C 2005) Digestive Diseases and Sciences, Vol. 50, No. 10 (October 2005), pp. 1938–1945 ( DOI: 10.1007/s10620-005-2964-3
Sensorineural Hearing Loss in Patients with Inflammatory Bowel Disease: A Subclinical Extraintestinal Manifestation ¨ MD,* N˙IHAT AKBAYIR, MD,* ASLI BATUR C ¸ ALIS¸, MD,† CANAN ALKIM, MD,* H. MEHMET SOKMEN, ¨ ¨ ¨ UKBAS ¨ LEVENT ERDEM, MD,* AYC¸A OZBAL, MD,† and FUSUN BOL ¸ , MD‡
Isolated case reports in which symptomatic hearing loss develops suddenly during the course of inflammatory bowel disease (IBD) have been reported, but the presence of subclinical sensorineural hearing loss (SNHL) associated with IBD has been investigated in only two preliminary studies. In order to research this further, we aimed to investigate the presence of subclinical SNHL in IBD by comparison with a control group and to examine possible relations between the bowel disease parameters and hearing loss. Otoscopy, tympanometry, and pure tone audiometry were carried out in 39 patients with IBD (21 Crohn’s disease [CD], 18 ulcerative colitis [UC]) and 25 healthy age- and sex-matched controls. All patients and control subjects had normal otoscopy findings and tympanometry was unremarkable, excluding middle ear disease and conductive hearing loss. Analysis of each frequency examined showed that the average hearing thresholds were increased significantly in the study group compared to those of the control group at higher frequencies (2, 4, and 8 kHz). When these parameters were compared with the control group according to subgroups of IBD, a significant difference was determined for the UC group at frequencies of 2, 4, and 8 kHz and for the CD group only at the frequency of 4 kHz. Although there was a trend of increment in SNHL as the age of the patient and duration and extent of UC increased, no significant correlation was observed between SNHL and these parameters or sex, activity, involvement site, medication history of IBD, and coexistence of other extraintestinal manifestations. In conclusion, it was demonstrated that a subclinical SNHL may be associated with UC and somewhat with CD, affecting mainly the high frequencies. In light of this finding, it may be advisable to investigate labyrinth functions as well as other extraintestinal manifestations in patients with IBD. KEY WORDS: sensorineural hearing loss; extraintestinal; Crohn’s disease; ulcerative colitis; inflammatory bowel disease.
Inflammatory bowel disease (IBD) is associated with a number of extraintestinal manifestations, including organs such as the skin, eyes, joints, blood, kidney, and Manuscript received November 23, 2004; accepted February 17, 2005. From the Departments of *Gastroenterology and †Otorhinolaryngology, S¸i¸sli Etfal Training and Research Hospital, Istanbul, and ‡Department of Gastroenterology, Faculty of Medicine, Harran University, Urfa, Turkey. This article was presented at the 12th United European Gastroenterology Week, 2004, in Prague, Czech Republic. Address for reprint requests: Dr. Nihat Akbayir, H¨useyin pa¸sa sok No. 23/10, Kiziltoprak Istanbul 34724, Turkey;
[email protected] or
[email protected].
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biliary tract. The complications outside the gastrointestinal tract in Crohn’s disease (CD) and ulcerative colitis (UC) are found in more than 50% of all patients (1, 2). In addition, the inner ear should also be considered as an extraintestinal involvement site of IBD. The auditory system can become the target of an autoimmune attack in two ways, primary autoimmune disease of the inner ear and secondary involvement by systemic autoimmune diseases including vasculitides, systemic lupus erythematosus, Cogan’s syndrome, Wegener granulomatosis, and rheumatoid arthritis (3, 4). Several case presentations have been published reporting acute hearing loss, which is Digestive Diseases and Sciences, Vol. 50, No. 10 (October 2005)
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INFLAMMATORY BOWEL DISEASE AND HEARING LOSS
thought to be immune-mediated, during the course (5–14), or as an early manifestation, of IBD (15). In these patients, sensorineural hearing loss (SNHL), usually with bilateral involvement, developed suddenly and deteriorated rapidly over weeks or months, particularly in the active period of the bowel disease as well as the quiescent period. Since uncontrolled inflammatory damage to the vulnerable and delicate sensory components of the inner ear may easily cause irreversible SNHL, immunosuppressive therapy must be initiated immediately (3, 8, 9). Apart from these isolated case reports in which sudden symptomatic hearing loss developed usually during the active period of the disease, the presence of subclinical SNHL associated with IBD has been investigated in only two preliminary studies so far (16, 17). In this prospective, controlled study, we aimed to investigate the presence of subclinical SNHL in IBD by comparison with a control group and to examine possible relations between the activity of bowel disease and hearing loss.
MATERIALS AND METHODS Study Patients and Control Group. A total of 44 consecutive patients with IBD in S¸i¸sli Etfal Training and Research Hospital between September 2003 and May 2004 were enrolled in the study. Five of these 44 patients were excluded from the study because of serous or chronic otitis media, and thus a total of 39 patients were included in the study. Demographic and clinical characteristics of study patients and control group are listed in Table 1. In all patients, duration of disease, type of disease, site of involvement, medications taken by the patients including immunosuppressive drugs ,with their duration and doses at the time of the study, and associated extraintestinal manifestations of IBD were recorded. Twenty-one of 39 patients had CD and 18 had UC. Patients with CD included eight with colonic
involvement, four with ileal disease, and nine with ileocolonic involvement, diagnosed by radiology, ileocolonoscopy, and histological examination. Eighteen patients with UC were diagnosed by colonoscopy (plus biopsy) and consisted of seven patients with the pancolitis form, four patients with left-sided disease, and seven patients with the distal form. None of the patients had a history of head trauma, noise exposure, family history of hearing loss, or exposure to ototoxic drugs. After explanation of the study protocol, which was in accordance with the Declaration of Helsinki and approved by the local ethics committee, all patients gave their consent to be included in the present investigation. The control group consisted of 25 healthy age- and sexmatched volunteers from the same community during the same time as the study group. Evaluation of Intestinal Disease Activity. For CD, a simple index of disease activity published by Harvey and Bradshaw was used (18). A score was derived from general well-being (score 0– 4), abdominal pain (0–3), number of liquid stools daily, abdominal mass (0–3), and presence of complications or extraintestinal manifestations (score 1 per item). Disease activity of patients with UC was evaluated according to the disease activity index developed by Sutherland et al. (19). This index is evaluated by stool frequency (score 0–3), rectal bleeding (0–3), mucosal appearance (0–3), and physician’s rating of disease activity (0–3). The scoring was conducted by the same investigator. Otoscopy, Tympanometry, and Pure Tone Audiometry. Otorhinolaryngological examination was performed by a single observer blinded to the results of all other examinations. Otoscopy, tympanometry, and pure tone audiometry were carried out in all patients and controls. Pure tone audiometry examined air and bone conduction at six frequencies: 0.25, 0.5, 1, 2, 4, and 8 kHz (Kamplex AC4 Audiometer, P. C. Worths, London). During audiometric test, air and bone conduction thresholds were measured separately for both right and left ear in patient and control groups, and then the highest of the four values measured was accepted as the representative hearing level for each individual patient and control subject at each frequency. Because patients who had an air–bone gap of more than 10 dB, indicating conductive hearing loss, were already excluded from the study, all values higher than 20 dB were deemed as an indicator of SNHL.
TABLE 1. DEMOGRAPHIC AND CLINICAL FEATURES OF PATIENTS AND CONTROLS
Number of patients Males Females Age (mean ± SD, yr) Range (yr) Duration of disease (mean ± SD, yr) Range (yr) Disease type (CD) Stenotic Fistulizing Inflammatory Location/extension Ileum Ileum + colon Colon Pancolitis Left colitis Distal colitis
CD
UC
Total patients
Controls
21 9 12 31.8 ± 11.03 15–53 4.2 ± 3.5 1–13
18 8 10 37.3 ± 15.2 21–67 3.5 ± 2.1 1–8
39 17 22 34.3 ± 13.2 15–67 3.9 ± 2.9 1–13
25 9 16 34.2 ± 14.1 15–72
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3 9 9 4 9 8 7 4 7
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Fig 1. The magnitude of sensorineural hearing loss at frequencies of 0.25–8 kHz in 21 patients with Crohn’s disease (O), 18 patients with ulcerative colitis (), and 25 controls (). Data are expressed as mean ± SE. *P < 0.05 and **P < 0.01 vs control values.
Statistical Analysis. Continuous data are expressed as mean value ± SE. ANOVA and chi-square tests were used to compare the data obtained from audiometric examination between IBD patients and controls, whenever appropriate. The presence of a correlation between SNHL and sex, age, bowel disease activity, and duration of disease as well as intakes and durations of prednisolone, mesalamine, and azathioprine was investigated using Spearman rank correlation test. A value of P < 0.05 was deemed significant. Statistical evaluations were performed by the statistical software package SPSS/PC+ (SPSS, Chicago, IL).
RESULTS None of the patients or controls complained of hearing loss and/or tinnitus. All patients and control subjects had normal otoscopy findings and tympanometry was unremarkable, excluding middle ear disease and conductive hearing loss. Detectable bilateral SNHL in pure tone audiometry was reported in 18 of 39 study patients (46.1%; 12 CD, 6 UC), and in 10 of 25 control subjects (40%), at particularly high frequencies, yielding no significant difference. However, analysis of each frequency examined showed that the average hearing thresholds were increased significantly in the study group compared to the control group
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at higher frequencies (2, 4, and 8 kHz). When these parameters were compared with the control group according to subgroups of IBD, a significant difference was determined for patients with CD only at the frequency of 4 kHz (P = 0.03 vs control values) and for patients with UC at frequencies of 2, 4, and 8 kHz (P = 0.004, P = 0.02, and P = 0.03 vs control values, respectively) (Figure 1). Comparisons of average hearing levels at high frequencies in with CD and UC patients and the control group are listed in Table 2. There was no significant difference between patients with CD and those with UC. The possible relation between activity of bowel disease and presence of SNHL was evaluated and the results are illustrated in Figure 2. It may be observed that the disease activity for both CD and UC was similar in patients with and without hearing loss (r = 0.05 and P = 0.81 for patients with CD and r = −0.13 and P = 0.6 for patients with UC). Although a tendency of increment in hearing loss by age in all IBD patients was observed, this did not reach statistical significance and the same tendency was not observed for patients with CD and UC separately. Besides there was no significant correlation between SNHL and sex. In the same way, a minor trend regarding a relation Digestive Diseases and Sciences, Vol. 50, No. 10 (October 2005)
INFLAMMATORY BOWEL DISEASE AND HEARING LOSS TABLE 2. COMPARISON OF AVERAGE HEARING LEVELS AT HIGH FREQUENCIES IN PATIENTS WITH CD, PATIENTS WITH UC, AND THE CONTROL GROUP: MEAN ± SE
Average hearing levels (dB) At 2 kHz At 4 kHz At 8 kHz
CD (n = 21)
UC (n = 18)
Total patients (n = 39)
Control (n = 25)
14.7 ±1.5 23.09 ± 3.5* 21.6 ± 2.2
23.6 ± 4.6† 27.5 ± 5.7* 29.4 ± 5.4*
18.8 ± 2.3† 25.1 ± 3.2* 25.2 ± 2.7*
13 ± 1 14.4 ± 1.3 16.4 ± 1.6
*P < 0.05 vs control values. †P < 0.01 vs control values.
between longer duration of UC and occurrence of SNHL was detected, but this was also not significant (Table 3). The relation between extent of UC and hearing loss was examined, and a trend of increment in SNHL was observed as the bowel disease extended proximally, but the relation did not reach statistical significance (P = 0.066; Table 4). In CD, SNHL did not correlate with site of involvement or type of disease (Tables 5 and 6).
Nine of 39 patients with IBD had evidence of extraintestinal involvement (3 patients with oral aphthous ulcer and arthritis, 1 with primary sclerosing cholangitis, 2 with deep venous thrombosis, 1 with uveitis, 1 with sacroileitis, and 1 with ankylosing spondylitis). These extraintestinal manifestations were equally distributed between patients with and patients without auditory dysfunction. The possible effects of the immunosuppressive drugs taken
Fig 2. Disease activity scores for patients with Crohn’s disease with (×) and without (O) sensorineural hearing loss and patients with ulcerative colitis with () and without (•) sensorineural loss. Bars represent the mean activity score in each patient group. r = 0.05, P = 0.81, for patients with Crohn’s disease and r = −0.13, P = 0.6, for patients with ulcerative colitis. Digestive Diseases and Sciences, Vol. 50, No. 10 (October 2005)
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AKBAYIR ET AL. TABLE 3. CORRELATION COEFFICIENTS FOR SNHL AND AGE OF PATIENTS AND FOR SNHL AND DURATION OF DISEASE
TABLE 5. COMPARISONS OF AVERAGE HEARING LEVELS IN PATIENTS WITH CD ACCORDING TO SITE OF INVOLVEMENT
Sensorineural hearing loss
Age of patients Duration of disease
Patients (N)
Correlation coefficient (r) (95% CI)
P
Total (39) CD (21) UC (18) Total (39) CD (21) UC (18)
0.29 (–0.02 to 0.5) 0.29 (–0.17 to 0.65) 0.31 (–0.19 to 0.6) 0.12 (–0.2 to 0.4) –0.06 (–0.4 to 0.3) 0.42 ( –0.06 to 0.7)
0.064 0.19 0.20 0.45 0.78 0.08
by patients on auditory function were investigated. Since there were no major differences in the doses of azathioprine taken by the patients (2–2.25 mg/kg/day), statistical analysis was performed only for the duration of azathioprine therapy. There was no correlation between SNHL and duration of azathioprine therapy. Steroid therapy was used in only 5 of the total 39 IBD patients (3 CD and 2 UC; 40 mg/day prednisolone for 4 patients and 9 mg/day budesonide for 1 patient). Correlation analysis showed that duration of steroid therapy had no impact on hearing loss, similar to azathioprine (Table 7). The presence of a relationship between hearing loss and use of steroid, mesalamine, and azathioprine was examined using Spearman rank correlation. This statistical analysis demonstrated that the hearing loss was not related to drug intake. DISCUSSION In the present study, we observed subclinical bilateral hearing loss of sensorineural type in patients with IBD. When these hearing losses were evaluated on the basis of frequency in pure tone audiometry, auditory dysfunction was observed at higher frequencies, including a range of 2–8 kHz. Despite the presence of sensorineural impairment, none of the study patients complained of hearing loss. Frequencies of 4, 8, and, somewhat, 2 kHz are not speech frequencies. Therefore hearing losses in these frequencies are often unrecognized by patients. The results obtained in our study showed that SNHL was more prominent in patients with UC than patients with CD, demonTABLE 4. COMPARISONS OF AVERAGE HEARING LEVELS IN PATIENTS WITH UC ACCORDING TO EXTENSION OF THE DISEASE Pankolitis Number of patients Average hearing levels (dB) Mean ± SE* Range
7
Left colitis Distal colitis 4
35.7 ± 10.7 37.5 ± 14.3 (20–95) (20–80)
7 21.4 ± 4.8 (15–50)
*P = 0.066; statistical significance was determined by analysis of variance (ANOVA).
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Number of patients Average hearing levels (dB) Mean ± SE* Range
Ileum
Ileum + colon
Colon
4
9
8
18.7 ± 3.7 (15–30)
30.5 ± 6.5 (10–80)
25 ± 3.4 (10–40)
*P = 0.32; statistical significance was determined by ANOVA.
strating hearing loss at frequencies of 2, 4, and 8 kHz for UC and only at a frequency of 4 kHz for CD. In the literature, so far, there are two studies investigating the presence of subclinical hearing loss in patients with IBD. In one of them, the study performed by Loft et al., hearing loss was found in 20 patients with UC at a frequency range of 2–8 kHz, compared with 30 control patients (16). No hearing loss was found at the same frequency range in 25 patients with CD. On the contrary, we demonstrated that SNHL may accompany CD as well as UC. The presence of reports concerning sudden onset of symptomatic SNHL in patients with CD (9, 14) may suggest that a subclinical form of auditory impairment may also be associated with this kind of bowel disease. In the other study published previously, Kumar et al. demonstrated that 20 patients with active UC had SNHL over all frequencies compared with the control group (17). But these hearing losses were determined around 20 dB, a clinically noticeable limit for hearing loss, up to 2 kHz, and over 20 dB for higher frequencies. Therefore, they concluded that hearing loss was a subclinical finding in their asymptomatic patients for auditory function. Although the relation between hearing loss and UC was emphasized by Levitan in 1973 (20), the first case report with regard to an association between sudden onset of hearing loss and UC was published in 1982 (10). Then, in following reports related to acute symptomatic hearing loss during the active course of IBD, immunosuppressive drugs such as steroids, methotrexate, or antitumor necrosis factor (TNF)-α antibodies were administered to interfere with the progression of hearing loss and have been found to improve hearing in most cases (8, 9, 14). Thus, the pathogenetic mechanism of hearing loss in IBD is thought to be immune-mediated. Immunemediated SNHL was first described by McCabe in 1979 (21). He reported 18 patients with hearing loss, all of whom responded to immunosuppressive therapy, and tissue biopsy of one patient demonstrated vasculitis involving tissues of the middle ear and mastoid. T lymphocytemediated cytotoxicity, vasculitis, and immune complex deposition are postulated to be responsible for immunemediated SNHL (3, 22). Preceding cochlear injury, T cells become sensitized by an unknown mechanism, and then Digestive Diseases and Sciences, Vol. 50, No. 10 (October 2005)
INFLAMMATORY BOWEL DISEASE AND HEARING LOSS TABLE 6. COMPARISONS OF AVERAGE HEARING LEVELS IN PATIENTS WITH CD ACCORDING TO TYPE OF DISEASE Stenotic type
Fistulizing type
Inflammatory type
3
9
9
18.3 ± 6.0 (10–30)
22.7 ± 1.6 (15–30)
27.7 ± 3.9 (10–50)
Number of patients Average hearing levels (dB) Mean ± SE* Range
*P = 0.33; statistical significance was determined by ANOVA.
delayed cell-mediated hypersensitivity results in damage to the organ of Corti. This cytotoxic etiology is supported by the finding of lymphocyte migration inhibition (21) and the presence of lymphocyte infiltration in a temporal biopsy of a UC patient (23). The other mechanism is immune complex deposition in the subendothelial layer of small labyrinthine vessels, which results in vasculitis and may cause ischemia and injury to the organ of Corti. Anti-endothelial cell autoantibodies may represent a serological marker of vasculitis, although not specific for the inner ear (24). Antibodies directed against collagen type II were detected in the serum of a patient with CD and sudden bilateral SNHL (9). Molecules considered as autoantigens in autoimmune SNHL are type II collagens, type IX collagens, 30-kD proteins of inner ear membranes, laminin, and other compounds such as 68-kD proteins (heat shock protein 70) of the inner ear, PO protein, Raf-1 protein, and β-tubulin (25). The mechanisms involved in the pathogenesis of extraintestinal manifestations of IBD are not clear, but increased bowel permeability during active disease may cause luminal antigens to be presented to the systemic immune system. As there is already activation of the immune system and proinflammatory cytokines such as interleukin (IL)-1, IL-12, and TNF-α, this may lead to significant inflammatory responses elsewhere in the body (1). The inner ear, like other extraintestinal involvement sites in IBD, can become the target of an autoimmune attack. This new localization may be involved independently from bowel
disease activity, showing a subclinical manner, in contrast to sudden, symptomatic SNHL developed during the active phase of the bowel disease.The current study and Loft’s paper including IBD patients with different bowel disease activity revealed that there was no correlation between SNHL and bowel disease activity, supporting this hypothesis. On the other hand, in their study, Kumar et al. demonstrated that subclinical hearing losses were present at all frequencies and correlated positively with bowel disease activity (17). However, in that study, patients with low activity or complete remission were excluded. Therefore, their finding about this positive correlation between bowel disease activity and hearing loss may not be considered as complete evidence. In our study, we have found hearing loss only at high frequencies, not at all frequencies, in patients with UC and CD and this finding was not related to IBD activity. Thus, when we compare our results with the study mentioned above (Kumar et al.), it may be speculated that subclinical SNHL seems to extend to the whole audiometric spectrum as bowel disease activity increases. Besides, it may be suggested that the patients presenting with symptomatic hearing loss may also have a silent period of subclinical hearing loss in their histories. These issues require further clinical and experimental studies investigating the natural course and autoimmune pathogenesis, including possible relations with autoantibodies for IBD such as pANCA (perinuclear antineutrophil cytoplasmic antibodies) and ASCA (anti-Saccaromyces cerevisiae antibodies).
TABLE 7. CORRELATION COEFFICIENTS FOR SNHL AND AZATHIOPRINE, STEROID, AND MESALAMINE USE AND FOR SNHL AND DURATIONS OF AZATHIOPRINE AND STEROID THERAPY Sensorineural hearing loss
Azathioprine use Steroid use Mesalamine use Duration of steroid therapy (mo)* Duration of azathioprine therapy†
Patients (N)
Correlation coefficient (r)
P
8 (7 CD + 1 UC) 5 (3 CD + 2 UC) 36 (20 CD + 16 UC) 5 8
0.27 −0.25 0.08 0.3 0.61
0.08 0.11 0.6 0.5 0.11
*Range, 2–7 months. †Range, 4–36 months. Digestive Diseases and Sciences, Vol. 50, No. 10 (October 2005)
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In our study, since the patients with SNHL were asymptomatic, it was planned either to follow them up only by audiometric examinations every 6 months or to perform these examinations whenever a new exacerbation of IBD occurs, aiming to observe the course and response of hearing loss to the therapy for the bowel disease. It has been known that some extraintestinal manifestations may correlate with several parameters of IBD such as extent of disease, type of disease, and duration of disease. In our study, subclinical SNHL seems to be influenced toward increment, as extension and duration of UC and age of patient increased, but this did not achieve a value of statistical significance. These findings may need to be elucidated by further studies performed with larger patient populations of IBD. In addition, since drugs used to treat IBD could theoretically cause auditory dysfunction, the relationship between hearing loss and intake of steroid, mesalamine, and azathioprine was also examined, but statistical analysis revelaed that the hearing loss was not related to drug intake. Analysis of the durations of immunosupressives including steroid and azathioprine did not show any effect on this extraintestinal manifestation. Sensorineural hearing loss has been reported in several autoimmune disorders such as rheumatoid arthritis, Sj¨ogren’s syndrome, and polyarteritis nodosa (3, 4, 22). Apart from the case reports showing acute hearing loss during the course of these diseases, in two different studies, authors revealed the presence of subclinical SNHL in rheumatoid arthritis and Sj¨ogren’s syndrome, particularly at high frequencies (26, 27). Thus, the association between different autoimmune diseases and subclinical SNHL may also be theoretically applied to IBD, which seems to be another autoimmune disease. Furthermore, similar results obtained in our study may support this possible relation. In conclusion, it was demonstrated that a subclinical SNHL affecting preferentially the high frequencies may be associated with UC and somewhat with CD. It is unknown whether asymptomatic hearing loss could progress to severe overt hearing loss or not. Therefore it may be advisable to investigate labyrinth functions as well as other extraintestinal manifestations in patients with IBD and to follow up the patients with positive findings periodically.
10.
ACKNOWLEDGMENTS
20.
We are grateful to Mr. Emre G¨urb¨uz from Roche Pharmaceuticals, Turkey, for his literature support.
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2. 3. 4. 5.
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8.
9.
11. 12. 13.
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18. 19.
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