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PepsinPepsin as a Biomarker: A Silent Biomarker for Reflux Aspiration or an Active Player in Extra-Esophageal Mucosal Injury? FREE TO VIEW

Peter J. Kahrilas, MD; Leila Kia, MD
Author and Funding Information

From the Department of Medicine, Northwestern University, Feinberg School of Medicine.

CORRESPONDENCE TO: Peter J. Kahrilas, MD, Northwestern University, Feinberg School of Medicine, Department of Medicine, 676 St. Clair St, 14th Floor, Chicago, IL; e-mail:p-kahrilas@northwestern.edu


FINANCIAL/NONFINANCIAL DISCLOSURES: The authors have reported to CHEST the following conflicts of interest: Dr Kahrilas has consulted for Reckitt Benckiser Group plc, AstraZeneca plc, and Pfizer Inc. Dr Kia has reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;148(2):300-301. doi:10.1378/chest.15-0506
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The interactions among pepsin, acid, and mucosal injury have been a subject of interest since studies in the 1960s implicated pepsin as a major determinant of reflux injury at low pH.1 In its enzymatically active form, pepsin is the primary proteolytic enzyme of the digestive tract and key to the pathogenesis of “peptic” esophagitis in gastroesophageal reflux disease (GERD). Synthesized primarily by chief cells of the gastric fundus as the zymogen pepsinogen, pepsin requires an acidic environment before it can be converted to its active form. Its pH activity curve peaks at pH 2, falls off rapidly above pH 4.5, and is negligible above pH 5.5.2 As a biomarker for reflux, it is easily detected and uniformly found in gastric refluxate.3 Consequently, the presence of pepsin in the oropharynx or the tracheobronchial tree is indicative of regurgitation with or without aspiration. However, its presence in and of itself does not establish a causal relationship to epithelial damage and/or symptom generation from supraesophageal reflux. There must be a mechanism for activation as well. One such proposed mechanism in patients who are thought to have proton pump inhibitor-refractory supraesophageal GERD pathology is that inactive (but not denatured) pepsin is sufficiently reactivated by subsequent weakly acidic refluxate to cause laryngeal mucosal injury. Evidence substantiating that hypothesis is the demonstration of pepsin-induced depletion of laryngeal protective proteins (carbonic anhydrase isoenzyme III and squamous epithelial stress protein) in patients with laryngopharyngeal reflux.4-6

The potential of pepsin as a biomarker of supraesophageal GERD has been reviewed (L. Kia, MD; J. Pandolfino, MD; P. J. Kahrilas, MD; unpublished data, 2015). One emerging problem with assaying for pepsin in the tracheobronchial tree is that, currently, available pepsin assays are not specific to pepsin A, the isoform found exclusively in the stomach. Other pepsin isoforms, mainly pepsin C (measured as its precursor pepsinogen C), are also produced in the lungs, pancreas, and seminal vesicles, thereby limiting specificity of pepsin as a biomarker for gastric juice. Moreover, most studies evaluating pepsin as a biomarker for GERD used assays that did not discriminate between these isoforms. In this issue of CHEST (see page 333), Hallal et al7 aimed to address this problem. They report on 34 children on mechanical ventilation in the ICU. The children were studied with 24-h pH-impedance monitoring, and tracheal secretion samples were collected and assayed for pepsin A and pepsin C. All patients tested positive for pepsin A in their secretions, while 76.5% tested positive for pepsin C. All patients also had multiple episodes (median, 60; interquartile range, 20-85) of weakly acidic reflux extending to the proximal esophagus. Moreover, three of the 15 children not on acid-suppressive therapy during the pH-impedance study had substantial acid reflux (13%, 14%, and 45% distal acid-exposure times). Based on these findings, the authors concluded that gastric aspiration is nearly universal in critically ill pediatric patients who are mechanically ventilated and may contribute to the development of pulmonary complications such as ventilator-associated pneumonias.

Although clearly of great interest, the full pathophysiologic significance of these findings is unclear. They confirm that the pepsin detected in these aspirates originated, in part, from the stomach, hence implicating aspiration of gastric juice. And they confirm that this critically ill population exhibits very substantial proximal esophageal reflux. Nonetheless, the role of pepsin in promoting organ injury remains speculative. Pepsin requires an acidic environment, both to be activated and to be active, so its presence in the tracheobronchial tree, which is nonacidic, is not necessarily pathologic. Pepsin-mediated cytokine release in bronchial epithelial cells has been reproducibly noted only at low pH levels, mainly at about pH 1.5.8 It has been hypothesized that reactivation may occur by subsequent acid reflux/aspiration or by endocytosis into an acidic intracellular environment, but neither mechanism has yet been demonstrated.5 Illustrative of that point, despite having pepsin in the airway and weakly acidic refluxate in the proximal esophagus, none of the children in this study had clinical symptoms of nosocomial pneumonia after 1-week follow-up.

In conclusion, the results of this study are interesting from both a clinical and a physiologic standpoint. The finding that 100% of tracheal aspirates were positive for pepsin A (but not C) suggests that discriminating between pepsin A and pepsin C is essential. Ideally, one would like to strengthen that supposition with data from a pediatric control population verifying that pepsin C can be a “normal” finding. Such data are available in adults, with the finding of 22% positive samples of pepsin C, but not A, in asymptomatic individuals undergoing elective orthopedic surgery.9 Together, these observations cast doubt on the validity of nonspecific pepsin assays. More importantly, it is unclear how these findings correlate with clinical outcomes, because the role of pepsin in mediating supraesophageal manifestations of GERD remains unclear. At this junction, all we can reliably say is that pepsin, specifically pepsin A, is a viable biomarker for gastric juice aspiration. It also seems prudent to prophylactically treat at-risk patients who are mechanically ventilated with proton pump inhibitors. Regardless, this study adds to the growing body of literature on pepsin and GERD; confirms our suspicions that pepsin in tracheal aspirates is, in part, gastric derived; and highlights important questions that will hopefully stimulate further research in this area.

References

Goldberg HI, Dodds WJ, Gee S, Montgomery C, Zboralske FF. Role of acid and pepsin in acute experimental esophagitis. Gastroenterology. 1969;56(2):223-230. [PubMed]
 
Piper DW, Fenton BH. pH stability and activity curves of pepsin with special reference to their clinical importance. Gut. 1965;6(5):506-508. [CrossRef] [PubMed]
 
Samuels TL, Johnston N. Pepsin as a marker of extraesophageal reflux. Ann Otol Rhinol Laryngol. 2010;119(3):203-208. [PubMed]
 
Johnston N, Dettmar PW, Lively MO, et al. Effect of pepsin on laryngeal stress protein (Sep70, Sep53, and Hsp70) response: role in laryngopharyngeal reflux disease. Ann Otol Rhinol Laryngol. 2006;115(1):47-58. [CrossRef] [PubMed]
 
Johnston N, Dettmar PW, Bishwokarma B, Lively MO, Koufman JA. Activity/stability of human pepsin: implications for reflux attributed laryngeal disease. Laryngoscope. 2007;117(6):1036-1039. [CrossRef] [PubMed]
 
Johnston 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(12):2129-2134. [CrossRef] [PubMed]
 
Hallal C, Chaves VS, Borges GC, et al. Acid and weakly acidic gastroesophageal reflux and pepsin isoforms (A and C) in tracheal secretions of critically ill children. Chest. 2015;148(2):333-339.
 
Bathoorn E, Daly P, Gaiser B, et al. Cytotoxicity and induction of inflammation by pepsin in acid in bronchial epithelial cells. Int J Inflam. 2011;2011:569416. [CrossRef] [PubMed]
 
Bohman JK, Kor DJ, Kashyap R, et al. Airway pepsin levels in otherwise healthy surgical patients receiving general anesthesia with endotracheal intubation. Chest. 2013;143(5):1407-1413. [CrossRef] [PubMed]
 

Figures

Tables

References

Goldberg HI, Dodds WJ, Gee S, Montgomery C, Zboralske FF. Role of acid and pepsin in acute experimental esophagitis. Gastroenterology. 1969;56(2):223-230. [PubMed]
 
Piper DW, Fenton BH. pH stability and activity curves of pepsin with special reference to their clinical importance. Gut. 1965;6(5):506-508. [CrossRef] [PubMed]
 
Samuels TL, Johnston N. Pepsin as a marker of extraesophageal reflux. Ann Otol Rhinol Laryngol. 2010;119(3):203-208. [PubMed]
 
Johnston N, Dettmar PW, Lively MO, et al. Effect of pepsin on laryngeal stress protein (Sep70, Sep53, and Hsp70) response: role in laryngopharyngeal reflux disease. Ann Otol Rhinol Laryngol. 2006;115(1):47-58. [CrossRef] [PubMed]
 
Johnston N, Dettmar PW, Bishwokarma B, Lively MO, Koufman JA. Activity/stability of human pepsin: implications for reflux attributed laryngeal disease. Laryngoscope. 2007;117(6):1036-1039. [CrossRef] [PubMed]
 
Johnston 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(12):2129-2134. [CrossRef] [PubMed]
 
Hallal C, Chaves VS, Borges GC, et al. Acid and weakly acidic gastroesophageal reflux and pepsin isoforms (A and C) in tracheal secretions of critically ill children. Chest. 2015;148(2):333-339.
 
Bathoorn E, Daly P, Gaiser B, et al. Cytotoxicity and induction of inflammation by pepsin in acid in bronchial epithelial cells. Int J Inflam. 2011;2011:569416. [CrossRef] [PubMed]
 
Bohman JK, Kor DJ, Kashyap R, et al. Airway pepsin levels in otherwise healthy surgical patients receiving general anesthesia with endotracheal intubation. Chest. 2013;143(5):1407-1413. [CrossRef] [PubMed]
 
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