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Sensorineural hearing loss in [beta]-thalassemia patients treated with iron chelation.


The predictive value of pure-tone audiometry (PTA) in the early detection of ototoxicity has been questioned, particularly in the higher frequencies. Otoacoustic emissions testing appears to be more sensitive to cochlear insult than conventional PTA. We conducted a cross-sectional descriptive study to compare the efficacy of distortion-product otoacoustic emissions (DPOAE) testing with that of PTA as a method of audiologic monitoring. Our study group was made up of 159 patients (318 ears)--69 males (43.4%) and 90females (56.6%), aged5 to 61 years (mean: 23.59 [+ or -] 12.55). All patients had been diagnosed with either [beta]-thalassemia major (BTM) or [beta]-thalassemia intermedia (BTI), and all had received at least 1 year of treatment within the previous year with an iron chelator--either deferasirox, desferrioxamine (deferoxamine in the United States), deferiprone, or a combination of desferrioxamine and deferiprone. PTA and DPOAE evaluations were performed by the same audiologist using the same audiometer for all patients. In the right ears, the overall incidence of ototoxicity as manifested by sensorineural hearingloss was 39.0% on PTA and 22.0% on DPOAE testing; in the left ears, the corresponding figures were 27.7 and 19.5%, respectively. There were no statistically significant differences in the incidence of ototoxicity between the BTM and BTI groups with any of the four different drug regimens on PTA (p = 0.765, p = 0.378, p = 0.265, and p = 0.579, respectively) or on DPOAE testing (p = 0.890, p = 0.263, p = 0.390, and p = 0.340, respectively). Based on these data, we found no significant difference between PTA and DPOAE testing in their ability to detect ototoxicity. We conclude that periodic testing with both PTA and DPOAE is necessary for patients with suspected [beta]-thalassemia in order arrive at a prompt diagnosis and initiate timely management.


The thalassemias are a group of inherited disorders of hemoglobin synthesis. Their clinical presentation varies widely, ranging from asymptomatic forms to severe and even fatal entities. In these disorders, the production of either alpha or beta chains of hemoglobin is reduced, resulting in a- and [beta]-thalassemia, respectively. [beta]-thalassemias are classified by phenotypic severity as major, intermediate, and minor)

For patients with thalassemia, frequent erythrocyte transfusions are performed to keep their hemoglobin levels above 10 g/dl. Except during infection, surgery, and some special stress states, the hemoglobin values of patients with [beta]-thalassemia generally range between 6 and 10 g/dl. However, recurrent blood transfusions can lead to an accumulation of iron in the body, as well as organ toxicities.

The purpose of iron chelation is to prevent the accumulation of iron in the body, to decrease existing surplus iron deposits, and to eventually curtail complications arising from increasing body iron stores. For patients with [beta]-thalassemia, the initiation of iron chelation treatment is recommended after completion of 1 year of regular transfusion therapy or after 12 to 15 transfusions, when the serum ferritin levels reach 1,000 ng/ml. (2)

Chelators are classified according to their iron-binding capacities. Many randomized clinical studies have shown that deferasirox, desferrioxamine (deferoxamine in the United States), and deferiprone are very effective iron-binding chelators for controlling iron load in the body. (3,4) However, very few authors have investigated the ototoxic effects of chelation therapy in |3-thalassemia. In this article, we describe our investigation of the ototoxic effects of these widely used iron chelators in patients with [beta]-thalassemia major (BTM) and [beta]-thalassemia intermedia (BTI).

Patients and methods

The predictive value of pure-tone audiometry (PTA) in the early detection of ototoxicity has been questioned, particularly in the higher frequencies. Distortion-product otoacoustic emissions (DPOAE) testing appears to be more sensitive to cochlear insult than is conventional PTA. Therefore, we conducted a cross-sectional descriptive study to compare the efficacy of PTA and DPOAE testing as a method of audiologic monitoring in patients with [beta]-thalassemia.

Our study group was made up of 159 patients (318 ears)--69 males (43.4%) and 90 females (56.6%), aged 5 to 61 years (mean: 23.59 [+ or -] 12.55). All patients had been diagnosed with either BTM or BTI, and all had received at least 1 year of treatment within the previous year with an iron chelator--either deferasirox, desferrioxamine, deferiprone, or a combination of desferrioxamine and deferiprone. A total of 134 patients (84.3%) had BTM and 25(15.7%) had BTI.

Our exclusion criteria included an active infection, a current or previous otologic disease, a tympanic membrane perforation, a history of ear surgery, a hearing loss secondary to acoustic trauma or hereditary factors, and an inability to satisfactorily undergo audiologic testing.

Iron chelation protocol. Patients were divided into four groups based on the type of iron chelation therapy they received:

* 82 patients (51.6%) received oral deferasirox at 10 to 40 mg/kg/day;

* 41 patients (25.8%) received subcutaneous or intravenous desferrioxamine at 40 to 60 mg/kg/day for 5 to 7 days a week;

* 20 patients (12.6%) received a daily total of 75 to 100 mg/kg of oral deferiprone in three divided doses; and

* 16 patients (10.1%) received a combination of the desferrioxamine and deferiprone regimens.

During the treatment period, hemoglobin, ferritin, aspartate transaminase, alanine transaminase, total bilirubin, and direct bilirubin levels were recorded daily.

Audiologic testing. PTA, DPOAE testing, and tympanometry were performed by the same audiologist using the same audiometer and tympanometer for all patients. PTA thresholds were measured in the standard increments from 0.25 to 8 kHz. A threshold shift >20 dB at one or more frequencies on PTA was considered to be significant.

For DPOAE testing, two simultaneous pure-tone signals (primaries) were presented to the ear at two different frequencies (f1 and f2, where f2 > f1), and the 2fl -f2 cubic distortion-product component was recorded. Recordings were obtained with a frequency ratio of f2/f1 fixed at 1.22. Nine pairs of equal-level primary frequencies (LI = L2 = 65 dB SPL) were used at three points per octave, spanning the f2 frequency range from 1,001 to 6,348 Hz. The 65-dB levels of the primary tones were used as the stimulus levels that would most reliably elicit DPOAE from ears with hearing difficulties. The amplitude was determined for each patient. Detection thresholds were calculated 6 dB higher than the noise floor. The accuracy of the calibrations had been confirmed earlier by DPOAE testing on 10 healthy individuals.

Statistical analysis. Data were analyzed with the Statistical Package for the Social Sciences, v. 11.5 for Windows. The chi-square, ANOVA, and Student unpaired t tests were used for statistical evaluation of parameters. The results were expressed as a mean with standard deviation (SD) and assessed within a 95% confidence level. A p value of <0.05 was considered to be statistically significant.

Ethical considerations. The study protocol was approved by the Ethics Committee of the Antalya Training and Research Hospital.


In the entire group, the overall mean pure-tone averages were 13.88 [+ or -] 11.227 dB in the right ear and 10.30 [+ or -] 13.534 dB in the left.

In the right ears, PTA examination at 4, 6, and 8 kHz showed that hearing threshold levels were between 0 and 20 dB in 97 patients (61.0%); in the remaining 62 patients (39.0%), sensorineural hearing loss (SNHL) was detected at [greater than or equal to] 21 dB. In the left ears, PTA at 4, 6, and 8 kHz revealed that hearing threshold levels were normal in 115 patients (72.3%), with SNHL being present in the remaining 44 patients (27.7%) (figure, table 1).

In the right ears, DPOE testing showed that the signal/noise ratios at 4,6, and 8 kHz were [greater than or equal to] 6 dB in 124 patients (78.0%) and <6 dB in the remaining 35 patients (22.0%) (table 1). In the left ears, the corresponding figures were 128 patients (80.5%) and 31 patients (19.5%) (table 2).

The frequency of SNHL in patients on deferasirox, desferrioxamine, deferiprone, and combination therapy was 39.0,26.8,55.0, and 50.0%, respectively. The results of PTA performed in both ears did not demonstrate any statistically significant difference in the incidence of ototoxicity between the BTM and BTI groups overall (p = 0.11) or with respect to any of the four individual regimens (p = 0.765 for deferasirox,p = 0.378 for desferrioxamine, p = 0.265 for deferiprone, and p = 0.579 for the desferrioxamine-deferiprone combination); nor did the results of DPOAE testing (p = 0.890, p = 0.263, p = 0.390, andp = 0.340, respectively) (table 2).

Based on these data, we found no significant difference between PTA and DPOAE testing in their ability to detect ototoxicity. In the evaluation of the consistency of PTA and DPOAE testing for the detection of ototoxicity in BTM and BTI, kappa values (k) were estimated to be 0.515 and 0.462, respectively.

Laboratory values are shown in table 3. The overall mean serum ferritin level was 2,249.7 ng/ml. The mean level was 1,602 [+ or -] 1,378 ng/ml in the patients with SNHL and 2,406 [+ or -] 1,909 ng/ml in the patients with normal hearing. The difference between the two groups was statistically significant (p = 0.016).

A statistically significant difference in the incidence of ototoxicity was seen with increasing age (p < 0.001). There was no significant difference with respect to sex (p = 0.825).


[beta]-thalassemia is a congenital microcytic hypochromic anemia caused by defects in [beta]-chain synthesis. Stem cell transplantation is curative, but regular transfusion is the standard therapy. (5) Regular transfusions retard ineffective erythropoiesis and correct anemia, but hemosiderosis secondary to a hypertransfusion regimen is inevitable.

The use of iron chelators is an accepted method of removing excess iron from these patients. (5) The most commonly used agent is desferrioxamine. (We used deferasirox more often in our study because of our hospital's policy.) Iron chelation therapy with desferrioxamine has been shown to improve the life expectancy of patients with BTM. (6) Since desferrioxamine ototoxicity has been shown to be dose-dependent, the recommended therapeutic dosage is 20 to 40 mg/kg/day; studies have not demonstrated any ototoxic side effect at dosages less than 50 mg/kg/day. (3) In some situations, such as hematologic evaluation, the dosage can be increased to 60 mg/kg/day, as sometimes occurred in our study.

Deferiprone has an advantage over desferrioxamine in that it is an oral agent, but its use is associated with life-threatening agranulocytosis and the need for regular measurements of white blood cell counts, and therefore it is used less often than desferrioxamine. (7) Still, deferiprone and another oral agent, deferasirox, are associated with ototoxicity in [beta]-thalassemia patients. (3) When ototoxicity occurs, it is the result of damage to the ciliated cells of the basal turn of the cochlea, which leads to high-frequency SNHL. Studies have shown that the incidence of SNHL in such cases ranges from 14 to 26%. (8)

Shamsian et al evaluated desferrioxamine ototoxicity in 67 BTM patients older than 5 years using PTA, and they found SNHL in 7.4% of cases. (7) Ambrosetti et al reported an incidence of 26.3% among 57 BTM patients aged 17 to 32 years. (8) Kontzoglou et al reported an incidence of 20.2% among 104 patients with BTM aged 6 to 35 years. (9) Karimi et al found SNHL in more than half of BTM patients undergoing regular chelation therapy with desferrioxamine. (10)

We determined the frequency of SNHL on PTA as 39.0% in the right ear and 27.7% in the left ear. Onerci et al reported audiologic and impedancemetric findings in 34 patients with thalassemia; 27 of them had BTM and 7 had BTI. (11) They found that most ears in the BTM group hada conductive hearing loss or a mixed hearing loss and that no patient in that group had a pure sensorineural deficit. Our study population also included both BTM and BTI patients. Our study differed from others in that we compared the ototoxicity of iron chelation therapy in both BTM and BTI patients, and we did not find any statistically significant difference between them in terms of hearing loss (p = 0.11).

Several authors have studied the ototoxicity of desferrioxamine, and they reported that the hearing loss it is associated with is the sensorineural type and that it mainly affects the high frequencies. (12-15) Chandra et al analyzed the effectiveness and safety of deferasirox in 40 patients with BTM who received deferiprone or desferrioxamine-deferiprone therapy prior to deferasirox therapy, and they found that deferasirox was safe in pediatric age groups. (16)

As far as we know, our study of 159 patients with BTM and BTI is the largest of its kind. We believe that it is also the most comprehensive investigation in that we analyzed four different drug therapies that included three different drugs. We have not encountered any other study that compared other chelation therapies.

In our study, the frequency of SNHL in patients under desferrioxamine therapy was 26.8%, which is consistent with other findings in the literature. The rates of SNHL in the patients treated with deferasirox, deferiprone, and combination therapy were 39.0, 55.0, and 50.0%, respectively. We assume the differences in these figures stem from the heterogeneous distribution of the patients among groups. To clarify this issue, new studies with standardized patient populations are needed.

Measurements of otoacoustic emissions as a method of objective cochlear investigation are especially helpful in children. (17) Distortion-product emissions have been by far the most intensely investigated type of otoacoustic emissions. DPOAE values can be reliably measured in nearly all human ears with normal cochlear and middle ear function. Their high degree of test-retest reliability and their accuracy and objectivity in assessing cochlear function (outer hair cell function in particular) makes them useful for monitoring dynamic changes in cochlear responsiveness before they become functionally significant as a hearing loss. (18,19)

In our study, we noted a significant decrease in amplitude, mainly in the higher frequencies (>4 kHz), which was consistent with the high-frequency hearing loss usually associated with desferrioxamine ototoxicity. (20) As an ototoxicity screening tool, DPOAE has been shown to be superior to PTA, as DPOE amplitudes fall significantly before behavioral threshold changes are noted at corresponding frequencies on PTA. (21) In our study, we estimated that the consistency of PTA and DPOAE testing for the detection of ototoxicity in BTM and BTI were of a moderate degree--[kappa] = 0.515 and [kappa] = 0.462, respectively.

For the determination of hearing loss secondary to ototoxic drug use, PTA and DPOAE testing exhibit a good degree of consistency, and either can be used for the early detection of SNHL. Arnold et al found that these two methods correlated with each other. (20) In our literature search on hearing loss in iron chelation therapy, we could not find any study that evaluated the high frequencies. PTA has been investigated at frequencies up to 8 kHz. (7,10,21) However, some recent studies of ototoxicity have shown that high-frequency PTA was highly significant in detecting threshold changes caused by ototoxicity. Beahan et al found that high-frequency PTA was reliable in detecting ototoxicity in patients aged 7 years and older. (22) We did not have a high-frequency audiometer at our institution.

SNHL is not directly related to serum ferritin levels or desferrioxamine dosage; other factors, including genetic and constitutional characteristics, may be related. (7) Porter et al studied 47 BTM patients and found that high-dose desferrioxamine therapy associated with low serum ferritin levels (<2,000 ng/ml) is a major risk factor for desferrioxamine ototoxicity. (12) Ambrosetti et al noted that there is no relationship between age, serum ferritin level, and therapeutic indices with hearing loss. (8)


Our study confirms that iron chelation therapy can induce ototoxicity, and therefore periodic assessment of patients with [beta]-thalassemia is necessary. PTA and DPOAE testing are recommended for regular monitoring of cochlear function with the goal of preventing permanent damage.


(1.) Thio D, Prasad V, Anslow P, Lennox P. Marrow proliferation as a cause of hearing loss in beta-thalassaemia major. J Laryngol Otol 2008;122(11): 1253-6.

(2.) Angelucci E, Barosi G, Camaschella C, et al. Italian Society of Hematology practice guidelines for the management of iron overload in thalassemia major and related disorders. Haematologica 2008;93(5):741-52.

(3.) Nathan DG. The thalassemias. In: Nathan DG, Orkin SH, Ginsburg D, Look AT. Nathan and Oski's Hematology of Infancy and Childhood. 6th ed. Philadelphia: W.B. Saunders; 2003:893-5.

(4.) Kolnagou A, Kleanthous M, Kontoghiorghes GJ. Efficacy, compliance and toxicity factors are affecting the rate of normalization of body iron stores in thalassemia patients using the deferiprone and deferoxamine combination therapy. Hemoglobin 2011;35(3):186-98.

(5.) Quiralo K, Vichinsky E. Thalassemia syndromes. In: Behrman RE, Kliegman RM, Jenson HB, eds. Nelson Textbook of Pediatrics. 17th ed. Philadelphia: W.B. Saunders; 2004:1630-4.

(6.) Borgna-Pignatti C, Rugolotto S, De Stefano P, et al. Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. Haematologica 2004;89(10):l 187-93.

(7.) Shamsian BS, Aminasnafi A, Moghadassian H, et al. Sensory neural hearing loss in beta-thalassemia major patients treated with deferoxamine. Pediatr Hematol Oncol 2008;25(6):502-8.

(8.) Ambrosetti U, Donde E, Piatti G, Cappellini D. Audiological evaluation in adult beta-thalassemia major patients under regular chelation treatment. Pharmacol Res 2000;42(5):485-7.

(9.) Kontzoglou G, Koussi A, Economou M, et al. Long term audiological evaluation of beta-thalassemia patients. Acta Otorhinolaryngol Belg 2004;58(2):113-17.

(10.) Karimi M, Asadi-Pooya AA, Khademi B, et al. Evaluation of the incidence of sensorineural hearing loss in beta-thalassemia major patients under regular chelation therapy with desferrioxamine. Acta Haematol 2002;108(2):79-83.

(11.) Onerei M, Aslan S, Gumruk F, et al. Audiologic and impedancemetric findings within thalassaemic patients. Int J Pediatr Otorhinolaryngol 1994;28(2-3):167-72.

(12.) Porter JB, Jaswon MS, Huehns ER, et al. Desferrioxamine ototoxicity: Evaluation of risk factors in thalassemie patients and guidelines for safe dosage. Br J Haematol 1989;73(3):403-9.

(13.) Chiodo AA, Alberti PW. Experimental, clinical and preventive aspects of ototoxicity. Eur Arch Otorhinolaryngol 1994;251 (7):37592.

(14.) Bentur Y, Koren G, Tesoro A, et al. Comparison of deferoxamine pharmacokinetics between asymptomatic thalassemie children and those exhibiting severe neurotoxicity. Clin Pharmacol Ther 1990;47(4):478-82.

(15.) Ryals B, Westbrook E, Schacht J. Morphological evidence of ototoxicity of the iron chelator deferoxamine. Hear Res 1997;112(1-2):44-8.

(16.) Chandra J, Chaudhary H, Pemde H, et al. Safety and efficacy of deferasirox in multitransfused Indian children with [beta]-thalassaemia major. Ann Trop Paediatr 2011;31(1):47-51.

(17.) Probst R. A review of otoacoustic emissions. J Acoust Soc Am 1991;89(5):2027-67.

(18.) Franklin DJ, McCoy MJ, Martin GK, Lonsbury- Martin BL. Test/retest reliability of distortion-product and transiently evoked otoacoustic emissions. Ear Hear 1992;13(6):417-29.

(19.) HotzMA, Harris FP, Probst R. Otoacoustic emissions: An approach for monitoring aminoglycoside-induced ototoxicity. Laryngoscope 1994; 104(9): 1130-4.

(20.) Arnold DJ, Lonsbury-Martin BL, Martin GK. High-frequency hearing influences lower-frequency distortion product otoacoustic emissions. Arch Otolaryngol Head Neck Surg 1999;25(2):215-22.

(21.) Delehaye E, Capobianco S, Bertetto IB, Meloni F. Distortion-product otoacoustic emission: Early detection in deferoxamine induced ototoxicity. Auris Nasus Larynx 2008;35(2):198-202.

(22.) Beahan N, Kei J, Driscoll C, et al. High-frequency pure-tone audiometry in children: A test-retest reliability study relative to ototoxic criteria. Ear Hear 2012;33(1):104-11.

Ustun Osma, MD; Erdal Kurtoglu, MD; Hulya Eyigor, MD; Mustafa Deniz Yilmaz, MD; Nurdan Aygener

From the Department of Otolaryngology-Head and Neck Surgery (Dr. Osma, Dr. Eyigor, and Dr. Yilmaz), the Department of Hematology (Dr. Kurtoglu), and the Audiology Unit (Ms. Aygener), Antalya Training and Research Hospital, Antalya, Turkey.

Corresponding author: Hulya Eyigor, MD, Department of Otorhinolaryngology, Antalya Training and Research Hospital, Varlik Mh. Kazim Karabekir Caddesi, 07100, Muratpaca, Antalya, Turkey. Email:

Table 1. Statistical evaluation of hearing loss based on the
results of PTA and DPOAE testing

                                         p Value

                                 4 kHz    6 kHz    8 kHz

Pure-tone audiometry (right)     0.558    0.785    0.734
Pure-tone audiometry (left)      0.692    0.811    0.810
Distortion-product otoacoustic   0.181    0.185    0.518
  emissions (right)
Distortion-product otoacoustic   0.913    0.930    0.474
  emissions (left)

Table 2. Mean DPOAE values

                              Mean [+ or -] SD

Side         0.5 kHz               1 kHz                2 kHz

Right   0.31 [+ or -] 6.09   7.31 [+ or -] 6.09   9.69 [+ or -] 6.58
Left    0.55 [+ or -] 6.69   7.77 [+ or -] 5.49   9.67 [+ or -] 5.21

                                Mean [+ or -] SD

Side           4 kHz                 6 kHz

Right   11.96 [+ or -] 7.37   13.01 [+ or -] 10.48
Left    11.48 [+ or -] 7.65   14.12 [+ or -] 10.37

Side           8 kHz

Right   12.32 [+ or -] 9.34
Left    13.17 [+ or -] 9.23

Table 3. Laboratory data

Analyte                              Range (mean)

Hemoglobin (g/dl)                 6.2 to 11.6 (8.46)
Ferritin (ng/ml)                106 to 8,463 (2,249.7)
Aspartate transaminase (U/L)       12 to 169 (39.2)
Alanine transaminase (U/L)         7 to 314 (44.8)
Total bilirubin (mg/dl)          0.37 to 10.6 (12.8)
Direct bilirubin (mg/dl)         0.14 to 4.43 (0.606)
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Author:Osma, Ustun; Kurtoglu, Erdal; Eyigor, Hulya; Yilmaz, Mustafa Deniz; Aygener, Nurdan
Publication:Ear, Nose and Throat Journal
Article Type:Report
Date:Dec 1, 2015
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