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A RATIO OF SEP70 AND PEPSIN EXPRESSION IN HYPOPHARYNX COMBINED WITH HYPOPHARYNGEAL MULTICHANNEL INTRALUMINAL IMPEDANCE INCREASES THE DIAGNOSTIC SENSITIVITY OF LARYNGOPHARYNGEAL REFLUX
Toshitaka Hoppo*, Ali H. Zaidi, Daisuke Matsui, Samantha Martin, Yoshihiro Komatsu, Emily J. Lloyd, Albert A. Civitarese, Natalie Boyd, Amit Shetty, Ashten N. Omstead, Emily Smith, Blair A. Jobe
Esophageal & Lung Institute, Allegheny Health Network, McMurray, PA
Background: We previously demonstrated that depletion of hypopharyngeal squamous epithelium stress protein (Sep70) in the presence of Pepsin indicates cellular injury due to LPR. The objectives of this study were to measure hypopharyngeal Pepsin and Sep70 expression in an asymptomatic non-GERD population and compare with a symptomatic population to assess whether these protein profiles combined with hypopharyngeal multichannel intraluminal impedance (HMII) have the potential to increase diagnostic sensitivity in evaluating LPR symptoms.
Methods: Asymptomatic subjects without a history of GERD or LPR were prospectively recruited. Absence of symptoms was confirmed by a score of 0 on both GERD-HRQL and Reflux Symptoms Index (RSI). Subsequently, subjects underwent unsedated transnasal endoscopy with hypopharyngeal biopsy and 24-hour HMII. HMII provided the following data: 1) abnormal proximal exposure (APE), defined as ≥1 LPR event and/or ≥5 proximal reflux events per 24 hours, and 2) DeMeester score (DMS). All subjects with a positive APE or DMS were excluded. Western blot analysis was performed to measure absolute values of Pepsin and Sep70 expression in the biopsy specimens. Then, a cut-off point was created using the lower limit of a 90% confidence interval for the ratio of Sep70 and Pepsin as a benchmark to indicate significant LPR. Next, a retrospective review of patients with LPR symptoms who had undergone HMII with hypopharyngeal biopsy was performed and compared with the normative group. The outcome of ARS was assessed using RSI at a mean follow-up of 8 months.
Results: Of 30 subjects enrolled, 23 (76%) 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. Demographic data are summarized in Table 1. Compared to the normative group, Pepsin expression was significantly higher in the symptomatic group, whereas there was no difference in Sep70 expression in the hypopharynx. However, the ratio of Sep70 and Pepsin was significantly lower in the symptomatic group, and the cutoff of the ratio for a diagnosis of LPR was determined to be 158 (Figure 1). Of 105 patients, 48 patients underwent ARS. Of 17 patients who completed both pre- and post-RSI, LPR symptoms have resolved or improved in 15 (88%), of whom 2 had negative APE but met criteria for a diagnosis of LPR based on a Sep70 Pepsin ratio of <158.
Conclusions: There is an inverse relationship between tissue levels of Sep70 and Pepsin in patients with APE and LPR symptoms. This indicates that LPR events deliver Pepsin and other caustic agents to the hypopharynx that results Sep70 depletion; these APE events may elude detection by HMII. This ratio may serve as a reliable biomarker in the diagnosis of LPR and help to identify those patients who have a false negative HMII result.
Demographic data of the normative and symptomatic patients
| | Normative (n=7) | Symptomatic (n=105) | | Mean age | 28 (23-39) | 58 (27-84) | | Mean BMI | n/a | 29 (17-48) | Gender
Male
Female | 2 (29%)
5 (71%) | 28 (27%)
77 (73%) | | HMII | | APE+/LPR+
(n=59) | APE+/LPR-
(n=30) | APE-
(n=16) | Symptoms
LPR only
Both GERD&LPR | | 33 (56%)
26 (44%) | 19 (63%)
11 (37%) | 13 (81%)
3 (19%) | Esophagitis
A
B
C
D
Unknown | | 37 (63%)
17 (46%)
14 (38%)
3 (8%)
2 (5%)
1 (2%) | 13 (43%)
8 (13%)
2 (15%)
1 (8%)
0 (0%)
2 (15%) | 3 (19%)
1 (33%)
2 (67%)
0 (0%)
0 (0%)
0 (0%) | Hiatal hernia
≤ 3cm
>3cm | | 29 (49%)
25 (86%)
4 (14%) | 9 (30%)
8 (89%)
1 (11%) | 7 (44%)
5 (71%)
2 (29%) | | Antireflux surgery (ARS) | | 31 (53%) | 11 (37%) | 6 (38%) |
 Comparison of Pepsin and Sep70 protein expression in the hypopharynx between the normative and symptomatic patients. The ratio of Sep70 and Pepsin was significantly lower in the symptomatic patients. The bar shows the cut-off point for the ratio to indicate significant LPR.
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