Increased risk of sudden sensorineural hearing loss in patients with hepatitis virus infection
Hsin-Chien Chen, Chi-Hsiang Chung, Chih-Hung Wang, Jung-Chun Lin, Wei-Kuo Chang, Fu-Huang Lin, Chang-Huei Tsao, Yung-Fu Wu, Wu-Chien Chien
Published: April 6, 2017
http://dx.doi.org/10.1371/journal.pone.0175266
Abstract
The etiology of sudden sensorineural hearing loss (SSNHL) remains unclear. Possible causes of SSNHL include vascular diseases, viral infection, and autoimmune disorders. Therefore, we investigated whether hepatitis virus infection is correlated with the risk of SSNHL. Using data from the Taiwan Longitudinal Health Insurance Database, we conducted a retrospective matched-cohort study to compare patients diagnosed with hepatitis B or C virus (HBV/HCV) infections from January 1, 2000, to December 31, 2010, (N = 170,942) with frequency-matched controls (N = 512,826) at a ratio of 1:3 by sex, age, and index year. We followed each patient until the end of 2010 and evaluated the incidence of SSNHL. At the end of the follow-up period, 647 (0.38%, 647/170,942) patients developed SSNHL in the HBV/HCV group compared with 978 (0.19%, 978/512,826) in the control groups, with a statistical significance of P < 0.001 (using the log-rank test). The incidence rate ratio of SSNHL was 5.743-fold higher in the HBV/HCV group than in the control group (283.17 vs. 49.31 per 100,000 person-years, P < 0.001). The risk of SSNHL increased with HBV/HCV infection, and an adjusted hazard ratio of 5.103 (95% CI, 4.585–5.678) was determined using Cox proportional hazards regression. This study contributes to the awareness of the increased risk of SSNHL in HBV/HCV-infected populations. Our findings suggest that an underlying viral infection contributes to the development of SSNHL.
Discussion Only
Hsin-Chien Chen, Chi-Hsiang Chung, Chih-Hung Wang, Jung-Chun Lin, Wei-Kuo Chang, Fu-Huang Lin, Chang-Huei Tsao, Yung-Fu Wu, Wu-Chien Chien
Published: April 6, 2017
http://dx.doi.org/10.1371/journal.pone.0175266
Abstract
The etiology of sudden sensorineural hearing loss (SSNHL) remains unclear. Possible causes of SSNHL include vascular diseases, viral infection, and autoimmune disorders. Therefore, we investigated whether hepatitis virus infection is correlated with the risk of SSNHL. Using data from the Taiwan Longitudinal Health Insurance Database, we conducted a retrospective matched-cohort study to compare patients diagnosed with hepatitis B or C virus (HBV/HCV) infections from January 1, 2000, to December 31, 2010, (N = 170,942) with frequency-matched controls (N = 512,826) at a ratio of 1:3 by sex, age, and index year. We followed each patient until the end of 2010 and evaluated the incidence of SSNHL. At the end of the follow-up period, 647 (0.38%, 647/170,942) patients developed SSNHL in the HBV/HCV group compared with 978 (0.19%, 978/512,826) in the control groups, with a statistical significance of P < 0.001 (using the log-rank test). The incidence rate ratio of SSNHL was 5.743-fold higher in the HBV/HCV group than in the control group (283.17 vs. 49.31 per 100,000 person-years, P < 0.001). The risk of SSNHL increased with HBV/HCV infection, and an adjusted hazard ratio of 5.103 (95% CI, 4.585–5.678) was determined using Cox proportional hazards regression. This study contributes to the awareness of the increased risk of SSNHL in HBV/HCV-infected populations. Our findings suggest that an underlying viral infection contributes to the development of SSNHL.
Discussion Only
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To the best of our knowledge, this is the first large-scale retrospective matched-cohort study to explore the association between SSNHL and HBV/HCV infection. The main finding of this study was that patients who were diagnosed as having HBV/HCV infections between January 1, 2000, and December 31, 2010, had a significantly higher incidence of SSNHL, with an IRR of 5.743 (P < 0.001), than did the general population without HBV/HCV infections.
The prevalence of HBV/HCV infections varies from <0.5% in Western countries to 8%–25% in endemic countries in East Asia [19]. In our study, the prevalence of HBV/HCV infections was 17.4%. Compared with females, males were predominantly infected with HBV/HCV (110,150 males vs. 60,792 females). The age at diagnosis of HBV/HCV infection was usually >40 years, which was compatible with a previous report describing a mean age at diagnosis of 42 years; 60% of these were male patients [20]. In addition, our study demonstrated that the development of SSNHL was most common in patients aged ≥40 years, and that most patients with development of SSNHL were men (395 males vs. 252 females).
At the end of follow-up, all comorbidities were significantly differentially distributed between the HBV/HCV and control groups (Table 1). In the HVB/HCV group, a lower rate of the participants with individual comorbidity was observed for most comorbidities, whereas for depression and SLE, a higher rate of the participants was observed compared with the control group. A higher frequency of some degree of depression was reported in both hepatitis B and C patients [21]. However, our finding of a higher percentage of SLE in patients with HBV/HCV infection was inconsistent with previous results [22]. Additional in-depth investigations are warranted to explore the codependence among these comorbidities and HBV/HCV infections through multivariate analyses.
Our data revealed that the incidence of SSNHL was approximately two-fold higher in the HBV/HCV group than in the control group, and that this difference was significant. The general estimated incidence of SSNHL varies from 5 to 20 cases per 100,000 per year [1]. In our study, the annual incidence of SSNHL was approximately 38 cases per 100,000 in the HBV/HCV group compared with 19 cases per 100,000 in the control group. The incidence noted in our study was relatively high because the use of a nationwide and large-scale survey may have increased the number of patients treated for SSNHL in outpatient and inpatient departments. In a previous report, the annual SSNHL incidence in Taiwan ranged between 6.49 and 10.21 per 100,000; this number included only the SSNHL patients with hospital admission [23].
Despite the association between HBV/HCV infection and several risk factors for SSNHL, the risk of SSNHL remained significantly higher in the HBV/HCV infection cohort, after adjustment for sex, age group, and comorbidities. The association between HBV/HCV infections and SSNHL may be because of shared risk factors. However, we can confidently claim that the increased risk of SSNHL in these patients was likely the effect of HBV/HCV infection, because the possible confounding factors for SSNHL were already substantially adjusted for in this study. Even in the subgroups of HBV or HCV infection alone, a significantly increased risk of SSNHL (with a higher adjusted HR) was observed compared with the control group. These data indicate that hepatitis virus infection has a very strong impact on the risk of SSNHL.
The underlying mechanisms linking HBV/HCV infections with SSNHL development remain unclear. We hypothesized that, in patients with HBV/BCV infections, SSNHL could occur due to an acute exacerbation of viral hepatitis and subsequent SNHL [8] or a chronic viral reaction causing chronic hearing loss [24, 25]. Viruses could gain access to the inner ear via the hematogenous route and induce severe pathophysiologic changes or an immune-mediated reaction [8]. HBV/HCV infections can stimulate the production of inflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1, and interleukin-6, which are injurious to the cochlear hair cells [26]. In addition, hepatitis virus infection has a well-documented association with polyarteritis nodosa, which is a life-threatening necrotizing vasculitis that may result in hearing loss [24, 27].
Our results demonstrate that a greatly increased risk of SSNHL was observed in patients with HBV/HCV infections, according to the data of a large population (170,942 patients with HBV/HCV and 512,826 controls) selected from a retrospective matched-cohort comprising 1,000,000 people covered by the National Health Insurance program; the large sample size benefitted the statistical analysis. This large data resource enables us to investigate the risk factors for SSNHL in Taiwan, with an acceptable selection bias and an enhanced statistical precision.
Our research has several shortcomings. First, several potentially confounding risk factors, such as alcohol consumption, smoking, ototoxic drug effects, and noise exposure for SSNHL, were unavailable in the data resource, which may have led to a certain bias [28]. Second, the database did not provide audiometric results regarding the degree of hearing impairment or routine blood and biochemistry tests data. Third, a population-based study cannot clarify the real mechanism underlying the association between HBV/HCV infection and SSNHL because extracting cochlear tissue pathogens or detecting cochlear injury through imaging is very difficult [7, 8]. In addition, patients who developed SSNHL due an ototoxic effect after antiviral drug administration for HVB/HCV infection (which has been reported in some studies) could not be excluded [10, 11]. However, a case–control study revealed pegylated interferon plus ribavirin therapy does not have any impact on the hearing thresholds of patients with HCV [29]. Finally, we could not exclude the possibility of virus-unrelated hepatitis, such as alcohol-related hepatitis, being correlated with the risk of SSNHL. Additional large-scale studies need to be performed to clarify the discrepancy between virus-induced SSNHL and hepatitis-induced SSNHL. Despite these limitations, this study contributes to the awareness of the increased risk of SSNHL in HBV/HCV-infected populations.
Conclusions
In this study, HBV/HCV infections present a clearly elevated risk for SSNHL. Regular audiometric tests are recommended for patients with HBV/HCV infection to assess their hearing ability and enable the earlier detection of SSNHL. We also suggest that HBV or HCV carriers presenting with the sudden onset of hearing loss should be examined for the possibility of acute exacerbation of chronic HBV/HCV infection.
To the best of our knowledge, this is the first large-scale retrospective matched-cohort study to explore the association between SSNHL and HBV/HCV infection. The main finding of this study was that patients who were diagnosed as having HBV/HCV infections between January 1, 2000, and December 31, 2010, had a significantly higher incidence of SSNHL, with an IRR of 5.743 (P < 0.001), than did the general population without HBV/HCV infections.
The prevalence of HBV/HCV infections varies from <0.5% in Western countries to 8%–25% in endemic countries in East Asia [19]. In our study, the prevalence of HBV/HCV infections was 17.4%. Compared with females, males were predominantly infected with HBV/HCV (110,150 males vs. 60,792 females). The age at diagnosis of HBV/HCV infection was usually >40 years, which was compatible with a previous report describing a mean age at diagnosis of 42 years; 60% of these were male patients [20]. In addition, our study demonstrated that the development of SSNHL was most common in patients aged ≥40 years, and that most patients with development of SSNHL were men (395 males vs. 252 females).
At the end of follow-up, all comorbidities were significantly differentially distributed between the HBV/HCV and control groups (Table 1). In the HVB/HCV group, a lower rate of the participants with individual comorbidity was observed for most comorbidities, whereas for depression and SLE, a higher rate of the participants was observed compared with the control group. A higher frequency of some degree of depression was reported in both hepatitis B and C patients [21]. However, our finding of a higher percentage of SLE in patients with HBV/HCV infection was inconsistent with previous results [22]. Additional in-depth investigations are warranted to explore the codependence among these comorbidities and HBV/HCV infections through multivariate analyses.
Our data revealed that the incidence of SSNHL was approximately two-fold higher in the HBV/HCV group than in the control group, and that this difference was significant. The general estimated incidence of SSNHL varies from 5 to 20 cases per 100,000 per year [1]. In our study, the annual incidence of SSNHL was approximately 38 cases per 100,000 in the HBV/HCV group compared with 19 cases per 100,000 in the control group. The incidence noted in our study was relatively high because the use of a nationwide and large-scale survey may have increased the number of patients treated for SSNHL in outpatient and inpatient departments. In a previous report, the annual SSNHL incidence in Taiwan ranged between 6.49 and 10.21 per 100,000; this number included only the SSNHL patients with hospital admission [23].
Despite the association between HBV/HCV infection and several risk factors for SSNHL, the risk of SSNHL remained significantly higher in the HBV/HCV infection cohort, after adjustment for sex, age group, and comorbidities. The association between HBV/HCV infections and SSNHL may be because of shared risk factors. However, we can confidently claim that the increased risk of SSNHL in these patients was likely the effect of HBV/HCV infection, because the possible confounding factors for SSNHL were already substantially adjusted for in this study. Even in the subgroups of HBV or HCV infection alone, a significantly increased risk of SSNHL (with a higher adjusted HR) was observed compared with the control group. These data indicate that hepatitis virus infection has a very strong impact on the risk of SSNHL.
The underlying mechanisms linking HBV/HCV infections with SSNHL development remain unclear. We hypothesized that, in patients with HBV/BCV infections, SSNHL could occur due to an acute exacerbation of viral hepatitis and subsequent SNHL [8] or a chronic viral reaction causing chronic hearing loss [24, 25]. Viruses could gain access to the inner ear via the hematogenous route and induce severe pathophysiologic changes or an immune-mediated reaction [8]. HBV/HCV infections can stimulate the production of inflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1, and interleukin-6, which are injurious to the cochlear hair cells [26]. In addition, hepatitis virus infection has a well-documented association with polyarteritis nodosa, which is a life-threatening necrotizing vasculitis that may result in hearing loss [24, 27].
Our results demonstrate that a greatly increased risk of SSNHL was observed in patients with HBV/HCV infections, according to the data of a large population (170,942 patients with HBV/HCV and 512,826 controls) selected from a retrospective matched-cohort comprising 1,000,000 people covered by the National Health Insurance program; the large sample size benefitted the statistical analysis. This large data resource enables us to investigate the risk factors for SSNHL in Taiwan, with an acceptable selection bias and an enhanced statistical precision.
Our research has several shortcomings. First, several potentially confounding risk factors, such as alcohol consumption, smoking, ototoxic drug effects, and noise exposure for SSNHL, were unavailable in the data resource, which may have led to a certain bias [28]. Second, the database did not provide audiometric results regarding the degree of hearing impairment or routine blood and biochemistry tests data. Third, a population-based study cannot clarify the real mechanism underlying the association between HBV/HCV infection and SSNHL because extracting cochlear tissue pathogens or detecting cochlear injury through imaging is very difficult [7, 8]. In addition, patients who developed SSNHL due an ototoxic effect after antiviral drug administration for HVB/HCV infection (which has been reported in some studies) could not be excluded [10, 11]. However, a case–control study revealed pegylated interferon plus ribavirin therapy does not have any impact on the hearing thresholds of patients with HCV [29]. Finally, we could not exclude the possibility of virus-unrelated hepatitis, such as alcohol-related hepatitis, being correlated with the risk of SSNHL. Additional large-scale studies need to be performed to clarify the discrepancy between virus-induced SSNHL and hepatitis-induced SSNHL. Despite these limitations, this study contributes to the awareness of the increased risk of SSNHL in HBV/HCV-infected populations.
Conclusions
In this study, HBV/HCV infections present a clearly elevated risk for SSNHL. Regular audiometric tests are recommended for patients with HBV/HCV infection to assess their hearing ability and enable the earlier detection of SSNHL. We also suggest that HBV or HCV carriers presenting with the sudden onset of hearing loss should be examined for the possibility of acute exacerbation of chronic HBV/HCV infection.
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