Table of Contents Author Guidelines Submit a Manuscript
International Journal of Otolaryngology
Volume 2012, Article ID 646901, 13 pages
http://dx.doi.org/10.1155/2012/646901
Review Article

Reflux Revisited: Advancing the Role of Pepsin

1Rotherham General Hospital, Moorgate Road, Rotherham, South Yorkshire S60 2UD, UK
2Technostics Ltd., The Deep Business Centre, Kingston Upon Hull, East Yorkshire HU1 4BG, UK

Received 28 July 2011; Accepted 9 September 2011

Academic Editor: Petros D. Karkos

Copyright © 2012 Karna Dev Bardhan et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. J. A. Koufman, “The otolaryngologic manifestations of gastroesophageal reflux disease (GERD): a clinical investigation of 225 patients using ambulatory 24-hour pH monitoring and an experimental investigation of the role of acid and pepsin in the development of laryngeal injury,” Laryngoscope, vol. 101, no. 4, pp. 1–78, 1991. View at Google Scholar · View at Scopus
  2. N. Vakil, S. V. van Zanten, P. Kahrilas et al., “The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus,” American Journal of Gastroenterology, vol. 101, no. 8, pp. 1900–1920, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  3. N. Johnson and R. J. Toohill,, Effects, Diagnosis and Management of Extra-Esophageal Reflux, Nova Science Publishers, New York, NY, USA, 2010.
  4. P. W. Dettmar, D. O. Castell, and R. C. Heading, “Reflux and its consequences,” Alimentary Pharmacology & Therapeutics, vol. 33, supplement 1, pp. 1–71, 2011. View at Google Scholar
  5. V. Savarino, F. di Mario, and C. Scarpignato, “Proton pump inhibitors in GORD. An overview of their pharmacology, efficacy and safety,” Pharmacological Research, vol. 59, no. 3, pp. 135–153, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  6. C. Scarpignato and R. H. Hunt, “Proton pump inhibitors: the beginning of the end or the end of the beginning?” Current Opinion in Pharmacology, vol. 8, no. 6, pp. 677–684, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  7. W. J. Dodds, W. J. Hogan, J. F. Helm, and J. Dent, “Pathogenesis of reflux esophagitis,” Gastroenterology, vol. 81, no. 2, pp. 376–394, 1981. View at Google Scholar · View at Scopus
  8. A. Winkelstein, “Peptic esophagitis,” The Journal of the American Medical Association, vol. 104, pp. 906–909, 1935. View at Google Scholar
  9. E. L. Wolf, “The esophagus,” Mount Sinai Journal of Medicine, vol. 67, no. 1, pp. 25–31, 2000. View at Google Scholar · View at Scopus
  10. H. I. Goldberg, W. J. Dodds, S. Gee, C. Montgomery, and F. F. Zboralske, “Role of acid and pepsin in acute experimental esophagitis,” Gastroenterology, vol. 56, no. 2, pp. 223–230, 1969. View at Google Scholar · View at Scopus
  11. J. W. Harmon, L. F. Johnson, and C. L. Maydonovitch, “Effects of acid and bile salts on the rabbit esophageal mucosa,” Digestive Diseases and Sciences, vol. 26, no. 1, pp. 65–72, 1981. View at Google Scholar · View at Scopus
  12. E. J. Schweitzer, J. W. Harmon, B. L. Bass, and S. Batzri, “Bile acid efflux precedes mucosal barrier disruption in the rabbit esophagus,” The American Journal of Physiology, vol. 247, no. 5, pp. G480–G485, 1984. View at Google Scholar · View at Scopus
  13. L. F. Johnson and J. W. Harmon, “Experimental esophagitis in a rabbit model. Clinical relevance,” Journal of clinical gastroenterology, vol. 8, pp. 26–44, 1986. View at Google Scholar · View at Scopus
  14. D. C. Gotley, A. P. Morgan, and M. J. Cooper, “Bile acid concentrations in the refluxate of patients with reflux oesophagitis,” British Journal of Surgery, vol. 75, no. 6, pp. 587–590, 1988. View at Google Scholar · View at Scopus
  15. S. Y. Iffikhar, S. Ledingham, R. J. Steele et al., “Bile reflux in columnar-lined Barrett's oesophagus,” Annals of the Royal College of Surgeons of England, vol. 75, no. 6, pp. 411–416, 1993. View at Google Scholar · View at Scopus
  16. F. Johnsson, B. Joelsson, C. H. Floren, and A. Nilsson, “Bile salts in the esophagus of patients with esophagitis,” Scandinavian Journal of Gastroenterology, vol. 23, no. 6, pp. 712–716, 1988. View at Google Scholar · View at Scopus
  17. M. F. Vaezi and J. E. Richter, “Role of acid and duodenogastroesophageal reflux in gastroesophageal reflux disease,” Gastroenterology, vol. 111, no. 5, pp. 1192–1199, 1996. View at Publisher · View at Google Scholar · View at Scopus
  18. W. K. Kauer, J. H. Peters, T. R. DeMeester et al., “Composition and concentration of bile acid reflux into the esophagus of patients with gastroesophageal reflux disease,” Surgery, vol. 122, no. 5, pp. 874–881, 1997. View at Publisher · View at Google Scholar · View at Scopus
  19. D. Nehra, P. Howell, C. P. Williams, J. K. Pye, and J. Beynon, “Toxic bile acids in gastro-oesophageal reflux disease: influence of gastric acidity,” Gut, vol. 44, no. 5, pp. 598–602, 1999. View at Google Scholar · View at Scopus
  20. H. Zhu, C. A. Hart, D. Sales, and N. B. Roberts, “Bacterial killing in gastric juice—effect of pH and pepsin on Escherichia coli and Helicobacter pylori,” Journal of Medical Microbiology, vol. 55, no. 9, pp. 1265–1270, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  21. N. B. Roberts, “Human pepsin multiplicity and function: role in reflux disease,” Alimentary Pharmacology and Therapeutics, vol. 24, no. 2, pp. 2–9, 2006. View at Publisher · View at Google Scholar · View at PubMed
  22. V. Walker and W. H. Taylor, “Pepsin 5 in gastric juice: determination and relationship to the alkali-stable peptic activity,” Gut, vol. 20, no. 11, pp. 977–982, 1979. View at Google Scholar
  23. J. P. Pearson, R. Ward, and A. Allen, “Mucus degradation by pepsin: comparison of mucolytic activity of human pepsin 1 and pepsin 3: implications in peptic ulceration,” Gut, vol. 27, no. 3, pp. 243–248, 1986. View at Google Scholar
  24. A. Allen, D. A. Hutton, A. J. Leonard, J. P. Pearson, and L. A. Sellars, “Pepsins,” in Endogenous Mediators of Gastrointestinal Disease, L. W. John, Ed., pp. 53–69, CRC Press, New York, NY, USA, 1990. View at Google Scholar
  25. N. B. Roberts and W. H. Taylor, “Comparative pepstatin inhibition studies on individual human pepsins and pepsinogens 1,3 and 5(gastricsin) and pig pepsin A,” Journal of Enzyme Inhibition and Medicinal Chemistry, vol. 18, no. 3, pp. 209–217, 2003. View at Publisher · View at Google Scholar · View at PubMed
  26. D. J. Etherington and W. H. Taylor, “The pepsins of normal human gastric juice,” Biochemical Journal, vol. 113, no. 4, pp. 663–668, 1969. View at Google Scholar
  27. A. L. Tasker, Otitis media with effusion: key factors, Ph.D. thesis, University of Newcastle Upon Tyne, 2003.
  28. L. A. Campos and J. Sancho, “The active site of pepsin is formed in the intermediate conformation dominant at mildly acidic pH,” FEBS Letters, vol. 538, no. 1–3, pp. 89–95, 2003. View at Publisher · View at Google Scholar
  29. D. W. Piper and B. H. Fenton, “pH stability and activity curves of pepsin with special reference to their clinical importance,” Gut, vol. 6, no. 5, pp. 506–508, 1965. View at Google Scholar
  30. N. Johnston, P. W. Dettmar, B. Bishwokarma, M. O. Lively, and J. A. Koufman, “Activity/stability of human pepsin: implications for reflux attributed laryngeal disease,” Laryngoscope, vol. 117, no. 6, pp. 1036–1039, 2007. View at Publisher · View at Google Scholar · View at PubMed
  31. R. W. Ten Kate, H. A. Tuynman, H. P. Festen, G. Pals, and S. G. Meuwissen, “Effect of high dose omeprazole on gastric pepsin secretion and serum pepsinogen levels in man,” European Journal of Clinical Pharmacology, vol. 35, no. 2, pp. 173–176, 1988. View at Google Scholar
  32. A. Babaei, V. Bhargava, S. Aalam, M. Scadeng, and R. Mittal, “Effect of proton pump inhibition on the gastric volume: assessed by magnetic resonance imaging,” Alimentary Pharmacology and Therapeutics, vol. 29, no. 8, pp. 863–870, 2009. View at Publisher · View at Google Scholar · View at PubMed
  33. C. Scarpignato and I. Pelosini, “Review article: the opportunities and benefits of extended acid suppression,” Alimentary Pharmacology and Therapeutics, vol. 23, no. 2, pp. 23–34, 2006. View at Publisher · View at Google Scholar · View at PubMed
  34. J. Labenz, B. Tillenburg, U. Peitz et al., “Helicobacter pylori augments the pH-increasing effect of omeprazole in patients with duodenal ulcer,” Gastroenterology, vol. 110, no. 3, pp. 725–732, 1996. View at Publisher · View at Google Scholar
  35. A. P. Tamhankar, J. H. Peters, G. Portale et al., “Omeprazole does not reduce gastroesophageal reflux: new insights using multichannel intraluminal impedance technology,” Journal of Gastrointestinal Surgery, vol. 8, no. 7, pp. 888–896, 2004. View at Publisher · View at Google Scholar · View at PubMed
  36. N. Johnston, J. Knight, P. W. Dettmar, M. O. Lively, and J. Koufman, “Pepsin and carbonic anhydrase isoenzyme III as diagnostic markers for laryngopharyngeal reflux disease,” Laryngoscope, vol. 114, no. 12, pp. 2129–2134, 2004. View at Publisher · View at Google Scholar · View at PubMed
  37. N. Johnston, C. W. Wells, J. H. Blumin, R. J. Toohill, and A. L. Merati, “Receptor-mediated uptake of pepsin by laryngeal epithelial cells,” Annals of Otology, Rhinology and Laryngology, vol. 116, no. 12, pp. 934–938, 2007. View at Google Scholar
  38. R. A. Franco Jr., D. G. Deschler, and P. Eamranond, “Laryngopharyngeal reflux,” UpToDate (http://www.uptodate.com/), vol. Version 17.3, 2009.
  39. N. Johnston, C. W. Wells, T. L. Samuels, and J. H. Blumin, “Pepsin in nonacidic refluxate can damage hypopharyngeal epithelial cells,” Annals of Otology, Rhinology and Laryngology, vol. 118, no. 9, pp. 677–685, 2009. View at Google Scholar
  40. N. Johnston, P. W. Dettmar, M. O. Lively et al., “Effect of pepsin on laryngeal stress protein (Sep70, Sep53, and Hsp70) response: role in laryngopharyngeal reflux disease,” Annals of Otology, Rhinology and Laryngology, vol. 115, no. 1, pp. 47–58, 2006. View at Google Scholar
  41. G. A. Gill, N. Johnston, A. Buda et al., “Laryngeal epithelial defenses against laryngopharyngeal reflux: investigations of E-cadherin, carbonic anhydrase isoenzyme III, and pepsin,” Annals of Otology, Rhinology and Laryngology, vol. 114, no. 12 I, pp. 913–921, 2005. View at Google Scholar
  42. T. L. Samuels, E. Handler, M. L. Syring et al., “Mucin gene expression in human laryngeal epithelia: effect of laryngopharyngeal reflux,” Annals of Otology, Rhinology and Laryngology, vol. 117, no. 9, pp. 688–695, 2008. View at Google Scholar
  43. W. J. Barlow and R. C. Orlando, “The pathogenesis of heartburn in nonerosive reflux disease: a unifying hypothesis,” Gastroenterology, vol. 128, no. 3, pp. 771–778, 2005. View at Publisher · View at Google Scholar
  44. N. A. Tobey, S. S. Hosseini, C. M. Argote, A. M. Dobrucali, M. S. Awayda, and R. C. Orlando, “Dilated intercellular spaces and shunt permeability in nonerosive acid-damaged esophageal epithelium,” American Journal of Gastroenterology, vol. 99, no. 1, pp. 13–22, 2004. View at Publisher · View at Google Scholar
  45. R. Farré, F. Fornari, K. Blondeau et al., “Acid and weakly acidic solutions impair mucosal integrity of distal exposed and proximal non-exposed human oesophagus,” Gut, vol. 59, no. 2, pp. 164–169, 2010. View at Publisher · View at Google Scholar · View at PubMed
  46. S. E. Axford, N. Sharp, P. Dettmar et al., “Cell biology of laryngeal epithelial defenses in health and disease: preliminary studies,” Annals of Otology, Rhinology and Laryngology, vol. 110, no. 12, pp. 1099–1108, 2001. View at Google Scholar
  47. L. F. Johnson and T. R. Demeester, “Twenty four hour pH monitoring of the distal esophagus. A quantitative measure of gastroesophageal reflux,” American Journal of Gastroenterology, vol. 62, no. 4, pp. 325–332, 1974. View at Google Scholar
  48. B. K. Oelschlager, E. Quiroga, J. A. Isch, and F. Cuenca-Abente, “Gastroesophageal and pharyngeal reflux detection using impedance and 24-hour pH monitoring in asymptomatic subjects: defining the normal environment,” Journal of Gastrointestinal Surgery, vol. 10, no. 1, pp. 54–62, 2006. View at Publisher · View at Google Scholar · View at PubMed
  49. G. J. Wiener, R. Tsukashima, C. Kelly et al., “Oropharyngeal pH monitoring for the detection of liquid and aerosolized supraesophageal gastric reflux,” Journal of Voice, vol. 23, no. 4, pp. 498–504, 2009. View at Publisher · View at Google Scholar · View at PubMed
  50. S. Ayazi, J. C. Lipham, J. A. Hagen et al., “A new technique for measurement of pharyngeal pH: normal values and discriminating pH threshold,” Journal of Gastrointestinal Surgery, vol. 13, no. 8, pp. 1422–1429, 2009. View at Publisher · View at Google Scholar · View at PubMed
  51. V. Strugala, P. W. Dettmar, and A. H. Morice, “Detection of pepsin in sputum and exhaled breath condensate: could it be a useful marker for reflux-related respiratory disease?” Gastroenterology, vol. 136, p. S1895, 2009. View at Google Scholar
  52. M. F. Vaezi, “Therapy Insight: gastroesophageal reflux disease and laryngopharyngeal reflux,” Nature Clinical Practice Gastroenterology and Hepatology, vol. 2, no. 12, pp. 595–603, 2005. View at Publisher · View at Google Scholar · View at PubMed
  53. S. Shay, R. Tutuian, D. Sifrim et al., “Twenty-four hour ambulatory simultaneous impedance and pH monitoring: a multicenter report of normal values from 60 healthy volunteers,” American Journal of Gastroenterology, vol. 99, no. 6, pp. 1037–1043, 2004. View at Publisher · View at Google Scholar · View at PubMed
  54. Y. L. Xiao, J. K. Lin, T. K. Cheung et al., “Normal values of 24-hour combined esophageal multichannel intraluminal impedance and pH monitoring in the Chinese population,” Digestion, vol. 79, no. 2, pp. 109–114, 2009. View at Publisher · View at Google Scholar · View at PubMed
  55. P. Zentilin, E. Iiritano, P. Dulbecco et al., “Normal values of 24-h ambulatory intraluminal impedance combined with pH-metry in subjects eating a Mediterranean diet,” Digestive and Liver Disease, vol. 38, no. 4, pp. 226–232, 2006. View at Publisher · View at Google Scholar · View at PubMed
  56. F. Zerbib, S. B. des Varannes, S. Roman et al., “Normal values and day-to-day variability of 24-h ambulatory oesophageal impedance-pH monitoring in a Belgian-French cohort of healthy subjects,” Alimentary Pharmacology and Therapeutics, vol. 22, no. 10, pp. 1011–1021, 2005. View at Publisher · View at Google Scholar · View at PubMed
  57. G. E. Boeckxstaens and A. Smout, “Systematic review: role of acid, weakly acidic and weakly alkaline reflux in gastro-oesophageal reflux disease,” Alimentary Pharmacology and Therapeutics, vol. 32, no. 3, pp. 334–343, 2010. View at Publisher · View at Google Scholar · View at PubMed
  58. V. Strugala, J. A. McGlashan, M. G. Watson et al., “Evaluation of a non-invasive pepsin dipstick test for the diagnosis of extra-oesophageal reflux—results of a pilot study,” Gastroenterology, vol. 132, pp. A99–A100, 2007. View at Google Scholar
  59. A. J. Bredenoord, R. Tutuian, A. J. Smout, and D. O. Castell, “Technology review: esophageal impedance monitoring,” American Journal of Gastroenterology, vol. 102, no. 1, pp. 187–194, 2007. View at Publisher · View at Google Scholar · View at PubMed
  60. F. D'Ovidio, M. Mura, M. Tsang et al., “Bile acid aspiration and the development of bronchiolitis obliterans after lung transplantation,” Journal of Thoracic and Cardiovascular Surgery, vol. 129, no. 5, pp. 1144–1152, 2005. View at Publisher · View at Google Scholar · View at PubMed
  61. C. Ward, I. A. Forrest, I. A. Brownlee et al., “Pepsin like activity in bronchoalveolar lavage fluid is suggestive of gastric aspiration in lung allografts,” Thorax, vol. 60, no. 10, pp. 872–874, 2005. View at Publisher · View at Google Scholar · View at PubMed
  62. A. Tasker, P. W. Dettmar, M. Panetti, J. A. Koufman, J. P. Birchall, and J. P. Pearson, “Reflux of gastric juice and glue ear in children,” Lancet, vol. 359, no. 9305, p. 493, 2002. View at Publisher · View at Google Scholar · View at PubMed
  63. J. J. Klokkenburg, H. L. Hoeve, J. Francke, M. H. Wieringa, J. Borgstein, and L. Feenstra, “Bile acids identified in middle ear effusions of children with otitis media with effusion,” Laryngoscope, vol. 119, no. 2, pp. 396–400, 2009. View at Publisher · View at Google Scholar · View at PubMed
  64. L. Gatta, D. Vaira, G. Sorrenti, S. Zucchini, C. Sama, and N. Vakil, “Meta-analysis: the efficacy of proton pump inhibitors for laryngeal symptoms attributed to gastro-oesophageal reflux disease,” Alimentary Pharmacology and Therapeutics, vol. 25, no. 4, pp. 385–392, 2007. View at Publisher · View at Google Scholar · View at PubMed
  65. O. Reichel, H. Dressel, K. Wiederänders, and W. J. Issing, “Double-blind, placebo-controlled trial with esomeprazole for symptoms and signs associated with laryngopharyngeal reflux,” Otolaryngology: Head and Neck Surgery, vol. 139, no. 3, pp. 414–420, 2008. View at Publisher · View at Google Scholar · View at PubMed
  66. B. D. Havemann, C. A. Henderson, and H. B. El-Serag, “The association between gastro-oesophageal reflux disease and asthma: a systematic review,” Gut, vol. 56, no. 12, pp. 1654–1664, 2007. View at Publisher · View at Google Scholar · View at PubMed
  67. J. G. Mastronarde, N. R. Anthonisen, M. Castro et al., “Efficacy of esomeprazole for treatment of poorly controlled asthma,” New England Journal of Medicine, vol. 360, no. 15, pp. 1487–1499, 2009. View at Publisher · View at Google Scholar · View at PubMed
  68. A. B. Chang, T. J. Lasserson, T. O. Kiljander, F. L. Connor, J. T. Gaffney, and L. A. Garske, “Systematic review and meta-analysis of randomised controlled trials of gastro-oesophageal reflux interventions for chronic cough associated with gastro-oesophageal reflux,” British Medical Journal, vol. 332, no. 7532, pp. 11–17, 2006. View at Google Scholar
  69. T. M. Ours, M. S. Kavuru, R. J. Schilz, and J. E. Richter, “A prospective evaluation of esophageal testing and a double-blind, randomized study of omeprazole in a diagnostic and therapeutic algorithm for chronic cough,” American Journal of Gastroenterology, vol. 94, no. 11, pp. 3131–3138, 1999. View at Publisher · View at Google Scholar
  70. J. H. Baron, R. J. Gribble, D. J. Holdstock, and J. J. Misiewicz, “Double-blind controlled trial of amylopectin sulphate (Depepsen) in the symptomatic treatment of duodenal ulcer,” Gut, vol. 18, no. 9, pp. 723–724, 1977. View at Google Scholar
  71. J. B. Cocking, “A trial of amylopectin sulfate (SN-263) and propantheline bromide in the long term treatment of chronic duodenal ulcer,” Gastroenterology, vol. 62, no. 1, pp. 6–10, 1972. View at Google Scholar
  72. K. D. Landecker, E. M. McCallum, D. I. Fevre et al., “Effect of sodium amylosulfate (Depepsen) on the healing of duodenal ulcer,” Gastroenterology, vol. 71, no. 5, pp. 723–725, 1976. View at Google Scholar
  73. O. Bonnevie, L. B. Svendsen, J. Holst-Christensen et al., “Double-blind randomised clinical trial of a pepsin-inhibitory pentapeptide (pepstatin) in the treatment of duodenal ulcer,” Gut, vol. 20, no. 7, pp. 624–628, 1979. View at Google Scholar
  74. V. Strugala, J. Avis, I. G. Jolliffe, L. M. Johnstone, and P. W. Dettmar, “The role of an alginate suspension on pepsin and bile acids—key aggressors in the gastric refluxate. Does this have implications for the treatment of GORD?” Journal of Pharmacy and Pharmacology, vol. 61, no. 8, pp. 1021–1028, 2009. View at Publisher · View at Google Scholar · View at PubMed
  75. J. A. McGlashan, L. M. Johnstone, V. Strugala, and P. W. Dettmar, “The value of a liquid alginate suspension (Gaviscon Advance) in the management of laryngopharyngeal reflux,” European Archives of Oto-Rhino-Laryngology, vol. 266, no. 2, pp. 243–251, 2009. View at Publisher · View at Google Scholar · View at PubMed
  76. V. Strugala and P. W. Dettmar, “Alginate in the treatment of extra-oesophageal reflux,” in Effects, Diagnosis and Management of Extra-Esophageal Reflux, N. Johnson and R. J. Toohill, Eds., pp. 145–168, Nova Science Publishers, New York, NY, USA, 2010. View at Google Scholar