|Year : 2020 | Volume
| Issue : 4 | Page : 199-204
Oral submucous fibrosis and risk of eustachian tube dysfunction: A meta-analysis
Surekha R Rathod1, Vivek Harkare2, Noopur P Gonde1, Suresh Ughade3
1 Department of Periodontics and Implantology, VSPM Dental College and Research Centre, Nagpur, Maharashtra, India
2 Department of ENT, NKP Salve Institute of Medical Sciences, Nagpur, Maharashtra, India
3 Department of PSM, Government Medical College, Nagpur, Maharashtra, India
|Date of Submission||28-Aug-2020|
|Date of Decision||09-Oct-2020|
|Date of Acceptance||19-Oct-2020|
|Date of Web Publication||23-Apr-2021|
Dr. Surekha R Rathod
Department of Periodontics and Implantology, VSPM Dental College and Research Centre, Digdoh Hills, Hingna Road, Nagpur, Maharashtra
Source of Support: None, Conflict of Interest: None
Introduction: Oral submucous fibrosis (OSF) is a chronic disease, affecting the oral cavity and sometimes the pharynx. It is always associated with juxtaepithelial inflammatory reaction followed by fibroelastic changes of the lamina propria, with epithelial atrophy leading to the oral mucosa and causing trismus and inability to eat. It may also involve the pharyngeal orifice of the eustachian tube (ET). Objective: The aim of this systematic review and meta-analysis was to synthesize the available evidence to determine the effect of OSF on ET function. Materials and Methods: Title and the protocol for the systematic review and meta-analysis were registered in Prospero. Individual with OSF, observational case–control study, human trials, and the article published in English language were included in the study. There were no limits on the number of patients were taken in cases or control groups. Results: The overall pooled odd ratio (OR) of hearing impairment for with OSF compared without OSF was 10.65 with 95% confidence interval (CI) =3.17–35.74. A positive association between OSF and prevalence of ET dysfunction was observed between the study characteristic. A strong and significant association between hearing impairment and OSF was observed (OR = 10.56, 95% CI = 3.17–35.75, P = 0.001). Conclusion: Results of our meta-analysis demonstrates increased risk of hearing impairment in patients with OSMF.
Keywords: Eustachian tube dysfunction, hearing impairment, hearing loss, oral submucous fibrosis, submucous fibrosis
|How to cite this article:|
Rathod SR, Harkare V, Gonde NP, Ughade S. Oral submucous fibrosis and risk of eustachian tube dysfunction: A meta-analysis. Indian J Otol 2020;26:199-204
| Introduction|| |
Oral submucous fibrosis (OSF) is defined as a chronic insidious disease, affecting any part of the oral cavity and sometimes the pharynx. Although occasionally precede by and/or associated with vesicle formation, it is always associated with juxtaepithelial inflammatory reaction followed by fibroelastic changes of the lamina propria, with epithelial atrophy leading to the oral mucosa and causing trismus and inability to eat.
In India, the prevalence of OSF is between 0.03% and 3.2%. An estimated number of 700,000–900,000 new cancers are diagnosed each year in India (National Cancer Registry Programme, 2001). Variety of factors such as betel nut alkaloids, capsaicin, hypersensitivity, autoimmunity, genetic predisposition, and chronic iron and Vitamin B-complex deficiency attributed to OSF. In the Indian subcontinent, areca nut chewing is a traditional practice and still retains its popularity as a chewing habit. OSF patients most often complain of soreness of the mouth, intolerance to chilies and spicy foods, burning sensation of the mouth, ulceration of oral mucosa, and difficulty in protruding the tongue and mouth opening.
It may also involve the pharyngeal orifice of the eustachian tube (ET) and paratubal muscles, thereby affecting its functions and causing pain along with other pathological changes in the middle ear that eventually lead to hearing impairment. Numerous researchers have elaborated on the pathological changes of soft palate muscles. The involvement of soft palate muscle such as tensor veli palatine and levatorveli palatine, along with the other accessory muscles is referred to as paratuble muscles. The functions of the ET are impaired by the extension of fibrosis into the nasopharynx involving the pharyngeal orifice of the ET and inside the muscles. In 1994, Gupta et al. 2004 clinically evaluated the function of the auditory tube using pure tone audiometry and found significant hearing impairment in patients with OSF. Significant correlation was observed between the degree of fibrosis of the palatal muscles and hearing deficit reported by Chaudhary et al.
Previous studies investigating the association between hearing loss and OSF have estimated hearing loss using objective measures such as pure tone audiometry and other measures, but some of studies also report subjective hearing loss measured as a self-reporting outcomes. As of today, no systematic review and meta-analysis have been carried out studying the association between OSF and ET dysfunction. Hence, the aim of this systematic review and meta-analysis was to synthesize the available evidence to determine the effect of OSMF on ET function.
| Materials and Methods|| |
The title and the protocol for the systematic review and meta-analysis were registered on Prospero with registration number CRD42020173490.
The inclusion criteria for review as follows: (1) individuals with OSF and ET function were included in the study, (2) observational case–control study, (3) human trials, and (4) the article published in English language. There were no limits on the number of patients were taken in cases or control groups.
The nonhuman, in vitro study, the article published in nonenglish language, retrospective, case reports, or case series, systemically unhealthy adults with other oral conditions, the technical or animal studies or reviews were excluded from the review.
This systematic review and meta-analysis was conducted in accordance with the meta-analysis of observational studies in epidemiology statement and was sent for registration in PROSPERO. Online database (PUBMED/MEDLINE and GOOGLE SCHOLAR) were searched to find the relevant studies till December 2017. The search term “OSF” or “OSMF” or “Submucous fibrosis” and “Hearing Impairment or “Hearing Loss'” or “ET dysfunction” were used. Reference list of published articles was also searched. The selection of the study was done step by step on the basis of PRISMA guidelines. At title stage, studies that included OSF with any other condition were excluded from the review. After that from the selected article, the reviewer did the complete screening of the full text for eligibility. At the full-text stage, two investigators read and assessed each of the articles based on the criteria used in previous stages. The full text article was extracted if the title did not provide sufficient information. After screening by reviewers, the studies that did not meet the inclusion criteria were further excluded from the study. Then, the relevant parameters with the corresponding data were extracted and included in the review [Figure 1].
The extraction of data from each publication was as follows: author's name, publication year, country, number of cases (with OSF) and controls (without OSF), number of total and hearing-impaired participant, mean or range of age, and definition of hearing loss for each study [Table 1].
The reader (XY and YZ) independently selected references on the basis of titles and abstract for the effect of OSF on ET dysfunction. The readers were standardized by discussion sessions after assessment of every ten abstracts. If necessary, the exclusion criteria were revised after discussion and abstracts already screened were re-adjusted to the selection.
Data analysis and statistical analysis
We computed a pooled odd ratio (OR) hearing impairment in person with OSF compared to those without OSF and relevant 95% confidence interval (CI) using the comprehensive meta-analysis software, “open meta analyst” to generate the forest plots and to assess heterogeneity of the included studies.
Cochrane's Q and I2 statistics were used to examine heterogeneity. If Q was statistically significant (P < 0.10), the I2 statistic estimated the percentage of variation across the samples due to heterogeneity. I2 values of 0%–40% (low), 41%–60% (medium), and 61%–100% (high) were used to categorize levels of heterogeneity. For pooled effect sizes with significant heterogeneity, mixed-effects Q-tests for analysis of variance were used to examine whether confounding variables accounted for variance within effect estimates. Sensitivity analyses were also conducted to examine whether removing studies with anomalous characteristics would account for heterogeneity and affect pooled effects.
Publication bias was statistically assessed by funnel plot method and P < 0.05 was considered statistically significant.
| Results|| |
Study selection and characteristics
From the 51 records initially found, articles involving seven case–control studies (Gupta et al. 2004, Shah et al. 2011, Siddiqui et al. 2014, Devi et al. 2015, Chandran et al. 2016, Sowbhagya et al. 2016, Kumar 2018.) were included in this meta-analysis. A detailed flow chart of the selection process is shown in [Figure 1]. Characteristics of included studies comprised total 300 cases and 300 controls from all the studies [Table 1]. Out of seven studies, four studies included both males and females. All the studies describe the method of hearing assessment. The hearing assessment was performed using a variety of methods such as pure tone audiometry, tympanography, Madsen Orbiter 922 audiometer test. Most studies have used a threshold of 25 dB for hearing impairment. The studies included were having bilateral hearing impairment. The OSF was diagnosed on the clinical diagnosis or on the measurement of interincisal distance.
Overall estimation of prevalence risk of eustachian tube dysfunction and oral submucous fibrosis
A total of seven studies were included in the meta-analysis. Due to the greater degree of heterogeneity observed between the study, estimates from the random effect model were considered. The overall pooled OR of hearing impairment for with OSF compared without OSF was 10.65 with 95% CI = 3.17–35.74 [Table 2]. Between-study heterogeneity was found highly significant factor in the observed association (I2 = 72.29%; P < 0.001) [Table 3]. An attempt was made to minimize between-the-study heterogeneity through sensitivity analysis and stratified analysis. Even after excluding two outlier studies by Gupta et al. 2004 and Shah et al. 2011 in the sensitivity analysis, the heterogeneity remains unchanged. Publication bias was not statistically detected by the funnel plot [Figure 2].
The results on the effect of OSF on ET dysfunction versus without OSF patients in this meta-analysis are supported further by the forest plots in [Figure 3]. The majority of the studies in the forest plot for show increased risk of ET dysfunction in OSF individuals as compared to the healthy individual.
The horizontal axis (X-axis) of forest plot represents the standardized mean differences and the vertical line in the plot indicates “line of null effect” or no statistically significant difference between OSF and ET dysfunction and control groups. The average effect sizes for ET dysfunction are illustrated by the square symbol in the bottom most row in the respective forest plots. The horizontal line passing the square symbol demonstrates a 95% CI for the average effect size. Each diamond symbol in the forest plot indicates the overall or combined effect size for all the studies taken together. It should be noted that the two studies that had large effect sizes and suggested outliers were removed from the analysis but even after removing them, no significant difference was observed in the final result.
The result of the stratified and meta-regression analyses across a number of key studies characteristic considered to explore the origin of heterogeneity and the influence of the characteristic on the study results. A positive association between OSF and prevalence of ET dysfunction was observed between the study characteristic. A strong and significant association between hearing impairment and OSF was observed (OR = 10.56, 95% CI = 3.17–35.75, P = 0.001).
| Discussion|| |
The present meta-analysis reveals that the risk of ET dysfunction was 10 folds higher in OSF patients than in without OSF. Previous studies reported anemia, vitamin, iron, and protein deficiency in OSF patients causing sideropenic dysphagia which leads to mucosal susceptibility to irritants such as chili and areca nut use. Functional impairment, such as reduced mouth opening, burning sensation of oral mucosa, can affect the normal food intake and results in nutritional deficiency.
It is well known that aging is associated with hearing impairment. However, ET dysfunction in OSF at younger age was discovered according to our finding. There is an increased occurrence of OSF in the younger age group due to increased use of areca quid and ghutka. OSF younger adults with ET dysfunction are likely to affect the quality of life.
The meta-analysis of observational studies in principal can never prove causality. However, a reasonable explanation is given as to how OSF could influence the ET function leading to hearing impaired progression. Physiologically, opening and closing function of the ET is important. This ET is connected to middle ear cavity by nasopharynx. Tensor veli palatine and levator veli palatine are the main muscles which is attached to the ET and soft palate. Dysfunction and patency of ET is due to the involvement of parapalatal muscle fibrosis, tensor veli palatine, and levator veli palatine muscles, which caused a discomfort in ear, leading to mild-to-moderate conductive hearing loss with OSF disease.
In OSF, the prominent features seen are the involvement of soft palate muscle like tensor veli palatine and levatorveli palatine. Numerous researchers have elaborated on the pathological changes of soft palate muscles. The author Oliver and Radden. conducted study on individuals with OSF and observed tissues under microscope and found that dense collagen bundles are oriented and extended into underlying muscle. Rajendra et al. reported extensive fatty infiltration between bundle of muscles, focal lysis, and hypercontraction of myofibers in OSF patients. ET dysfunction in OSF can be due to palatal muscle fibrosis, leading conductive hearing loss. EL Labban and Caniff 1985 compared ultrastructural changes in normal individuals' muscle fibers and OSF patients and found severe degenerative changes in a high proportion in patients with OSF. There were two outlier studies which may affect the heterogeneity of the meta-analysis, but after excluding the studies, no statistical difference was found in the heterogeneity. Finding of this meta-analysis therefore suggests that there is increased risk of ET dysfunction in OSF. Previous available data suggested that, after surgical management, there is an improvement in mouth opening and hearing efficiency which also improves the quality of life. Our results suggest an independent association of ET dysfunction and OSF, although it is impossible to eliminate the possibility of residual confounding factors.
Limitations of this meta-analysis must be considered. First, our meta-analysis is based on findings of observational studies; therefore, it is impossible to consider the confounding factor in linking OSF and hearing impairment (e.g., age, consumption of areca nut, and tobacco in any form). Second, limited data were provided on the prevalence of the severity of grading of OSF in the included studies and extent of the involvement of the muscle. Third, the onset of occurrence of hearing impairment and OSF was not considered. It is possible that patient with OSF may develop asymptomatic hearing impairment which is diagnosed after patient experienced burning sensation and reduced mouth opening due to OSF. Fourth, there were no studies that matched OSF with hearing impairment and without OSF subject, with respect to location where source of noise exposure were similar. Therefore, the extent of noise exposure might have been different between OSF and without OSF group.
The methods which are commonly used to differentiate healthy mucosa from OSF affected mucosa are clinical and histopathologic method. However, these methods have inherent limitation that the disease condition is diagnosed with a delayed stage and progression of once the patient develops OSF then it requires extensive treatment including nonsurgical and surgical therapy, which in some cases turns into malignancy and requires extensive chemotherapy and surgical therapy. All this increases the treatment time as well as cost of treatment. Hence, it is advantageous to forecast the future disease activity at an earlier stage, by knowing the exact stage of OSF and ET dysfunction. This is the first meta-analysis performed to study the risk of association between OSF and ET dysfunction. Statistical analysis of data suggested a strong association between OSF patients and ET function. Therefore, when treating OSF, it is important to take into account hearing loss due to eustachian dysfunction and vice versa because treatment of hearing impairment without treating OSF will not succeed.
| Conclusion|| |
The previous literature suggests that the causative factor for OSF is the contents of areca nut mainly arecoline and tannin. These chemical agents interfere with the molecular process of deposition or degradation of collagen, and it could cause further imbalance in the normal process. Results of our meta-analysis demonstrate an increased risk of hearing impairment in patients with OSF. In addition, the outcome is likely to be independent of the staging, grading, and interincisal distance in OSF patients. Further studies are required to elucidate the association between staging of OSF and prevalence of ET dysfunction in terms of hearing deficient.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Yoithapprabhunath TR, Maheswaran T, Dineshshankar J, Anusushanth A, Sindhuja P, Sitra G. Pathogenesis and therapeutic intervention of oral submucous fibrosis. J Pharm Bioallied Sci 2013;5:S85-8.
Saraswathi TR, Ranganathan K, Shanmugam S, Sowmya R, Narasimhan PD, Gunaseelan R. Prevalence of oral lesions in relation to habits: Cross-sectional study in South India. Indian J Dent Res 2006;17:121-5.
] [Full text]
Krishna Priya M, Srinivas P, Devaki T. Evaluation of the prevalence of oral mucosal lesions in a population of eastern coast of South India. J Int Soc Prev Community Dent 2018;8:396-401.
Swarup N, Nayak MT, Chowdhary Z, Nayak A, Naina, Vermani MC. Does oral submucous fibrosis affect the hearing ability of an individual? A cross-sectional study in north Indian population. Pesqui Bras Odontopediatria Clín Integr 2019;19:47-5.
Pindborg JJ, Sirsat SM. Oral submucous fibrosis. Oral Surg Oral Med Oral Pathol 1966;22:764-79.
Binnie WH, Cawson RA. A new ultrastructural finding in oral submucous fibrosis. Br J Dermatol 1972;86:286-90.
Gupta SC, Singh M, Khanna S, Jain S. Oral submucous fibrosis with its possible effect on eustachian tube functions: A tympanometric study. Indian J Otolaryngol Head Neck Surg 2004;56:183-5.
Chaudhary MS, Mohite DP, Gupta R, Patil S, Gosavi S, Gawande M, et al
. Evaluation of Hearing efficiency in patients with oral sub mucous fibrosis. Otolaryngology 2013;3:143.
Shah M, Khatarkar A, Shah P, Alam N, Modh D. Tympanometric study of ET function in oral submucous fibrosis. Indian J Otol 2011;17:80-2. [Full text]
Siddiqui SN, Saawarn N, Nair PP, Singh P, Gharote HP, Hegde K. ET dysfunction in OSMF Often present seldom discovered. J Clin Exp Dent 2014;6:e369-73.
Devi P, Singh I, Setru R, Tyagi K, Singh D, Thiyam B. Evaluation of hearing deficit in patients with oral submucous fibrosis. J Oral Sci 2015;57:109-13.
Chandran A, Aswath N. Assesment of function of ET in oral submucous fibrosis – A Tympanometric study. J Clin Diag Res 2016;10:13-5.
Sowbhagya. Audiometric and tympanometric assessment in patients with oral submucous fibrosis. Br J Med Med Res 2016;13:1-7.
Kumar A. Effect of oral submucous fibrosis on Auditory tube function: A case control study. Int J Sci Stud 2018;6:8-10.
Karthik H, Nair P, Gharote HP, Agarwal K, Ramamurthy Bhat G, Kalyanpur Rajaram D. Role of hemoglobin and serum iron in oral submucous fibrosis: A clinical study. ScientificWorldJournal 2012;2012:254013.
Hoffmann D, Brunnemann KD, Prokopczyk B, Djordjevic MV. Tobacco-specific N-nitrosamines and Areca-derived N-nitrosamines: Chemistry, biochemistry, carcinogenicity, and relevance to humans. J Toxicol Environ Health 1994;41:1-52.
Schames J, Schames M, King K, Boyd J, Ulansey S. Trigeminal pharyngioplasty: Treatment of the forgotten accessory muscles of mastication which are associated with Orofacial Pain and Ear Symptomatology. AJPM 2002;12:102-12.
Dhingra PL, Dhingra S. Diseases of ear, nose, throat. In: Physiology of Ear Ch. 3., 5th
ed. India: Elsevier; 2010. p. 63-8.
Oliver AJ, Radden BG. Oral submucous fibrosis. Case report and review of the literature. Aust Dent J 1992;37:31-4.
Rajendra R, George B, Sivakaran S, Narendranathan N. Visceral organ involvement is infrequent in oral submucous fibrosis (OSF). Indian J Dent Res 2001;12:7-20.
El-Labban NC, Canniff JP. Ultrastructural finding of Muscles degeneration in oral submucous fibrosis. J Oral Pathol 1985;14:709-17.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]