Desferioximine induced Ototoxicity in Thalassemic patients

Abstract

Background

Thalassemia is a hereditary disorder requiring regular blood transfusion.

Purpose

To determine hearing sensitivity in transfusion-dependent thalassemics who were receiving desferioximine and on oral iron chelation (desferioximine) therapy.

Methods

26 patients with B-thelassemia in the age range of 5-22 years were enrolled in the thalassemia transfusion unit in the Advanced Pediatric Center of Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India. The patients to be enrolled in this study were randomly selected.

Results

It was observed that the hearing deteriorated in patients who were given injected desferioximine whereas it fell within normal limits in case of those who were given oral iron chelation therapy.

Concluson

This study confirms the necessity of regular audiological monitoring during the course of the disease.

Introduction

β- Thalassemia is a major chronic hereditary disorder, which usually manifests with severe anemia in infancy. These patients receive regular red cell transfusion at intervals of 3-4 weeks to sustain life. The repeated transfusion and the basic disease results in an iron overload state with consequent complications of cardiac / liver failure in the second or third decade of life.

Iron chelation therapy with desferioximine removes excess iron and helps to prevent organ damage in patients receiving regular erythrocytes transfusion. Until recently, desferioximine was considered generally free from major side effects. Clinical and sub-clinical studies have shown that visual and auditory neuro- toxicity was present in about one and a half of the patients receiving subcutaneous infusions of desferioximine.¹ An oral iron chelator, deferiprone was evaluated in multicentric study in the early 1990’s. Efficacy in reducing/preventing iron overload was documented in most patients. The cost is less than one fifth of the cost of desferioximine and hence making it more affordable.

The only curative treatment available is bone-marrow transplant (BMT) which is possible only if a matched HLA sibling donor is available. The cost of a BMT in India is approximately Rs. 9.0 lacs, an expense that is beyond the reach of almost 95% of the patients.

The major side effects which have been observed in patients receiving oral iron chelation are musculoskeletal pain (25-30%) and severe neuropaenia (1-2%). The aim of this study was to determine auditory sensitivity changes in the patients receiving desferioximine and oral chelator-deferiprone and to correlate the threshold differences in relation to duration of iron chelation therapy.

Methods

Patients with β- Thallasemia referred for blood transfusion in the Advance Pediatric Centre, PGIMER, Chandigarh who came to Speech and Hearing Unit of Otolaryngology Department were included in this study. The patients enrolled in this study were randomly selected according to the following criteria and informed consent was obtained:

Inclusion criteria

1. Patients requiring diagnosed cases of β- Thalassemia.

2. Patients requiring multiple red cell transfusion manifested in infancy.

3. Patients receiving injected iron chelation therapy (Desferioxamine) or defriprone for a period ranging from 0-3 years.

4. Patients receiving oral iron chelation therapy (defriprone) for a period ranging from 0-6 years.

Exclusion criteria

1. Post- transfusion age -18 months.

2. Overt evidence of serious infection.

3. Neurological deficits, history of seizures.

4. Those suffering from CSOM, and

5. Hearing impairment.

Total number of subjects was 26 (19 males and 7 females). 8 patients were on injectable desferioximne while 18 were on oral iron chelation therapy. These patients were visiting Advanced Pediatric Centre of Post Graduate Institute of Medical Education and Research, Chandigarh, in the Thalassemia clinic for regular blood transfusion and were referred to the Speech and Hearing Unit of the Department of Otolaryngology and Head and Neck Surgery where the brief history of these patients was taken with reference to past, present and recurrent hearing disturbances. Objective examination of external auditory meatus and tympanic membrane was performed and all the audiological testing was done in the sound treated rooms of Speech and Hearing Unit of the same department.

1. A thorough evaluation of the patients was carried out in the Department of Otolaryngology, which included history, clinical examination and hearing evaluation.

2. The hearing assessment was done at different octave frequencies, i.e., 250 Hz, 500 Hz, 1 KHz, 2 KHz, 4 KHz, and 8 KHz, using an Amplaid 309 – Audiometer.

3. Normal hearing was defined as threshold sensitivity equal to or less than 26 dB hearing threshold level (ANSI-1969).

Results

The sample characteristics of the homozygous β- Thalassemia for iron chelation therapy is given in Table-1.

Table 1: Sample Characteristics of thalassemic patients.

No of patients	Age Range	Sex
52	5-22	M	F
		38	14

Table-2 shows the hearing thresholds of Oral/injected deferioximine. Mean threshold increase was observed at octave intervals i.e., 250 to 8000 Hz during 0-3 years of treatment.

Table 2: Thresholds of hearing sensitivity in patients receiving Oral/Injected iron chelation therapy n = 52 (0-3 yrs) requencies H₂.

Freq.(Hz)	250	500	1k	2k	4k	8kHZ
Freq =Frequency
Intensity (oral) in dB	20.18	19.52	20.41	27.33	32.74	35.27
Intensity (Injected).	15.85	19.64	14.77	21.49	33.74	35.50

Table-3 shows that the mean hearing threshold increased in patients receiving injectable iron chelation therapy only but the hearing thresholds of the patients receiving oral iron chelation therapy decreased and almost came under the normal values as per the ANSI 1969 standards for 0-6 years period.

Table 3: Threshold of hearing sensitivity changes with different dosages of oral/iron chelation therapy on thalassemia patients (0-6 yrs) n = 52.

Freq.	250	500	1k	2k	4k	8k
Freq = Frequency
Intensity (oral) in dB	18.46	15.55	16.66	14.16	12.83	17.49
Intensity (Injected)	19.52	19.27	17.18	25.37	48.91	33.05

The present study revealed that those Thalassemia patients who received injectable iron chelation therapy for 3 years had lesser deterioration of hearing threshold as compared to those who received therapy for 6 years. These results were nearly similar to the results obtained by Styles et. al.² They had done serial audiograms with chronically chelated patients over a period of 5 years.

However, those who received oral iron chelation therapy for 3 years had hearing impairement but by the time, they received therapy continuously for 6 years they became audiologically within normal limits which is in accordance with the long - term treatment of transfusion iron overload with the oral iron chelation deferiprone.³

Discussion

The iron chelated desferioximine was introduced more than 30 years ago⁴⁵ and remains the only chelator approved for regular use in North America and the only first-line agent approved for use in Europe. Desferioxamine improves hepatic, cardiac and endocrine dysfunction and lengthens survival in patients with iron overload.^6-8 The disadvantages include high cost⁹ the requirement for daily parental administration and local and systemic toxic effects that include visual¹⁰ and auditory neuro toxic effects¹ skeletal abnormalities¹¹ and growth retardation.¹²

The present study reveals that percentage of normal hearing at low frequencies and impairment at high frequencies is only 8% and 12% at 4 KHz and 8 KHz respectively. Therefore, it can be stated that hearing is affected at higher frequencies to some extent. These results are quite similar to another study done by Cohen et. al.¹³ Shirane and Harrison¹⁴ also reported similar findings that cochlear action potential threshold elevated from 20-40 dB and were most evident in high frequency region which is in agreement with the present findings. They examined the effect of desferoximine mesylate and hypoxia on the cochlea in Chinchillas. They administered the desferioximene mesylate, 100 mg/kg/day for five days/week intramuscularly to 19 Chinchillas for three months. They reported no changes in cochlea in chronic experiment scheduled to be similar to the clinical long-term chelation therapy but on the other hand acute administration of desferioximene gives rise to respiratory suppression accompanied by impairment of cochlear function and histological changes of sensory epithelium. The functional and histological damage to the cochlea is in the form of cytoplasmic protrusions and disarrangement of sensory hair cells at the level of inner hair cells, leaving outer cells mostly intact. It was also observed in acute experiments that a close correlation was also present between respiratory suppression and desferioximine mesylate. They concluded that it had very little direct toxic effect on cochlea and cochlear hypoxia seemed to be have been largely responsible for damage to sensory epithelium in acute experiments.

In another experiment Kimura et. al.¹⁵ found that it interrupted the blood flow to the cochlea of Guinea pigs and it was observed that degenerative changes occurred in the cochlea. They also reported that inner hair cells are affected first and cell degeneration spreads to the outer hair cells. In other publication like Fernandez et. al.¹⁶ Jordan et. al.¹⁷ and Theopold¹⁸ it was reported that post mortem changes in the sensory epithelium occur at the level of inner hair cells and then spreads to the outer hair cells. The histopathological changes in the cochlea were described in the above reports, which seem to be responsible for hearing impairment in thalassemic patients receiving the drug desferioximene and iron chelation deferioxamine at higher frequencies as observed in the present study.

Conclusion

The patients with β- Thalassemia receiving injectable and oral iron chelation therapy need to be followed up for regular audiological monitoring to detect any early changes in the hearing. A larger sample of data and the longer follow up i.e. 6-9 months would help us to reach a definite conclusion.