, Lim HJ, Ulualp SO, et al. Meta-analysis of upper probe measurements in normal subjects and patients with laryngopharyngeal reflux. Ann Otol Rhinol Laryngol 2005;114:177-182.
21. Ford CN. Evaluation and management of laryngopharyngeal reflux. JAMA 2005;294:1534-1540.
22. Book DT, Rhee JS, Toohill RJ, Smith TL. Perspectives in laryngopharyngeal reflux: an international survey. Laryngoscope 2002;112:1399-1406.
23. Branski RC, Bhattacharyya N, Shapiro J. The reliability of the assessment of endoscopic laryngeal findings associated with laryngopharyngeal reflux disease. Laryngoscope 2002;112:1019-1024.
24. Dippold S, Nusseck M, Richter B, Echternach M. The use of narrow band imaging for the detection of benign lesions of the larynx. Eur Arch Otorhinolaryngol 2016: DOI 10.1007/s00405-016-4300-2.
25. Mahieu HF. Review article: the laryngological manifestations of reflux disease: why the skepticism? Aliment Pharmacol Ther 2007;26 (Suppl 2):17-24.
26. Jacob P, Kahrilas PJ, Herzon G. Proximal esophageal pHmetry in patients with ‘reflux laryngitis’. Gastroenterology 1999;100:305-310.
27. Shaker R, Milbrath M, Ren J, et al. Esophagopharyngeal distribution of refluxed gastric acid in patients with reflux laryngitis. Gastroenterology 1995;109:1575-1582.
28. Ylitalo R, Lindestad PA, Remal S. Symptoms, laryngeal findings, and 24-hour pH monitoring in patients with suspected gastroesophago-pharyngeal reflux. Laryngoscope 2001;111:1735-1741.
29. Vaezi MF, Schroeder PL, Richter JE. Reproducibility of proximal probe pH parameters in 24-hour ambulatory esophageal pH monitoring. Am J Gastroenterol 1997;92:825-829.
30. Shaker R, Bardan E,GuC, et al. Intrapharyngeal distribution of gastric acid refluxate. Laryngoscope 2003;113:1182-1191.
31. Park W, Hicks DM, Khandwala F, et al. Laryngopharyngeal reflux (LPR): Prospective cohort study evaluating optimal dose of PPI therapy and pre-therapy predictors of response. Laryngoscope 2005;115:1230-1238.
32. Ulualp SO, Toohill RJ, Shaker R. Outcomes of acid suppressive therapy in patients with posterior laryngitis. Otolaryngol Head Neck Surg 2001;124:16-22.
33. Ross JA, Noordzji JP, Woo P. Voice disorders in patients with suspected laryngo-pharyngeal reflux disease. J Voice 1998;12:84-88.
34. Beaver ME, Stasney CR, Weitzel E, et al. Diagnosis of laryngopharyngeal reflux disease with digital imaging. Otolaryngol Head Neck Surg 2003;128:103-108.
35. Song JY, Kim HH, Cho EJ, Kim TY. The relationship between gastroesophageal reflux disease and chronic periodontitis. Gut liver 2014;8:35-40.
36. Adibi P, Keshteli AH, Saneei M, et al. Relationship between Tooth Loss, Functional Dyspepsia and Gastro-Esophageal Reflux Disorder among Isfahani Adults. Arch Iran Med 2016;19:123-130.
37. Zee PC, Turek FW. Sleep and health: Everywhere and in both directions. Archives of internal medicine. 2006;166:1686-1688.
38. Suzuki M, Saigusa H, Kurogi R, et al. Arousals in obstructive sleep apnea patients with laryngopharyngeal and gastroesophageal reflux. Sleep Med 2010;11:356-360.
39. Górecka-Tuteja A, Jastrzębska I, Składzień J, Fyderek K. Laryngopharyngeal reflux in children with chronic otitis media with effusion. J Neurogastroenterol Motil. 2016;22:452-458.
40. Ozmen S, Yücel OT, Sinici I, et al. Nasal pepsin assay and pH monitoring in chronic rhinosinusitis. Laryngoscope. 2008;118:890-894.
41. Harding SM, Richter JE, Guzzo MR, et al. Asthma and gastroesophageal reflux: acid suppressive therapy improves asthma outcome. Am J Med 1996;100:395-405.
42. Shaw GY, Searl JP, Young JL, et al. Subjective, laryngoscopic, and acoustic measurements of laryngeal reflex before and after treatment with omeprazole. J Voice 1996;10:410-418.
43. Shaw GY, Searl JP. Laryngeal manifestation of gastroesophageal reflux before and after treatment with omeprazole. South Med J 1997;11:1115-1122.
44. Hanson DG, Conley D, Jitang J, et al. Role of esophageal pH recording in management of chronic laryngitis: an overview. Ann Otol Rinol Laryngol Suppl 2000;184:4-9.
45. El-Serag HB, Lee P, Buchner A, et al. Lansoprazole treatment of patients with chronic idiopathic laryngitis: a placebo-controlled trial. Am J Gastroenterol 2001;96:979-983.
46. Noordzij JP, Khidr A, Evans BA, et al. Evaluation of omeprazole in the treatment of reflux laryngitis: a prospective, placebo-controlled, randomized, double-blind study. Laryngoscope 2001;111:2147-2151.
47. Karkos PD, Wilson JA. Empiric treatment of laryngopharyngeal reflux with proton pump inhibitors: a systematic review. Laryngoscope 2006;116:144-148.
48. Hopkins C, Yousaf U, Pedersen M. Acid reflux treatment for hoarseness. Cochrane Database Syst Rev. 2006;25:CD005054.
49. Sen P, Georgalas C, Bhattacharyya AK. A systematic review of the role of proton pump inhibitors for symptoms of laryngopharyngeal reflux. Clin Otolaryngol 2006;31:20-24.
50. Lindstrom DR, Wallace J, Loehrl TA, et al. Nissen fundoplication surgery for extraesophageal manifestations of gastroesophageal reflux (EER). Laryngoscope 2002;112:1762-1765.
51. Bough IDJr, Sataloff RT, Castell DO, et al. Gastroesophageal reflux laryngitis resistant to omeprazole therapy. J Voice 1995;9:205-211.
52. Adachi K, Katsube T, Kawamura A, et al. CYP2C19 genotype status and intragastric pH during dosing with lansoprazole or rabeprazole. Alim Pharmacol Ther 2000;14:1259-1266.
53. Ishizaki T, Horai Y. Review article: cytochrome P450 and the metabolism of proton pump inhibitors--emphasis on rabeprazole. Alim Pharmacol Ther 1999;13 (Suppl 3):27-36.
54. Shirai N, Furuta T, Moriyama Y, et al. Effects of CYP2C19 genotypic differences in the metabolism of omeprazole and rabeprazole on intragastric pH. Alim Pharmacol Ther 2001;15:1929-1937.
55. Inatomi N, Matsukawa J, Sakurai Y, Otake K. Potassium-competitive acid blockers: Advanced therapeutic option for acid-related diseases. Pharmacol Ther 2016;168:12-22.
56. Fackler WK, Ours TM, Vaezi MF, Richter JE. Long term effect of H2RA therapy on nocturnal gastric acid breakthrough. Gastroenterology 2002;122:625-632.
57. Adachi K, Komazawa Y, Fujishiro H, et al. Nocturnal gastric acid breakthrough during the administration of rabeprazole and ranitidine in Helicobacter pylori-negative subjects: effects of different regimens. J Gastroenterol 2003;38:830-835.
58. Altman KW, Waltonen JD, Hammer ND, et al. Proton pump (H+/K+-ATPase) expression in human laryngeal seromucinous glands.Otolaryngol Head Neck Surg 2005;133:718-724.