Chung S, Chen P, Lin H, Hung S. Sudden Sensorineural Hearing Loss Associated With Iron-Deficiency AnemiaA Population-Based Study. JAMA Otolaryngol Head Neck Surg. 2014;140(5):417-422. doi:10.1001/jamaoto.2014.75
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Vascular events play a big part in the development of sudden sensorineural hearing loss (SSNHL), but only those associated with sickle-cell anemia have been previously associated with SSNHL. This study demonstrates an association between SSNHL and prior iron-deficiency anemia (IDA).
To evaluate the association between IDA and SSNHL using a nationwide population-based database.
Design, Setting, and Participants
In this case-control study in Taiwan, participants with SSNHL (n = 4004) were identified, and controls (n = 12 012) were randomly selected.
Main Outcomes and Measures
Conditional logistic regression was used to calculate the ORs (95% CIs) for IDA in participants with SSNHL vs controls.
Of the 16 016 sampled participants, 533 (3.3%) had previously been diagnosed with IDA, including 172 (4.3%) participants with SSNHL and 361 (3.0%) controls. The χ2 test revealed a significant difference (P < .001) in the prevalence of prior IDA between participants with SSNHL and controls. By conditional logistic regression, we found that the OR for previous IDA among the participants with SSNHL was 1.34 (95% CI, 1.11-1.61) (P < .01) after adjusting for monthly income, geographic region, urbanization level, and comorbidities (ie, hypertension, diabetes, hyperlipidemia, renal disease, and coronary heart disease). The significant relationship between SSNHL and prior IDA was most pronounced among those 44 years or younger (adjusted OR, 1.91; 95% CI, 1.35-2.72) (P < .001) for the participants with SSNHL compared with controls, and the strength of this relationship decreased with age.
Conclusions and Relevance
There is an association between SSNHL and prior IDA. Patients with IDA, especially those younger than 60 years, should be more aggressively surveyed and managed to reduce hearing-related morbidities.
Sudden sensorineural hearing loss (SSNHL) is a type of hearing loss in which the vestibular cochlear nerve, inner ear, or central processing centers of the brain are suddenly affected, leading to a deterioration of hearing function. The disease is reported to have an annual incidence of 5 to 300 cases per 100 000 population.1,2 Despite many theories regarding its causes, most cases are idiopathic.3 Proposed causes of idiopathic SSNHL include viral infection, autoimmune disease, vascular insults, and labyrinthine membrane rupture.4- 10 Among these, vascular events are believed to contribute to a certain degree of SSNHL development. Thrombosis, embolus, reduced blood flow, or vasospasms may lead to vascular compromise of the cochlea. This pathogenesis is supported by findings that increased risks of cardiovascular and cerebrovascular events are associated with SSNHL.11,12
Anemia is the most common blood disorder and is highly associated with cardiovascular diseases and cerebrovascular events.13- 17 Results of the large-scale Framingham study, for instance, clearly imply that hematocrit is an important risk factor for some cardiovascular diseases.18 However, only sickle-cell anemia has been associated with SSNHL. The relationship between anemia and SSNHL remains unclear.19- 23 The present study evaluates the association of iron-deficiency anemia (IDA) and the development of SSNHL using a nationwide, population-based database.
This study used Longitudinal Health Insurance Database (LHID2000) data, which are deidentified, secondary data released to the public for research purposes. Therefore, Taipei Medical University waived full review and approval by the institutional review board.
Data on the sampled subjects were retrieved from the LHID2000, which contains data for 1 million enrollees derived from medical claims records of the Taiwan National Health Insurance (NHI) program. The 1 million enrollees were randomly selected from all enrollees listed in the 2000 Registry of Beneficiaries (n = 23.72 million) under the NHI program. The Taiwan National Health Research Institute has collected data from the NHI program and sorted them into the LHID2000 every year since the inception of the NHI program in 1995. Previous researchers have demonstrated the high validity of data from the NHI program,24,25 and hundreds of studies using the LHID2000 have been published in internationally peer-reviewed journals.26
This case-control study identified 4004 participants 18 years or older who received a first-time diagnosis of SSNHL (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 388.2) in an ambulatory care visit (including the outpatient departments of hospitals and clinics) or during hospitalization from January 1, 2001, to December 31, 2011. There was no universal consensus on a definition of SSNHL, so only participants with at least 2 consecutive SSNHL diagnoses in the ambulatory care settings or 1 SSNHL diagnosis during hospitalization were included in this study, to increase the diagnostic validity of SSNHL. The first ambulatory care visit or hospitalization for treatment of SSNHL was assigned as the index date for a case of SSNHL.
Controls were selected from the remaining enrollees of the LHID2000. Those with a history of SSNHL since the beginning of the NHI program in 1995 were excluded. Thereafter, the Proc Surveyselect program of SAS, version 8.2 (SAS Institute) was used to randomly select 12 012 controls matched to the participants with SSNHL (3 controls per participant with SSNHL) in terms of sex, age group (18-39, 40-44, 45-49, 50-54, 55-59, 60-64, 65-69, and >69 years), and index year. While the index year of the SSNHL cases was the year of the first diagnosis of SSNHL, the index year for the controls was simply a matched year when the control first utilized the health care system.
This study identified IDA participants with SSNHL based on ICD-9-CM codes 280, 280.0, 280.1, 280.8, and 280.9. To increase the validity of the IDA diagnoses, only participants with SSNHL with at least 2 diagnoses of IDA prior to the index date were considered to represent SSNHL cases with IDA.
The SAS software system, version 8.2, was used for all statistical analyses, and χ2 tests were first conducted to compare statistical differences between participants with SSNHL and controls in geographic location (northern, central, eastern, and southern Taiwan), residence urbanization level (1, most urbanized; 5 least urbanized), and monthly income measured in New Taiwan dollars (NT$) (0-15 840, 15 841-25 000, and ≥25 001). (At the time of this study, the average exchange rate for US dollars was approximately NT$30 for $1.)
A conditional logistic regression analysis (conditioned on sex, age group, and index year) was used to calculate the odds ratios (ORs) (95% CIs) for having a previous diagnosis of IDA between participants with and without SSNHL. Medical comorbidities, including diabetes, hypertension, coronary heart disease (CHD), hyperlipidemia, renal disease, and alcohol abuse/alcohol dependence syndrome, were taken into consideration in the regression model. Statistical significance was set at P ≤ .05.
Data from 16 016 participants were evaluated, including 4004 with SSNHL and 12 012 controls; mean (SD) age, 51.6 (17.5) years. The distribution of demographic characteristics between participants with SSNHL and controls after matching for sex and age group (Table 1) revealed significant differences in geographic region and urbanization level. In terms of medical comorbidities, the participants with SSNHL had a higher prevalence of diabetes (P < .001), hypertension (P < .001), CHD (P < .001), hyperlipidemia (P < .001), and renal disease (P < .001) than controls. There was no significant difference in the prevalence of alcohol abuse.
Evaluation of prior IDA prevalence among participants with SSNHL and controls (Table 2) demonstrated that 533 (3.3%) of the 16 016 sampled participants were diagnosed as having IDA prior to the index date, including 172 with SSNHL (4.3%) and 361 controls (3.0%). Correspondingly, the χ2test revealed a significant difference in the prevalence of prior IDA between participants with SSNHL and controls (P < .001). The conditional logistic regression (conditioned on sex, age group, and index year) further suggested that the OR of prior IDA for participants with SSNHL was 1.45 (95% CI, 1.20-1.74) (P < .001) compared with controls.
In detailed analysis of the adjusted OR for SSNHL (Table 3) we found that the OR of having a previous IDA diagnosis among participants with SSNHL was 1.34 (95% CI, 1.11-1.61) (P < .01), after adjusting for monthly income, geographic region, urbanization level, and comorbidities (ie, hypertension, diabetes, hyperlipidemia, renal disease, and CHD).
Further analysis of the OR for prior IDA by age group (Table 4) indicated that the significant relationship between SSNHL and prior IDA decreased with age. This relationship was strong in patients younger than 60 years and was most pronounced among those 44 years or younger (adjusted OR, 1.91; 95% CI, 1.35-2.72) (P < .001) for participants with SSNHL compared with controls. However, for those 66 years or older, there was no significant increase in the OR of prior IDA among participants with SSNHL compared with controls (adjusted OR, 0.90; 95% CI, 0.67-1.22).
This study reveals a possible relationship between IDA and SSNHL using a large-scale population-based database. The findings suggest that underlying IDA should be considered in patients with SSNHL and that more aggressive management of patients with IDA should be undertaken, especially patients younger than 60 years.
One of the important theories on the pathogenesis of SSNHL is vascular compromise of the cochlea caused by thrombosis, embolus, reduced blood flow, or vasospasms. Based on this understanding, SSNHL has been found to be a comorbidity of many disorders. The association between increased risk of cardiovascular and cerebrovascular events with SSNHL is well documented.11,12,27 More recently, Hsu et al28 found that SSNHL was even more highly associated with an increased risk of erectile dysfunction.
Iron-deficiency anemia is a common form and accounts for approximately half of all anemia cases worldwide. The disease is caused by insufficient dietary intake and/or absorption of iron and/or loss of iron through bleeding of the intestinal, uterine, or urinary tracts or elsewhere. It is not difficult to acknowledge that a decrease in the hemoglobin level in the bloodstream will likely result in compromised tissue oxygen delivery. Several reports also indirectly suggest IDA as a risk factor for ischemic stroke.29- 31 Furthermore, adverse cerebrovascular and cardiovascular effects related to decreased hemoglobin concentrations are well documented in many studies.32- 34
While it seems reasonable that the disturbance in hemodynamics in IDA may contribute to the traditional SSNHL theory of vascular compromise, findings based on a temporal bone histopathologic study35 propose a viral origin rather than a vascular origin for SSNHL. Concepts of membrane breaks, perilymphatic fistulae, and vascular occlusions as common causes of idiopathic SSNHL are being challenged, and new mechanisms involving the pathologic activation of cellular stress pathways are being further proposed.36,37 One possible nonvascular explanation for the elevated risk of SSNHL among patients with IDA is a disturbance in iron metabolism. Sun et al38 first reported evidences of cochlear damage with iron deficiency in a rat model. They further induced the occurrence of SSNHL in growing rats with an iron-deficient diet. A significant reduction in spiral ganglion cells and a rapid involvement of stereocilia of the outer and inner hair cells were noted among affected rats.39 These findings were further supported when the same research group achieved significant improvements in clinical results using iron therapy in patients with SSNHL.40 However, their clinical success only warranted the use of iron therapy in managing SSNHL, and their limited case numbers meant that the relationship between IDA and SSNHL should still be further elucidated.
Another assumption is that the immune system may have a nonhemodynamic role in linking IDA and SSNHL, since IDA has long been associated with autoimmunity.41,42 Moreover, immune-mediated disorders such as factors leading to SSNHL have begun to garner greater attention in recent years. Naarendorp and Spiera43 described 6 patients with systemic lupus erythematosus or lupuslike syndrome who developed SSNHL and were found to have elevated levels of anticardiolipin antibodies. More recently, a prospective study involving 51 patients with SSNHL established an association of SSNHL with various autoantibodies.44 The study revealed that various indicators of autoimmunity, including antinuclear antibodies, antithyroid antibodies, rheumatoid factor, and anticardiolipin, were elevated in the patients compared with controls. Based on these findings, it is possible that both IDA and SSNHL are consequences of immune-related disorders.
It is already known that older people are more likely to experience IDA-related morbidity and mortality.45 The findings that patients of a younger age with IDA are more likely to experience SSNHL is especially interesting but not easily explained. The results of the present study imply that possible mechanisms connecting SSNHL to IDA may not be so closely related to the factors contributing to most IDA cases in elderly patients, such as gastrointestinal bleeding.46 Considering the fact that most autoimmune diseases affect younger and middle-aged people, the findings here indirectly support a possible underlying immune-mediated mechanism. Nevertheless, more studies are needed to reveal the actual relationship between IDA and SSNHL.
The primary limitation of this study, as in other studies relying on a health insurance database, is the possibility of surveillance bias. As noted, SSNHL is comorbid with many disorders like cardiovascular and cerebrovascular events.12,47 Even though all dates of IDA diagnosis in the present study were prior to the SSNHL diagnosis, which rendered an IDA diagnosis irrelevant to various examinations following the SSNHL event, it was still possible that the SSNHL population received laboratory tests more frequently than the control group because of other comorbid diseases. Nonetheless, this potential bias would have little effect on the conclusions. Since well-known comorbidities of SSNHL commonly occur in the elderly, this bias would be more apparent in the older age group. However, this speculation obviously does not correlate with the findings that the incidence of SSNHL does not differ between patients with IDA and controls in participants 60 years or older.
Second, treatment information regarding IDA is unknown, and it is possible that some IDA cases were well controlled at the time SSNHL developed. Thus, the increased risk of SSNHL may be attributed to other factors such as the treatment received for anemia.
Third, although a large number of participants were enrolled through the population-based database, information regarding many important predisposing factors for SSNHL was not complete because the database originated from a health insurance system. The status and extent of involvement of conditions like prior infections, associated otologic conditions, noise exposure, and genetic conditions were difficult to determine. Thus, it is possible that participants with SSNHL with a known cause would have been included, contributing to a degree of bias in the final data. However, such case numbers would be relatively small compared with most SSNHL cases with an idiopathic etiology. Moreover, by including cases of SSNHL with a known cause, we would theoretically move the results toward the null hypothesis. Therefore, this potential bias would have had little effect on the conclusions.
In conclusion, there is an association between SSNHL and prior IDA. Although the true relationship between IDA and SSNHL warrants further investigation, patients found to have IDA, particularly those younger than 60 years, should be investigated for possible underlying problems leading to iron deficiency and to reduce chances of subsequent SSNHL.
Corresponding Author: Shih-Han Hung, MD, Division of Urology, Department of Otolaryngology, Taipei Medical University Hospital, Wu-Hsin St, 250, Taipei, Taiwan (firstname.lastname@example.org)
Published Online: March 13, 2014. doi:10.1001/jamaoto.2014.75.
Author Contributions: Dr Hung had full access to all of the data in this study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Chung, Chen, Lin, Hung.
Acquisition of data: Lin.
Analysis and interpretation of data: Lin.
Drafting of the manuscript: Chung, Chen, Lin, Hung.
Critical revision of the manuscript for important intellectual content: Chung, Lin, Hung.
Statistical analysis: Lin.
Administrative, technical, and material support: Chung, Chen, Hung.
Study supervision: Hung.
Conflict of Interest Disclosures: None reported.