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Hearing impairment in persons with the hemoglobin SC genotype.

Abstract

The hemoglobin (Hb) SC genotype is seen in persons who have inherited the gene for hemoglobin S from one parent and the gene for hemoglobin C from the other. Some people with this genotype develop Hb SC disease, a variant of sickle cell disease. Hb SC disease, a compound heterozygous condition, is the most common of the hemoglobinopathies and the least severe, although it is still serious. One of the documented complications of the presence of the Hb SC genotype is sensorineural hearing loss (SNHL). We conducted a prospective case-control study of 43 subjects, aged 15 to 65 years, who had the Hb SC genotype to determine the incidence of SNHL and to determine if the hearing loss in these subjects was correlated with sex or age. Our Control group was made up of 100 generally healthy, sex- and age-matched subjects with the normal Hb AA genotype. SNHL was defined as a loss of more than 25 dB HL at two or more frequencies in the same ear or at one or more frequencies in both ears. We found that SNHL was present in 12 of the 43 subjects (27.9%) in the Hb SC group (17 of 86 ears [19.8%]) and in 17 of the 100 subjects (17.0%) in the Hb AA group (21 of 200 ears [10.5%]; the difference between the two groups was not statistically significant ([chi square] = 1.589; p = 0.105). We found that in the Hb SC group, SNHL was more common among females than males (38.5 vs. 11.8%), although the difference was not quite significant statistically ([chi square] = 2.435; p = 0.056); in the Hb AA group, the incidence was fairly equal--15.4 and 18.8%, respectively ([chi square] = 0.033; p = 0.427). Therefore, we conclude that the hearing loss in the subjects of this study was not correlated with the presence of the Hb SC genotype in either sex. In terms of age, SNHL was significantly more common in subjects aged 41 to 65 years than in those aged 15 to 40 years in both genotype groups. In the Hb SC group, SNHL was present in 4 of the 33 younger subjects (12.1%) and in 8 of the 10 older subjects (80.0%) ([chi square] = 14.354; p < 0.001). In the Hb AA group, the corresponding figures were 7 of 85 (8.2%) and 10 of 15 (66.7%) ([chi square] = 26.840; p < 0.001). Therefore, we conclude that the hearing loss in the subjects of this study was a function of age and was not associated with the presence of the Hb SC genotype.

Introduction

Among the sickle cell diseases, the most common is hemoglobin (Hb) SC disease. This hemoglobulinopathy is a compound heterozygous condition that can occur in persons who have inherited the gene for hemoglobin S from one parent and the gene for hemoglobin C from the other. Hb SC disease is the least severe of the hemoglobinopathies, and patients generally have less morbidity and mortality than do patients with homozygous Hb SS disease (sickle cell anemia). Lehmann and colleagues observed that children with Hb SC disease were more likely to survive into adulthood than children with Hb SS disease. (1,2) Based on those observations, they proposed that Hb SC disease may be an adult-onset infarctive disease. They also noted that anemia was generally noncontributory to the clinical status of patients with Hb SC disease. Nevertheless, Hb SC disease is still serious, as many affected patients do not survive to adulthood. (3-6)

Many of the effects of Hb SC disease are similar to those of Hb SS disease. Sickled red blood cells develop as a consequence of low oxygen tension, which leads to vaso-occlusion and subsequent ischemic tissue damage in almost all organs of the body. The cochlea is vulnerable when there is involvement of the blood supply to the neurons and supporting cells along the peripheral and central auditory pathways and when there is spontaneous labyrinthine hemorrhage. (7,8) As a result, one of the complications of the sickle cell diseases is hearing loss. (9-13) It has been reported that in patients with any of the sickle cell diseases, hearing loss affects the high frequencies (4 to 8 kHz) more than the low frequencies (125 to 250 HZ). (9-11,14-16) This finding might be attributable to the chronic occlusion of the cochlear capillaries and venous channels that occurs in these patients. The significance of this is that the four tested speech frequencies (500 Hz and 1, 2, and 4 kHz) are not likely to be affected early in a vaso-occlusive condition unless the entire cochlear organ suddenly becomes affected. It has been documented that the hearing loss in patients with Hb SC disease is usually cochlear in nature, while the hearing loss in Hb SS disease is usually neural in nature. (17) Also, hearing loss in Hb SC disease usually occurs later than hearing loss in Hb SS disease. (17)

In this article, we describe our study of hearing loss in subjects with the Hb SC genotype. There is a paucity of information on this topic in the literature. Our goals were to compare the incidence of hearing impairment between subjects with the Hb SC genotype and normal controls with the Hb AA genotype and to determine if there were any correlations between hearing loss and either sex or age in the Hb SC group.

Subjects and methods

For this prospective case-control study, we identified subjects with the Hb SC genotype, the presence of which had been confirmed in our hematology outpatient clinic. A total of 43 such subjects met our eligibility criteria. For a control group, we recruited 100 generally healthy, sex- and age-matched subjects with the normal Hb AA genotype from among other patients and employees at our tertiary care hospital. Exclusion criteria included a history of illness that could affect hearing, a family history of hearing loss, a congenital ear anomaly, an inflammatory or infectious condition of the ear, a chronic ear problem, previous ear surgery, and a history of cerebrovascular accident, head injury, or ototoxicity. Ethical clearance for the study protocol was obtained from our Institutional Review Board, and oral and written consent was obtained from all participants.

The Hb SC group was made up of 17 males and 26 females, aged 15 to 65 years (mean: 31.4 [+ or -] 14.3; median: 26). The control group was made up of 48 males and 52 females, aged 15 to 65 years (mean: 28.7 [+ or -] 11.9; median: 25). The male-to-female ratios in the two groups were 1:1.5 and 1:1.1, respectively. The Hb SC group included 33 subjects aged 15 to 40 years and 10 subjects aged 41 to 65 years, for a younger-older ratio of 3:1; the corresponding figures for the control group were 85, 15, and 6:1. There was no significant difference in the mean age between the two groups (p = 0.29).

All participants had undergone a thorough physical examination. Ear wax was removed prior to audiometric evaluation, which included pure-tone air- and bone-conduction testing. Audiometry was conducted in a sound-proof booth that met American National Standards Institute (ANSI) specifications for permissible ambient noise during testing involving all the octave frequencies from 250 Hz to 8 kHz.

SNHL was defined as a loss of more than 25 dB HL at two or more frequencies in the same ear or at one or more frequencies in both ears. The degree of hearing loss was categorized according to the World Health Organization classification as slight (26 to 40 dB), moderate (41 to 60 dB), severe (61 to 80 dB), and profound ([greater than or equal to] 81 dB), all in the better ear. (18)

In each study participant, a hearing level (dB HL) was ascertained in each ear at the four tested speech frequencies, and a mean dB HL was calculated by adding the four values and dividing by four. We also tested high-frequency (8 kHz) hearing.

For statistical analysis, between-group comparisons of the prevalence of SNHL were made with a 2-tailed (control variables) or 1-tailed (outcome variables) chi-square ([chi square]) test with Yates correction for continuity. Where appropriate, the Fisher exact test was also used. Comparisons of continuous variables were performed according to the Student t test where appropriate. The level of significance was p < 0.05 at either a 95 or 99% confidence interval (CI).

Results

In the Hb SC group, SNHL was present in 12 of the 43 subjects (27.9%) and in 17 of the 86 ears (19.8%) (table 1). In the Hb AA group, hearing loss was present 17 of the 100 subjects (17.0%) and in 21 of 200 ears (10.5%). The difference in the SNHL between the two groups of subjects was not statistically significant ([chi square] = 1.589; p = 0.105).

In both groups, unilateral SNHL was more common than bilateral loss. Also, hearing loss was more common in the right ear than in the left in both groups (table 1).

The degree of hearing loss ranged from 26 to 60 dB. Most cases were in the slight category (26 to 40 dB); no subject had a severe or profound hearing loss (table 2). Of the 43 subjects in the Hb SC group, 14 (32.6%) had a slight hearing loss and 3 (7.0%) had a moderate loss. The corresponding figures in the control group were 19 (19.0%) and 2 (2.0%).

Sex. In the Hb SC group, SNHL was three times more common in the females than in the males--38.5 vs. 11.8%--but the difference was not statistically significant ([chi square] = 2.435; p = 0.056) (table 3). In the Hb AA group, the incidence of SNHL among the females and males was much closer to equal--15.4 and 18.8%, respectively ([chi square] = 0.033; p = 0.427).

Based on these findings, we concluded that the hearing loss in the subjects of this study was not correlated with the presence of the Hb SC genotype in either sex.

Age. In both groups, the incidence of SNHL was significantly higher among the older participants (table 4). In the Hb SC group, SNHL was present in 4 of the 33 subjects (12.1%) aged 15 to 40 years and in 8 of the 10 subjects (80.0%) aged 41 to 65 years ([chi square] = 14.354; p < 0.001). In the Hb AA group, SNHL was present in 7 of the 85 younger subjects (8.2%) and in 10 of the 15 older subjects (66.7%) ([chi square] = 26.840; p < 0.001).

These findings indicated that the hearing loss in the subjects of this study was a function of age and was not associated with the presence of the Hb SC genotype.

High-frequency hearing loss. High-frequency (8 kHz) hearing loss was observed in 48 of the 86 ears (55.8%) in the Hb SC group and in 62 of the 200 ears (31.0%) in the Hb AA group. The younger patients had a milder degree of high-frequency hearing loss than did the older patients. The difference in the db HL at 8 KHz between the younger and older subjects in each genotype group was statistically significant ([chi square] = 31.903; p < 0.001 in the Hb SC group and [chi square] = 45.999; p < 0.001 in the Hb AA group). The overall difference between the entire genotype groups was obviously not statistically significant ([chi square] = 3.912; p = 0.05). In the Hb SC group, the hearing loss ranged from 26 to 35 dB HL among those aged 15 to 40 years and from 37 to 70 dB HL among those aged 41 to 65.

Discussion

The degree of clinical morbidity among individual adults with Hb SC disease varies. (19) In patients with a sickle cell disease, hearing loss is among the least reported sequelae, which should not be surprising in view of the more serious challenges these patients face. (9) For example, while life expectancy is on the rise among sickle cell disease patients, it is still lower than that of the general population. (20) Male and female patients with Hb SS disease are reported to have median life expectancies of 42 and 48 years, respectively. (21) Life expectancy is somewhat longer in patients with Hb SC disease, and some of these patients survive into their seventh decade. (21)

In our study, we found a highly significant correlation between hearing impairment and age, regardless of Hb genotype. In both of our study groups, hearing loss was more common in the older participants than in the younger participants--80.0 vs. 12.1% in the Hb SC group and 66.7 vs. 8.2% in the Hb AA group. Therefore, we conclude that the difference in hearing levels is more a function of age than anything else, including genotype.

We also observed that hearing loss was three times more common among the females in the Hb SC group than the males, although the difference was not statistically significant. Heifer noted that variations in endogenous and exogenous influences may be responsible for differences in morbidity and mortality between men and women; for example, women live longer than men and, as a result, they experience more chronic illness. (22) Differences in hearing between the sexes in older humans based on pure-tone thresholds have been well replicated. Among middle-aged and elderly people with the normal Hb AA genotype, high-frequency hearing loss is more common among men than women and low-frequency hearing loss is more common among women than men. (23-25) Further research is needed to determine if this pattern is true in patients with sickle cell diseases. Some studies have demonstrated that certain aspects of hearing, including the perception of binaural beats and auditory thresholds, vary according to the phase of the menstrual cycle in women with the Hb AA genotype. (26-29) Hearing changes might be related to the changes in physiology (e.g., body temperature and blood pressure) that occur during various stages of the menstrual cycle. (30)

Acknowledgment

We appreciate the contribution of Mrs. Wemimo Osisanya, the audiologist at the Department of Otorhinolaryngology at University College Hospital, for conducting the pure-tone audiometry on all study participants.

References

(1.) Lehmann H, Huntsman RG. Man's Haemoglobins: Including the Haemoglobins and Their Investigation. Philadelphia: J.B. Lippincott; 1974.

(2.) Edington GM, Lehmann H. A case of sickle cell haemoglobin C disease and a survey of haemoglobin C incidence in West Africa.

Trans R Soc Trop Med Hyg 1954;48(4):332-6.

(3.) Moll S, Orringer EP. Hemoglobin SC disease. Am J Hematol 1997; 54(4):313.

(4.) Serjeant GR, Serjeant BE. Sickle Cell Disease. 3rd ed. Oxford: Oxford University Press; 2001.

(5.) Nagel RL, Fabry ME, Steinberg MH. The paradox of hemoglobin SC disease. Blood Rev 2003;17(3):167-78.

(6.) Powars DR, Hiti A, Ramicone E, et al. Outcome in hemoglobin SC disease: A four-decade observational study of clinical, hematologic, and genetic factors. Am J Hemato1 2002;70(3):206-15.

(7.) Gould HJ, Crawford MR, Smith WR, et al. Hearing disorders in sickle cell disease: Cochlear and retrocochlear findings. Ear Hear 1991;12(5):352-4.

(8.) Whitehead RE, MacDonald CB, Melhem ER, McMahon L. Spontaneous labyrinthine hemorrhage in sickle cell disease. AJNR Am J Neuroradiol 1998;19(8):1437-40.

(9.) Onakoya PA, Nwaorgu OG, Shokunbi WA. Sensorineural hearing loss in adults with sickle cell anaemia. Afr J Med Med Sci 2002;31 (1):21-4.

(10.) Tavin ME, Rubin JS, Camacho FJ. Sudden sensorineural hearing loss in haemoglobin SC disease. J Laryngol Otol 1993;107(9):831-3.

(11.) Schreibstein JM, MacDonald CB, Cox LC, et al. Sudden hearing loss in sickle cell disease: A case report. Otolaryngol Head Neck Surg 1997;116(4):541-4.

(12.) Crawford MR, Gould HI, Smith WR, et al. Prevalence of hearing loss in adults with sickle cell disease. Ear Hear 1991;12(5):349-51.

(13.) Ajulo SO, Osiname AI, Myatt HM. Sensorineural hearing loss in sickle cell anaemia--a United Kingdom study. J Laryngol Otol 1993;107(9):790-4.

(14.) O'Keeffe LJ, Maw AR. Sudden total deafness in sickle cell disease. J Laryngol Otol 1991;105(8):653-5.

(15.) Tavin ME, Rubin JS, Camacho FJ. Sudden sensorineural hearing loss in haemoglobin SC disease. J Laryngol Otol 1993; 107(9):831-3.

(16.) Tsibulevskaya G, Oburra H, Aluoch JR. Sensorineural hearing loss in patients with sickle cell anaemia in Kenya. East Afr Med J 1996;73(7):471-3.

(17.) Jovanovic-Bateman L, Hedreville R. Sensorineural hearingloss with brainstem auditory evoked responses changes in homozygote and heterozygote sickle cell patients in Guadeloupe (France). J Laryngol Otol 2006;120(8):627-30.

(18.) World Health Organization. Grades of hearing impairment, http:// www.who.int/pbd/deafness/hearing_impairment_grades/en/index. html. Accessed March 3, 2010.

(19.) Varricchio F, Ahuja J, Rao K. An octogenarian with hemoglobin S-C disease. Am J Hematol 1993;43(4):330.

(20.) Schnog JB, Duits AJ, Muskiet FA, et al. Sickle cell disease: A general overview. Neth J Med 2004;62(10):364-74.

(21.) Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med 1994;330(23):1639-44.

(22.) Helfer K. Gender, age and hearing. Semin Hear 2001;22(3):271-86.

(23.) Gates GA, Cooper JC Jr., Kannel WB, Miller NJ. Hearing in the elderly: The Framingham cohort, 1983-1985. Part I. Basic audiometric test results. Ear Hear 1990;11(4):247-56.

(24.) Corso IF. Age and sex differences in pure-tone thresholds. Survey of hearing levels from 18 to 65 years. Arch Otolaryngol 1963;77:385-405.

(25.) Megighian D, Savastano M, Salvador L, et al. Audiometric and epidemiological analysis of elderly in the Veneto region. Gerontology 2000;46(4): 199-204.

(26.) Pearson JD, Morrell CH, Gordon-Salant S, et al. Gender differences in a longitudinal study of age-associated hearing loss. J Acoust Soc Am 1995;97(2):1196-1205.

(27.) Haggard M, Gaston JB. Changes in auditory perception in the menstrual cycle. Br J Audiol 1978;12(4):105-18.

(28.) Baker MA, Weiler EM. Sex of listener and hormonal correlates of auditory thresholds. Br J Audiol 1977;11 (3):65-8.

(29.) Davis MJ, Ahroon WA. Fluctuations in susceptibility to noise-induced temporary threshold shift as influenced by the menstrual cycle. J Aud Res 1982;22(3):173-87.

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Paul A. Onakoya, FWACS; Onyekwere G.B. Nwaorgu, FWACS; Wuraola A. Shokunbi, FWACP

From the Department of Otorhinolaryngology (Dr. Onakoya and Dr. Nwaorgu) and the Department of Haematology and Blood Transfusion (Dr. Shokunbi), University College Hospital, Ibadan, Nigeria.

Corresponding author: Dr. Paul A. Onakoya, Department of Otorhinolaryngology, University College Hospital, PMB 5116, Ibadan, Nigeria. E-mail: paonak@yahoo.com or ponakoya@comui.edu.ng
Table 1. Hearing status according to genotype

                               Hb SC, n (%)

                          Subjects      Ears
Status                    (n = 43)    (n = 86)

Normal hearing            31 (72.1)   69 (80.2)
Hearing loss ([dagger])   12 (27.9)   17 (19.8)
Right ear only            5 (11.6)     5 (5.8)
Left ear only              2 (4.7)     2 (2.3)
Both ears                 5 (11.6)    10 (11.6)

                              Hb AA, n (%)

                          Subjects       Ears
Status                    (n = 100)   (n = 200)

Normal hearing            83 (83.0)   179 (89.5)
Hearing loss ([dagger])   17 (17.0)   21 (10.5)
Right ear only            12 (12.0)    12 (6.0)
Left ear only              1 (1.0)     1 (0.5)
Both ears                  4 (4.0)     8 (4.0)

                          Fisher exact test,
Status                    1-tailed *

Normal hearing            [chi square] = 1.589; p = 0.105
Hearing loss ([dagger])
Right ear only
Left ear only
Both ears

* Hb SC vs. Hb AA group; number of subjects.

([dagger]) Hearing loss was defined as a loss of >25 dB HL at two or
more frequencies in the same ear or at one or more frequencies in
both ears.

Table 2. Degree of hearing loss * in each ear

                               Hb SC (n = 43) (%)

                              Right ear   Left ear

None (normal hearing)         33 (76.7)   36 (83.7)
Slight loss (26 to 40 dB)      9 (20.9)    5 (11.6)
Moderate loss (41 to 60 dB)    1 (2.3)     2 (4.7)

                               Hb AA (n = 100) (%)

                              Right ear     Left ear

None (normal hearing)         84 (84.0)    95 (95.0)
Slight loss (26 to 40 dB)     14 (14.0)     5 (5.0)
Moderate loss (41 to 60 dB)    2 (2.0)         0

* Hearing loss was defined as a loss of >25 dB HL at two or more
frequencies in the same ear or at one or more frequencies in both
ears.

Table 3. Hearing status according to sex

                                 Hearing loss *

                              Absent      Present
Genotype   Sex                 n (%)       n (%)

Hb SC      Male (n = 17)     15 (88.2)    2 (11.8)
           Female (n = 26)   16 (61.5)   10 (38.5)
           Total (n = 43)    31 (72.1)   12 (27.9)

Hb AA      Male (n = 48)     39 (81.3)    9 (18.8)
           Female (n = 52)   44 (84.6)    8 (15.4)
           Total (n = 100)   83 (83.0)   17 (17.0)

                             Fisher exact test,
Genotype   Sex               1-tailed ([dagger])

Hb SC      Male (n = 17)     [chi square] = 2.435; p = 0.056
           Female (n = 26)
           Total (n = 43)

Hb AA      Male (n = 48)     [chi square] = 0.033; p = 0.427
           Female (n = 52)
           Total (n = 100)

* Hearing loss was defined as a loss of >25 dB HL at two or more
frequencies in the same ear or at one or more frequencies in both
ears.

([dagger]) Male vs. female.

Table 4. Hearing status according to age

                                  Hearing loss *

                                Absent      Present
Genotype   Age (yr)              n (%)       n (%)

Hb SC      15 to 40 (n = 33)   29 (87.9)    4 (12.1)
           41 to 65 (n = 10)    2 (20.0)    8 (80.0)
           Total (n = 43)      31 (72.1)   12 (27.9)

Hb AA      15 to 40 (n = 85)   78 (91.8)    7 (8.2)
           41 to 65 (n = 15)    5 (33.3)   10 (66.7)
           Total (n = 100)     83 (83.0)   17 (17.0)

                               Fisher exact test,
Genotype   Age (yr)            1-tailed ([dagger])

Hb SC      15 to 40 (n = 33)   [chi square] = 14.354; p < 0.001
           41 to 65 (n = 10)
           Total (n = 43)

Hb AA      15 to 40 (n = 85)   [chi square] = 26.840; p < 0.001
           41 to 65 (n = 15)
           Total (n = 100)

* Hearing loss was defined as a loss of >25 dB HL at two or more
frequencies in the same ear or atone or more frequencies in both
ears.

([dagger]) Younger vs. older group.
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Title Annotation:ORIGINAL ARTICLE
Author:Onakoya, Paul A.; Nwaorgu, Onyekwere G.B.; Shokunbi, Wuraola A.
Publication:Ear, Nose and Throat Journal
Article Type:Clinical report
Geographic Code:6NIGR
Date:Jul 1, 2010
Words:3772
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