Abstract
Ocular and ophthalmological adverse effects may be seen in β-thalassemia major (BTM) patients treated with regular blood transfusions and iron-chelating agents. We hypothesized that olfactory dysfunction may be present in this population. In this study, we aimed to investigate olfactory dysfunction in patients with BTM and determine the etiological factors. A total of 43 patients with BTM were included in the study. Forty-three patients without any nasal complaints, history of facial trauma, or nasal surgery were included as the controls. All participants had nasal endoscopy. The iron-chelating agents used, their duration of use, as well as hemoglobin and ferritin levels of the BTM patients were recorded. Sniffin’ Sticks test (SST) was used to assess olfactory functions, and BTM and control groups were compared for the results. The correlations of SST scores with the other study parameters were analyzed. Eight (18.6%) of 43 patients in the BTM group had hyposmia while none of the patients in the control group had hyposmia (P < .001). Older age, low-hemoglobin level, and longer use of deferoxamine were found to be correlated with olfactory dysfunction. Olfactory dysfunction may be seen in BTM patients treated with iron-chelating agents. The results of this study suggest that screening for olfactory function may be needed in routine follow-up of BTM patients.
Introduction
Beta-thalassemia major (BTM) is a congenital disease that starts in childhood, and causes hypochromic microcytic anemia. It develops due to defective synthesis of β chain needed for formation of hemoglobin, and specific mutations in β-globin gene. 1 Regular blood transfusions are carried out in patients with BTM starting from childhood to improve quality of life, and increase survival. 2 Regular blood transfusions result in iron deposition, in other words secondary chromatosis, which causes various organ dysfunctions, such as hepatic fibrosis and cirrhosis, hyperpigmentation of skin, diabetes mellitus, hypogonadism, pulmonary dysfunction, and cardiac disorders. 3
Iron-chelating agents are used to decrease complications related to transfusion-induced hemochromatosis in patients BTM. The first chelating agent used for this purpose is deferoxamine (DFO), which introduced in 1962. 4 Life expectancy of patients with BTM increased from 20 years to approximately 50 years after use of chelating agents in treatment. The adverse effects of DFO were first described in 1980s. 4 Its reported systemic adverse effects are flushing at the site of injection, urticaria, hypotension, reversible nephrotoxicity, hearing loss, and optic neuropathy. 5 Deferasirox (DFS) and deferiprone (DFP) are new iron-chelating agents that are used orally. Deferasirox was approved by Food and Drug Administration (FDA) in 2005, and its use increased in the recent years. Its most frequent adverse effect is temporary, mild, or moderate gastrointestinal dysfunction, however hearing loss has also been reported. 6 Deferiprone was approved by FDA in 2011. It may rarely cause severe adverse effects such as neutropenia and agranulocytosis, therefore it is not widely used. 6
Although hearing loss was reported as an adverse effect related to regular use of iron-chelating agents, olfactory dysfunction has not been studied before in this group of patients. In fact, olfactory dysfunction may lead to poor quality of life, inability to recognize smells of dangerous gases, and depression. 7 Sniffin’ Sticks Test (SST) is one of the most popular tests used to identify olfactory dysfunction.
In this study, we aimed to investigate olfactory dysfunction in patients with BTM that were administered iron-chelating agents, and to analyze correlation of olfactory dysfunction with the patient’s characteristics and the medications used.
Material and Methods
Patients
A total of 43 patients followed up in Thalassemia Follow-up Center of Muğla University Medical Faculty with the diagnosis of BTM were included in our study. Age, gender, complaints, comorbidities, and previous surgical operations of the patients were recorded. Mean hemoglobin level in the previous 2 months, and mean ferritin level in previous 4 months were also recorded. The use of iron-chelating agents, the agents used, and their durations of use were recorded. Deferoxamine was administered at 30 to 50 mg/kg/d subcutaneously, DFP at 75 to 100 mg/kg/d orally, and DFS at 20 to 40 mg/kg/d orally.
A total of 43 patients who did not have any olfactory complaints or the complaints of nasal obstruction, chronic rhinitis or rhinosinusitis, or any previous nasal surgery were included in the study as the controls.
Nasal Examination and Exclusion Criteria
All patients with BTM and control patients had endoscopic examination of nose and nasopharynx. They were searched for any findings regarding mucosal diseases, such as allergic rhinitis, nasal septal deviation causing severe nasal obstruction, nasal polyps, nasal masses, acute upper airway infection, and rhinosinusitis. They were not included in the study if any aforementioned disorders were detected on nasal endoscopy.
In addition, the ones with the history of facial trauma or nasal surgery, neurological diseases, hypothyroidism, diabetes mellitus, chronic rhinosinusitis, nasal polyps, and/or smoking were excluded.
Olfactory Assessment
Olfactory functions were analyzed using the 3 stages of SST (Burghart Messtechnik GmbH, Wedel, Germany), which is based on a pen-like odor-dispensing device. 8 Patients were asked not to eat or drink anything except for water 15 minutes before testing, and similarly were asked to refrain from smoking and chewing gum. The smell test room was silent and ventilated well. The test sequence was the threshold test, discrimination test, and finally identification test, with 3 minute-breaks between the tests.
In odor threshold (OT) test (stage 1), OT was assessed using n-butanol as a single odorant. The smell threshold was determined in a so called “staircase procedure.” After a start concentration of the smell is found out, the dilution step was identified at which the smell could just be distinguished from nonsmelling pens. The odor thresholds were determined as the mean of the last 4 from a total of 7 staircase reversals.
In odor discrimination (OD) test (stage 2), discrimination between 2 different odorants was assessed. The patient was presented with 3 pens; 2 contained the same odorant and 1 contained a different one. The patient’s task was to indicate which one smells different. This comparison was performed for 16 triplets. Presentation of triplets was separated by at least 30 seconds. The result was a sum score of correctly identified pens.
In odor identification (OI) test (stage 3), the ability to identify everyday smells by means of a card with 4 choices was determined. It was a multiple-choice procedure, which means the patient has to pick 1 of the 4 terms. Altogether, 16 odors were presented in the identification test. Patients were free to sample the odors as often as necessary to make a decision. The experimenter presented each odorant in intervals of at least 30 seconds to minimize olfactory desensitization. The OI score was the sum score of the correctly identified odors.
The maximum score in each stage was 16 points, with a maximum possible total score of 48 points for the stages of threshold, discrimination and identification (TDI) combined. Patients with a TDI score >30 were considered to have normal olfactory function (normosmia); patients with a score of 15 to 30 were considered to have decreased olfactory function (hyposmia); and patients with a score <15 were considered to have a loss of olfactory function (anosmia). 9
The OT, OD, OI, and TDI scores of the patients and controls were recorded.
Statistical Analysis
The BTM and the control groups were compared for demographic data, and the results of SST including OT, OI, OD, and TDI scores. The ratios of hyposmic patients were also compared between the groups. In study group, the correlations of OT, OI, OD, and TDI scores were analyzed with age, gender, hemoglobin and ferritin levels, duration of DFO use, and total use of 3 iron-chelating agents.
Data analysis was made using the Statistical Package for the Social Sciences (SPSS), version 21 (SPSS Inc, Chicago, Illinois). Means and standard deviations were used to describe continuous variables. The t test was used for continuous variables. Mann-Whitney U test was used to compare the results of the SST between the study and the control groups. Correlations were analyzed using the Pearson correlation test. P value was set at <.05.
Results
Demographic Data and Iron-Chelating Agents
Among 43 patients with BTM, 25 (58.1%) were males, and 18 (41.9%) were females and the mean age was 24.76 (8.24) years. There were 21 (48.8%) males and 22 (51.2%) females, and a total of 43 patients in the control group with a mean age of 27.41 (8.94) years. The BTM and control groups were similar for age and genders (P = .157 and P = .393, respectively). Demographic characteristics and mean hemoglobin and ferritin levels of the BTM patients are presented in Table 1.
Demographic Characteristics and Mean Hemoglobin and Ferritin Levels of β-Thalassemia Major Patients.
Mean duration of DFO use was 14.81 (7.02) years in BTM group. Mean total duration of 3 iron-chelating agents was 23.68 (8.79) years.
Results of Sniffin’ Stick Test
Threshold test (stage 1): The mean OT score was 6.99 (2.14) (1.5-11.25) in the BTM and 7.41 (1.75) (3.25-11.75) in the control groups. The OT scores were not significantly different between BTM and control groups (P = .328). Discrimination test (stage 2): The mean OD score was 12.95 (2.35) (3-16) in the BTM group, while this score was found as 14.13 (1.40) (11-16) in the control group. The OD score was significantly smaller in BTM group when compared to the control group (P = .015). Identification test (stage 3): The mean OI score was 13.23 (1.91) (7-16) in the BTM group. The control group’s mean OI score was 13.86 (1.39) (11-16). Beta-thalassemia major and control groups were similar for OI scores (P = .157). Threshold discrimination identification score: The TDI score was obtained by summing up the scores obtained in stages 1-3. The mean TDI score was 33.19 (4.89) (15-42.25) in the BTM, and 35.44 (2.39) (31-41.5) in the control groups. Threshold discrimination identification scores were significantly smaller in BTM group when compared to the control group (P = .012).
The results of SST are presented in Table 2. e) The participants with hyposmia: In accordance with the normative values determined for SST, the ones with TDI scores between 15 and 30 were diagnosed with hyposmia. There were 8 (18.6%) patients with hyposmia in BTM group while there were no hyposmic patients in the control group. Comparison of the BTM and the control groups for the proportion of the patients with hyposmia revealed that hyposmia was significantly more frequent in patients with BTM when compared to controls (P < .001). None of the participants included in the BTM or control groups had anosmia (TDI score < 15).
Sniffin’ Sticks Test Results of β Thalassemia Major Patients and the Controls.
Abbreviations: BTM, β-thalassemia major; OD, odor discrimination score; OI, odor identification score; OT, odor threshold score; TDI, threshold discrimination identification score.
Those results indicated that olfactory dysfunction was significantly more in patients with BTM who were administered iron-chelating agents when compared to the control group.
Correlation of Smell Test Results with Age, Hemoglobin and Ferritin Levels, Gender, and Use of Iron-Chelating Agents
Age: There was a significant and negative correlation between age and OT, OD, OI, and TDI (P = .016, P = .019, P = .022, and P = .001, respectively). The scores of the smell tests decreased as the age of the patient increased. Hemoglobin level: Hemoglobin level was found to be significantly correlated with OD, OI, and TDI scores (P < .001, P = .001, and P < .001, respectively). Smell test scores decreased as the hemoglobin level decreased. There was no correlation between hemoglobin level and OT (P = .078). Ferritin level: Ferritin level was not correlated with OT, OD, OI, or TDI scores (P = .815, P = .510, P = .121, and P= .425, respectively). Gender: Gender was not correlated with OT, OD, OI, or TDI scores (P = .058, P = .983, P = .976, and P = .435, respectively). Duration of DFO use: Duration of DFO use had significant negative correlations with OI and TDI scores (P = .014 and P = .021, respectively). Both OI and TDI scores decreased as duration of DFO use increased. There were no correlations between duration of DFO use and OT or OD scores (P = .083 and P = .280, respectively).
There were no significant correlations between total duration of use of 3 iron-chelating agents (DFO, DFS, and DFP) and OT, OD, OI, or TDI scores (P = .090, P = .290, P = .210, and P = .072, respectively).
The results of correlation study are presented in Table 3.
Correlation Analysis of Smell Test Results and other Parameters Studied.
Abbreviations: OD, odor discrimination score; OI, odor identification score; OT, odor threshold score, TDI, threshold discrimination identification score.
Discussion
The results of this study indicated that hyposmia was more frequent in patients with BTM administered iron chelating agents regularly when compared to the control group. An older age, low hemoglobin level, and long-term use of DFO negatively affected olfactory functions in patients with BTM.
Beta-thalassemia major is a life-threatening, autosomal recessive disease, and regular blood transfusions and iron-chelating agents form the mainstay of treatment. 10 The prevalence of thalassemia is high in the Mediterranean region. 11 Its prevalence is high in Turkey, and in our city located at the Mediterranean coast. 11 Regular blood transfusions and use of iron-chelating agents increased life expectancy in patients with BTM; however long survival increased prevalence of complications of the disease in the organs. 10
Deferoxamine is one of the first, and most effective iron-chelating agents used in patients that had regular blood transfusions. 4 It has been used since 1960s, and it does not have an oral form; it is used by subcutaneous injections. Deferiprone and DFS are other iron-chelating agents, and they may be used orally.
Deferoxamine has been considered as a minimally toxic agent with mild-moderate adverse effects. 5 Adverse effects related to DFO treatment are ophthalmic and auditory neurotoxicity, sensorimotor neuropathy, renal toxicity, pulmonary syndrome, growth retardation and bone abnormalities, local irritation at subcutaneous injection site, and allergic reactions. 3 Ophthalmic and auditory adverse effects have been studies extensively. Reduced peripheral vision, abnormal color vision, deteriorated dark adaptation, thinning of the retinal vessels, decreased visual acuity, and retinal stippling have been reported as the adverse effects of the agent. 3,12,13
Auditory toxic effects of DFO emerge as high-frequency sensorineural hearing loss. 4 Chen et al demonstrated 25 dB or more high-frequency sensorineural hearing loss in 20% of 30 patients treated with DFO. 4 Shamsian et al found sensorineural hearing loss at 2000 to 4000 Hz in 7.4% of 67 patients. 2 Karimi et al studied auditory adverse effects of DFO, reported that DFO ototoxicity was determined not only by the total amount of the drug given but also by its maximal plasma concentration, and suggested periodical audiological checkups and a low dosage of DFO (below 50 mg/kg/d) given on at least 5 to 6 days a week for the prevention and prompt diagnosis of audiological complication. 3
The pathophysiology for neurotoxic effects of DFO is not yet clear. It was suggested that DFO reacted with superoxide free radicals to form more stable nitroxide free radicals, and those reacted with methionine, cysteine, glutathione, vitamin C, and alcohol dehydrogenase to decrease enzymatic activity. 14
Aforementioned neurotoxic effects of DFO imply that it might cause olfactory dysfunction. A search in English literature did not reveal any studies concerning olfactory testing in BTM patients, or the ones on DFO treatment. Our study is the first one that investigated olfactory function in patients with BTM on regular treatment with iron chelating agents, and compared the results with a control group.
Olfactory dysfunction is not rare. It is evident in 1% to 2% of the population below 65 years of age, and may increase up to 50% above 65 years of age. 15 Approximately, 20 easy-to-use and commercially available olfactory tests were described in recent years. 15 Sniffin’ Sticks test is one the most frequently used one. Test-retest reliability and validation studies of SST have been done, and it has been used over 50 clinics all over the world. 16
The most frequent causes of olfactory dysfunction are chronic rhinosinusitis, postinfectious anosmia, and post-traumatic anosmia. 7 Neurological diseases, such as Alzheimer disease, nasal and intracranial tumors, Cushing disease, exposure to toxic substances such as some metals and solvents, and use of some antimicrobial, chemotherapeutic, and antithyroid agents may result in olfactory dysfunction. No studies up to date have reported olfactory dysfunction related to BTM or use of iron-chelating agents. In the present study, we found hyposmia in 18.6% of the patients with BTM treated with iron-chelating agents, and this rate was found significantly higher when compared to the control group.
The pathophysiology of neurotoxic side effects such as high-frequency sensorineural hearing loss and retinal neurotoxicity is not yet clear in patients with BTM on iron chelating agents, however olfactory dysfunction may share the same pathophysiological mechanism. A number of studies have been performed to identify factors related to hearing loss and retinal adverse effects. Those studies reported that ferritin level and neurotoxicity were not correlated. 2 -4,10,16 In our study, we did not find any correlation between ferritin level and olfactory dysfunction, either. Karimi et al 3 reported that they did not find any correlation between the neurotoxic effects of DFO and mean hemoglobin concentration of the previous 3 months. However, in our study we found that low mean hemoglobin levels in the previous 2 months showed correlation with olfactory dysfunction.
Chen et al reported that DFO could be used safely at doses below 50 mg/kg. 4 In our study, we could not perform a correlation analysis since different DFO doses were administered in accordance with the ferritin levels. Shamsian et al reported that total duration of DFO use was not correlated with the adverse effects. 2 However, we found that olfactory dysfunction increased as the duration of DFO use increased.
It was reported that ageing increased olfactory dysfunction, however gender did not have any effect on it. 16 Similar to previous studies, we did not find any correlation between gender and olfactory dysfunction. However, we found that an older age and olfactory dysfunction were correlated. In patients with BTM, ageing goes together with an increased duration of DFO use, therefore we suppose that both conditions cause olfactory dysfunction in those patients.
The correlation study we performed indicated that older age, longer use of DFO, and low hemoglobin levels were correlated with olfactory dysfunction.
Deferasirox and DFP are the other iron chelating agents used in BTM. Those 2 agents are preferred in some patients since they have oral forms. 17,18 Ocular and auditory side effects of DFS and DFP are rare. 6,19 Some patients included in our study were administered DFS and DFP due to intolerance to subcutaneous injections. However, some patients used one or both of them for different periods and for a short time, therefore we could not perform statistical analysis for those agents. We calculated duration of DFO use and total duration of use for all 3 agents, and analyzed their correlations with other variables. We found a correlation between duration of DFO use and olfactory dysfunction, however we did not find any correlation of olfactory dysfunction with total duration of use for all 3 agents. We suppose that lack of correlation of olfactory dysfunction with duration of use of all 3 drugs may be related to minimal neurotoxic effects of the agents other than DFO.
The studies on olfactory function have investigated subscores of SST, namely OT, OD, and OI, in addition to TDI. 20 -22 Fu et al reported that OT was correlated with age. 20 It was reported that all subscores were affected in idiopathic inflammatory myopathy patients, however OT and OD were affected in patients with systemic lupus erythematosus. 21,22 In our study, we found correlations of age with all SST subscores. However, among the subscores, we found that only OD was smaller in BTM group when compared to the control group.
Limitations of the Study
Our sample size is relatively small, and further studies should be performed on a larger patient population. Another limitation is that we did not have patients with BTM that did not use any iron-chelating agents. A third limitation is we could not compare the patients that used DFP and DFS with the ones that used DFO. Further studies on a larger sample size may enable comparison of 3 iron-chelating agents for olfactory dysfunction.
Conclusion
We found a significantly higher hyposmia rate in patients with BTM treated with iron-chelating agents. Both TDI score and OD score were significantly smaller in BTM group when compared to the control group. Olfactory dysfunction was significantly correlated with age, low hemoglobin levels, and duration of DFO use. It must be kept in mind that olfactory dysfunction may be seen in patients with BTM. Routine follow up of the patients with BTM for olfactory function may be suggested if further studies support the findings of our study.
Footnotes
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Mugla Sitki Kocman University, Department of Scientific Research Projects.