Insulin Resistance is Associated with Chronic Laryngitis in Korean Women

Abstract

Objectives

The aim of this study was to investigate the association between chronic laryngitis (CL) and insulin resistance (IR) in South Korea using data from the 2010 Korea National Health and Nutrition Examination Surveys (KNHANES).

Design, setting and participants

Cross-sectional data of 4,261 adults who completed KNHANES were analyzed. CL was considered when participants experienced a voice change and demonstrated flexible laryngoscopic findings of diffuse laryngeal inflammation. All participants were assessed for IR using the homeostasis model assessment of insulin resistance (HOMA-IR).

Results

Among the Korean population older than 19 years, the prevalence of chronic laryngitis was 3.8±0.7%. Univariate analysis demonstrated that CL was significantly associated with smoking and systolic and diastolic blood pressure in men and with age, diastolic blood pressure, HDL cholesterol, insulin, and HOMA-IR in women. Multiple regression analysis demonstrated that the mean value of HOMA-IR was significantly associated with CL in women only. In addition, CL was more prevalent in the highest compared with the lowest HOMA-IR quartile (OR [95% CI]: 2.268 [1.053-4.884] after adjusting for age, OR [95% CI]: 2.235 [1.040-6.181] after adjusting for confounding factors of age, body mass index, smoking status, alcohol intake, regular exercise, education, and income).

Conclusions

These findings indicate that IR characterized by HOMA-IR is significantly associated with CL in Korean women only. Our results suggest that HOMA-IR could be an early predictive factor of increased risk of CL in Korean women.

Introduction

Chronic laryngitis (CL) is defined as diffuse laryngeal inflammation for longer than 3 weeks. Typical symptoms of CL are chronic or intermittent hoarseness, weakening of the voice, chronic cough, and chronic need to clear the throat. Laryngopharyngeal reflux disease is one of the most common causes of CL but it can also arise due to infection (e.g., bacteria, mycobacterium, fungus), poor laryngeal hygiene (e.g., tobacco, excessive alcohol or caffeine consumption), voice abuse, and a dusty atmosphere that contains a large amount of fumes (1, 2, 3).

Metabolic syndrome (MetS) has become one of the major health problems throughout world. MetS has been increasing in developed countries including South Korea (4, 5). It is a known risk factor of cardiovascular disease, type 2 diabetes mellitus, and other chronic diseases (6, 7). Insulin resistance (IR) is a pathological condition in which peripheral tissues fail to respond to the normal actions of insulin despite high circulating insulin level (8). IR stimulates systemic lowgrade inflammation, which can increase the risk of chronic inflammatory diseases (9). IR has been regarded as the key feature leading to MetS in the last several decades (10).

Accurate epidemiological information contributes to the proper provision of healthcare, preventive screenings, and rehabilitative services. The Korean National Health and Nutrition Examination Surveys (KNHANES), which are government-driven surveys conducted by the Korea Center for Disease Control and Prevention, have been conducted since 1998 (11). The surveys contain reliable and extensive data for investigating the national prevalence of disease conditions. The relationship between CL and IR in adults has not been investigated using a population-based study. The present study was performed to determine the national prevalence of CL in South Korea based on survey data obtained 2010 KNHANES and to investigate the association between CL and IR according to gender.

Methods

Ethical consideration

Written informed consent was obtained from all participants prior to the survey, and approval for this study was obtained from the Institutional Review Board of The Catholic University of Korea.

Survey for chronic laryngitis

KNHANES was conducted under the National's Health Promotion Act in Korea, designed to gather data on health status, attitudes and behavior towards health, diet, and nutrition of Korean population. Each year, 10000 to 12000 individuals in 4600 households are selected from a panel to represent the Korean population by using the multistage cluster and stratified random sampling method that is based on the Na-tional Census Data. Trained interviewers conducted all the interviews using structured questionnaires to obtain information including sociodemographic factors, health-related factors, lifestyle factors, and the use of medical services.

Participants 19 years of age or older were exam-ined. Laryngologic interviews and vocal fold examinations were performed using a 4-mm 70° angled rigid endoscope equipped with a CCD camera. The chronic laryngitis diagnostic protocol was designed by the Epidemiologic Survey Committee of the Korean Otolaryngologic Society. A laryngologic questionnaire was administered to assess voice problems. The participants with a positive response were considered to have CL. Participants who responded positively to this question were then queried concerning the duration of symptoms with the following question: “How long has this voice problem existed?” (> 3 weeks or < 3 weeks). Laryngoscopic findings of laryngitis and/or inflammation, including Reinke's edema, pseudosulcus, erythema, edema, or thick endolaryngeal mucus, were diagnosed as chronic laryngitis. The Epidemiologic Survey Committee of the Korean Otolaryngologic Society verified the quality of the survey, which was conducted by periodically visiting mobile examination units, educating the partici-pating residents, obtaining laryngeal examination data, and data-proofing using video documentation of the larynx throughout the study. Two otolaryngologic surgeons from the Korean Otolaryngologic Society subsequently verified the video documentation and assessed the disease decision pro-tocol. Documentation of the video was obtained with 640 × 480-sized Audio Video Interleave files, which were com-pressed by DivX 4.12 codec using a compression rate of 6 Mb/sec.

Lifestyle habits

Medical history and lifestyle habits were collected using selfreported questionnaires. Smoking history was categorized as current smoker or nonsmoker. Subjects who drank more than 30 g/day of alcohol were designated as drinkers. Regular exercise was defined as strenuous physical activity performed for a minimum of 20 minutes, three times a week.

Anthropometric and laboratory measurements

Weight and height were measured by trained medical professionals. Standing height was measured without shoes; feet together; arms at the sides; and heels, buttocks, and upper back in contact with the wall. Height was measured in centimeters to the nearest decimal point using SECA 225 (Germany, SECA). Waist circumference (WC) was measured at the level of the midpoint between the iliac crest and the costal margin at the end of a normal expiration to the nearest 0.1 cm. Weight was measured using a GL-6000-20 scale (Cass Korea) in kilograms to the nearest decimal point. BMI was calculated as weight (kg)/height (m2). Blood pressure (BP) was measured while subjects were in a sitting position following a 5-minute rest period. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured in the right arm using a mercury sphygmomanometer (Baumanometer, W. A. Baum Co., Copiague, NY, USA). To assess serum levels of biochemical markers, blood samples were obtained from the antecubital vein of subjects following a 10-12 hour fast. Serum levels of fasting blood sugar (FBS), total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol were measured using an enzymatic method (Hitachi Automatic Analyzer 7600, Hitachi, Tokyo, Japan). Immunoradiometric assays using a 70 WIZARD gamma-counter (PerkinElmer, Finland) were used for measurement of insulin level. The homeostasis model assessment of insulin resistance (HOMA-IR) value was calculated using the following formula: HOMA-IR = FBS (mg/dL) x fasting insulin (mIU/mL)/405 (12). Individuals in the highest quartile of HOMA-IR were defined as insulin resistant, and those in the lowest quartile were defined as insulin sensitive. Quartile HOMA-IR values were calculated according to sex, as described previously (13, 14).

Statistical analysis

Statistical analyses were performed using the Statistical Analysis Software (SAS) survey procedure (v. 9.3; SAS Institute, Cary, NC, USA) in order to reflect the complex sampling design and sampling weights of KNHANES and to provide nationally representative prevalence estimates. The procedures included unequal probabilities of selection, oversampling, and nonresponse so that inferences could be made regarding the Korean adolescent participants.

The prevalence and 95% confidence intervals (CI) of chronic laryngitis were calculated. In the univariate analysis, the Rao-Scott Chi-square test (using PROC SURVEYFREQ in SAS) and logistic regression analysis (using PROC SURVEYLOGISTIC in SAS) were used to test the associations between chronic laryngitis and risk factors using a complex sampling design. Participant characteristics were described using mean and standard error (SE) for continuous variables and number and percentage for categorical variables. Simple and multiple linear regression analyses were used to examine the association between chronic laryngitis and insulin resistance. The models included no adjustments (model 1), adjustment for age (model 2), and adjustment for the variables in model 2 plus BMI, smoking status, alcohol intake, regular exercise, education, and income (model 3). P-values were two-tailed, and a P < 0.05 was considered significant.

Results

The demographics of the study subjects are summarized in Table 1. Among the 4,261 participants older than 19 years, 154 experienced CL, resulting in a prevalence of 3.8±0.7%. The mean age of men with CL was significantly higher than that of men without CL. Current smoking, high SBP, and high DBP were significantly associated with CL in men. Mean values of DBP, HDL cholesterol, insulin, and HOMA-IR were significantly different among women with CL than among women without CL.

Table 1.

Analysis of factors potentially associated with chronic laryngitis (n=4,261)

Parameter		Male			Female
	Yes (n=81)	No (n=1733)	P-value	Yes (n=73)	No (n=2374)	P-value
Age (years)	49.3±1.8	41.9±0.6	<0.0001*	45.8±2.4	43.6±0.5	0.3643
Body mass index (kg/m2)	23.8±0.3	24.0±0.1	0.4571	23.3±0.5	22.9±0.1	0.3546
Waist circumference (cm)	84.0±1.1	83.7±0.3	0.8207	77.9±2.1	76.5±0.3	0.5080
Systolic BP (mmHg)	127.9±2.0	120.8±0.5	0.0011*	118.0±2.2	115.5±0.5	0.2497
Diastolic BP (mmHg)	83.8±1.4	80.1±0.4	0.0090*	76.9±1.3	73.9±0.3	0.0166*
Glucose (mM)	93.8±1.1	93.1±0.3	0.5660	92.6±1.3	90.5±0.2	0.1225
Total cholesterol (mM)	193.8±4.7	186.8±1.2	0.1456	191.0±5.6	185.0±1.1	0.2866
HDL cholesterol (mM)	50.6±1.7	50.0±0.4	0.7315	52.5±1.8	56.4±0.3	0.0317*
LDL cholesterol (mM)	113.4±6.2	108.0±1.1	0.3917	114.4±4.7	108.1±0.9	0.1804
Triglyceride (mM)	132.0 (112.6-154.7)	122.8 (117.6-128.3)	0.4127	103.6 (83.4-128.6)	87.9 (85.4-90.5)	0.1377
Insulin (µIL/mL)	9.6 (8.7-10.6)	9.5 (9.3-9.8)	0.9195	10.8 (9.9-11.7)	9.5 (9.2-9.7)	0.0047*
HOMA-IR	2.2 (2.0-2.4)	2.2 (2.1-2.3)	0.9921	2.4 (2.2-2.7)	2.1 (2.1-2.2)	0.0054*
Current Smoker (%)	61.5±8.3	41.8±1.5	0.0243*	7.5±3.2	5.6±0.7	0.4992
Routine exercise (%)	23.7±4.3	25.9±1.3	0.6476	17.6±5.6	20.2±1.2	0.6593
Employed (%)	91.3±3.5	81.0±1.2	0.0345*	56.2±8.9	54.8±1.4	0.8754
Married (%)	89.7±4.3	67.7±1.7	0.0010*	68.1±7.4	66.6±1.5	0.8487
Residential area; Rural (%)	84.4±6.1	78.5±3.2	0.3498	85.1±7.1	78.0±3.4	0.3864
Education; ≥ High school (%)	72.4±7.1	81.2±1.4	0.1635	60.8±5.7	68.7±1.7	0.1871
Income; lower quartile (%)	15.6±5.6	12.8±1.2	0.5996	22.6±5.5	17.0±1.2	0.2335

Values are mean ± SE or % ± SE; * Significant at p<0.05

Table 2 shows mean comparison of HOMA-IR values according to CL status for both genders after adjustment for confounders. The mean value of HOMA-IR for women was significantly associated with CL (2.42 vs. 2.10, p=0.0054 in model 1, 2.42 vs. 2.11, p=0.0073 in model 2, and 2.21 vs. 2.11, p= 0.0140 in model 3). However, the adjusted mean value of HOMA-IR for CL was not significantly different in men.

Table 2.

Mean comparison of HOMA-IR values according to the presence or absence of chronic laryngitis by gender

Model		Male			Female
	Presence of CL	Absence of CL	P-value	Presence of CL	Absence of CL	P-value
Model 1	2.19 (1.96-2.43)	2.18 (2.12-2.25)	0.9921	2.42 (2.20-2.66)	2.10 (2.05-2.15)	0.0054*
Model 2	2.19 (1.96-2.43)	2.19 (2.13-2.25)	0.9970	2.42 (2.20-2.67)	2.11 (2.06-2.16)	0.0073*
Model 3	2.19 (2.05-2.34)	2.17 (2.15-2.20)	0.8055	2.21 (2.13-2.29)	2.11 (2.10-2.13)	0.0140*

Model 1: Non-adjusted; Model 2: Adjusted for age; Model 3: Adjusted for age, body mass index, smoking status, alcohol intake, regular exercise, education, and income; CI = confidence interval

^*Significant at p<0.05

As shown in Table 3, CL was more prevalent in the highest compared with the lowest HOMA-IR quartile among women (OR [95% CI]: 2.268 [1.053-4.884] in model 1, OR [95% CI]: 2.235 [1.040-6.181] in model 2) after adjusting for confounders. However, the adjusted OR for CL was not significant for men with higher HOMA-IR quartiles. A gradual increase in prevalence of CR according to HOMA-IR quartile was observed in women (p for trend = 0.0322) but not in men (p for trend =0.9865) (Fig. 1).

Table 3.

Adjusted ORs (95% CI) of chronic laryngitis by gender-specific quartile of HOMA-IR

Quartile	Odds ratio (95% CI)
		Male			Female
	Model l		Model 2	Model l		Model 2
1st Quartile	1		1	1		1
2nd Quartile	0.757 (0.383-1.497)		0.813 (0.418-1.583)	1.473 (0.685-3.166)		1.659 (0.738-3.729)
3rd Quartile	1.433 (0.842-2.441)		1.607 (0.939-2.751)	0.245 (0.620-2.502)		1.364 (0.657-2.883)
4th Quartile	0.766 (0.404-1.492)		0.812 (0.385-1.716)	2.268 (1.053-4.884)		2.235 (1.040-6.181)

Model 1: Adjusted for age; Model 2: Adjusted for age, body mass index, smoking status, alcohol intake, regular exercise, education, and income; CI = confidence interval

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Figure 1.

Prevalence of chronic laryngitis according to insulin resistance quartile in men and women

Discussion

In this cross-sectional study, a positive and independent relationship was observed between CL and IR in women but not in men, in whom no association was observed. This is the first population-based study to investigate the association between CL and IR in adults, with a separate assessment depending on gender.

Gastroesophageal reflux disease (GERD) such as gastric acid or pepsin affects the larynx (1). Chronic damage to the laryngeal mucosa by gastric contents can be the result of laryngopharygeal reflux disease or CL (2). According to the Korean Standard Classification of Diseases, the prevalence of GERD in Korea has increased rapidly since 2005 (15). In particular, middle-aged people and women have a high incidence of GERD. The larynx can be affected by contact with refluxed material from the stomach. The prevalence of abnormal laryngoscopic findings among patients with suspected GERD was previously shown to be 69% (16). When GERD affects the laryngopharynx, the disease entity is called extraesophageal reflux or laryngopharygeal reflux. Upper esophageal sphincter dysfunction is associated with extraesophageal manifestation. The most common extraesophageal manifestation in patients with GERD is hoarseness (2). The presence of gastric contents in the laryngopharynx causes a variety of mucosal responses such as vocal edema, erythyema of the posterior larynx, psedusulcus, and edema of the subglottis (17, 18).

Laryngitis is a common condition and is often seen by primary care practitioners and otolaryngologists. CL is long-term irritation of the laryngeal mucosa. Therefore, laryngeal examination using a fiber optic laryngoscope generally reveals diffuse edema or erythema of the laryngeal mucosa. CL has diverse causes related to laryngeal irritation: (1) gastric contents that reflux into the larynx, (2) inhaled substances such as tobacco or industrial smoke, and (3) inhalation or ingestion of noxious or toxic chemicals (19). Among these causes, CL is most commonly attributed to gastric reflux.

MetS is a cluster of metabolic abnormalities that has been highlighted as a risk factor of cardiovascular and other chronic diseases. The strong relationship between GERD and MetS has been pathophysiologically analyzed in terms of obesity, mechanical factors, and metabolic changes (20, 21). IR is a condition in which cells become less sensitive to insulin. This is frequent in people with visceral adiposity, hypertension, hyperglycemia, and dyslipidemia. Therefore, IR is known to play a pivotal role in MetS. Several previous studies have reported positive correlation between IR and GERD (20, 22, 24). The HOMA-IR, developed by Matthews et al., has been widely used for the estimation of IR in research (25). In our study, among women, HOMA-IR was the only metabolic risk factor associated with CL in multiple regression analysis. Estrogen might be the cause of the gender-based differences in association between CL and HOMA-IR. The lack of estrogen in postmenopausal status is related to the increased risk of visceral obesity. Obesity is the major contributory factor of development of IR. In addition, we recently reported that obese women in Korea have an elevated risk for developing CL (26). Although the underlying pathophysiology of this phenomenon is not clearly understood, it might be explained by considering CL as a part of the many consequences of chronic systemic inflammation that accompanies IR.

The major strength of this study was the many covariates for which the model was adjusted. In addition, we present the first association between CL and IR. However, there are some limitations to be noted. First, this study relies on cross-sectional data and is not amenable to defining the relationship between CL and IR. Nonetheless, a significant association between these two variables was established. Second, we did not determine the relative severity or grade of CL due to the absence of objective testing and more detailed questions. In practice, the diagnosis of CL is first based on exclusion and is suspected when a history including symptoms and laryngoscopic findings is suggestive of the diagnosis. Therefore, we followed this practical approach for diagnosis of CL. Finally, the concept of HOMA-IR was employed to define IR. Unlike this study, a few other studies have relied on fasting serum insulin as a marker for IR. However, there are no standardized diagnostic criteria or methods to define IR. Further studies employing prospective, randomized methods to examine CL are warranted.

In conclusion, we showed that IR characterized by HOMAIR was significantly associated with CL in only adult Korean women. Therefore, the treatment of CL might include measures to correct metabolic disorders such as IR, especially in women.

Conflict interest

None declared.