[en] [en] OBJECTIVE: The aim of this paper is to shed light on the pathogenesis and pathophysiological mechanisms underlying the development of hoarseness related to laryngopharyngeal reflux disease (LPRD).
MATERIAL AND METHODS: PubMed, Embase, and The Cochrane Library were searched for the terms reflux, laryngopharyngeal, laryngitis, voice, and hoarseness. Experimental and clinical studies providing substantial information about the occurrence of voice disorders, laryngeal histologic changes, or any pathophysiological processes related to LPRD were included by two independent investigators.
RESULTS: Of the 104 studies reviewed, 47 studies that met our inclusion criteria were analyzed. LPRD leads to significant macroscopic and microscopic histopathologic changes in the mucosa of the vibratory margin of the vocal folds. More and more studies suspect that epithelial cell dehiscence, microtraumas, inflammatory infiltrates, Reinke space dryness, mucosal drying, and epithelial thickening are probably responsible for the hoarseness related to reflux and the impairment of the subjective and objective voice quality evaluations.
CONCLUSION: Future clinical studies examining the pathophysiology of hoarseness related to LPRD should take into consideration all potential mechanisms involved in the development of hoarseness.
Disciplines :
Otolaryngology
Author, co-author :
Lechien, Jerome R; Laboratory of Anatomy and Cell Biology, Faculty of Medicine, UMONS Research Institute for Health Sciences and Technology, University of Mons (UMONS), Mons, Belgium, Department of Otolaryngology - Head Neck Surgery, CHU Saint-Pierre, 1000 Brussels, Belgium, Laboratory of Phonetics, Faculty of Psychology, Research Institute for Language Sciences and Technology, University of Mons (UMONS), Mons, Belgium. Electronic address: jerome.lechien@umons.ac.be
Saussez, Sven; Laboratory of Anatomy and Cell Biology, Faculty of Medicine, UMONS Research Institute for Health Sciences and Technology, University of Mons (UMONS), Mons, Belgium, Department of Otolaryngology - Head Neck Surgery, CHU Saint-Pierre, 1000 Brussels, Belgium
Harmegnies, Bernard; Laboratory of Anatomy and Cell Biology, Faculty of Medicine, UMONS Research Institute for Health Sciences and Technology, University of Mons (UMONS), Mons, Belgium
Finck, Camille ; Université de Liège - ULiège > Département des sciences cliniques > Phoniatrie
Burns, James A; Department of Surgery, Harvard Medical School, Center for Laryngeal Surgery and Voice Rehabilitation, Massachusetts General Hospital, Boston, Massachusetts
Language :
English
Title :
Laryngopharyngeal Reflux and Voice Disorders: A Multifactorial Model of Etiology and Pathophysiology.
Koufman, J.A., Aviv, J.E., Casiano, R.R., et al. 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 127 (2002), 32–35.
Sen, P., Georgalas, C., Bhattacharyya, A.K., A systematic review of the role of proton pump inhibitors for symptoms of laryngopharyngeal reflux. Clin Otolaryngol 31 (2006), 20–24.
Jin, B., Lee, Y.S., Jeong, S.W., et al. Change of acoustic parameters before and after treatment in laryngopharyngeal reflux patients. Laryngoscope 118 (2008), 938–941.
Koufman, J.A., Amin, M.R., Panetti, M., Prevalence of reflux in 113 consecutive patients with laryngeal and voice disorders. Otolaryngol Head Neck Surg 123 (2000), 385–388.
Lechien, J.R., Finck, C., Costa de Araujo, P., et al. Voice outcomes of laryngopharyngeal reflux treatment: a systematic review of 1483 patients. Eur Arch Otorhinolaryngol 274 (2016), 1–23.
Koufman, J.A., 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 101:4 suppl 53 pt 2 (1991), 1–78.
Sataloff, R.T., Castell, D.O., Katz, P.O., et al. Reflux Laryngitis and Related Disorders. 3rd ed, 2006, Plural Publishing, Inc, San Diego, CA.
Jacob, P., Kahrilas, P.J., Herzon, G., Proximal esophageal pH-metry in patients with “reflux laryngitis.”. Gastroenterology 100 (1991), 305–310.
Eubanks, T.R., Omelanczuk, P.E., Maronian, N., et al. Pharyngeal pH monitoring in 222 patients with suspected laryngeal reflux. J Gastrointest Surg 5 (2001), 183–190 discussion 190–191.
Ford, C.N., Evaluation and management of laryngopharyngeal reflux. JAMA 294 (2005), 1534–1540.
Mesallam, T.A., Stemple, J.C., Sobeih, T.M., et al. Reflux symptom index versus reflux finding score. Ann Otol Rhinol Laryngol 116 (2007), 436–440.
Lechien, J.R., Khalife, M., Delvaux, V., et al. Pathophysiology, assessment and treatment of laryngopharyngeal reflux. Rev Laryngol Otol Rhinol (Bord) 135 (2014), 163–170.
Lechien, J.R., Huet, K., Khalife, M., et al. Impact of laryngopharyngeal reflux on subjective and objective voice assessments: a prospective study. J Otolaryngol Head Neck Surg, 45, 2016, 59.
Moher, D., Liberati, A., Tetzlaff, J., et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol 62 (2009), 1006–1012.
Schardt, C., Adams, M.B., Owens, T., et al. Utilization of the PICO framework to improve searching PubMed for clinical questions. BMC Med Inform Decis Mak, 7, 2007, 16.
Howick, J., Chalmers, I., Glasziou, P., et al. The 2011 Oxford CEBM Levels of Evidence. Oxford Centre for Evidence-Based Medicine, 2011.
Adhami, T., Goldblum, J.R., Richter, J.E., et al. The role of gastric and duodenal agents in laryngeal injury: an experimental canine model. Am J Gastroenterol 99 (2004), 2098–2106.
Cohen, S.M., Huang, S., Garrett, C.G., et al. Acute histologic effects of extraesophageal reflux on vocal fold healing. Ann Otol Rhinol Laryngol 114 (2005), 296–303.
Johnston, N., Knight, J., Dettmar, P.W., et al. Pepsin and carbonic anhydrase isoenzyme III as diagnostic markers for laryngopharyngeal reflux disease. Laryngoscope 114 (2004), 2129–2134.
Gill, G.A., Johnston, N., Buda, A., et al. Laryngeal epithelial defenses against laryngopharyngeal reflux: investigations of E-cadherin, carbonic anhydrase isoenzyme III, and pepsin. Ann Otol Rhinol Laryngol 114 (2005), 913–921.
Ylitalo, R., Thibeault, S.L., Relationship between time of exposure of laryngopharyngeal reflux and gene expression in laryngeal fibroblasts. Ann Otol Rhinol Laryngol 115 (2006), 775–783.
Franchi, A., Brogelli, B., Massi, D., et al. Dilation of intercellular spaces is associated with laryngo-pharyngeal reflux: an ultrastructural morphometric analysis of laryngeal epithelium. Eur Arch Otorhinolaryngol 264 (2007), 907–911.
Johnston, N., Wells, C.W., Blumin, J.H., et al. Receptor-mediated uptake of pepsin by laryngeal epithelial cells. Ann Otol Rhinol Laryngol 116 (2007), 934–938.
Rees, L.E., Pazmany, L., Gutowska-Owsiak, D., et al. The mucosal immune response to laryngopharyngeal reflux. Am J Respir Crit Care Med 177 (2008), 1187–1193.
Reichel, O., Mayr, D., Durst, F., et al. E-cadherin but not beta-catenin expression is decreased in laryngeal biopsies from patients with laryngopharyngeal reflux. Eur Arch Otorhinolaryngol 265 (2008), 937–942.
Shimazu, R., Kusano, K., Kuratomi, Y., et al. Histological changes of the pharynx and larynx in rats with chronic acid reflux esophagitis. Acta Otolaryngol 129 (2009), 886–892.
Johnston, N., Wells, C.W., Samuels, T.L., et al. Rationale for targeting pepsin in the treatment of reflux disease. Ann Otol Rhinol Laryngol 119 (2010), 547–558.
Vaezi, M.F., Slaughter, J.C., Smith, B.S., et al. Dilated intercellular space in chronic laryngitis and gastro-oesophageal reflux disease: at baseline and post-lansoprazole therapy. Aliment Pharmacol Ther 32 (2010), 916–924.
Bulmer, D.M., Ali, M.S., Brownlee, I.A., et al. Laryngeal mucosa: its susceptibility to damage by acid and pepsin. Laryngoscope 120 (2010), 777–782.
Erickson, E., Sivasankar, M., Simulated reflux decreases vocal fold epithelial barrier resistance. Laryngoscope 120 (2010), 1569–1575.
Jiang, A., Liang, M., Su, Z., et al. Immunohistochemical detection of pepsin in laryngeal mucosa for diagnosing laryngopharyngeal reflux. Laryngoscope 121 (2011), 1426–1430.
Hu, Y., Xu, X., Xu, L., et al. Dilated intercellular space in the larynx and esophagus of a rabbit reflux model. Auris Nasus Larynx 40 (2013), 379–382.
Durkes, A., Sivasankar, M.P., Bicarbonate availability for vocal fold epithelial defense to acidic challenge. Ann Otol Rhinol Laryngol 123 (2014), 71–76.
Axford, S.E., Sharp, N., Ross, P.E., et al. Cell biology of laryngeal epithelial defenses in health and disease: preliminary studies. Ann Otol Rhinol Laryngol 110 (2001), 1099–1108.
Johnston, N., Bulmer, D., Gill, G.A., et al. Cell biology of laryngeal epithelial defenses in health and disease: further studies. Ann Otol Rhinol Laryngol 112 (2003), 481–491.
Johnston, N., Dettmar, P.W., Bishwokarma, B., et al. Activity/stability of human pepsin: implications for reflux attributed laryngeal disease. Laryngoscope 117 (2007), 1036–1039.
Samuels, T.L., Johnston, N., Pepsin as a causal agent of inflammation during nonacidic reflux. Otolaryngol Head Neck Surg 141 (2009), 559–563.
Erickson-Levendoski, E., Sivasankar, M.P., Role for ion transport in porcine vocal fold epithelial defense to acid challenge. Otolaryngol Head Neck Surg 146 (2012), 272–278.
Ali, M.E.S., Bulmer, D.M., Dettmar, P.W., et al. Mucin gene expression in reflux laryngeal mucosa: histological and in situ hybridization observations. Int J Otolaryngol, 2014, 2014, 264075.
Min, H.J., Hong, S.C., Yang, H.S., et al. Expression of CAIII and Hsp70 is increased the mucous membrane of the posterior commissure in laryngopharyngeal reflux disease. Yonsei Med J 57 (2016), 469–474.
Ross, J.A., Noordzji, J.P., Woo, P., Voice disorders in patients with suspected laryngo-pharyngeal reflux disease. J Voice 12 (1998), 84–88.
Pribuisiene, R., Uloza, V., Kupcinskas, L., et al. Perceptual and acoustic characteristics of voice changes in reflux laryngitis patients. J Voice 20 (2006), 128–136.
Oguz, H., Tarhan, E., Korkmaz, M., et al. Acoustic analysis findings in objective laryngopharyngeal reflux patients. J Voice 21 (2007), 203–210.
Kumar, R., Bhat, J.S., Aerodynamic analysis of voice in persons with laryngopharyngeal reflux. Online J Health Allied Sci, 7, 2008, 5.
Akyildiz, S., Ogut, F., Varis, A., et al. Impact of laryngeal findings on acoustic parameters of patients with laryngopharyngeal reflux. ORL J Otorhinolaryngol Relat Spec 74 (2012), 215–219.
Shaw, G.Y., Searl, J.P., Laryngeal manifestations of gastroesophageal reflux before and after treatment with omeprazole. South Med J 90 (1997), 1115–1122.
Habermann, W., Eherer, A., Lindbichler, F., et al. Ex juvantibus approach for chronic posterior laryngitis: results of short-term pantoprazole therapy. J Laryngol Otol 113 (1999), 734–739.
Hamdan, A.L., Sharara, A.I., Younes, A., et al. Effect of aggressive therapy on laryngeal symptoms and voice characteristics in patients with gastroesophageal reflux. Acta Otolaryngol 121 (2001), 868–872.
Noordzij, J.P., Khidr, A., Evans, B.A., et al. Evaluation of omeprazole in the treatment of reflux laryngitis: a prospective, placebo-controlled, randomized, double-blind study. Laryngoscope 111 (2001), 2147–2151.
Selby, J.C., Gilbert, H.R., Lerman, J.W., Perceptual and acoustic evaluation of individuals with laryngopharyngeal reflux pre- and post-treatment. J Voice 17 (2003), 557–570.
Siupsinskiene, N., Adamonis, K., Toohill, R.J., Quality of life in laryngopharyngeal reflux patients. Laryngoscope 117 (2007), 480–484.
Williams, R.B., Szczesniak, M.M., Maclean, J.C., et al. Predictors of outcome in an open label, therapeutic trial of high-dose omeprazole in laryngitis. Am J Gastroenterol 99 (2004), 777–785.
Sereg-Bahar, M., Jansa, R., Hocevar-Boltezar, I., Voice disorders and gastroesophageal reflux. Logoped Phoniatr Vocol 30 (2005), 120–124.
Ogut, F., Ersin, S., Engin, E.Z., et al. The effect of laparoscopic Nissen fundoplication on laryngeal findings and voice quality. Surg Endosc 21 (2007), 549–554.
Sala, E., Salminen, P., Simberg, S., et al. Laryngopharyngeal reflux disease treated with laparoscopic fundoplication. Dig Dis Sci 53 (2008), 2397–2404.
Vashani, K., Murugesh, M., Hattiangadi, G., et al. Effectiveness of voice therapy in reflux-related voice disorders. Dis Esophagus 23 (2010), 27–32.
Fass, R., Noelck, N., Willis, M.R., et al. The effect of esomeprazole 20 mg twice daily on acoustic and perception parameters of the voice in laryngopharyngeal reflux. Neurogastroenterol Motil 22 (2010), 134–141.
Ayazi, S., Pearson, J., Hashemi, M., Gastroesophageal reflux and voice changes: objective assessment of voice quality and impact of antireflux therapy. J Clin Gastroenterol 46 (2012), 119–123.
Park, J.O., Shim, M.R., Hwang, Y.S., et al. Combination of voice therapy and antireflux therapy rapidly recovers voice-related symptoms in laryngopharyngeal reflux patients. Otolaryngol Head Neck Surg 146 (2012), 92–97.
Wan, Y., Yan, Y., Ma, F., et al. LPR: how different diagnostic tools shape the outcomes of treatment. J Voice 28 (2014), 362–368.
Sahin, M., Kirazli, T., Ogut, M.F., et al. The effect of antireflux surgery on laryngeal symptoms, findings and voice parameters. Eur Arch Otorhinolaryngol 272 (2015), 3375–3383.
Lechien, J.R., Delvaux, V., Huet, K., et al. Phonetic approaches of laryngopharyngeal reflux disease: a prospective study. J Voice 31 (2016), 119.e11–119.e20.
Lechien, J.R., Finck, C., Huet, K., et al. Impact of laryngopharyngeal reflux (LPR) disease on aerodynamic, subjective and objective voice assessments: a multi-centric prospective study of 80 patients. Congress of the French Speaking Otolaryngology Society, Paris, 2016.
Johnston, N., Yan, J.C., Hoekzema, C.R., et al. Pepsin promotes proliferation of laryngeal and pharyngeal epithelial cells. Laryngoscope 122 (2012), 1317–1325.
Galli, J., Calò, L., Agostino, S., et al. Bile reflux as possible risk factor in laryngopharyngeal inflammatory and neoplastic lesions. Acta Otorhinolaryngol Ital 23 (2003), 377–382.
Contencin, P., Adjoua, P., Viala, P., et al. Long-term esophageal and oropharyngeal pH-metry in ORL manifestations of gastroesophageal reflux in children. Ann Otolaryngol Chir Cervicofac 109 (1992), 129–133.
Tauber, S., Gross, M., Issing, W.J., Association of laryngopharyngeal symptoms with gastroesophageal reflux disease. Laryngoscope 112 (2002), 879–886.
Arruda Henry, M.A., Martins, R.H., Lerco, M.M., et al. Gastroesophageal reflux disease and vocal disturbances. Arq Gastroenterol 48 (2011), 98–103.
Na, S.Y., Kwon, O.E., Lee, Y.C., et al. Optimal timing of saliva collection to detect pepsin in patients with laryngopharyngeal reflux. Laryngoscope 126 (2016), 2770–2773.
Johnston, N., Wells, C.W., Samuels, T.L., et al. Pepsin in nonacidic refluxate can damage hypopharyngeal epithelial cells. Ann Otol Rhinol Laryngol 118 (2009), 677–685.
Hom, D.B., Growth factors and wound healing in otolaryngology. Otolaryngol Head Neck Surg 110 (1994), 560–564.
Lord, R.V., Park, J.M., Wickramasinghe, K., et al. Vascular endothelial growth factor and basic fibroblast growth factor expression in esophageal adenocarcinoma and Barrett esophagus. J Thorac Cardiovasc Surg 125 (2003), 246–253.
Sereg-Bahar, M., Jerin, A., Jansa, R., et al. Pepsin and bile acids in saliva in patients with laryngopharyngeal reflux—a prospective comparative study. Clin Otolaryngol 40 (2015), 234–239.
Tack, J., Koek, G., Demedts, I., et al. 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 99 (2004), 981–988.
Becker, V., Drabner, R., Graf, S., et al. New aspects in the pathomechanism and diagnosis of the laryngopharyngeal reflux-clinical impact of laryngeal proton pumps and pharyngeal pH metry in extraesophageal gastroesophageal reflux disease. World J Gastroenterol 21 (2015), 982–987.
Altman, K.W., Haines, G.K. 3rd, Hammer, N.D., et al. The H+/K+-ATPase (proton) pump is expressed in human laryngeal submucosal glands. Laryngoscope 113 (2003), 1927–1930.
Sivasankar, M., Erickson, E., Schneider, S., et al. Phonatory effects of airway dehydration: preliminary evidence for impaired compensation to oral breathing in individuals with a history of vocal fatigue. J Speech Lang Hear Res 51 (2008), 1494–1506.
Voynow, J.A., Gendler, S.J., Rose, M.C., Regulation of mucin genes in chronic inflammatory airway diseases. Am J Respir Cell Mol Biol 34 (2006), 661–665.
Hirano, M., Morphological structure of the vocal cord as a vibrator and its variations. Folia Phoniatr (Basel) 26 (1974), 89–94.
Birchall, M.A., Bailey, M., Barker, E.V., et al. Model for experimental revascularized laryngeal allotransplantation. Br J Surg 89 (2002), 1470–1475.
Gray, S.D., Cellular physiology of the vocal folds. Otolaryngol Clin North Am 33 (2000), 679–698.
Belafsky, P.C., Postma, G.N., Koufman, J.A., The validity and reliability of the reflux finding score (RFS). Laryngoscope 111 (2001), 1313–1317.
Hirano, M., Clinical Examination of Voice. 1981, Springer, New York, NY, 56–64.
Nakagawa, H., Fukuda, H., Kawaida, M., et al. Lubrication mechanism of the larynx during phonation: an experiment in excised canine larynges. Folia Phoniatr Logop 50 (1998), 183–194.
Leydon, C., Sivasankar, M., Falciglia, D.L., et al. Vocal fold surface hydration: a review. J Voice 23 (2009), 658–665.
Gray, S.D., Basement membrane zone injury in vocal nodules. Vocal Fold Physiology, 1991, Whurr Publishers, 21–27.
Chan, R.W., Estimation of viscoelastic shear properties of vocal-fold tissues based on time-temperature superposition. J Acoust Soc Am 110:3 pt 1 (2001), 1548–1561.
Ward, P.D., Thibeault, S.L., Gray, S.D., Hyaluronic acid: its role in voice. J Voice 16 (2002), 303–309.
Garcia, I., Krishna, P., Rosen, C.A., Severe laryngeal hyperkeratosis secondary to laryngopharyngeal reflux. Ear Nose Throat J, 85, 2006, 417.
Pribuisiene, R., Uloza, V., Kupcinskas, L., Diagnostic sensitivity and specificity of laryngoscopic signs of reflux laryngitis. Medicina (Kaunas) 44 (2008), 280–287.
Ylitalo, R., Lindestad, P.A., A retrospective study of contact granuloma. Laryngoscope 109 (1999), 433–436.
Yana, M., Renard, M.C., Stroebel, V., The place of speech therapy in the dysfunctional dysphonias with gastro-esophageal reflux. Rev Laryngol Otol Rhinol (Bord) 122 (2001), 323–330.
Van Lierde, K.M., Claeys, S., De Bodt, M., et al. Long-term outcome of hyperfunctional voice disorders based on a multiparameter approach. J Voice 21 (2007), 179–188.
Datta, K., Datta, R., Venkatesh, M.D., et al. 24-hour dual-probe ambulatory pH-metry findings in cases of laryngopharyngeal reflux disease. J Laryngol Voice 1 (2011), 18–21.
