Hostname: page-component-6766d58669-tq7bh Total loading time: 0 Render date: 2026-05-18T09:26:04.575Z Has data issue: false hasContentIssue false
  • English
  • Français

Biomarkers and laryngopharyngeal reflux

Published online by Cambridge University Press:  14 September 2011

J M Wood ,
D J Hussey ,
C M Woods ,
D I Watson  and
A S Carney
J M Wood*
Affiliation:
ENT Unit, Department of Surgery, Flinders University and Flinders Medical Centre, Bedford Park, South Australia, Australia
D J Hussey
Affiliation:
ENT Unit, Department of Surgery, Flinders University and Flinders Medical Centre, Bedford Park, South Australia, Australia
C M Woods
Affiliation:
ENT Unit, Department of Surgery, Flinders University and Flinders Medical Centre, Bedford Park, South Australia, Australia
D I Watson
Affiliation:
ENT Unit, Department of Surgery, Flinders University and Flinders Medical Centre, Bedford Park, South Australia, Australia
A S Carney
Affiliation:
ENT Unit, Department of Surgery, Flinders University and Flinders Medical Centre, Bedford Park, South Australia, Australia
*
Address for correspondence: Prof A.S. Carney, Flinders ENT, Department of Surgery, Room 3D204, Flinders Medical Centre, Bedford Park, South Australia 5042, Australia Fax: +61 8 8204 3987 E-mail: scarney@ent-surgery.com
Get access Rights & Permissions [Opens in a new window]

Abstract

Laryngopharyngeal reflux is a controversial but increasingly made diagnosis used in patients with a collection of often non-specific laryngeal symptoms. It is a clinical diagnosis, and its pathophysiology is currently poorly understood.

Previous reflux research has focused on injurious agents, acid, pepsin and biomarker expression. Failure of intrinsic defences in the larynx may cause changes in laryngeal epithelia, particularly alterations in carbonic anhydrases and E-cadherin. Carbonic anhydrase III levels vary in the larynx in response to laryngopharyngeal reflux, depending on location. Expression of E-cadherin, a known tumour suppressor, is reduced in the presence of reflux. Mucin expression also varies according to the severity of reflux.

Further research is required to define the clinical entity of laryngopharyngeal reflux, and to identify a definitive mechanism for mucosal injury. Understanding this mechanism should allow the development of a comprehensive model, which would enable future diagnostic and therapeutic interventions to be developed.

Keywords

LarynxMucinsPepsin AGastroesophageal RefluxCarbonic AnhydrasesCadherins

Information

Type
Review Articles
Information
The Journal of Laryngology & Otology , Volume 125 , Issue 12 , December 2011 , pp. 1218 - 1224
Copyright
Copyright © JLO (1984) Limited 2011

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Article purchase

Temporarily unavailable

References

1Dent, J, El-Serag, HB, Wallander, M-A, Johansson, S. Epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut 2005;54:710–17CrossRefGoogle ScholarPubMed
2Heading, RC. Prevalence of upper gastrointestinal symptoms in the general population: a systematic review. Scand J Gastroenterol Suppl 1999;231:3–8Google ScholarPubMed
3Koufman, JA. 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 1991;101(suppl 53):1–78CrossRefGoogle Scholar
4Koufman, JA, Aviv, JE, Casiano, RR, Shaw, GY. Laryngopharyngeal reflux: position statement of the Committee on Speech, Voice and Swallowing Disorders of the American Academy of Otolaryngology – Head and Neck Surgery. Otolaryngol Head Neck Surg 2002;127:32–5CrossRefGoogle Scholar
5Kendall, KA. Controversies in the diagnosis and management of laryngopharyngeal reflux disease. Curr Opin Otolaryngol Head Neck Surg 2006;14:113–15CrossRefGoogle ScholarPubMed
6Joniau, S, Bradshaw, A, Esterman, A, Carney, AS. Reflux and laryngitis: a systematic review. Otolaryngol Head Neck Surg 2007;136:686–92CrossRefGoogle ScholarPubMed
7Vaezi, MF. We should learn from important negative results. Laryngoscope 2006;116:1718CrossRefGoogle Scholar
8Karkos, PD, Wilson, JA. Empiric treatment of laryngopharyngeal reflux with proton pump inhibitors: a systematic review. Laryngoscope 2006;11:144–8CrossRefGoogle Scholar
9Ratnasingam, D, Irvine, T, Thompson, SK, Watson, DI. Laparoscopic antireflux surgery in patients with throat symptoms: A word of caution. World J Surg 2011;35(2):342–8CrossRefGoogle Scholar
10Feldman, M, Friedman, LS, Sleisenger, MH, ed. Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 7th edn.Philadelphia: Saunders, 2002Google Scholar
11Ylitalo, R, Baugh, A, Li, W, Thibeault, S. Effect of acid and pepsin on gene expression in laryngeal fibroblasts. Ann Otol Rhinol Laryngol 2004;113:866–71CrossRefGoogle ScholarPubMed
12Johnston, N, Knight, J, Dettmar, PW, Lively, MO, Koufman, J. Pepsin and carbonic anhydrase isoenzyme III as diagnostic markers for laryngopharyngeal reflux disease. Laryngoscope 2004;114:2129–34CrossRefGoogle ScholarPubMed
13Samuels, TL, Johnston, N. Pepsin as a causal agent of inflammation during nonacidic reflux. Otolaryngol Head Neck Surg 2009;141:559–63CrossRefGoogle Scholar
14Piper, DW, Fenton, BH. pH stability and activity curves of pepsin with special reference to their clinical importance. Gut 1965;6:506–8CrossRefGoogle ScholarPubMed
15Johnston, N, Dettmar, PW, Bishwokarma, B, Lively, MO, Koufman, JA. Activity/stability of human pepsin: implications for reflux attributed laryngeal disease. Laryngoscope 2007;117:1036–9CrossRefGoogle ScholarPubMed
16Johnston, N, Wells, CW, Blumin, JH, Toohill, RJ, Merati, AL. Receptor-mediated uptake of pepsin by laryngeal epithelial cells. Ann Otol Rhinol Laryngol 2007;116:934–8CrossRefGoogle ScholarPubMed
17Bollschweiler, E, Wolfgarten, E, Pütz, B, Gutschow, C, Holscher, AH. Bile reflux into the stomach and esophagus for volunteers older than 40 years. Digestion 2005;71:63–4CrossRefGoogle Scholar
18Tack, J, Koek, G, Demedts, I, Sifrim, D, Janssens, J. Gastroesophageal reflux disease poorly responsive to single-dose proton pump inhibitors in patients without Barrett's esophagus: acid reflux, bile reflux or both? Am J Gastroenterol 2004;99:989–90CrossRefGoogle ScholarPubMed
19Saskai, CT, Marotta, J, Hundal, J, Chow, J, Eisen, RN. Bile-induced laryngitis: is there a basis of evidence. Ann Otol Rhinol Laryngol 2005;114:192–7CrossRefGoogle Scholar
20Lillemoe, KD, Johnson, LF, Harmon, JW. Role of the components of the gastroduodenal contents in experimental acid esophagitis. Surgery 1982;92:276–84Google ScholarPubMed
21Van Roon, AH, Mayne, GC, Wijnhoven, BP, Watson, DI, Leong, MP, Neijman, GE et al. Impact of gastro-esophageal reflux on mucin mRNA expression in the esophageal mucosa. J Gastrointest Surg 2008;12:1331–40CrossRefGoogle ScholarPubMed
22Hirano, T. Interleukin 6 in autoimmune and inflammatory diseases: a personal memoir. Proc Jpn Acad Ser B Phys Biol Sci 2010;86:717–30CrossRefGoogle Scholar
23Thibeault, SL, Smith, ME, Peterson, K, Ylitalo-Moller, R. Gene expression changes of inflammatory mediators in posterior laryngitis due to laryngopharyngeal reflux and evolution with PPI treatment: A preliminary study. Laryngoscope 2007;117:2050–6CrossRefGoogle ScholarPubMed
24Oh, DS, DeMeester, SR, Vallbohmer, D, Mori, R, Kuramochi, H, Hagen, JA et al. Reduction of interleukin 8 gene expression in reflux esophagitis and Barretts’ esophagus with antireflux surgery. Arch Surg 2007;142:554–60CrossRefGoogle ScholarPubMed
25Waugh, DJJ, Wilson, C. The interleukin-8 pathway in cancer. Clin Cancer Res 2008;14:6735–41CrossRefGoogle ScholarPubMed
26Tobey, NA, Powell, DW, Schreiner, VJ, Orlando, RC. Serosal bicarbonate protects against acid injury to rabbit esophagus. Gastroenterology 1989;96:1466–77CrossRefGoogle ScholarPubMed
27Axford, SE, Sharp, N, Ross, PE, Pearson, JP, Dettmar, PW, Panetti, M et al. Cell biology of laryngeal epithelial defenses in health and disease: preliminary studies. Ann Otol Rhinol Laryngol 2001;110:1099–108CrossRefGoogle ScholarPubMed
28Johnston, N, Bulmer, D, Gill, GA, Panetti, M, Ross, PE, Pearson, JP et al. Cell biology of laryngeal epithelial defenses in health and disease: further studies. Ann Otol Rhinol Laryngol 2003;112:481–91CrossRefGoogle ScholarPubMed
29Gill, GA, Johnston, N, Buda, A, Pignatelli, M, Pearson, J, Dettmar, PW et al. Laryngeal epithelial defenses against laryngopharyngeal reflux: investigations of E-cadherin, carbonic anhydrase isoenzyme III, and pepsin. Ann Otol Rhinol Laryngol 2005;114:913–21CrossRefGoogle ScholarPubMed
30Christie, KN, Thomson, C, Xue, L, Lucocq, JM, Hopwood, D. Carbonic anhydrase isoenzymes I, II, III, and IV are present in human esophageal epithelium. J Histochem Cytochem 1997;45:35–40CrossRefGoogle ScholarPubMed
31Reichel, O, Mayr, D, Durst, F, Berghaus, A. E-cadherin but not β-catenin expression is decreased in laryngeal biopsies from patients with laryngopharyngeal reflux. Eur Arch Otorhinolaryngol 2008;265:937–42CrossRefGoogle Scholar
32Kurtz, KA, Hoffman, HT, Zimmermann, MB, Robinson, RA. Decreased E-cadherin but not B-catenin expression is associated with vascular invasion and decreased survival in head and neck squamous carcinomas. Otolaryngol Head Neck Surg 2006;134:142–6CrossRefGoogle ScholarPubMed
33Samuels, TL, Handler, E, Syring, ML, Pajewski, NM, Blumin, JH, Kerschner, JE et al. Mucin gene expression in human laryngeal epithelia: effect of laryngopharyngeal reflux. Ann Otol Rhinol Laryngol 2008;117:688–95CrossRefGoogle ScholarPubMed
34Namiot, Z, Sarosiek, J, Marcinkiewicz, M, Edmunds, MC, McCallum, RW. Declined human esophageal mucin secretion in patients with severe reflux esophagitis. Dig Dis Sci 1994;39:2523–9CrossRefGoogle ScholarPubMed
35Ho, SB, Dvorak, LA, Moor, RE, Jacobson, AC, Frey, MR, Corredor, J et al. Cysteine-rich domains of muc3 intestinal mucin promote cell migration, inhibit apoptosis, and accelerate wound healing. Gastroenterology 2006;131:1501–17CrossRefGoogle ScholarPubMed
36Louis, NA, Hamilton, KE, Canny, G, Shekels, LL, Ho, SB, Colgan, SP. Selective induction of mucin-3 by hypoxia in intestinal epithelia. J Cell Biochem 2006;99:1616–27CrossRefGoogle ScholarPubMed
37Bafna, S, Kaur, S, Batra, SK. Membrane-bound mucins: the mechanistic basis for alteration in the growth and survival of cancer cells. Oncogene 2010;29:2893–904CrossRefGoogle ScholarPubMed
38Gendler, SJ. MUC1, the renaissance molecule. J Mammary Gland Biol Neoplasia 2001;6:330–53CrossRefGoogle ScholarPubMed
39Zhao, Q, Guo, X, Nash, GB, Stone, PC, Hilkens, J, Rhodes, JM et al. Circulating galectin-3 promotes metastasis by modifying MUC1 localization on cancer cell surface. Cancer Res 2009;69:6799–806CrossRefGoogle ScholarPubMed
40Jeannon, J-P, Stafford, FW, Soames, JV, Wilson, J. Altered MUC1 and MUC2 glycoprotein expression in laryngeal cancer. Otolaryngol Head Neck Surg 2001;124:199–202CrossRefGoogle ScholarPubMed
41Paleri, V, Pearson, JP, Bulmer, D, Jeannon, J-P, Wight, R, Wilson, J. Expression of mucin gene products in laryngeal squamous cancer. Otolaryngol Head Neck Surg 2004;131:84–8CrossRefGoogle ScholarPubMed
42Mahieu, HF. Review article: the laryngological manifestations of reflux disease; why the scepticism? Aliment Pharmacol Ther 2007;26(suppl 2):17–24CrossRefGoogle ScholarPubMed
43Sato, K, Umeno, H, Chitose, S, Nakashima, T. Tetra-probe, 24-hour pH monitoring for laryngopharyngeal reflux: a technique for simultaneous study of hypopharynx, oesophagus and stomach. J Laryngol Otol 2009;123(suppl S31):117–22CrossRefGoogle Scholar
44Galli, J, Calò, L, Agostino, S, Cadoni, G, Sergi, B, Cianci, R et al. Bile reflux as possible risk factor in larynopharyngeal inflammatory and neoplastic lesion. Acta Otorhinolaryngol Ital 2003;23:377–82Google Scholar
45Samuels, TL, Johnston, N. Pepsin as a marker of extraesophageal reflux. Ann Otol Rhinol Laryngol 2010;119:203–8CrossRefGoogle ScholarPubMed