Original Paper O R L 1992:54:66-70

Departments o f Otolaryngology Haematology, and Isotopy. Changhai Hospital, and Shanghai Ear. Nose, and Throat Hospital. Shanghai Medical University, Shanghai. People's Republic o f China

Key Words Idiopathic sudden hearing loss Iron metabolism Iron therapy

Idiopathic Sudden Hearing Loss and Disturbance of Iron Metabolism A Clinical Survey of 426 Cases

Abstract The role of disturbances of the iron metabolism (DIM) in idiopathic sudden hearing loss (ISHL) was investigated in 426 patients with ISH L who received iron therapy. anti-DIM medication, vitamins, and a combined regimen in a randomized study which was stratified by stages and groups. Low concentra­ tions of haemoglobin, serum iron, serum ferrilin, and red cell basic ferritin as well as abnormal circadian variations in the serum iron level were observed. The results were significantly better in patients receiving iron therapy than in those receiving anti-DIM medication, vitamins, and the combined regimen. Hearing improvement was achieved in 53.26% of the patients whose treat­ ment started later than 3 months after the onset of the disease. The clinical association of DIM and ISH L is discussed.

Introduction Idiopathic sudden hearing loss (ISHL) is a frequent problem in otolaryngological practice. Unfortunately, even after intensive investigations, the exact aetiological mechanism remains obscure. Thus, therapy has been purely empirical in the past in most clinics [1.2], Our pre­ liminary studies showed that the patients with sensori­ neural deafness including ISHL usually had a disturbance of iron metabolism (DIM) such as iron deficiency and abnormal iron metabolism and that iron-deficient rats tended to have sensorineural hearing loss associated with changes of the cochlear iron enzymes, impairment of the

Received: M ay 28.1991 Accepted after revision: September 2. 1991

hair cell stereocilia, and strial atrophy as well as reduction of spiral ganglion cells [3-6], In the present work we have extended our preliminary investigation by an assessment of DIM in 426 patients with ISHL.

Patients and Methods Patients During the years 1977-1990. 426 patients (470 ears) with ISH L were investigated in a prospective study. Before treatment, each patient received a thorough checkup, including history and physical examination, tuning fork test, pure-tone and impedance audiometry, auditory brain stem response and caloric testing, electronystagmo-

Dr. Ai-Hua Sun Department ofOlolar\ngolog\ Changhai Hospital Shanghai 200433 (People's Republic of China)

© 1992 S. Karger AG. Basel 0301- 1 569/92/0542-0066 $2.75/0

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A i-H uaSuna, Zheng-Min Wangh Shi-Zhi Xia oa, Zhao-Ji L ia Jin-Cheng Ding*, Jin -Y in g L ic Ling-Shan Kongd

Table 1. Treatment protocols and drugs

Protocols

Drugs

Iron therapy

Iron dextran 50 mg i.m .. twice a day, or ferrosi sulfas 0.6 g or ferrosi fumarus 0.4 g p.o., three times a day A nti-D IM medication: magnititum 60 g, radix Puerariac 45 g. rhizoma Drynaride 45 g. rhizoma Dioscoreae 30 g. radix Paeoniac alba 15 g. rhizoma Licustici Chuanxiong 15 g. radix ct rhizoma Rhei 3 g. and radix Glucyrrhizae 12 g. one dose orally, twice a day

A nti-D IM medication

Ditto - one dose orally, twice a day

Vitamins

Vitamin E 100 mg, vitamin C 200 mg. vitamin B(, 20 mg. and vitamin A (10,000 IU ) in combination with vitamin D (1,000 IU ), one pill, three times a day: niacin 100 mg orally, three times a day: vitamin B n 100 pg i.m ., daily

Combined regimen

Decadron 10 mg in dextrose 10%, 500 ml i.v., daily: Salvia miltiorrhiza 16 g in dextran 40, 500 ml i.v.. daily

Improvement. The threshold curve rose 15-30 dB in the majority o f frequencies, and subjective symptoms were also less. No Change. Hearing improvement for the majority o f frequencies was less than 15 dB. irrespective o f any improvement in subjective symptoms. Iftherc was bilateral involvement, each ear was evaluated separately. To ensure objectivity, follow-up audiograms were re­ peated every month for 0.5-2 years. Laboratory Methods The haemoglobin concentration was determined by the cyanmcthaemoglobin method [8]. Content and circadian variation of serum iron were measured by atomic absorption spectrophotometry [9], Serum ferritin was assayed using a radioimmunoassay based on antibodies against human spleen ferritin. Red cell basic ferritin was determined as described earlier [10]. Statistical Analysis The statistical methods employed in the analysis o f these data were Student’s t test and the %2 test. The results are expressed as mean values ± SD .

Results Evidence o f D IM Haemoglobin. One hundred and eighty-one (42.49%) patients whose haemoglobin concentration was less than the cut-off value of 130 g/1 in men, 120 in women, and 105 g/1 in children were considered anaemic [11, 12], Serum Iron. The mean concentrations were 19.71 ± 5.16 pmol/1 in 284 patients with ISH L and 27.49 ± 6.22 pmol/1 in 268 healthy subjects with normal hearing. The serum iron content in cases of ISHL was significantly lower than that in normal controls (p < 0.001). Circadian Variation in Serum Iron. This was studied in 282 patients with ISHL and in 260 normal individuals. The circadian variation in the serum iron concentration, the peak being in the morning and the trough in the early evening, was over ± 3.582 pmol (normal range of circa­ dian variation in our laboratory) in 32 (1 1.35%) of the 282 cases with ISH L and in 246 (94.62%) of 260 healthy subjects with normal hearing. Statistically, the difference was significant (p < 0.001). Serum Ferritin. This was measured in 112 cases with ISH L and in 103 healthy subjects with normal hearing. Twenty-five patients (22.32%) with ISH L who had either iron deficiency or iron deficiency anaemia had serum fer­ ritin levels < 0 .7 0 nmol/1. Red Cell Basic Ferritin. The mean levels were 10.842 ± 6.812 ag/cell in 61 patients with ISHL and 26.194 ± 14.498 ag/cell in 55 normal subjects, significantly lower in the patients with ISH L (p < 0.001).

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gram, and radiographs o f skull, neck, and internal canals. Laboratory work includied a complete blood cell count and determination of haemoglobin, serum iron, circadian variation in the serum iron level, scrum ferritin, and red cell basic ferritin. Those patients for whom no cause o f the sudden sensorineural hearing loss could be found were considered to have ISH L . The delay since the onset o f hearing loss was less than 1 month in 231 cases. 1-3 months in 97 cases, and 4-24 months in 98 cases. One hundred and ninety-eight patients received no prior treatment, and the remaining 228 cases received classical treatment regimens, including vasodilators, plasma expanders, ste­ roids, diuretics, and carbogen and/or hyperbaric oxygen, w ith neither aural improvement nor audiogram changes and stopped treatment for 14 days to 20 months. All patients were treated for at least 14 days with one o f the proto­ cols that consisted o f iron therapy, anti-D IM medication [3], vita­ mins, and combined regimen (table 1) in a randomized and stratified (stages and groups) design. When the patients were subdivided according to variables known to influence recovery from ISH L , such as time since onset, hearing level, audiogram type, vertigo, and age, there was no statistical difference in any o f these subgroups. Hearing improvement was evaluated according to the definitions proposed in 1975 by the Section o f Audiology, Beijing Research Institute o f Ear, Nose and Throat [7], The major criteria are as fol­ lows: Recovery. The auditory' threshold curve reached a normal level or approached that o f the unaffected ear. The patients felt well; tinnitus diminished gradually and then disappeared. M arked Effect. The rise in the auditory threshold curve was more than 30 dB or into the speech score, and subjective symptoms w'ere greatly diminished.

Table 2. C o m p a r is o n o f the treatm ent results

Treatment

Number o f ears

Improvement, %

Marked effect, %

recovery

marked effect

improved unchanged

88

109

53

56

81.70a

64.38b

A nti-D IM medication

6

15

25

19

70.76

32.31

Vitamins

2

1

14

46

26.98

4.76

Combined regimen

5

7

6

18

50.00

33.33

Iron therapy

a b

p < 0.01 in comparison with vitamins and combined regimen. p < 0.01 in comparison with anti-D IM medication, vitamins, and combined regimen.

Table 3. Correlation between D IM and the treatment results

Protocol

Iron therapy

Number o f patients

Improvement, %

Marked effect, %

without D IM

with D IM

without D IM

total

with D IM

without D IM

with D IM

273

241

32

87.97a

34.38

70.54a

18.75

A nti-D IM medication

63

55

8

76.36a

25.00

30.16b

12.50

Vitamins

58

49

9

28.57

22.22

4.08

11.11

Combined regimen

32

26

6

50.00

50.00

38.46b

16.67

p < 0 .0 1 ,b p < 0.05 versus without D IM .

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reached normal limits in 91 (73.39%) of 124 patients who responded to iron therapy and anti-DIM medication. In the 58 cases who showed no therapeutic effect, no signifi­ cant changes in the serum iron concentration and in the circadian variation were seen after iron therapy or antiD IM medication.

Discussion Various epidemiological surveys, both in developing and industrialized countries, have demonstrated the high prevalence of D IM in many ethnic groups, and, yet. iron overload is rare and nutritional iron deficiency extremely widespread [12, 13]. There seem to be more than 500 mil­ lion persons throughout the world with iron deficiency and perhaps more than 100 million in China [14, 15], As

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Disturbance of Iron Metabolism in Sudden Hearing Loss

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Treatment Effects Iron therapy tended to provide better recovery than the other two protocols (table 2), irrespective of sex, age, hearing levels, days after onset of hearing loss, presence or absence of dizziness, and shape of the audiogram. The treatment protocols could be completed without any severe side effect in all the patients. A correlation between DIM and the results of treat­ ment is summarized in table 3. No improvement was observed in 49 ears of patients affected for over 3 months who received anti-DIM medi­ cation, vitamins, or a combined regimen. However, iron therapy was found to be favourable in patients whose treatment started later than 3 months after the onset of the disease (table 4). The mean serum iron concentrations increased from 18.27 ± 4.81 to 27.40 ± 7.23 pmol/1 (p < 0.01), and the circadian variations in the serum iron concentration

Time months

Number o f ears recovery

marked effect

improved unchanged

Improve­ ment, %

Marked effect, %

39.58

3-5

7

12

10

19

60.42

6-11

3

5

4

11

52.17

34.78

12-24

1

5

2

13

38.10

28.57

11

22

16

43

53.26

35.87

Total

fas as the role of DIM in the pathogenesis of ISH L is con­ cerned, several points deserve attention. Firstly, the iron nutritional status of many of these patients with ISH L described in this paper was poor, and their serum iron, serum ferritin, haemoglobin, and red cell basic ferritin contents were lower than that of healthy subjects with normal hearing. It was found that most patients with ISH L had an abnormal circadian variation in the serum iron level. However, few of these patients had severe anaemia induced by iron deficiency. This could indicate a special relationship between tissue iron deficiency and hearing loss among the ISH L group, but no such correlation seems to exist between anaemia and hearing loss. Secondly, ISH L may be caused by iron deficiency through the following mechanisms: (1) When iron is insufficient, various reductions in the activity of some of iron-containing enzymes in certain inner-ear tissues can be supposed, which in turn could be a direct cause of sensorineural hearing loss or which could provide a pathological basis for cochlear deafness [4], (2) It is now accepted that iron deficiency increases the red cell membrane stiffness, decreases the red cell deformability, increases blood viscosity, and decreases the ability of red cells to pass through small-pore polycar­ bonate fibres [ 16], Consequently, the involvement of red cells in iron deficiency may produce various vascular embarrassments at the levels of the labyrinthine artery, the common cochlear artery, and the anterior vestibular artery; in combination, these may lead, finally, to distur­ bances of the blood circulation in the inner ear. (3) ISH L can be induced easily when there are insuffi­ cient adjustments of the inner ear iron metabolism to the high iron requirement and changing functional demands. Indeed, in this study, we sometimes failed to reverse hearing loss associated with D IM . It is possible, however, that ISH L may be a result of D IM , but it reached an irre­

versible stage by the time therapy was initiated. We tenta­ tively conclude from our work that DIM may act as a direct cause of ISH L or as a pathological basis for ISHL through the effects of DIM on the iron-containing en­ zymes and on the red cell membrane stiffness in the inner ear. As the natural history of recovery from ISH L remains controversial, some difficulty exists in evaluating the effectiveness of the treatment of ISHL. The prognosis seems to be predetermined, irrespective of the treatment employed in some cases. Spontaneous recovery may occur in patients with a slight degree, and no improvement can be expected in patients with profound hearing loss [17, 18], All authors agree that, although ISHL appears to have a chance of spontaneous recovery during the first 2 weeks, sponta­ neous recovery is unlikely after 3 months. Treatment then is extremely difficult [2, 7, 17, 18]. The present results suggest effectiveness of iron therapy of > 3 months after onset of the disease. Iron therapy may become the firstchoice treatment of ISHL and can be used in cases who failed to respond to classical treatment regimens.

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Table. 4. Outcome o f iron therapy in the ears affected < 3 months

1 Haug O . Draper W L. Haug SA: Stellate gan­ glion blocks for idiopathic sensorineural hear­ ing loss. Arch Otolaryngol Head Neck Surg 1976:102:5-8. 2 Yanagita N . Suzuki Y . Murahashi K . Miyake H: Prognosis and pathogenesis o f sudden deaf­ ness with scaling out. O R L 1983:45:15 4 -165. 3 Sun A H : A preliminary report on combined traditional Chinese and Western medicine in sensorineural hearing loss: An analysis o f 108 cases. J Tradit Chin Med 1982:2:215-222. 4 Sun A H . Li J Y . X iao S Z . Li Z J , Wang T Y : Changes in the cochlear iron enzymes and adenosine triphosphatase in experimental iron deficiency. Ann Otol Rhinol Laryngol 1990:99: 988-992.' 5 Sun A H . X ia o S Z , Zh en gZ . Li BS. Li Z J . Wang T Y : A scanning electron microscopic study o f cochlear changes in iron-deficient rats. Acta Otolaryngol (Stockh) 1987;104:211-216. 6 Sun A H . X iao S Z . Li BS. Li Z J . Wang. T Y , Zhang Y S : Iron deficiency and hearing loss: Experimental study in growing rats. O R L 1987; 49:118-122.

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7 Section o f Audiology. Beijing Research Insti­ tute o f Ear. Nose and Throat: Treatment o f sudden deafness with radix Puerariae: A com­ parative analysis o f therapeutic results in 294 cases. Chin Med J 1975:88:343-349. 8 Seiverd C E: Hemoglobin determination: in Seiverd C E (ed): Hematology for Medical Technologists. Philadelphia, Lea & Febiger, 1983. pp 178-210. 9 Rodgerson D O . Heifer RE: Determination o f iron in serum or plasma by atomic absorption spectrophotometry. Clin Chem 1966:12:338— 349. 10 Sun A H . Wang Z M . Xiao S Z . Li Z J . Li J Y , Kong LS: Red cell basic ferritin concentration in sensorineural hearing loss. O R L 1991 ;53: 270-272. 11 Madanat F . El-Khatccb M , Tarawaneh M . Hijazi S: Serum ferritin in evaluation o f iron sta­ tus in children. Acta Haematol (Basel) 1984:71: 111-115. 12 Bothwcll T H . Charlton RW , Cook J D . Finch C A : Iron Metabolism in Man. Oxford. Blackwell. 1979. pp 8-10.

13 Galan P, Hcrcbcrg S. Touiton Y : The activity o f tissue enzymes in iron-deficient rat and man: An overview. Com p Biochem Physiol [B] 1984;77:647-653. 14 Finch C A . Huebers H: Perspectives in iron metabolism. N Engl J Med 1982:306:1520— 1528. 15 He Z -C . Wu W Y , Jiang Z Q . X u Y C . Zhang Y H . Li Y Z . Chen W H : Preliminary study o f preventing iron deficiency anemia by iron for­ tification o f table salt (in Chinese). Acta Nutr Sin (Tianjin) 1988:10:46-49. 16 Y ip R, Mohandas N . Clark M R . Jain S. Shohet SB, Dallman PR: Red cell membrane stiffness in iron deficiency. Blood 1983:62:99—106. 17 Mattox D E . Simmons FB: Natural history o f sudden sensorineural hearing loss. Ann Otol Rhinol Laryngol 1977;86:463-480. 18 Kubo T , Matsunaga T . Asai H , Kawamoto K . Kusakari J , Nomura Y , Oda M . Yanagita N , Niwa H , Uemura T . Komune S: Efficacy o f defibrinogenation and steroid therapies on sudden deafness. Arch Otolary ngol Head Neck Surg 1988:114:649-652.

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References

Idiopathic sudden hearing loss and disturbance of iron metabolism. A clinical survey of 426 cases.

The role of disturbances of the iron metabolism (DIM) in idiopathic sudden hearing loss (ISHL) was investigated in 426 patients with ISHL who received...
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