Prevalence of Laryngopharyngeal Reflux Disease in Patients With Diabetes Mellitus

Prevalence of Laryngopharyngeal Reflux Disease in Patients With Diabetes Mellitus *Abdul-latif Hamdan, *Jad Jabbour, *Randa Barazi, *Zeina Korban, and †Sami T. Azar, *yNew York, New York Summary: Objective. To study the prevalence of laryngopharyngeal reflux disease (LPRD) in patients with type 2 diabetes mellitus (T2DM) and report the correlation between LPRD and glycemic control, duration of the disease, and presence of neuropathy. Materials and Methods. This is a cross-sectional study of 100 patients with T2DM and 33 controls matched according to age and gender. The reflux symptom index (RSI) was used to assess the presence of LPRD. A score greater than 10 was considered diagnostic of LPRD. Results. Twenty-two percent of patients with T2DM had RSI above 10 versus 9.1% of controls. The difference was not statistically different (P value of 0.100). The average score of all symptoms of LPRD was higher in the diabetic group compared with the control group. There was a significant increase in the average score of ‘‘throat clearing’’ and ‘‘lump sensation in throat,’’ with a borderline significant increase in ‘‘annoying cough’’ in patients with diabetes versus controls (respective P values of 0.03, 0.025, and 0.066). There was no correlation between LPRD and any of the demographic variables except neuropathy. Conclusion. Patients with T2DM are more likely to have LPRD compared with controls. However, the prevalence of LPRD is not significantly higher in diabetic patients compared with controls. When present, LPRD correlates with neuropathy. Level of Evidence. 2c. Key Words: LPRD–RSI–GERD–Type II diabetes–HbA1c.

INTRODUCTION Gastrointestinal (GI) symptoms are commonly reported in patients with diabetes mellitus. The prevalence of these symptoms has varied in different reports with respect to the methodology used and the selection of subjects.1–5 Bytzer et al1 has reported a higher frequency of GI symptoms in patients with diabetes mellitus compared with controls. Using a validated questionnaire, his results indicated an association between diabetes mellitus and both upper and lower GI symptoms. Similarly, in the evaluation of 110 adult patients with long-standing type 1 diabetes mellitus, Schvarcz et al2 has reported an increased prevalence of upper GI symptoms such as anorexia and vomiting. In a study by Ko et al,3 all types of GI symptoms were more prevalent in patients with type 2 diabetes mellitus (T2DM) compared with controls. On the other hand, a recent study by Maleki et al4 has refuted the association between GI symptoms and diabetes mellitus. The study has failed to detect differences in the prevalence rates of GI symptoms in patients with and without diabetes. The results of this population-based crosssectional study supported those of the previous studies namely that of Janatuinen et al.5 Accepted for publication July 12, 2012. The authors declare that they have no conflict of interest. Financial Disclosure: None reported. From the *Department of Otolaryngology and Head and Neck Surgery, American University of Beirut Medical Center, New York, New York; and the yDivision of Endocrinology, Department of Internal Medicine, American University of Beirut Medical Center, New York, New York. Address correspondence and reprint requests to Sami T. Azar, Division of Endocrinology and Metabolism, Department of Internal Medicine, American University of Beirut Medical Center, 3 Dag Hammarskjold Plaza, 8th floor, New York, NY 10017. E-mail: [email protected] Journal of Voice, Vol. 27, No. 4, pp. 495-499 0892-1997/$36.00 Ó 2013 The Voice Foundation http://dx.doi.org/10.1016/j.jvoice.2012.07.010

Despite the presence of numerous studies on the prevalence of GI symptoms in patients with diabetes mellitus, there are no reports on the prevalence of laryngopharyngeal reflux disease (LPRD) in diabetic patients. LPRD is considered by some authors as a variant of gastroesophageal reflux disease (GERD) and by many others as a separate entity.6,7 It is a spectrum of abnormalities that are identified in almost one of two patients with laryngeal disorders. The diagnosis is often missed because the classic symptoms of dyspepsia and pyrosis are invariably absent. Instead, patients with LPRD complain of globus pharyngeus, change in voice quality, throat clearing, cough, and excessive phlegm. On laryngoscopy, signs of posterior laryngitis, mucosal edema and redness, ventricular obliteration, and muscle tension patterns are observed.8 In view of the poor defense mechanism to guard the laryngeal and pharyngeal mucosa against the refluxate material, namely acid and pepsin,6–8 diligent diagnosis and treatment of laryngopharyngeal disease in diabetic patients are important. The purpose of this study was to look at the prevalence of LPRD in patients with T2DM. The correlation between the symptoms of LPRD and glycemic control, duration of the disease, and presence of neuropathy will be analyzed.

MATERIALS AND METHODS A total of 100 consecutive type 2 diabetic patients presenting to the endocrine clinic at the American University of Beirut were asked to participate in this study after having read and signed the informed consent that was approved by the institutional review board. Exclusion criteria were patients with recent history of upper respiratory tract infection, laryngeal manipulation, and/or surgery. Demographic data included age of the subject, gender, history of smoking, allergy (allergic rhinitis), duration

496 of the disease, glycemic control, and presence or absence of neuropathy. Allergic rhinitis was evaluated using a standardized validated questionnaire in which a score above 0 was considered positive.9 Duration of disease was stratified as less than 5 years, between 5 and 10 years, and more than 10 years. The glycemic control was described as good, average, or poor based on HbA1c level (HbA1c <7% is good, between 7% and 9% average, and above 9% poor). Presence of neuropathy was defined by a positive history of neuropathy and positive sensory symptoms including limb numbness, pricking sensation, aching pain, burning pain, and at least one of the following positive neurologic signs on examination: (1) decreased pressure or pain sensation (positive monofilament test), (2) decrease of light tough sensations (positive cotton wool swab test), and (3) decreased tendon reflexes. A group of 33 subjects matched according to age and gender were used as controls. The authors made sure that the prevalence of allergy and smoking was almost similar in both patients and controls in view of their confounding effect. The reflux symptom index (RSI) designed by Belafsky et al10 was used to assess the presence of LPRD. The following nine questions were answered: (1) hoarseness or problem of voice; (2) clearing your throat; (3) excessive throat mucus or postnasal drip; (4) difficulty swallowing food, liquids, or pills; (5) coughing after you ate or lying down; (6) breathing difficulties or chocking episodes; (7) troublesome or annoying cough; (8) lump in the throat or sticking sensation; and (9) heartburn, chest pain, and indigestion. The symptoms were graded from 0 to 5 in which 0 ¼ no problem and 5 ¼ severe problem. If the total score was greater than 10, patient was diagnosed clinically with LPRD. The correlation between LPRD and demographic data, mainly duration of the disease, glycemic control, and presence of neuropathy, was reported. Frequencies and means (±standard deviation) were used to describe categorical and continuous variables, respectively. At the bivariate level, normal distribution was not assumed for the total reflux symptoms in Table 2 and Wilcoxon and Mann-Whitney rank sum tests were used to determine any significant differences in means of each continuous variable when compared between patients and controls. In Table 4, the independent t test was used for age. Pearson chi-square test and Fisher test were applied as appropriate to assess the presence of any correlation. All analyses were conducted using the SPSS version 17 software package (IBM Corp, Armonk, NY). A two-tailed P value of less than 0.05 was considered statistically significant. RESULTS Demographic data A total of 100 patients with T2DM were recruited for this study. The mean age was 39.55 ± 13.25 years. The male to female ratio was 3:2, and almost one-third of the patients were smokers (33 were smokers). More than 50% had the disease for more than 5 years. Forty-three percent had a good glycemic control, and 29% had a history of neuropathy (Table 1).

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TABLE 1. Descriptive Data of Diabetic Patients and Controls Demographic Variable

Patient

Age (mean ± SD) 53.46 ± 9.51 Gender, n (%) Males 59 (59.0) Females 41 (41.0) Smoking, n (%) No 65 (65.0) Yes 33 (33.0) Missing 2 (2.0) Allergies, n (%) Absent 90 (90) Present 10 (10.0) Duration of disease, y, n (%) <5 47 (47.0) 5–10 15 (15.0) >10 38 (38.0) Glycemic control, n (%) Good 43 (43.0) Average 37 (37.0) Poor 20 (20.0) Neuropathy, n (%) Absent 71 (71.0) Present 29 (29.0)

Control 38.55 ± 13.25 19 (57.6) 14 (42.4) 20 (60.6) 13 (39.4)

30 (90.9) 3 (9.1) N/A

N/A

N/A

Abbreviation: SD, standard deviation; N/A, not applicable.

Prevalence of LPRD in patients with T2DM and controls Twenty-two percent of patients with T2DM had RSI above 10 indicating the presence of LPRD versus 9.1% of controls. The difference was not statistically different (P value of 0.100) (Table 2). Average scores of laryngopharyngeal symptoms in patients with T2DM and controls There was a significant increase in the average score of ‘‘throat clearing’’ and ‘‘lump in the throat,’’ with a borderline significant increase in ‘‘annoying cough’’ in patients with diabetes versus controls (respective P values of 0.03, 0.025, and 0.066). It is also worth noting that the average score of all symptoms was higher in the diabetic group compared with the control group (Table 3 and Figure 1). Correlation between LPRD and demographic variables There was no correlation between LPRD and any of the demographic variables except neuropathy. Patients with neuropathy TABLE 2. Reflux Among Patients and Controls Reflux* No, n (%) Yes, n (%)

Patient

Control

P Value

78 (78.0) 22 (22.0)

30 (90.9) 3 (9.1)

0.100

* RSI: No 10 and yes >10.

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TABLE 3. Average Score of Reflux Symptoms (RSI) Among Patients and Controls Laryngopharyngeal Reflux Symptoms Hoarseness or problem of voice Clearing of throat Excessive throat mucus or postnasal drip Difficulty swallowing food, liquids, or pills Coughing after you ate or lying down Breathing difficulties or choking episodes Troublesome or annoying cough Sensations of something sticking in throat or a lump in throat Heartburn, chest pain, indigestion, or stomach acid coming up

Patients, Mean ± SD

Controls, Mean ± SD

P Value

0.88 ± 1.26 1.30 ± 1.32 0.65 ± 1.11 0.31 ± 0.78 0.48 ± 0.75 0.34 ± 0.79 0.43 ± 0.78 1.09 ± 1.33 1.14 ± 1.21

0.58 ± 0.87 0.73 ± 0.98 0.39 ± 0.83 0.24 ± 0.71 0.39 ± 0.66 0.18 ± 0.53 0.15 ± 0.44 0.55 ± 0.94 1.09 ± 1.33

0.318 0.030* 0.342 0.538 0.654 0.269 0.066** 0.025* 0.699

*Significant results at P < 0.05; **Borderline significance. Abbreviation: SD, standard deviation.

were more likely to have LPRD compared with those with no neuropathy (Table 4).

DISCUSSION LPRD is an underdiagnosed entity in otolaryngology. The low diagnostic rate has been attributed to the low incidence of heartburn and esophagitis in patients presenting with laryngeal complaints.7,8 Instead, nonspecific symptoms such as globus pharyngeus, throat clearing, and cough are often reported. These can be because of the direct effect of the refluxate material on the laryngeal mucosa or can be reflex mediated secondary to irritation of the distal esophagus with subsequent vagal stimulation. Both acid and pepsin have been shown to induce mucosal damage to various extents.11,12 The lack of defense mechanisms in the larynx, namely peristalsis and bicarbonate production, makes the laryngeal mucosa very susceptible to acidic and nonacidic reflux. Subsequently, the presence of laryngeal signs such as interarytenoid pachydermia and edema of the posterior commissure should alert the treating physician to the diagnosis of LPRD. The

low diagnostic yield of the conventional diagnostic tests used in GERD such as barium swallow and esophagoscopy should not deter otolaryngologists from making the proper diagnosis. Wiener et al,13 for instance, has reported normal esophageal manometry in 32 patients with hoarseness and normal esophageal biopsies in 72%. Despite the fact that several studies agree on the higher prevalence of GI symptoms in patients with T2DM, no study has examined the prevalence of LPRD in this group of population. Our study indicates a higher prevalence of LPRD in diabetic patients compared with controls. However, the difference between the two groups was not statistically significant. This higher prevalence can be explained on the basis that LPRD and GERD are two points of one spectrum of a disease. In a study looking at the prevalence of LPRD in 1383 patients with GERD symptoms documented by endoscopy, the results indicated that those with severe GERD had significantly higher LPRD scores compared with those with mild (P < 0.01), moderate (P < 0.05), or inactive disease (P < 0.001). The authors suggested that LPRD is likely to represent a supraesophageal manifestation of GERD that is often underestimated.14 Based

FIGURE 1. Average score of RSI among patients and controls.

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TABLE 4. Possible Correlations Between Demographic Variables and LPRD (RSI >10) Total RSI Demographic Variable

Absent (10)

Present (>10)

P Value

Age (mean ± SD) Gender, n (%) Male Female Duration of disease, y, n (%) <5 5–10 >10 Glycemic control, n (%) Good Average Poor Neuropathy, n (%) Absent Present

53.29 ± 9.79

54.05 ± 8.62

0.745 0.331

48 (81.4) 30 (73.2)

11 (18.6) 11 (26.8)

37 (78.7) 9 (60.0) 32 (84.2)

10 (21.3) 6 (40.0) 6 (15.8)

37 (86.0) 26 (70.3) 15 (75.0)

6 (14.0) 11 (29.7) 5 (25.0)

60 (84.5) 18 (62.1)

11 (15.5) 11 (37.9)

0.157

0.221

0.014*

*Significant results at P < 0.05. Abbreviation: SD, standard deviation.

on the aforementioned, a high prevalence of GI symptoms in diabetic patients would lead us to expect a high prevalence of LPRD as well. What is striking in our study is the higher average score of all nine laryngopharyngeal symptoms in diabetic patients compared with controls and the significant difference in two of these symptoms (Figure 1). The pathogenesis of these symptoms can be explained on the basis of several theories speculated in the understanding of the GI symptoms in diabetic patients. Several theories have been suggested, and these include autonomic neuropathy, poor glycemic control, coexistence of psychiatric illnesses, duration of the disease, obesity and body mass index, and last but not least, the type of medication received by the subjects.3,4,15–18 Evidence to support autonomic neuropathy behind the abnormal GI motility is limited. Clouse and Lustman19 have reported poor correlation between GI symptoms and neuropathy. Similarly, Ko et al in their study on 149 Chinese type 2 diabetic patients failed to demonstrate an association between the presence of GI symptoms and peripheral neuropathy. On multivariate analysis, the duration of diabetes was the only independent parameter associated with the high total score of GI symptoms in diabetic patients.3 On the other hand, our results indicated a correlation between LPRD and neuropathy. This conclusion is in alignment with the emerging consensus on laryngeal sensory neuropathy as a confounding etiological entity in patients suffering from laryngopharyngeal symptoms that are refractory to antireflux treatment. Laryngeal sensory neuropathy is a rare diagnosis based on the lack of objective laryngeal findings. Patients present with symptoms of chronic cough, throat discomfort, and globus pharyngeus in the absence of bronchitis, asthma, postnasal drip, and/or angiotensin-converting enzyme inhibitor intake. The etiology is believed to be a lower threshold for sensory laryngeal nerve firing, which at times may be accompanied by a motor neurop-

athy as well.20 The correlation between LPRD and neuropathy and the significantly higher average scores of two LPRD symptoms in our diabetic group compared with controls suggest that neuropathy might be behind these aforementioned symptoms. However, it should be noted that laryngeal sensory neuropathy and other forms of laryngeal neuropathy have not been investigated in this study and thus remain a hypothesis that warrants future investigation. Other studies have pointed to the acute change in blood glucose level as being a cause of the GI symptoms in diabetic patients. Poor glycemic control has been incriminated in the pathogenesis of diabetic neuropathy, with the most common picture being that of a peripheral neuropathy. Jamali and Mohseni have reported that hypoglycemia elicits degenerative alterations in large myelinated axons of the vagus and recurrent laryngeal nerves in diabetic rats. Diabetic patients with no GI symptoms may still suffer from delayed gastric emptying with resultant unexplained episodes of hypoglycemia.21–23 This indicates that hypoglycemia and gastric symptoms are interrelated.24–27 The results of our study failed to show a correlation between LPRD, glycemic control, and duration of disease. This study has two limitations. One is the lack of 24-hour pH metry to objectively document the presence of LPRD, and the other is the lack of laryngeal examination to assess the laryngeal signs of reflux and the mobility of the vocal folds. Laryngeal assessment would have helped in supporting the correlation between the LPRD and neuropathy. Nevertheless, this is the first study to look at the prevalence of LPRD in diabetic patients and its correlation with neuropathy, glycemic control, and duration of disease. CONCLUSION Patients with T2DM are more likely to have laryngopharyngeal reflux symptoms compared with controls. The prevalence

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of LPRD correlates with the presence of neuropathy but not with the duration of the disease and/or glycemic control. Treating physicians must be diligent in diagnosing reflux disease in diabetic patients and in initiating proper treatment when needed. REFERENCES 1. Bytzer P, Talley NJ, Leemon M, et al. Prevalence of gastrointestinal symptoms associated with diabetes mellitus. A population-based survey of 15,000 adults. Arch Intern Med. 2001;161:1989–1996. 2. Schvarcz E, Palmer M, Ingberg CM, Aman J, Berne C. Increased prevalence of upper gastrointestinal symptoms in long-term type 1 diabetes mellitus. Diabet Med. 1996;13:478–481. 3. Ko GT, Chan WB, Chan JC, Tsang LW, Cockram CS. Gastrointestinal symptoms in Chinese patients with type 2 diabetes mellitus. Diabet Med. 1999;16:670–674. 4. Maleki D, Locke GR, Camilleri M, et al. Gastrointestinal tract symptoms among persons with diabetes mellitus in the community. Arch Intern Med. 2000;160:2808–2816. 5. Janatuinen E, Pikkarainen P, Laakso M, Pyorala K. Gastrointestinal symptoms in middle-aged diabetic patients. Scand J Gastroenterol. 1993;28: 427–432. 6. Park W, Chun HJ, Keum B, et al. An electron microscopic study—correlation of gastroesophageal reflux disease and laryngopharyngeal reflux. Laryngoscope. 2010;120:1303–1308. 7. Koufman JA. Laryngopharyngeal reflux is different from classic gastroesophageal reflux disease. Ear Nose Throat J. 2002;81(9 Suppl 2):7–9. 8. Cohen JT, Bach KK, Postma GN, Koufman JA. Clinical manifestations of laryngopharyngeal reflux. Ear Nose Throat J. 2002;81:19–23. 9. Bauchau V, Philippart D, Durham S. A simple and efficient screening tool for allergic rhinitis. Poster presented at: 23rd Congress of the European Academy of Allergology and Clinical Immunology; June 12-16, 2004; Amsterdam, The Netherlands. 10. Belafsky PC, Postma GN, Koufman JA. Validity and reliability of the reflux symptom index (RSI). J Voice. 2002;16:274–277. 11. Knight J, Lively MO, Johnston N, Dettmar PW, Koufman JA. Sensitive pepsin immunoassay for detection of laryngopharyngeal reflux. Laryngoscope. 2005;115:1473–1478. 12. Koufman JA. 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

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