INTRODUCTION

The association between thyroid dysfunction and auditory disorders has been a topic of interest for researchers for a long time. The first concluding results were described by Bircher, in 1883 and confirmed in 1888 when the members of the Myxoedema Committee of the Clinical Society of London found hearing deficits in 38 out of 69 patients who had myxoedema .1

From then on, many other studies were developed to more clearly define the association as well as to define the lesion site caused by hypometabolism of the auditory system.

Currently, hypothyroidism can be defined as a state in which there is reduction of thyroid gland function and consequent reduction in the production of its hormones: thyroxin or T4 and T3, regardless of the etiology. Under such concept, we can define clinical hypothyroidism. However, there are situations in which there is elevation of TSH (thyrotrophic hormone), with no corresponding affection of serum levels of free fractions of thyroid hormone - such cases are classified as subclinical hypothyroidism, or pre-clinical or minimally invasive condition, since the patients manifest mild symptoms and signs of the dysfunction 2.

It is currently estimated that 1 to 1.5 billion people in the world have a risk of suffering from diseases resultant from iodine deficiency, including the nearly 600 million people who have goiter 3.

In most population studies, the prevalence of the clinical form of the disease in adults ranges at about 1% to 2%, whereas the subclinical form reaches 5% to 10%. Women are markedly more affected than men, at a ratio of 4:1, respectively, and there is increasing incidence as a result of aging, which may reach 15% of subclinical hypothyroidism in women aged 60 years or older 4-6.

Considering the condition of thyroid hypofunction, be it congenital or acquired, body energy metabolism and the uptake of oxygen by tissues are generally reduced, protein anabolism is deficient, and consumption of lipids and carbohydrates as well as sensitivity and insulin secretion are affected 7. The resulting clinical manifestations are expressed translations of such metabolic disorders, originating anomalies that affect many organs and systems of the body, including the hearing system.

At the beginning of the 20th century, there were individual reports of cases of adult patients with clinical pictures of hypothyroidism that presented hearing loss 8, 9. Decades later, other researchers tried to focus the action of thyroid insufficiency over the ear of adults, pointing to interferences in the external portion, the tympanum and the labyrinth 10, 11. In 1956, there were the first descriptions of auditory disorders related to the subclinical forms of gland hypofunction 12.

Some researchers still use tools to apply supraliminar tests in adults with hypothyroidism in order to define the location - cochlear or retrocochlear - of the sensorineural loss identified in these patients 1, 13.

After some decades of investigation in this area using conventional diagnostic methods, the discovery of evoked potentials and the development of electronic computer technology became reality, which allowed clinical use of electrophysiological diagnostic methods as the safest and most reliable way of analyzing the conduction of the nervous stimuli throughout the auditory pathway.

Out of the instruments used to study auditory evoked potentials, ABR (Auditory Brainstem Response) is the simplest one from a technical, it is objective, has excellent applicability, which allows the detection of the electrical activity of different neurons of the auditory pathway up to the level of the inferior colliculus, therefore, it is not restricted to the estimation of electrophysiological auditory thresholds.

The study of ABR is based on the analysis of five first waves (I, II, III, IV and V) and absolute latency (LA) measures of waves I, III and V and interpeak latency (LIP) I-III, III-V and I-V. The signals that generate these waves have already been investigated and are still under study. An updated interpretations suggested the following: wave I - potential of the eighth nerve; wave II - there is some controversy whether it would be generated by the proximal portion of the eighth nerve or the cochlear nucleus; wave III - superior olivary complex; wave IV - lateral lemniscus; wave V - inferior colliculus 14.

Many authors investigated the interference of some physiological factors over the record of ABR. Thus, some characteristics related to the subject such as age and gender should be taken into account. Generally speaking, children up to the age of 18 months manifest wave latency delay, especially of wave V, and this fact is related to immaturity of auditory pathways. There are also reports of the prolongation of latency in people over the age of 60 years. As to gender, many studies mentioned that men have increased measures of latency (especially of wave V) and increased interpeak measure (especially interval I-V)14, 15, 16.

As a result of the evolution of the knowledge about the techniques, some authors tried to correlate clinical status of thyroid and hormones and the abnormalities found in the ABR test.

One of the first studies that tried to correlate ABR findings and thyroid insufficiency used patients with both affections - congenital and acquired - and already undergoing hormone replacement therapy. As to the acquired type, the results revealed that there had been no ABR tracing modifications 17.

The literature reveals many studies dedicated to electrophysiological investigation of patients with thyroid disorders and, in most cases, the authors studied the clinical form of the pathology 18-21. In general, the results of such studies evidenced disorders of nervous conductibility throughout the brainstem auditory pathways, pointed to the prolongation of the absolute latencies of waves and their respective intervals (I-III, III-V and I-V).

Upon studying the literature, we found two studies that focused on patients with subclinical hypothyroidism studied with ABR. In none of them they found modifications in the tracings of the test 22, 23.

The fact whether acquired hypothyroidism is associated or not with hearing loss has not been well defined. Even among authors that consider this a define relation, the anatomical structures, the mechanisms involved in the process, as well as the reversibility or not of lesions are still points of controversy. Parallel to these issues, there is the fact that the subclinical form of gland insufficiency has not found a consensus yet among researchers of the area concerning its real interference over electrophysiological parameters, in addition to the ascertained lack of studies in the literature that addressed specifically this type of hypothyroid manifestations.

The purpose of the present study was to determine whether there are or nor abnormal responses to ABR in female adult patients with subclinical untreated hypothyroidism when compared to the control group formed by health women.

MATERIAL AND METHOD

The present study was conducted at the Area of Special Methods, Service of Otorhinolaryngology, University Hospital Clementino Fraga Filho - HUCFF, Federal University of Rio de Janeiro (UFRJ).

We analyzed 16 female patients ages ranging from 19 to 60 years (mean age of 44.3 years), with subclinical hypothyroidism and no treatment. Patients were selected and referred to the Division of Endocrinology of HUCFF and IEDE (State Institute of Diabetes and Endocrinology), with clinical and laboratory diagnosis of thyroid disease, and without undergoing any specific replacement treatment.

The control group comprised 15 female volunteers, aged 19 to 61 years (mean age of 39.4 years), no history of thyroid disorders, selected among undergraduates and employees of HUCFF.

The inclusion criteria were: age older than 18 years; normal otoscopy; pure tone audiometry equal or below 25dB in frequencies of 250, 500, 1000, 2000, 4000 and 8000Hz; immittanciometry within the normal range with stapedial reflexes; subclinical untreated hypothyroidism.

The exclusion criteria were: clinical or past history of otologic disease (chronic and/or recurrent episodes); neurological diseases; syphilis, diabetes mellitus; use of drugs, alcohol abuse, renal failure; head trauma; patients under clinical treatment.

The study protocol was previously analyzed and approved by the Research Ethics Committee and the participants signed the Informed Consent Term.

Initially, subjects were submitted to physical examination comprising otoscopy to check auditory canal and tympanic membrane status. Next, pure tone audiometry, using audiometer brand Amplaid, model 508, in an acoustically treated room, in order to confirm the presence of normal psychoacoustic thresholds for pure tones of 250Hz, 500Hz, 1000Hz, 2000Hz, 4000Hz and 8000Hz. Next, we proceeded with immittanciometry, device branded Interacoustic, model AZ-7, to ensure integrity of middle ear.

After confirming the normal results of the tests above referred, we conducted the ABR with the device branded Amplaid, model MK-15, in a soundproof room. The positive electrode was placed on the top of the midface on the forehead, close to the hairline (Fz), the ground electrode was placed on the mentalis region, and the negative electrodes were placed on the anterior aspect of both ear lobes (A1 = left ear and A2 = right ear). We considered as acceptable the impedance of the electrodes when below 5 KOhms and the difference between electrodes below 3 KOhms, and these values were checked and confirmed throughout the test.

The recording was made with bipolar set-up, using ipsilateral, contralateral and horizontal derivation, according to the international system 10-20. The last two derivations were only used in case of difficulties to identify the waves in ipsilateral tracing. All responses were filtered between 100 and 2500Hz. The duration of analysis was 12ms and sensitivity was 10 to 25 mV.

After placement of the headsets TDH-49 we checked the stimuli with unfiltered clicks, duration of 100ms, rarefied, in the stimulation frequency of 11 clicks/s, monoaurally, first on the right ear and then on the left ear. The investigated intensity was 100dB SPL, without masking.

For each recording, we presented 2,000 stimuli, presented at each twice in order to confirm reproducibility of the waves, with overlapping of both curves. Next, we measured absolute latencies of waves I, III and V, as well as interpeak latencies I-III, III-V and I-V, for each ear. At the end, recordings were printed, as provided by the device.

All procedures described above were applied individually in each of the 15 female volunteers of the control group, corresponding to 30 ears and in each of the 16 patients, also amounting to 30 ears. The fact that the group of 16 people amounted to 30 ears is that one of the participants had one ear excluded from the study because the left side had a mild sensorineural hearing loss. In another patient, we conduced ABR on the right but we did not manage to complete the test on the other side owing to technical problems.

The results were submitted to statistical analysis with the collaboration of the Scientific Investigation Commission of HUCFF. We conducted descriptive and statistical analysis in order to compare absolute and interpeak latency of waves found in the ABR of the control group and the patients' group. The level of significance was 5% (p £ 0.05).

RESULTS

In this series, both the normal group and the patients' group comprised only female subjects, excluding gender difference. Therefore, we tried to match age ranges between the groups. Data analysis showed that the mean age of patients was 44.3 years (SD + 10.6 years) whereas in the control group, it was 39.4 years (SD + 10.1 years), and the difference was not statistically significant (p > 0.05).
We used t Student test for independent samples for the values of absolute latency of waves I, III and V and interpeak latencies of waves I-III, III-V and V-I of ABR, to check the existence of statistically significant differences between the control and the patient group.

The results revealed that there was statistically significant difference in the mean absolute latency LA III (p = 0.039), LA V (p = 0.006), LIP I-III (p = 0.017), LIP III-V (p = 0.044) and LIP I-V (p = 0.002) comparing patients and controls, revealing that measures of such latencies in the group with hypothyroidism were significantly greater than in the control group. There was no statistically significant difference concerning absolute latency of wave I (Table 1).







DISCUSSION

In our study, all participants were female subjects. This selection of female hypothyroidism contributed to yielding more reliable results, since the influence of gender on ABR recordings has been well documented in many studies 14-16.

In order to prevent the influence of factors that are known to interfere in the results of ABR, a control group was studied including people of the same gender and approximately the same age as the patients, who were submitted to the same procedures and technical-environmental conditions.

The mean age was 44.3 years and 39.4 years for patients and controls, respectively, whose difference was not statistically significant (p>0.05). Thus, we made sure that the responses were not influenced by age range.

Among the researchers dedicated to the topic, it is an almost unanimous opinion that hormone replacement promotes partial or total regression of hearing affections, be them peripheral or central 10, 12, 18, 20. Therefore, in our investigation, we selected patients with subclinical disease who were not undergoing specific treatment, because we wanted to make sure that the changes in electrophysiological tracings of these patients were exempt from therapeutic activity.

After the determination of the values of peak and interpeak latency, the analyzed data revealed the following results: significant increase of absolute latency of waves III and V and increase of LIP I-III, III-V and I-V of hypothyroidism patients compared to normal controls.

Most studies conducted in adults with clinical hypothyroidism submitted to ABR resulted in evidence of increase in LA V and LIP I-V 19-21, 23. It is worth mentioning that all researchers above described focused on clinical hypothyroidism, whereas we focused on the subclinical manifestations. That is, our results pointed to the fact that even when thyroid deficiency has not reached more advanced levels, there may be central auditory conductibility disorders, characterized by delayed stimulus propagation. Such phenomena may take place throughout the whole brainstem auditory pathway.

LA I was the only ABR parameter proposed here that was not affected. Most researchers did not find LA I abnormalities either. Only in one clinical study there was an increase in that measure 21. Based on investigations of generating sites of ABR potentials 14, wave I is considered as being generated by the auditory nerve close to the cochlea. Widening of LA I, therefore, suggests impairment of the more distal portions of the auditory nerve and it may cause sensorineural hearing loss. In the study referred above, there was no report of audiometry; thus, we cannot rule out the possibility that hearing impaired patients were included in the study, which could have contributed to the detection of the electrophysiological abnormality. Therefore, we can define a difference between the results of this study and ours, because in out study we included only people who had normal hearing.

The fact that we detected ABR affections in patients with endocrine compromise points to a certain level of retrocochlear affection. The conclusion of some researchers were in accordance with our findings, despite the fact that they did not use electrophysiological means they raised the hypothesis that acquired hypothyroidism could lead to retrocochlear disorders since by applying supraliminar tests in myxedematous cases, they did not find signs of recruitment, concluding that the audiological phenomenon observed would result from central origin 1, 13.

We detected disagreeing results in the study that analyzed patients in course of hormone replacement 17. As well argued by many authors 18, 20, therapy to thyroid deficiency promotes partial or total regression of electrophysiological abnormalities, reason why some authors did not detect abnormal hearing tests in their patients. In our patients, however, none of them were currently under treatment with any kind of medication regimen, which revealed the phenomena generated from nervous transmission of the brainstem auditory pathways.

The study of the literature revealed few studies that focused on the subclinical condition of hypothyroidism over the hearing system. We found only two studies that used ABR in adults with hypothyroidism hat had been previously classified as subclinical 22, 23. In none of them we detected any modification in the electrophysiological recording of patients comparing to the controls. Both investigations, similarly to ours, also used untreated patients. The first group of subclinical hypothyroidism cases comprised 11 men and 16 women compared to 8 male and 12 female controls 22. As mentioned before, the influence of gender on ABR leads to wave V absolute latency and I-V interpeak values that are greater in male than in female subjects. Thus, the fact that a series comprised over 40% male patients and controls could have been interpreted as a misguiding factor to the interpretation of the results, preventing correct identification of abnormal tests. The second study 23 did not differentiate men and women in the subclinical group nor in the controls, and it is not possible to compare the samples. Gender uniformity in our participants provided more reliable results in ABR tracings, since this factor did not interfere in the conclusion of the study.

Upon identifying signs of central auditory impairment in subclinical patients with thyroid insufficiency, even though it had not been quantitatively translated in confirmed hearing loss by conventional hearing audiometry, it is evidenced that there is the need to conduct more studies to assess the response to treatment of hormone replacement in order to observe the recovery of conductibility of the central airways and allow medicine to have a more preventive role in the conservation of the human hearing function.

CONCLUSIONS

Our results led us to the conclusion that there was statistically significant difference in the means of absolute latency of waves III and V, and interpeak intervals I-III, III-V and I-V, revealing that these latency measures in the group of adult normal hearing women with subclinical hypothyroidism was greater than in the control group. Such findings suggest that even without psychoacoustic thresholds affection, there can be some degree of central hearing abnormality.

REFERENCES

1. Stephens SD. Temporary threshold drift in myxoedema. J Laryngol Otol 1970;84: 317-21.
2. Vaisman M, Reis F.A. Hipotireoidismo. RBM 2000;57(n. esp.)169-72:174-5.
3. Knipper M, Zinn C, Maier H, Praetorius M, Rohbock K, Kupschall L et al. Thyroid hormone deficiency before the onset of hearing causes irreversible damage to peripheral and central auditory system. J Neurophysiol 2000;83:3101-12.
4. Cooper DS. Subclinical hypothyroidism. JAMA 1987;258:246-7.
5. Mariotti S, Franceschi C, Cossarizza A, Pinchera A. The aging thyroid. Endocr Rev 1995;16:686-715.
6. Woeber K. A. Subclinical thyroid dysfunction. Arch Intern Med 1995;157:1065-8.
7. Nicolau W, Mendonça BB. Hipotireoidismo no adulto. J Bras Med 1981;40:14-24.
8. Kemp WR. Deafness in myxoedema. Br Med J 1907;1:375.
9. King JW. Deafness in myxoedema. Br Med J 1907;1:562-3.
10. Hilger JA. Otolaryngologic aspects of hypometabolism. Ann Otol Rhinol Laryngol 1956;65:395-413.
11. Howarth AE, Lloyd HE. Perceptive deafness in hypothyroidism. Br Med J 1956; 1:431-3.
12. Hollender AR. Hypometabolism in relation to ear nose and throat disorders. Arch Otolaryngol 1956; 63:135-41.
13. De Vos JA. Deafness in hypothyroidism. J Laryngol Otol 1963;77:390-414.
14. Lima MAMT. In: Frota S. Fundamentos em Fonoaudiologia. 1ª ed. Rio de Janeiro: Guanabara Koogan; 1998. Volume: Audiologia. 147-160.
15. Bento RF, Silveira JAM, Ferreira MRM, Fuess VLR, Miniti A. Estudo do padrão de normalidade da audiometria de tronco cerebral (B.E.R.A.) nas diversas faixas etárias. Rev Bras Otorrinolaringol 1988;54(2):37-41.
16. Hassan S, Dimitrov R, Munhoz MSL, Caovilla HH. Da influência do sexo da intensidade do estímulo e do perímetro cefálico nas latências da audiometria de tronco encefálico. ACTA AWHO 1997;16(4):150-60.
17. Korine E, Rubinstein M, Jancu D. Influence of hypometabolic state due to hypothyroidism on the latency period in ERA responses. Rev Laryngol Otol Rhinol 1975;96:127-32.
18. Himelfarb M. Z, Lakretz T, Gold S, Shannon E. Auditory brain stem responses in thyroid dysfunction. J Laryngol Otol 1981;95:679-86.
19. Anand VT, Mann SB, Dash RJ, Mehra YN. Auditory investigations in hypothyroidism. Acta Otolaryngol 1989;108:83-7.
20. Höhmann D, Kahaly G, Warzelhan J. Einfluss von hyperlipidämien und hypothyreosen auf die akustisch evoziertenn hirnstammreizantworten. HNO 1990;38:446-50.
21. Khedr EM, El Toony LF, Tarkhan MN, Abdella G. Peripheral and central nervous system alterations in hypothyroidism: electrophysiological findings. Neuropsychobiology 2000;41:88-94.
22. Ozata M, Ozkardes A, Corakci A, Gundogan M. A. A. Subclinical hypothyroidism does not lead to alterations either in peripheral nerves or brainstem auditory evoked potentials (BAEPs). Thyroid 1995;5:201-5.
23. Di Lorenzo L, Foggia L, Panza N, Calabrese MR, Motta G, Tranchino G et al. Auditory brainstem response in thyroid diseases before and after therapy. Horm Res 1995;43:200-5.

---

1 Master studies in Otorhinolaryngology under course, Federal University of Rio de Janeiro (UFRJ).
2 Joint Professor of Otorhinolaryngology, Medical School, UFRJ.
3 Joint Professor of Endocrinology, Medical School, and Head of the Service of Endocrinology, University Hospital Clementino Fraga Filho (HUCFF) - UFRJ
Address correspondence to: Lília Cristiane Mendes Soares Figueiredo - Rua Debret, 23 sala 1216 Centro 20030-080 Rio de Janeiro RJ.
Tel (55 21) 2544-2035/ 2544-2036 - E-mail: lcmsf@hotmail.com
Master Dissertation submitted to the Program of Post-Graduation in Otorhinolaryngology, Medical School, UFRJ, in fevereiro/2003.
Tutor: Prof Dr Marco Antonio de Melo Tavares de Lima.
Article submitted on March 16, 2003. Article accepted on July 01, 2003.