Surgical Endoscopy

, Volume 32, Issue 5, pp 2434–2441 | Cite as

Sep70/Pepsin expression in hypopharynx combined with hypopharyngeal multichannel intraluminal impedance increases diagnostic sensitivity of laryngopharyngeal reflux

  • Toshitaka Hoppo
  • Ali H. Zaidi
  • Daisuke Matsui
  • Samantha A. Martin
  • Yoshihiro Komatsu
  • Emily J. Lloyd
  • Juliann E. Kosovec
  • Albert A. Civitarese
  • Natalie H. Boyd
  • Amit Shetty
  • Ashten N. Omstead
  • Emily Smith
  • Blair A. Jobe
Article

Abstract

Background

Improved methods of diagnosis of laryngopharyngeal reflux (LPR) would enable surgeons to better identify patients who may benefit from antireflux surgery (ARS). The objective of the present study was to assess if hypopharyngeal Pepsin and Sep70 expression combined with hypopharyngeal multichannel intraluminal impedance (HMII) has the potential to increase diagnostic sensitivity of LPR.

Methods

This study was performed on patients who underwent unsedated transnasal endoscopy with hypopharyngeal biopsy and 24-h HMII to determine abnormal proximal exposure (APE) and DeMeester score (DMS) from 2013 to 2016. Pepsin and Sep70 protein expression was assessed by Western blots of biopsy specimens. The outcomes of ARS were assessed using reflux symptom index (RSI). HMII APE classification, Sep 70, and Pepsin protein levels were compared in normative and symptomatic LPR patients and further analyzed alongside quality of life changes following ARS.

Results

Of 30 subjects enrolled, 23 were excluded for abnormal HMII results or endoscopic evidence of esophagitis. Seven subjects and 105 patients were included in the normative and symptomatic groups, respectively. Compared to the normative group, only Pepsin expression was significantly higher in the symptomatic group [APE+/LPR+ (p = 0.000), APE+/LPR− (p = 0.001), and APE− (p = 0.047)]. Further, the ratio of Sep70/Pepsin was significantly lower in the symptomatic group [APE+/LPR+ (p = 0.008), APE+/LPR− (p = 0.000), and APE− (p = 0.050)], and a cutoff ratio for a diagnosis of LPR was established as < 158. Of 105 symptomatic patients, 48 patients underwent ARS. Of these, 17 patients had complete pre- and post-RSI questionnaires. LPR symptoms improved in 15 (88%), of whom 2 were APE− but met criteria for a diagnosis of LPR based on the Sep70/Pepsin cutoff.

Conclusions

The identified Sep70/Pepsin ratio may serve as a reliable biomarker for the diagnosis of LPR. As a result, this may help identify additional patients who have a false-negative HMII result due to the 24-h testing window.

Keywords

Laryngopharyngeal reflux Hypopharyngeal multichannel intraluminal impedance Sep70 Pepsin 

Notes

Acknowledgements

We would like to thank David Gold and Irene Blumenkranz for funding support.

Compliance with ethical standards

Disclosures

T. Hoppo, A. H. Zaidi, D. Matsui, S. A. Martin, Y. Komatsu, E. J. Lloyd, J. E. Kosovec. A. A. Civitarese, N. H. Boyd, A. Shetty, A. N. Omstead, E. Smith, and B. A. Jobe have no conflict of interest or financial ties to disclose.

Supplementary material

464_2017_5943_MOESM1_ESM.docx (15 kb)
Supplementary material 1 (DOCX 15 KB)

References

  1. 1.
    Koufman JA, Amin MR, Panetti M (2000) Prevalence of reflux in 113 consecutive patients with laryngeal and voice disorders. Otolaryngol Head Neck Surg 123(4):385–388CrossRefPubMedGoogle Scholar
  2. 2.
    Patti MG, Debas HT, Pellegrini CA (1993) Clinical and functional characterization of high gastroesophageal reflux. Am J Surg 165(1):163–166 (discussion 166–168).CrossRefPubMedGoogle Scholar
  3. 3.
    Pellegrini CA, DeMeester TR, Johnson LF, Skinner DB (1979) Gastroesophageal reflux and pulmonary aspiration: incidence, functional abnormality, and results of surgical therapy. Surgery 86(1):110–119PubMedGoogle Scholar
  4. 4.
    Raghu G, Yang ST, Spada C, Hayes J, Pellegrini CA (2006) Sole treatment of acid gastroesophageal reflux in idiopathic pulmonary fibrosis: a case series. Chest 129(3):794–800CrossRefPubMedGoogle Scholar
  5. 5.
    Koufman JA, Aviv JE, Casiano RR, Shaw GY (2002) 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(1):32–35CrossRefPubMedGoogle Scholar
  6. 6.
    Reulbach TR, Belafsky PC, Blalock PD, Koufman JA, Postma GN (2001) Occult laryngeal pathology in a community-based cohort. Otolaryngol Head Neck Surg 124(4):448–450CrossRefPubMedGoogle Scholar
  7. 7.
    Belafsky PC, Postma GN, Koufman JA (2002) Validity and reliability of the reflux symptom index (RSI). J Voice 16(2):274–277CrossRefPubMedGoogle Scholar
  8. 8.
    Postma GN (2000) Ambulatory pH monitoring methodology. Ann Otol Rhinol Laryngol Suppl 184:10–14CrossRefPubMedGoogle Scholar
  9. 9.
    Belafsky PC, Postma GN, Koufman JA (2001) The validity and reliability of the reflux finding score (RFS). Laryngoscope 111(8):1313–1317CrossRefPubMedGoogle Scholar
  10. 10.
    Hicks DM, Ours TM, Abelson TI, Vaezi MF, Richter JE (2002) The prevalence of hypopharynx findings associated with gastroesophageal reflux in normal volunteers. J Voice 16(4):564–579CrossRefPubMedGoogle Scholar
  11. 11.
    Koufman JA (1991) 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 Pt 2 Suppl 53):1–78CrossRefPubMedGoogle Scholar
  12. 12.
    Vaezi MF (2003) Extraesophageal manifestations of gastroesophageal reflux disease. Clin Cornerstone 5(4):32–38 (discussion 39–40).CrossRefPubMedGoogle Scholar
  13. 13.
    Ciovica R, Gadenstatter M, Klingler A, Neumayer C, Schwab GP (2005) Laparoscopic antireflux surgery provides excellent results and quality of life in gastroesophageal reflux disease patients with respiratory symptoms. J Gastrointest Surg 9(5):633–637CrossRefPubMedGoogle Scholar
  14. 14.
    Kaufman JA, Houghland JE, Quiroga E, Cahill M, Pellegrini CA, Oelschlager BK (2006) Long-term outcomes of laparoscopic antireflux surgery for gastroesophageal reflux disease (GERD)-related airway disorder. Surg Endosc 20(12):1824–1830CrossRefPubMedGoogle Scholar
  15. 15.
    Rakita S, Villadolid D, Thomas A, Bloomston M, Albrink M, Goldin S, Rosemurgy A (2006) Laparoscopic Nissen fundoplication offers high patient satisfaction with relief of extraesophageal symptoms of gastroesophageal reflux disease. Am Surg 72(3):207–212PubMedGoogle Scholar
  16. 16.
    Swoger J, Ponsky J, Hicks DM, Richter JE, Abelson TI, Milstein C, Qadeer MA, Vaezi MF (2006) Surgical fundoplication in laryngopharyngeal reflux unresponsive to aggressive acid suppression: a controlled study. Clin Gastroenterol Hepatol 4(4):433–441CrossRefPubMedGoogle Scholar
  17. 17.
    Hoppo T, Sanz AF, Nason KS, Carroll TL, Rosen C, Normolle DP, Shaheen NJ, Luketich JD, Jobe BA (2012) How much pharyngeal exposure is “normal”? Normative data for laryngopharyngeal reflux events using hypopharyngeal multichannel intraluminal impedance (HMII). J Gastrointest Surg 16(1):16–24 (discussion 24–15).CrossRefPubMedGoogle Scholar
  18. 18.
    Hoppo T, Jarido V, Pennathur A, Morrell M, Crespo M, Shigemura N, Bermudez C, Hunter JG, Toyoda Y, Pilewski J, Luketich JD, Jobe BA (2011) Antireflux surgery preserves lung function in patients with gastroesophageal reflux disease and end-stage lung disease before and after lung transplantation. Arch Surg 146(9):1041–1047CrossRefPubMedGoogle Scholar
  19. 19.
    Hoppo T, Komatsu Y, Jobe BA (2013) Antireflux surgery in patients with chronic cough and abnormal proximal exposure as measured by hypopharyngeal multichannel intraluminal impedance. JAMA Surg 148(7):608–615CrossRefPubMedGoogle Scholar
  20. 20.
    Komatsu Y, Hoppo T, Jobe BA (2013) Proximal reflux as a cause of adult-onset asthma: the case for hypopharyngeal impedance testing to improve the sensitivity of diagnosis. JAMA Surg 148(1):50–58CrossRefPubMedGoogle Scholar
  21. 21.
    Johnston N, Knight J, Dettmar PW, Lively MO, Koufman J (2004) Pepsin and carbonic anhydrase isoenzyme III as diagnostic markers for laryngopharyngeal reflux disease. Laryngoscope 114(12):2129–2134CrossRefPubMedGoogle Scholar
  22. 22.
    Campagnolo AM, Priston J, Thoen RH, Medeiros T, Assuncao AR (2014) Laryngopharyngeal reflux: diagnosis, treatment, and latest research. Int Arch Otorhinolaryngol 18(2):184–191PubMedGoogle Scholar
  23. 23.
    Komatsu Y, Kelly LA, Zaidi AH, Rotoloni CL, Kosovec JE, Lloyd EJ, Waheed A, Hoppo T, Jobe BA (2015) Hypopharyngeal pepsin and Sep70 as diagnostic markers of laryngopharyngeal reflux: preliminary study. Surg Endosc 29(5):1080–1087CrossRefPubMedGoogle Scholar
  24. 24.
    Crapko M, Kerschner JE, Syring M, Johnston N (2007) Role of extra-esophageal reflux in chronic otitis media with effusion. Laryngoscope 117(8):1419–1423CrossRefPubMedGoogle Scholar
  25. 25.
    Farhath S, He Z, Nakhla T, Saslow J, Soundar S, Camacho J, Stahl G, Shaffer S, Mehta DI, Aghai ZH (2008) Pepsin, a marker of gastric contents, is increased in tracheal aspirates from preterm infants who develop bronchopulmonary dysplasia. Pediatrics 121(2):e253-259CrossRefGoogle Scholar
  26. 26.
    Knight J, Lively MO, Johnston N, Dettmar PW, Koufman JA (2005) Sensitive pepsin immunoassay for detection of laryngopharyngeal reflux. Laryngoscope 115(8):1473–1478CrossRefPubMedGoogle Scholar
  27. 27.
    Stovold R, Forrest IA, Corris PA, Murphy DM, Smith JA, Decalmer S, Johnson GE, Dark JH, Pearson JP, Ward C (2007) Pepsin, a biomarker of gastric aspiration in lung allografts: a putative association with rejection. Am J Respir Crit Care Med 175(12):1298–1303CrossRefPubMedGoogle Scholar
  28. 28.
    Yates DH, Krishnan A, Chow S, Thomas PS (2011) Non-invasive assessment of exhaled biomarkers in lung transplantation. J Breath Res 5(2):024001CrossRefPubMedGoogle Scholar
  29. 29.
    Hayat JO, Gabieta-Somnez S, Yazaki E, Kang JY, Woodcock A, Dettmar P, Mabary J, Knowles CH, Sifrim D (2015) Pepsin in saliva for the diagnosis of gastro-oesophageal reflux disease. Gut 64(3):373–380CrossRefPubMedGoogle Scholar
  30. 30.
    Wassenaar E, Johnston N, Merati A, Montenovo M, Petersen R, Tatum R, Pellegrini C, Oelschlager B (2011) Pepsin detection in patients with laryngopharyngeal reflux before and after fundoplication. Surg Endosc 25(12):3870–3876CrossRefPubMedGoogle Scholar
  31. 31.
    Welch WJ, Brown CR (1996) Influence of molecular and chemical chaperones on protein folding. Cell Stress Chaperones 1(2):109–115CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Yagui-Beltran A, Craig AL, Lawrie L, Thompson D, Pospisilova S, Johnston D, Kernohan N, Hopwood D, Dillon JF, Hupp TR (2001) The human oesophageal squamous epithelium exhibits a novel type of heat shock protein response. Eur J Biochem/FEBS 268(20):5343–5355CrossRefGoogle Scholar
  33. 33.
    Johnston N, Dettmar PW, Lively MO, Postma GN, Belafsky PC, Birchall M, Koufman JA (2006) Effect of pepsin on laryngeal stress protein (Sep70, Sep53, and Hsp70) response: role in laryngopharyngeal reflux disease. Ann Otol Rhinol Laryngol 115(1):47–58CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2017

Authors and Affiliations

  • Toshitaka Hoppo
    • 1
  • Ali H. Zaidi
    • 1
  • Daisuke Matsui
    • 1
  • Samantha A. Martin
    • 1
  • Yoshihiro Komatsu
    • 1
  • Emily J. Lloyd
    • 1
  • Juliann E. Kosovec
    • 1
  • Albert A. Civitarese
    • 1
  • Natalie H. Boyd
    • 1
  • Amit Shetty
    • 1
  • Ashten N. Omstead
    • 1
  • Emily Smith
    • 1
  • Blair A. Jobe
    • 1
  1. 1.Esophageal and Lung Institute, Allegheny Health NetworkPittsburghUSA

Personalised recommendations