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Dilated intercellular spaces as a marker of GERD

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Abstract

Gastroesophageal reflux disease (GERD) is typically heralded by the substernal burning pain of heartburn. On endoscopic examination, about one third of GERD subjects with heartburn have erosive disease, and the remainder have nonerosive reflux disease (NERD). Unlike patients with erosive disease, those with NERD (∼ 50%) often do not respond to therapy with proton pump inhibitors (PPIs), raising the question of whether they have NERD and, if they do, whether the cause of their symptoms is similar to those who respond to PPIs. Recently, biopsies established that subjects with heartburn and PPI-responsive NERD, like those with erosive esophagitis, have lesions within the esophageal epithelium known as dilated intercellular space (DIS). In this article, we discuss the physicochemical basis for DIS in acid-injured esophageal epithelium and its significance in GERD. Although DIS is not pathognomic of GERD, it is a marker of a break in the epithelial (junctional) barrier reflecting an increase in paracellular permeability.

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References and Recommended Reading

  1. Orlando RC: Reflux esophagitis. In Textbook of Gastroenterology. Edited by Yamada T, Alpers D, Owyang C, et al.: Philadelphia: Lippincott Williams & Wilkins; 1995:1214–1242.

    Google Scholar 

  2. Orlando RC: Gastroesophageal reflux disease: Offensive factors and tissue resistance. In Gastroesophageal Reflux Disease. Edited by Orlando RC. New York: Marcel Dekker; 2000:165–192.

    Google Scholar 

  3. Bernstein LM, Baker LA: A clinical test for esophagitis. Gastroenterology 1958, 34:760–781.

    PubMed  CAS  Google Scholar 

  4. Dean BB, Gano AD Jr, Knight K, et al.: Effectiveness of proton pump inhibitors in nonerosive reflux disease. Clin Gastroenterol Hepatol 2004, 2:656–664.

    Article  PubMed  CAS  Google Scholar 

  5. Pehlivanov N, Liu J, Mittal RK: Sustained esophageal contraction: a motor correlate of heartburn symptom. Am J Physiol Gastrointest Liver Physiol 2001, 281:G743–G751.

    PubMed  CAS  Google Scholar 

  6. Fass R, Gasiorowska A: Refractory GERD: what is it? Curr Gastroenterol Rep 2008, 10:252–257.

    Article  PubMed  Google Scholar 

  7. Tobey NA, Carson JL, Alkiek RA, Orlando RC: Dilated intercellular spaces: a morphological feature of acid reflux-damaged human esophageal epithelium. Gastroenterology 1996, 111:1200–1205.

    Article  PubMed  CAS  Google Scholar 

  8. Solcia E, Villani L, Luinetti O, et al.: Altered intercellular glycoconjugates and dilated intercellular spaces of esophageal epithelium in reflux disease. Virchows Arch 2000, 436:207–216.

    Article  PubMed  CAS  Google Scholar 

  9. Niessen CM: Tight junctions/adherens junctions: basic structure and function. J Invest Dermatol 2007, 127:2525–2532.

    Article  PubMed  CAS  Google Scholar 

  10. Garrod D, Chidgey M: Desmosome structure, composition and function. Biochim Biophys Acta 2008, 1778:572–587.

    Article  PubMed  CAS  Google Scholar 

  11. Tobey NA, Hosseini SS, Argote CM, et al.: Dilated intercellular spaces and shunt permeability in nonerosive acid-damaged esophageal epithelium. Am J Gastroenterol 2004, 99:13–22.

    Article  PubMed  CAS  Google Scholar 

  12. Pope CI: Gastroesophageal reflux disease (reflux esophagitis). In Gastrointestinal Disease: Pathophysiology, Diagnosis, Management, edn 2. Sleisenger M, Fordtran J, eds. Philadelphia: WB Saunders; 1978:541–568.

    Google Scholar 

  13. Hopwood D, Milne G, Logan KR: Electron microscopic changes in human oesophageal epithelium in oesophagitis. J Pathol 1979, 129:161–167.

    Article  PubMed  CAS  Google Scholar 

  14. Caviglia R, Ribolsi M, Maggiano N, et al.: Dilated intercellular spaces of esophageal epithelium in nonerosive reflux disease patients with physiological esophageal acid exposure. Am J Gastroenterol 2005, 100:543–548.

    Article  PubMed  Google Scholar 

  15. Calabrese C, Bortolotti M, Fabbri A, et al.: Reversibility of GERD ultrastructural alterations and relief of symptoms after omeprazole treatment. Am J Gastroenterol 2005, 100:537–542.

    Article  PubMed  CAS  Google Scholar 

  16. Bove M, Vieth M, Dombrowski F, et al.: Acid challenge to the human esophageal mucosa: effects on epithelial architecture in health and disease. Dig Dis Sci 2005, 50:1488–1496.

    Article  PubMed  Google Scholar 

  17. Kahrilas PJ: Dilated intercellular spaces: extending the reach of the endoscope. Am J Gastroenterol 2005, 100:549–550.

    Article  PubMed  Google Scholar 

  18. Carney CN, Orlando RC, Powell DW, Dotson MM: Morphologic alterations in early acid-induced epithelial injury of the rabbit esophagus. Lab Invest 1981, 45:198–208.

    PubMed  CAS  Google Scholar 

  19. Orlando RC, Powell DW, Carney CN: Pathophysiology of acute acid injury in rabbit esophageal epithelium. J Clin Invest 1981, 68:286–293.

    Article  PubMed  CAS  Google Scholar 

  20. Tobey NA, Gambling TM, Vanegas XC, et al.: Physicochemical basis for dilated intercellular spaces in non-erosive acid-damaged rabbit esophageal epithelium. Dis Esophagus 2008, 21:757–764.

    Article  PubMed  CAS  Google Scholar 

  21. Robles-Chillida EM, Rodrigo J, Mayo I, et al.: Ultrastructure of free-ending nerve fibres in oesophageal epithelium. J Anat 1981, 133:227–233.

    PubMed  CAS  Google Scholar 

  22. Rodrigo J, Hernandez CJ, Vidal MA, Pedrosa JA: Vegetative innervation of the esophagus. III. Intraepithelial endings. Acta Anat (Basel) 1975, 92:242–258.

    Article  CAS  Google Scholar 

  23. Tobey NA, Orlando RC: Mechanisms of acid injury to rabbit esophageal epithelium. Role of basolateral cell membrane acidification. Gastroenterology 1991, 101:1220–1228.

    PubMed  CAS  Google Scholar 

  24. Tobey NA, Reddy SP, Keku TO, et al.: Mechanisms of HCl-induced lowering of intracellular pH in rabbit esophageal epithelial cells. Gastroenterology 1993, 105:1035–1044.

    PubMed  CAS  Google Scholar 

  25. Sifrim D: Acid, weakly acidic and non-acid gastro-oesophageal reflux: differences, prevalence and clinical relevance. Eur J Gastroenterol Hepatol 2004, 16:823–830.

    Article  PubMed  Google Scholar 

  26. Bor S, Caymaz-Bor C, Tobey NA, et al.: Effect of ethanol on the structure and function of rabbit esophageal epithelium. Am J Physiol 1998, 274:G819–G826.

    PubMed  CAS  Google Scholar 

  27. Long JD, Marten E, Tobey NA, Orlando RC: Effects of luminal hypertonicity on rabbit esophageal epithelium. Am J Physiol 1997, 273:G647–G654.

    PubMed  CAS  Google Scholar 

  28. Farre R, van Malenstein H, De Vos R, et al.: Short exposure of oesophageal mucosa to bile acids, both in acidic and weakly acidic conditions, can impair mucosal integrity and provoke dilated intercellular spaces. Gut 2008, 57:1366–1374.

    Article  PubMed  CAS  Google Scholar 

  29. Farre R, De Vos R, Geboes K, et al.: Critical role of stress in increased oesophageal mucosa permeability and dilated intercellular spaces. Gut 2007, 56:1191–1197.

    Article  PubMed  CAS  Google Scholar 

  30. Bielefeldt K, Davis BM: Differential effects of ASIC3 and TRPV1 deletion on gastroesophageal sensation in mice. Am J Physiol Gastrointest Liver Physiol 2008, 294:G130–G138.

    Article  PubMed  CAS  Google Scholar 

  31. Matthews PJ, Aziz Q, Facer P, et al.: Increased capsaicin receptor TRPV1 nerve fibres in the inflamed human oesophagus. Eur J Gastroenterol Hepatol 2004, 16:897–902.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Lori A. Orlando.

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Orlando, L.A., Orlando, R.C. Dilated intercellular spaces as a marker of GERD. Curr Gastroenterol Rep 11, 190–194 (2009). https://doi.org/10.1007/s11894-009-0030-6

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