Portuguese Version

Year:  2004  Vol. 70   Ed. 3 - (11º)

Artigo Original

Pages: 361 to 367

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The relationship between hypozincemia and tinnitus

Author(s): Osmar Clayton Person 1,
José Carlos Nardi 2,
Maria Cristina Lancia Cury Féres 3

Keywords: tinnitus, zinc, hypozincemia

Abstract:
The zinc is an oligoelement involved in several organic reactions and it has been recognized as an essential component in the synthesis of proteins and as a probable factor in the stabilization of cell membranes. In the cochlea it is considered to be the principal protective component against reactive oxygen species, and it also acts as a synaptic modulator in some glutamatergic systems. Its participation in synapses in the auditory system and in the treatment of tinnitus has been largely studied in the past few years. Aim: The objective of the present study was to investigate the serum zinc levels in patients with tinnitus, before and after the treatment with drugs containing zinc, and to compare them with a control group. Study Design: Clinical prospective. Patients and Method: We evaluated 41 patients (22 with tinnitus and 19 control) that were split into two groups (I and II), respectively. Both groups were submitted to audiologic evaluation, metabolic and biochemical exams, including determination of the serum zinc levels in order to attend the criterion of approval or not. The patients were treated with drugs containing zinc for 90 days, and after that they were submitted to exams to determinate the serum zinc levels again. Results: In terms of serum zinc levels, the relationship between the group with tinnitus and the control group was not statistically significant, but the treatment significantly increased the serum zinc levels in the group with tinnitus, making it closer to the control group. 45,5% of the patients treated with zinc presented a reduction in their tinnitus. Conclusion: Patients with tinnitus and normal population did not present different serum zinc levels in this study.

INTRODUCTION

Tinnitus is an otoneurological symptom that corresponds to an auditory illusion, that is, a sound sensation which is not related to any external stimulation source 1. It affects subjects both physically and psychologically, sometimes causing great suffering, which can lead them to suicidal attempts 2. It may be associated with over 300 diseases 3, 4 but despite recent scientific advances, it remains as one of the main challenges in Otorhinolaryngology 5.

There are a number of theories to explain the pathophysiology of generation and perception of tinnitus, but it is a consensus that it results from aberrant neural activity of auditory pathways 6, interpreted as sound by the auditory cortex 5.

Zinc is part of Group IIB of Periodical Table, presenting atomic number 30, atomic mass of 65,380, melting point at 419.5ºC and boiling point at 908ºC. It is a solid, white-bluish metal practically insoluble in water and alcohol, but soluble in diluted acids 7. Its presence in human muscles and liver was described in 1877 8, being one of the most important elements in the body, essential to infants, adults and elderly 9. It is considered the second most prevalent trace element in the human body, presenting high concentration in mammals' brain 10.

In human body, zinc is carried most of the time by tissue proteins. In plasma, its main carrier is albumin, being that only 2% are at free form 11. Despite representing only 0.003% (1.4 to 2.3g) of human body, it is an extremely important component acting as a macromolecule and biological membrane stabilizer 12. Its function in the body encompasses regulation and initialization of immune response, acting as enzyme cofactor, steroidogenesis and spermatogenesis, vitamin A metabolism, storage and insulin release, energy metabolism, protein synthesis, macromolecule stabilization, regulation of DNA transcription, cell division and antioxidant function 13, 14.

In the nervous system, it has been found in neural circuits related to functioning of glutamatergic excitation synaptic networks. It is believed that it has a modulating action in some glutamatergic synapses, acting in post-synaptic receptors 15, 16.

Zinc has been described in the cochlea, being that dismutase superoxide enzyme (Cu/Zn SOD) is considered the first line defense against the action of free radicals in this area 17.

Some authors have related zinc physiology with the onset of tinnitus and systematic management of zinc has been described as an alternative for tinnitus treatment 18, 19.

The assessment of zinc in the human body has been conducted through measurements of biological fluid and in many tissues, such as plasma, serum, saliva, sweat, red blood cells, white blood cells, hair, nails and urine 20.

Shambaugh (1985)21 suggested the existence of a correlation between progressive sensorineural hearing loss, similar to presbyacusis, and serum hypozincemia. Zinc supplementation to these patients would lead to improvement of tinnitus in up to 25% of the cases, which can also result in 20% improvement of pure tone levels of the patients.

Zinc is an essential element in the maintenance of the bind Na-K-ATPase and its deficiency may affect pump physiology. In this situation, there would be change to endocochlear potential, which would affect cochlear electrophysiology and could generate tinnitus 22.

Zinc deficiency increases after the age of 60 years and it should be a predisposing factor in some cases of presbyacusis, tinnitus and body imbalance 23. Therefore, patients with tinnitus may require six times more zinc than the minimum recommended daily intake 24.

In an attempt to correlate tinnitus and serum hypozincemia, Gersdorff et al. (1987)19 assessed a group of 115 patients with tinnitus and did not confirm the relation; however, the authors did not exclude the possibility that this correlation would hold true for cases of intermittent tinnitus.

Assessing the clinical response to administration of zinc sulfate to 27 patients with tinnitus and serum hypozincemia, Gersdorff et al. (1987)18 detected symptom improvement in 52% of the cases, even though there had been no direct relationship between hypozincemia and therapeutic success.

In a double-blind randomized study with a group of patients with tinnitus, Paaske et al. (1991)25 in an attempt to confirm the correlation between serum hypozincemia and clinical improvement of tinnitus, administered zinc sulfate to patients. The authors did not notice significant improvement of tinnitus, and few observed relative hypozincemia in the group with symptom. However, the administration of zinc sulfate generated significant increase in serum levels of the ion after treatment.

Differently from other studies, Miniti et al.26 found relative hypozincemia in a group of patients with tinnitus when compared to the control group. After treatment with systemic administration of zinc sulfate, there was improvement of tinnitus in 52.17% of the cases. The authors proposed that relative hypozincemia could have resulted from hypoprotein levels and consequent increase of zinc free fractions, considering that 90% of the metal is bound to plasma proteins; another possibility would be intracell hypozincemia that would not be representative extracellularly.

A statistically significant difference in zinc serum levels among patients with tinnitus and normal patients was described by Ochi et al. (1997)27. After daily administration of zinc to symptomatic patients for two weeks, serum levels of the element increased significantly in the group, concomitantly to improvement of symptom, assessed using a numeric scale. The authors suggested there was a relation between low serum levels and tinnitus, but they reminded the readers that preliminary studies have suggested that zinc supplementation would be beneficial only in patients with tinnitus and zinc deficiency.

Arda et al. (2003)28 assessed a group of patients with tinnitus treated with 50mg of zinc sulfate for 2 weeks, and compared it to a group treated with placebo; they concluded that there was a clinically favorable significant response to tinnitus in patients treated with zinc. The authors noticed improvement of 82% in tinnitus intensity after treatment with zinc and they believe that this finding can be related to reduction of free radicals, mediated by zinc, even though they suggested the conduction of new studies about the correlation between zinc and tinnitus to explain such findings.

The present study aimed at assessing zinc serum levels in patients with tinnitus before and after treatment with systemic administration of zinc compounds compared to a group of patients without the symptom.

MATERIAL AND METHOD

The study was conducted between January 2002 and January 2003 during which we assessed 41 patients followed up in the Ambulatory of Otorhinolaryngology, Hospital das Clínicas, Medical School, Marília (FAMEMA).

Patients were divided into 2 groups (I and II), being that group I (treated) comprised 22 patients and group II (control) had 19 patients. Group I had patients from the Ambulatory of Tinnitus, Hospital das Clínicas, FAMEMA, originally referred from primary care centers in the city of Marília and adjacent region. Group II comprised patients with no otological complaints from the Ambulatory of Laryngology and Voice, Service of Otorhinolaryngology, Hospital das Clínicas, FAMEMA. The patients were asked and accepted to take part in the study.

All patients were submitted to anamnesis and ENT physical examination, according to inclusion and exclusion criteria (Table 1). To meet the criteria, patients in both groups were submitted to pure tone audiometry, speech discrimination and immittanciometry to characterize uni or bilateral hearing loss, undergoing routine audiological assessment in patients with tinnitus.

Audiometric assessment was conducted by the same audiologist at the Division of Audiology, Hospital das Clínicas, FAMEMA, using audiometer AC 33 by Interacoustics.

We investigated frequencies of 256, 512, 1024, 2048, 4096 and 8192 Hz, using descending threshold detection, in which the intensity of the initial stimulus was above the threshold and it was progressively decreased 5 dB in sequence of stimuli, up to absence of response. To confirm the thresholds, we detected the lowest intensity with at least 50% response to the stimuli. The same procedure was applied to all frequencies.

Contralateral masking was used as routine in the assessment of bone thresholds, being that its use in pure tone investigation was used when the thresholds between both ears exceeded 40dB HL.

To complement the test, we identified speech recognition index. The patients were instructed to produce verbal responses to a list of phonetically balanced monosyllable and/or dissyllable. If the hit score was below 88%, we used disyllables.

Immittanciometry was conducted using device CATZ A42 by Dicton, in the same room where audiometry had been conducted. We investigated complacency of tympanic-ossicle system and stapedial reflexes. We also looked for Metz recruiting by comparing pure tone detected thresholds and reflex thresholds, being considered positive when the difference between the thresholds was below or equal to 60dB for each frequency.

Typanometric curves were classified as A (normal), A-r (rigidity of ossicle chain), A-d (flaccid tympanic membrane or rupture of ossicle chain), B (serous otitis media or atelectasia of tympanic membrane with adherences), and C (auditory tube dysfunction).

Patients from both groups (Group I, before treatment and Group II) were also submitted to laboratory tests (complete blood count, fast glucose levels, total cholesterol, triglycerides, TSH, free T4, sodium, potassium, urea, creatinine, uric acid), conducted at the Blood Bank in Marília. Patients in group I were submitted to serum zinc level detection before and after treatment, test which was also conducted with patients in group II. The method used to analyze serum zinc was atomic absorption spectrophotometry (reference value: 59.0 to 121.00 g/dl).

Patients in group I were treated with a formulated compound represented in Table II. The medication was formulated in one single drugstore, by the same pharmacist, and provided to patients in group I in 30-tablet packages. Patients came to visits every 30 days, occasion in which the physician gave more drugs and instructed them to take one daily tablet, taken between breakfast and lunch for 90 days.

The level of discomfort and intensity of tinnitus was assessed using a numeric scale from 0 to 10 (for discomfort) and 0 to 10 (for intensity), which allowed patients to characterize the negative importance of tinnitus in their daily lives. The scale was presented to patients before and after the treatment.

Based on the numeric scale, the level of discomfort and intensity of symptom was classified as mild (equal or below 3), moderate (between 4 and 6) and severe (equal or above 7).

Owing to the nature of the variables in the study, the results and differences were submitted to statistical analysis using tests for samples with non-parametric distribution and significance level of 5% (P 0.05).

RESULTS

Group I comprised 22 patients (13.6% Black and 86.4% Caucasian subjects) all of them with bilateral tinnitus being that in 36.4% of the cases the symptom was intermittent and in 63.3% it was continuous; 41% of the patients presented complaint of dizziness, and 59.1% had complaint of hearing loss, secondary to the main complaint. The average time of tinnitus was 41.7 months; in 31.8% of the cases, the patients characterized the level of intensity and discomfort of tinnitus as moderate and in 68.2% as severe. No patient characterized the symptom as of mild intensity.

Group II comprised 19 patients (4.5% Black and 95.5% Caucasian subjects) without hearing system-related complaints, according to the pre-defined inclusion and exclusion criteria.

The average age in Group I was 53.9 years and in Group II it was 51.2 years. The mean age values between the groups were not statistically significant (p=0.488). As to gender distribution, there was predominance of female subjects in both groups, representing 54.6% in Group I and 73.7% in Group II.

As to hearing levels, they were worse in Group I, showing statistically significant difference when compared to group II for frequencies higher than 1000Hz, which shows worse audiometric profile in high frequencies in the group of patients with tinnitus. All patients presented immittanciometry with curve type A.

All patients in group I regularly used the prescribed compound for a period of 90 uninterrupted days. There were no severe adverse events, even though 8 patients (31.8%) reported mild gastric complaints (epigastralgia), which in general occurred within 2 weeks after beginning of treatment.

In 45.5% of the cases there was improvement of tinnitus after treatment, being that in 1 case (10%) there was no further symptom, in 2 (20%) there was moderate improvement, and in 7 (70%) there was slight improvement. All patients that reported tinnitus improvement described the response as reduction in symptom intensity.

As to zinc serum levels, descriptive statistics of the levels in groups I and II are presented in Table 3, whereas the comparison between the groups is presented in Table 4.

Table 1. Inclusion and exclusion criteria in Groups I and II.



Table 2. Formulated compound used to treat Group I.

*6-O-dimethylaminoacetyl- D- gluconic acid: substance described by Krebs in 1938 naturally found in organisms and in biological functions related to cell breathing stimulation (mitochondrial action), ** Vitamin B6.


Table 3. Descriptive statistics of serum levels of zinc in Groups I and II.



Table 4. Comparative statistics of zinc serum levels between Groups I and II.

DISCUSSION

Zinc serum levels did not evidence statistically significant difference between patients with tinnitus (Group I) and patients without symptoms (Group II), differently from the observation by Shambaugh (1985)21, in which the groups of patients with tinnitus presented serum hypozincemia. Differently, in group I there were patients with hypozincemia, normozincemia and hyperzincemia, which did not allow the confirmation of direct correlation between zinc serum levels and patients with tinnitus, even though the only patient that had complete remission of symptom with the defined treatment presented serum levels of the ion (73.3 g/dl) below group I average.

We did not confirm linear correlation between serum levels of zinc and clinical response to treatment, considering that 90% of the patients that reported improvement after treatment presented normal zinc levels.

Administration of zinc compounds, however, generated significant increase (p=0.042) to serum levels of oligoelements in Group I, after treatment, making patients in this group closer to those in the control group II. The significant increase in serum zinc levels after administration of oral zinc, as found in this study, had already been described by Ochi et al. (1997)27.

The way through which zinc gets into the cell is still unknown 30, but its absorption occurs in the small intestine, especially in jejune and ileum, being that very small amounts are absorbed in the stomach and large intestine 31. The amount of zinc in the intestinal lumen increases one to three times owing to the sum between zinc coming from the diet and that secreted by digestive juice, but the mechanisms of absorption and excretion of this oligoelement comply with high sensitivity self-regulating systems, which result in storage readjustment depending on ion need and bioavailability in the body 30. Thus, it is fair to assume that zinc absorption depends on the levels of ion in body storage, being lower if there are reasonable amounts in the body and greater in cases of deficit.

Zinc serum levels to be used as assessment parameters of zinc deficiency in the body, even if they present doubtful reliability as claimed by some authors, increased significantly in the present study. This fact strengthens the idea that if there was absorption of a specific amount of zinc provided by the treatment, it means that patients really required zinc replacement.

Much has been said about the best way to assess reliability of zinc body storage status. The presence of the oligoelement in different concentrations in intra and extracellular media means that zinc serum levels should be carefully interpreted. It is known that zinc levels in the erythrocyte are 8 times higher than outside the cell 32. Logically, concentrations of the ion can suffer interference of factors such as hemolysis, when the blood is collected, or by increased degradation of erythrocytes in the spleen.

Miniti et al.26 reminded us that plasma zinc depends on protein carriers, especially albumin, which means that plasma levels could be modified by hypoprotein status, situations in which zinc free fractions in plasma could cause relative hyperzincemia, which would not reflect the actual level of the element in the body. In fact, serum levels of zinc may have clinical meaning when they are low, but in situations of normal or elevated levels, the meaning as criterion for not indicating zinc administration loses its value, based on the knowledge of transportation physiology, storage and bioavailability.

Many studies have been conducted in an attempt to find the best way to assess zinc storage. Studies with zinc storage in the hair 33 and urine 34, 35 have shown that multiple clinical factors can relevantly interfere in dosage, which can produce values that may generate unreliable interpretations.

Solomons (1979)36 defined that leukocytes were a hematopoietic component of elevated metabolic potential, presenting zinc concentrations 25 times greater than erythrocytes. A variation in zinc storage in the body is reflected within few days in the quantity of ion inside the leukocyte. Therefore, we can assume that zinc leukocyte level could be an alternative in searching for a reliable method to assess zinc body storages; however, there are few studies of zinc dosage in leukocytes.

In practice, serum levels have been used as parameter to assess zinc body storage. However, as pointed out by Shuttleworth (1986)8, the checking of zinc body levels through dosage of the metal in fluids and tissues has not been fully understood yet. Laboratory data should be carefully analyzed, being that high level of clinical suspicion (patients with zinc-deprived diet, patients with gastrointestinal disorders and supposedly those that have difficulty to absorb zinc, and the elderly) is still the best parameter to be used when indicating zinc replacement.

Considering that it has been observed clinical improvement of tinnitus in patients with low, normal or elevated zinc levels, zinc serum level as parameter for indication of metal replacement in patients with tinnitus has relative value. It was shown here that concerning absorption physiology and body zinc storage, zinc serum dosage is important if it is low, but normal or hyper zinc level patients can benefit from treatment since factors such as protein level or hemolysis could influence the results.

In clinical practice, it has been detected that some patients with tinnitus, especially elderly patients, present improvement in symptoms with administration of zinc compounds. However, these observations do not allow zinc to be used to all patients with tinnitus, since the indication should be based on the assumed need to replace the metal in the body. Moreover, we should bear in mind that tinnitus is a symptom, and not a disease and that multiple pathophysiological mechanisms can be involved in generation and perception of symptom.

In the present study, administration of zinc compounds showed improvement of symptoms in 45.5% of the treated patients, but it was not a randomized trial, since there were no objectives related to clinical response. Even in randomized double-blind trials, the results have been contradicting: Paaske et al. (1991)25 did not observe significant improvement of tinnitus in patients treated with zinc, whereas Arda et al. (2003)28 observed 82% improvement in tinnitus intensity measured in patients that had used zinc sulfate.

As pointed out by Jastreboff (1990)6, tinnitus could be generated by peripheral affections, normally cochlear, but its perception would involve the participation of non-auditory systems, related with emotion. Thus, changes in emotional status, particularly mood fluctuations or anxiety could increase global stimulation, making us more capable of finding out the potential threats in our environment 37. The modulating participation of the limbic system could have relevantly influenced the varied responses found in randomized studies, not only with zinc, but also with other measurements.

CONCLUSIONS

Based on the present study, we concluded that patients with tinnitus did not present zinc serum levels different from the normal population.

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1 Master in Otorhinolaryngology, Medical School, Ribeirão Preto, University of Sao Paulo - FMRP/USP. Responsible for the Ambulatory of Tinnitus, Discipline of Otorhinolaryngology, Medical School, ABC - FMABC.
2 Master in Otorhinolaryngology, Medical School, Ribeirão Preto, University of Sao Paulo - FMRP/USP. Professor, Discipline of Otorhinolaryngology, State Medical School, Marília - FAMEMA.
3 Ph.D., Professor, Discipline of Otorhinolaryngology, Medical School, Ribeirão Preto, University of Sao Paulo - FMRP/USP.
Affiliation: Medical School, Ribeirão Preto, University of Sao Paulo - FMRP/USP, Department of Ophthalmology, Otorhinolaryngology and Head and Neck Surgery.
Address correspondence to: Osmar C. Person - Departamento de Oftalmologia, Otorrinolaringologia e Cirurgia de Cabeça e Pescoço da Faculdade de Medicina de Ribeirão Preto, USP - Rua Sílvia, 2269 Nova Gerty Sao Caetano do Sul SP 09571-300.
Tel (55 11) 9628-4097 - E-mail: ocperson@ig.com.br.
This paper is part of the Master Dissertation by Osmar Clayton Person, submitted to Medical School, Ribeirão Preto, University of Sao Paulo- FMRP/USP, and approved in January 2002 by the Human Research Ethics Committee (CEP), State School of Medicine, Marília - FAMEMA.

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