Human Vocal Fold Tissue Modifications Related to Laryngopharyngeal Reflux Disease: A Systematic Review.

Background: The vocal fold tissue modifications and related dysphonia caused by laryngopharyngeal reflux disease (LPRD) remain a controversial topic in laryngology. Investigation of human vocal fold tissue exposed to reflux content can provide valuable insights. This systematic review aimed to summarize the current knowledge about LPRD-induced human vocal fold tissue modifications to better understand LPRD pathophysiology and LPRD-related voice disorders.

Methods: A PubMed, Embase, and Web of Science database search was carried out by two investigators for studies investigating human laryngeal mucosa injuries and histological modifications related to LPRD refluxate, and their potential mechanistic associations with voice quality impairments according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses statements.

Results: Of 389 retrieved articles, 24 experimental studies met the inclusion criteria. Studies demonstrate that laryngeal, particularly vocal fold, biopsies of patients with suspected LPRD reveal a substantial number of histological and functional alterations, including inflammatory cell infiltration, cell junction proteolysis, intercellular space dilatation, pepsin-induced cell DNA damage, and increases in oxidative stress mediators and tissue injuries. Functional impairment of defensive mechanisms through downregulation of carbonic anhydrases (CA III) and protective mucins (MUC2, MUC4, and MUC5AC) can consist of favoring factor of tissue injuries. Emerging studies reported evidence of tissue remodeling through matrix metalloproteinase activation and metabolic alterations included increased Glut-1 and sphingosine pathway activation, potentially linking LPRD to leukoplakia development. No studies addressed the potential effects of elastase, bile salts, trypsin, and lipases in non-acidic (weakly acidic or alkaline) gaseous environment.

Conclusion: This systematic review demonstrates that LPRD and pepsin induce cellular alterations in vocal fold and laryngeal tissues, highlighting potential pathogenic mechanisms and identifying biomarkers that may guide future diagnostic and therapeutic strategies.