Hoarseness In Iranian Patients With Nonerosive Gastroesophageal Reflux Disease: A Case Control Study

 

Hashem FakhreYaseri^1,2,*, Mahboobe Asadi³

¹Gastroenterology, Research Center for Gastroenterology and Liver Disease, Firoozgar Hospital,

Iran University of Medical Sciences, Tehran, Iran

²Department of Internal Medicine, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran

³Departement of Otolaryngology, Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran

 

ABSTRACT:

Background/Aims: The concept of laryngopharyngeal reflux (LPR) that causes aerodigestive symptoms has gained increasing attention in the recent years. Reflux into the oesophagus is successfully detected by multichannel intraluminal impedance monitoring (MII/pH). The present study aimed at determining the frequency of hoarseness in Iranian patients with nonerosive gastroesophageal reflux disease (NERD). Methods: This case control study was conducted on 425 patients aged 11 to 65 years, with dyspepsia and gastroesophageal reflux disease (GERD), diagnosed based on the questionnaire and esophaggastrodoudenoscopy findings. The case group included 345 patients with nonerosive reflux disease (NERD), and the control group included 80 dyspeptic patients without gastroesophageal reflux disease. Esophageal multichannel intraluminal impedance-pH (MII-pH) monitoring was done for 345 of the patients who did not have esophageal injuries (NERD). RESULTS: Hoarseness was more prevalent in NERD patients (33%) than in those patients with dyspepsia (8.75%) (OR: 5.15, 95%CI: 1.9-13.6, P = 0.008). Moreover, of the 345 patients, 147 (42.6%) were positive for esophageal acid exposure time (EAET). Conclusions: The present study revealed that  hoarseness was more prevalent in patients with nonerosive reflux disease (NERD) than in those with dyspepsia, moreover, nearly half of the patients with NERD were EAET positive. Thus, collaboration between gastroenterologists and otorhinolaryngologists could  improve the the quality of life of patients with GERD and may also help the early diagnosis of the laryngeal symptoms.

 

 

 

 

 

 

INTRODUCTION:

Gastroesophageal reflux disease (GERD) is a chronic disease that has been defined based on Montreal Consensus as the reflux of gastric contents into the esophagus.¹ Although it may be asymptomatic or have bizarre symptoms, it presents with heartburn or acid regurgitation, ranging from 10% to 20% in Western countries and less than 2.5%  to 6% in Asian countries.² Nonerosive reflux disease (NERD) is a subcategory of GERD, which is characterized by absence of esophageal mucosal erosions, or breaks at esophagogastrodoudeonscopy (EGD). Patients with NERD are subdivided in to 2 groups based on esophageal multichannel intraluminal impedance-pH (MII-pH) monitoring: a patient with positive or negative acid exposure time.^3,4 The vocal cords are made of membranous structures in the larynx and are responsible for sound production.⁵ Hoarseness is a type of dysphonia, which is associated with burning throat sensation. It can be secondary to the chronic local irritation caused by the acid material that returns to the hypopharynx during  GERD.⁶ Hoarseness is known as a symptom of GERD or a manifestation of extresophageal reflux (EER) complications,^5,7 especially in laryngopharyngeal reflux (LPR), which is characterized by altered vocal quality and impairs communication or reduces voice-related quality of life.⁸ However, Fannin et al. reported that the typical and atypical laryngeal symptoms do not correlate statistically with the values of reflux nor the resting LES and UES pressure. In a recent study, Koufman et al. studied 113 consecutive laryngeal disorders and found that 69% of patient with laryngeal symptoms had reflux disease, moreover, pathological pH-manometric findings were reported in 50% of these patients.⁶ The present study aimed at determining the frequency of hoarseness in Iranian patients with nonerosive gastroesophageal reflux disease.

 

MATERIALS AND METHODS:

Patients:

We conducted a case control study of patients with upper gastrointestinal disease (defined as the disease persistence for >3 months) from September 2012 to January 2017. The study population consisted of 3578 patients, with the age range of 11 to 80 years. All patients provided informed consent and accepted to complete a standard questionnaire. Esophagogastroduodenoscopy (EGD) was performed for all the patients in the same center by expert endoscopists. Of the total participants, 345 patients aged 11 to 65 years  who had GERD symptoms without esophagitis, called nonerosive reflux disease (NERD), were selected as the case group.  Esophageal manometry and esophageal multichannel intraluminal impedance-pH (MII-pH) monitoring were done for all of them. The control group included 80 patients with dyspepsia without esophagitis and GERD symptoms who were randomly selected. The exclusion criteria were as follow: history of malignant diseases, previous foregut surgery, cardiovascular diseases, pregnancy, breast-feeding, psychiatric illness, history of alcohol or drug abuse, large hiatal hernia, and esophageal varices. Patients with dyspepsia, GERD symptoms, and negative esophagitis in EGD were included. Achalasia finding in barium swallow, esophageal manometry or EGD was excluded. The hoarseness symptom was recorded in the 2 groups. Those patients with severe dysphonia referred to an othorhinolaryngologist for examination and pharyngolaryngoscopy. Frequency of the hoarseness symptom was graded on a 3-point Likert scale as follows: mild = symptoms that can be easily ignored; moderate = awareness of symptoms but easily tolerated; and advanced severity = symptoms sufficient to interfere with normal activities. Smoking was recorded as positive or negative. The Body mass index (BMI) was calculated by weight in kilogram in fasting state divided by square of height in meters. All patients accepted to undergo esophageal manometry.

 

Esophageal Multichannel Intraluminal Impedance-pH (MII-pH) Monitoring:

MII-pH monitoring was performed on an outpatient basis using an ambulatory MII-pH system (manufactured by Mui Scientific, Ontario, CA).The MII-pH catheter (Unisensor AG, Bahnstr, Switzerland),with 6 impedance electrodes and 1 pH sensor (K6011-EI-0632), was inserted transnasally. Impedance measuring sites were located in the distal esophagus at 3, 5, 7 and 9 cm and 2 impedance measuring sites in the proximal esophagus at 15 and 17 cm above the LES. One antimony pH sensor was located 5 cm above the LES, allowing the simultaneous pH analysis in the distal esophagus. MII-pH data were recorded for at least 23 hours and properly downloaded. The location of the lower esophageal sphincter was determined by high resolution manometry (HRM) using 23-channel silicone-customized water-perfused catheter (manufactured by Mui Scientific, Ontario,CA).The proton pump inhibitors (PPIs) were evaluated and the patients were asked to discontinue PPIs for at least 2 weeks, and H2-antagonist, prokinitic agents, and antacid for at least 3 days  prior to MII-PH study. The patients were advised to continue daily regular activities and to have a minimum of 3 standard meals during the study period. In addition, the patients were asked to avoid eating fruit juice and acidic beverages including apple, orange, or lemon juice during the examination and to push the symptom indicator button on the MII-pH each time they experienced heartburn and regurgitation. The following parameters were obtained from MII-pH recordings. The esophageal acid exposure of time (EAET) provided a quantitative measure of the time in which esophageal pH remained below 4 in the distal esophagus, expressed as a percentage. A total EAET of >4.0% was used to define elevated acid exposure; upright and recumbent were not separately calculated. This test had a sensitivity of 91% and specificity of 85% for discriminating acid reflux.³

 

Statistical Analysis:

Data were entered into SPSS Version 19 after encoding for each participant. Age and BMI were reported with mean ± standard deviation. The results were expressed as odds ratios (ORs) with 95% confidence interval (CIs). Comparison of statistical significance was made between the symptom categories using either the Mantel-Haenszel chi-squared test with Yates correction, or the Fisher’s exact probability test. A p value less than 0.05 was considered statistically significant.

 

RESULTS:

In this study, 3578 patients had dyspepsia (2012- 2017). After exclusion of patients with achalasia based on manometric findings and barium swallow, we found that 29.7% (1065/3578) of the patients had GERD symptoms (heartburn, regurgitation, or both), 28.2% (300/1065)of the patients with GERD had erosive esophagitis, and 71.8% (765/1065) showed normal results in esophagogastroduodenoscopy for nonerosive gastroesophageal disease (NERD). In the case group, 345 patients with NERD were included and esophageal multichannel intraluminal impedance-pH (MII-PH) monitoring was done for them. The MII-pH monitoring results revealed that 57.4% (198/345) of these patients were negative for esophageal acid exposure of time (EAET) and 42.6% (147/345) were positive for EAE. Furthermore, 48.2% (55/114) of the patients who had hoarseness were EAET positive ( not shown in the table). As presented in Table 1, hoarseness was more prevalent in NERD patients (33%) than in those with dyspepsia (8.75%)(OR:5.15, 95%CI:1.9-13.6, P = 0.008).The rate of smoking was the same in  case and control patients. Body mass index (BMI) of the 2 groups was the same. Thus, smoking and BMI did not affect hoarseness, at least in this study.

 

Table1- Demographic Information of 345 Patients with NERD and 80 Patients With Dyspepsia and Relation With Hoarseness

NERD: Nonerosive Reflux Disease; CI: Coefficient Interval;n: Numbers; SD: Standard Deviation

 

DISCUSSION:

To the best of our knowledge, this was the first Iranian case-control study to date to examine the relationship between hoarseness and nonerosive reflux disease (NERD) association with esophageal multichannel intraluminal impedance-pH(MII-PH) monitoring. Our results revealed that 33.0% of the patients in the case (NERD) group had hoarseness and that this rate was higher than that of the control group (8.7% patients with dyspepsia without gastroesophageal reflux disease).Only 48.2% (55/114)of the patients who had hoarseness were EAET positive, similar to previous reports.³ On the other hand, 51.8% (59/114) of these patients were EAET negative. In this study, the rate of smoking was the same in case and control groups. In addition, body mass index (BMI) of the 2 groups was similar. Thus, smoking and BMI did not have an impact on hoarseness, at least in this study.

 

The causal relationship between hoarseness and NERD has been poorly understood. Although some studies showed negative effects of acid reflux on mucosa of the larynx, other researchers suggested functional impact of acid reflux on voice- related parameters.⁹ Primary care physicians (PCPs) have recommended proton pump inhibitors (PPIs) and prokinitic agents prescription as an empirical therapy to manage and confirm the diagnosis of GERD.^9,10 Acid reflux is responsible for several extraesophageal symptoms including globus  pharynges, hoarseness, chronic laryngitis, contact ulcers, sore throat, chronic cough, and granulomas.⁶ Spantideas  et al. found that more than 50% of patients with hoarseness have reflux-related diseases. Smoking and chronic voice abuse are the most common causes of chronic laryngitis.⁷ Laryngopharyngeal reflux (LPR) occurs when refluxate material escapes the esophagus and reaches to structures superior to the level of the upper esophageal sphincter (UES).⁹ Mucosal exposure of the pharynx and the larynx to the different components of the gastric refluxate (eg, acid) are the proposed mechanism for supraoesophageal complications of GERD.⁶ The physiological barriers protect the upper aerodigestive tract from reflux injury, which are as follow: the lower esophageal sphincter (LES), esophageal motor function with acid clearance, esophageal mucosal tissue resistance, and the upper esophageal sphincter (UES). Laryngoscopy, esophagodoudenal endoscopy, esophageal manometry, and multichannel intraluminal impedance (MII/pH), especially by double-probe pH monitoring are recommended for diagnosis of LPR.^2,9 Although the findings of the present study have revealed a positive relationship between hoarseness and NERD, 51.8% (59/114) of the patients with hoarseness were EAET negative. In our opinion, evaluation of hoarseness and LPR based on acid or nonacid reflux could not be sufficient to make a decision about treatment because hoarseness and laryngeal disorders can be functional, or hypersensitive hoarseness may be used as esophageal classification of NERD patients. The present study had some limitations. First and foremost was that hoarseness had overlap symptoms with other causes of laryngeal inflammation despite all the otolaryngologist’s workups. Second, not all our patients had accepted MII/pH- metry, so it could have had a different prevalence.Third, using double probe pH monitoring to diagnose proximal esophageal reflux may have different results. Fourth, as have recently been reported, 49% of patients with GERD without heartburn had extraesophageal manifestations (eg, hoarseness).²

 

CONCLUSIONS:

The present study revealed that hoarseness was more prevalent in patients with  nonerosive reflux disease than in those with dyspepsia. Moreover, nearly half of these patients were EAET positive. Other modalities such esophageal peristaltic study and combined dual channel multichannel intraluminal impedance (MII)/pH-metry in 'off-proton pump inhibitor (PPI) are required for correct diagnosis and management. Furthermore, collaboration between gastroenterologists and otorhinolaryngologists may help the early diagnosis of laryngeal symptoms in patients with GERD and may improve their quality of life. Undoubtedly, the findings of the present study should also be tested on a larger sample sizes using double probe pH monitoring.

 

ACKNOWLEDGMENTS:

We express our appreciation to the Departments of Gastroenterology, Endoscopy, Pathology, and the Motility Disorders Laboratory of Firoozgar Teaching Hospital.

 

REFERENCES:

1.     Vakil N,Zanten SV,Kahrilas P,et al.“The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus,” American Journal of Gastroenterology.2006;101(8);1900-43

2.     Lee B E,Kim G H, Ryu D Y, Kim D U, Cheong J H,Lee D G, and Song G A.Combined Dual Channel Impedance/pH-metry in Patients With Suspected LaryngopharyngealReflux. J Neurogastroenterol Motil, 2010;16(2);157-65

3.     Savarino E,Pohl D,Zentilin P, Dulbecoo P, Sammito G,Sconfienza L,Vigneri S,Camerini G,Tutuian R and Savarino V.Functional heartburn has more in common with functional dyspepsia than with non-erosive reflux disease.Gut.2009;58;1185-91

4.     Yaseri H F. Functional heartburn in Iranian patients with non erosive gastroesophageal reflux disease. Bali Medical Journal.2018;7(1);161 4.

5.     Francis D O and Vaezi M F.Should the Reflex Be Reflux? Throat Symptoms and Alternative Explanations.Clinical Gastroenterology and Hepatology 2015;13:1560–6

6.     Mosca F,Rossillo V, and Leone C A.Manifestations of gastro-pharyngo-laryngeal reflux disease .Acta Otorhinolaryngol Ital. 2006 Oct;26(5); 247–51

7.     Spantideas N,Drosou E,Karatsis A, and Assimakopoulos D. Voice Disorders in the General Greek Population and in Patients With Laryngopharyngeal Reflux. Prevalence and Risk Factors. Journal of Voice.2015;29(3); 389.e27–389.e32

8.     Printza A,Kyrgidis A,Oikonomidou E, and Triaridis S. Assessing Laryngopharyngeal Reflux Symptoms with the Reflux Symptom Index:Validation and Prevalence in the Greek Population.Otolaryngology– Head and Neck Surgery.2011;145(6);974–80

9.     Park J O,Shim M R,Hwang Y S,Cho K J,Joo Y H,Cho J H,Nam I C,Kim M S and Sun D I.Combination of  Voice Therapy and Antireflux Therapy Rapidly Recovers Voice-Related  Symptoms in Laryngopharyngeal Reflux Patients .Otolaryngology–Head and Neck Surgery. 2012;146(1); 92–7

10.   Ciorba A,Bianchini C,Zuolo M and Feo C V .Upper aerodigestive tract disorders and gastro-oesophageal reflux disease .World J Clin Cases. 2015;3(2):102–11

 

 

 

 

 

 

 

 

 

 

Accepted on 26.04.2018           © RJPT All right reserved

Research J. Pharm. and Tech 2018; 11(7): 2961-2964.