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ORIGINAL ARTICLE
Year : 2021  |  Volume : 24  |  Issue : 2  |  Page : 199-204

Does inflammation play a role in the pathophysiology of tinnitus?


Department of Clinical Biochemistry, Istinye University, Istanbul, Turkey

Date of Submission23-Jul-2019
Date of Acceptance28-May-2020
Date of Web Publication19-Feb-2021

Correspondence Address:
Dr. M Demir
Department of Clinical Biochemistry, Istinye University, Istanbul
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njcp.njcp_381_19

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   Abstract 


Objective: The present study aimed to investigate the potential of neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR) and mean platelet volume (MPV) as prognostic markers in tinnitus patients at inflammatory process. Methods: This study consisted of 216 subjects (124 males and 92 females), Routine laboratory CBC test results were calculated in this study. All the patients were divided into three groups according to their hearing thresholds: a high frequency hearing loss-tinnitus group (HFHL-TN) consisted of 55 subjects, an hearing loss in all frequencies tinnitus group (AFHL-TN) consisted of 53 subjects and a normal hearing-tinnitus group (NH-TN) consisted of 51 subjects. The control group (CNT) included 57 age-and sex-matched healthy subjects. Results: NLR, PLR and MPV were observed in the HFHL-TN group when compared to AFHL-TN, NH-TN and CNT group (P < 0.001). An increase in NLR was observed in the AFHL-TN group compared with the CNT group (P = 0.004). The PLR value of the HFHL-TN group was significantly higher than that of the AFHL-TN (P = 0.028) and NH-TN,CNTgroup (P < 0001). The PLR value of the HFHL-TN group was significantly higher than that of the AFHL-TN (p=0.028) and NH-TN, CNT group (P < 0001). MPV values in HFHL-TN group was slightly higher AFHL-TN group and significantly higher than NH-TN (P = 0.025) and CNT (P < 0.001) group. Conclusion: Our results confirm that elevated NLR, PLR and MPV values has been suggested to be a useful inflammatuar prognostic biomarker of tinnitus patients.

Keywords: Mean platelet volume,neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, tinnitus


How to cite this article:
Demir M. Does inflammation play a role in the pathophysiology of tinnitus?. Niger J Clin Pract 2021;24:199-204

How to cite this URL:
Demir M. Does inflammation play a role in the pathophysiology of tinnitus?. Niger J Clin Pract [serial online] 2021 [cited 2022 Dec 8];24:199-204. Available from: https://www.njcponline.com/text.asp?2021/24/2/199/309817




   Introduction Top


Tinnitus is a universal disorder that arises from abnormal neural activity in the auditory pathway which is pathologically interpreted by the brain as an acoustic signal.[1] There is no consensus about the neurophysiological etiology and the treatment of tinnitus despite its high prevalence rate. Recently, some researchers have advocated several mechanisms involving brain plasticity and proposed that tinnitus may be associated with any changes at one or more points along the peripheral and central auditory pathways.[2],[3] However, not all people with hearing loss experience tinnitus; there are many people with tinnitus who have clinically normal hearing.[4],[5] There have been no studies investigating the inflammatory processes in pathophysiology of tinnitus in the literature.

The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and mean platelet volume (MPV) have been defined as potential biomarkers of inflammation and can be measured easily in peripheral blood samples.[6],[7],[8] Chronic neuroinflammation caused by noise exposure and hearing loss has been presented in the early stages of the central auditory pathway.[9] It is widely accepted that the circulating white blood cells (WBC) classification undergoes relative changes under systemic inflammation, typically represented by lymphopenia and neutrophilia. In recent years, WBC and subtype counts have been identified as biomarkers of inflammation in several diseases.[10] To our knowledge, the correlation between the NLR, PLR, and MPV values, and tinnitus and hearing loss have not been investigated. Therefore, we investigated the relationship between hearing loss, subjective tinnitus, and inflammation based on NLR, PLR, and MPV values. This method uses values that are measured routinely in complete blood count (CBC) tests with no additional cost.


   Materials and Methods Top


This retrospective study included 216 subjects, 124 males and 92 females, ranging from 21 to 67 years of age who were admitted to otolaryngology clinic with the complaint of tinnitus between September 2015 and September 2017. The study group consisted of patients whose symptoms had begun in a 3-month period. The study protocol was approved by the local ethics committee and conducted in accordance with the ethical principles of the Declaration of Helsinki.

Hearing thresholds were assessed using the Clinical Audiometer AC33 (Interacoustics A/S, Assens, Denmark). The audio/vestibular system was studied through Pure-Tone Audiometry (considering the frequencies 0.5–1–2–4–8 kHz), tympanometry with stapedius reflex. Audiometric threshold was considered as the pure-tone average for the frequencies 0.5–1–2–4–8 kHz and divided into five groups: normal hearing (<20 dB), mild hearing loss (21–40 dB), moderate hearing loss (41–70 dB), severe hearing loss (71–90 dB), and profound hearing loss (>90 dB).

The AT235 (Interacoustics A/S, Assens, Denmark) Tympanometry was used and results were classified into types A, B, and C. Type A denotes the normal tympanometry, whereas types B and C evaluated as abnormal. Stapes reflex was also recorded, and otoacoustic emissions were evaluated by measuring transient evoked otoacoustic emission device. The patients were divided into three groups according to their audiometry: high-frequency hearing loss (high frequency hearing loss tinnitus [HFHL-TN]) 4–8 kHz, hearing loss in all frequencies (all frequencies tinnitus [AFHL-TN]) 0.5–8 kHz, and normal hearing group (normal hearing tinnitus [NH-TN]) at all test frequencies. NLR, PLR, WBC, platelet, MPV, neutrophil, and lymphocyte counts, demographic characteristics, and audiometric data of the patients were also analyzed.

The patients who had coexisting neurological or psychiatric disorders, middle ear disease, retrocochlear lesions and ototoxic medications, history of trauma to the ear, undue exposure to loud or prolonged noise, and cerumen impaction were excluded. In this study, none of the cases had acute inflammatory or infectious disease and/or malignancy. To compare the CBC profile, age- and sex-matched healthy people with no chronic illnesses who came to our hospital for regular health checkups were also included in this study.

CBC was obtained within 12 h after audiometry in all patients. NLR was calculated as the absolute count of neutrophils divided by the absolute count of lymphocyte and PLR by calculating the absolute platelet count divided by the absolute lymphocyte count is suggested as a potential marker to determine inflammation. MPV is a machine-calculated measurement of the average size of platelets found in blood and is typically included in blood tests as part of the CBC.

Blood samples were obtained using a vacutainer and collected in tubes containing standard K2-EDTA. Hematological parameters were determined using a Sysmex 1000i analyzer (Sysmex, Kobe, Japan). CBC analysis was performed within 2 h after blood sampling.

Statistical analysis

All statistical analyses were performed using the SPSS statistical software (SPSS for Windows, version 22.0; SPSS, Inc., Chicago, IL, USA). Continuous variables are presented as mean ± standard deviation, and categorical variables are expressed as median. The normality of data distribution was determined using the Kolmogorov–Smirnov or Shapiro–Wilk tests. Numeric values compatible with the normal distribution were compared using one-way ANOVA test. Data corresponding to an abnormal distribution were compared using the nonparametric Kruskal–Wallis test. Pairwise comparisons were made using Bonferroni posthoc test. Differences were considered significant at P < 0.05.


   Results Top


This study included 159 patients with tinnitus (90 males, 69 females) and 57 healthy people (34 males, 23 females). A total of 216 participants, of whom 124 (57.4%) were men and 92 (42.6%) were women, were included in this study. Prior to our analysis, the demographic characteristics of the patients were analyzed. All the patients were divided into three groups according to their hearing thresholds: HFHL-TN group consisted of 55 subjects (37 males and 18 females), hearing loss in AFHL-TN group consisted of 53 subjects (28 males and 25 females), and NH-TN group consisted of 51 subjects (25 males and 26 females). The control (CNT) group included 57 (34 males and 23 females) age- and sex-matched healthy subjects. We observed no statistical differences in sex among the groups (P = 0.388).

The average age for the HFHL-TN group was 42.20 ± 11.62, AFHL-TN group was 43.30 ± 12.6, NH-TN group was 41.23 ± 13.09, and CNT group was 37.42 ± 7.49 years. Statistically, there were no significant differences among the groups regarding age (P = 0.077). Patients' group had similar ages and genders with CNT group (P > 0.05).

Demographic and laboratory characteristics of all groups are compared in [Table 1] and [Table 2]. For all of the CBC measurements, at least one group was significantly different compared with the other groups (P < 0.05). When the data were evaluated, a significant increase in NLR was observed in the HFHL-TN group compared with AFHL-TN, NH-TN, and CNT groups (P < 0.001). The increase in NLR observed in the AFHL-TN group compared with the CNT group was also found as statistically significant (P = 0.004). When the AFHL-TN (P = 0.060) and CNT (P = 0.999) groups were compared with the NH-TN group, NLR values were not found to be significantly different. [Figure 1].
Table 1: Demographic characteristics of study and control groups

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Table 2: Hematologic values in the study and control groups

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Figure 1: The mean NLR values of the study and control groups

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The PLR value of the HFHL-TN group was significantly higher than that of the AFHL-TN (P = 0.028), and NH-TN and CNT (P < 0001) groups. The PLR value of the AFHL-TN group was significantly higher than those of the CNT group (P = 0.016).

We observed a significant decrease in the PLR value of the CNT group relatively to the NH-TN group, but these differences were not statistically significant (P = 0.999). AFHL-TN group mean PLR value was higher than NH-TN group, but there was no statistical significance (P = 0.281) [Figure 2].
Figure 2: The mean PLR values of the study and control groups

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Mean MPV value in HFHL-TN group was slightly higher than AFHL-TN group but there was no statistical significance (P = 0.340). Other than HFHL-TN group, MPV values were significantly higher than NH-TN (P = 0.025) and CNT (P < 0.001) groups. The MPV values of the AFHL-TN group were significantly higher than those of the CNT group (P = 0.012). When compared NH-TN and AFHL-TN (P = 0.999) groups and CNT (P = 0.230) group, the difference was not statistically significant [Figure 3].
Figure 3: The mean MPV values of the study and control groups

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   Discussion Top


Tinnitus is a frequent problem that still remains poorly understood by medicine. Tinnitus affects approximately 5–15% of the world population.[11] Some studies also showed that 20% of the tinnitus patients experience a quality-of-life impairment.[12] Tinnitus may be seen with serious and minor disorders of the ear and of the body in general.[13]

Tinnitus is not a disease so it may result from very different pathological situations. The most frequent reasons of tinnitus are otologic diseases, such as underlying ear infections, cerumen and noise damages, and foreign body in the ear.[14] Besides, drug intakes which lower serotonin levels secondarily and hearing loss related with exposures to high and severe sounds cause tinnitus frequently. Ototoxic drugs can cause tinnitus, secondary to hearing loss or without hearing loss.[15]

The severity of tinnitus is defined by patients to be exacerbated by stress.[16] There are two major systems that mediate most components of the stress response.[17] Hypothalamic–pituitary–adrenal pathway stimulates the adrenal cortex to release glucocorticoids such as cortisol and corticosterone into the blood, and the sympathetic-adrenomedullary system influences the stress response by two different pathways working in parallel.[18]

Besides, stress and depression may cause an increased number of leukocytes and neutrophils, as well as decreased lymphocytes. Tuglu et al. and Demir et al. also showed that increased NLR values are determined in depressive patients when compared with healthy subjects.[19],[20] It is well known that stress causes inflammation.[21] Neutrophil increase and lymphocyte decrease are physiological responses to stress, and a high NLR is a new precise marker of inflammation.[22]

Inflammation is part of the body's immune response to infection or damage. Hearing loss is known to cause inflammation in the inner ear and parts of the hearing brain. Acoustic injury results in the destruction of hair cells and numerous nonsensory cells of the cochlea, which may also cause an inflammatory response with the production of proinflammatory cytokines. Circulating leukocytes accumulate in the inner ear when an acoustic trauma causes cochlear inflammatory response. Macrophages and other leukocytes may contribute to cochlear repair. The production of proinflammatory cytokines is also important in cochlear injury.[23] After acoustic trauma, cochlear macrophages multiply and migrate throughout the cochlea. It remains uncertain why the mononuclear phagocytes appear in the ligament and limbus after noise exposure in the ear. It may be that cochlear macrophages accumulate in the spiral ligament and limbus, because it is here where blood vessels are the most numerous and, possibly, the most permeable.[24] Changes in blood components such as neutrophils, lymphocytes, and platelets can be observed in the system in inflammatory response. Therefore, NLR and PLR can be potentially considered to indicate inflammation-related tinnitus patients. There has been increasing evidence demonstrated that activated platelets could provoke leukocyte invasion to the vessel wall and trigger the inflammation that can mainly be seen in the pathologic mechanism of atherosclerosis.[25] Seo et al. determined that NLR and PLR values which were related to atherosclerosis in idiopathic sudden sensorineural hearing loss patients were significantly high and that endothelial disruption may play a crucial role in the pathophysiology of hearing loss by the way of inflammatory processes microvascular disturbances.[26]

Recent studies, which focused on platelet count, demonstrated that thrombocytosis was associated with more advanced diseases such as inoperable cancer.[27]

In this study, we found that NLR and PLR levels are higher in the HFHL-TN group, which may indicate an inflammatory process in the pathophysiology of tinnitus in this group of patients. NLR and PLR can be calculated easily and less costly compared with the detection of other inflammatory cytokines. NLR and PLR are also inflammatory indexes in routine blood tests.

MPV was the subject of investigation as a potential marker of platelet reactivity and a surrogate parameter for a broad variety of diseases, and optimal stability was detected in K2-EDTA after 120 min.[28] For pathophysiology of diseases prone to thrombosis and inflammation, platelet activation is a link. Several platelet markers have been investigated in connection with both thrombosis and inflammation including MPV.[29] In literature, increased MPV values are reported in inflammatory diseases such as juvenile idiopathic arthritis, Crohn's disease, ulcerative colitis, diabetes, acute pancreatitis, and acute ischemic stroke patients.[30],[31] Values of MPV levels are still controversial in the literature. Hence, for studies, a uniformity of measurement should be used to make the results comparable with each other.[28]

In our study, MPV values were found to be significantly increased in HFHL-TN group and it was significantly higher than NH-TN and CNT groups. According to our study results, hearing loss and tinnitus are closely related, as previously known; and stress and depression are also closely associated with hearing loss and tinnitus.

The present study has some limitations. First, the subjectivity of tinnitus and the instability of the outcome variables connotes uncertainties as a limitation in the study.

Second, this study was designed as a retrospective study. Further studies should include larger populations that show correlations between NLR, PLR, and MPV, and the clinical characteristics of tinnitus patients.


   Conclusion Top


According to the data obtained from the present study, patients with HFHL tinnitus are exposed to potent inflammation. Our results confirm that NLR, PLR, and MPV values may be a useful index of inflammation, especially in HFHL group tinnitus patients. Chronic inflammation may be a key contributing factor in the pathogenesis of tinnitus. However, larger sample sizes are needed to define the exact role of NLR, PLR, and MPV in the pathogenesis and treatment of the tinnitus, and these findings need to be verified in further research.

Ethics Committee Approval

The study was approved by local ethics committees; written informed consent was obtained for all patients before the application and conforms to the code of ethics of the World Medical Association (Declaration of Helsinki).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2]



 

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