Introduction: Zinc deficiency may worsen the severity of olfactory dysfunction; however, the relationship between serum zinc levels and therapeutic effects on olfactory dysfunction remains uncertain. This study investigated the relationship between normalising serum zinc levels and the therapeutic effects on olfactory dysfunction. Methods: Forty-two patients diagnosed with post-infectious, post-traumatic, and idiopathic olfactory dysfunction, with serum zinc levels <70 μg/dL, were included in the study. All patients were treated with mecobalamin, tokishakuyakusan, and polaprezinc. The patients were divided into 2 groups: the zinc-normalised (≥70 μg/dL) and zinc-deficient (<70 μg/dL) groups, based on their post-treatment serum zinc levels. Olfactory test results were compared in each of the 2 groups. Results: The patients were treated for a median of 133 days. The zinc-normalised group had significantly better results in all olfactory tests (detection/recognition thresholds of the T&T olfactometer, odour identification test (Open Essence), Visual Analogue Scale for olfactory dysfunction, and self-administered odour questionnaire). In contrast, only the self-administered odour questionnaire showed a significant improvement in the zinc-deficient group, with no significant differences observed in the other olfactory tests. When comparing the changes in the olfactory test scores between the 2 groups, significant differences were observed in the detection/recognition thresholds of the T&T olfactometer test and Open Essence results. Conclusion: These findings suggest that patients with olfactory dysfunction may have difficulty improving their olfactory function if they also have zinc deficiency. Furthermore, normalisation of zinc deficiency may contribute to the improvement of olfactory dysfunction with general treatment.

This study examined how zinc levels relate to problems with smelling, which is called olfactory dysfunction. We studied 42 participants who had trouble smelling due to infections, injuries, or unknown reasons and who also had low zinc levels in their blood. After the participants consumed a zinc supplement to treat their low zinc levels, we placed the participants either in the group for those who had their zinc levels go back to normal or in the group for those who remained zinc deficient. We tested the participants’ sense of smell in different ways, including using an olfactometer, a card with different scents, and questionnaires. The group with normal zinc levels did much better in all the smell tests; the zinc-deficient group only improved in 1 test, which was the questionnaire. These results suggest that if someone has trouble smelling and they also lack the appropriate level of zinc, it might be difficult for them to get better. However, if they can improve their zinc level and bring it to a normal level, their sense of smell could improve. In summary, this study demonstrated a connection between zinc levels and smelling ability, indicating that repairing zinc deficiency may aid in treating olfactory dysfunction.

Recently, animal studies have demonstrated a potential relationship between zinc deficiency and olfactory dysfunction, such as the apoptosis of olfactory ensheathing cells (OECs) [1]. OECs can act as phagocytes responsible for cleaning apoptotic olfactory receptor neurons; the clearance of these dying cells is crucial in creating a favourable environment for olfactory nerve turnover and axon regeneration [2]. A previous study found evidence supporting the notion that zinc deficiency can worsen the severity of olfactory dysfunction [3]. Therefore, the lack of OECs caused by zinc deficiency may hinder the regeneration of olfactory receptor neurons and contribute to the development of sensorineural olfactory dysfunction [3]. However, whether zinc preparations improve olfactory function or not remains inconclusive. In a study by Yoshida et al. [4], olfactory function improved in patients with low serum zinc levels who were administered an oral zinc preparation (polaprezinc), and Aiba et al. [5] demonstrated that patients with post-traumatic olfactory dysfunction who received zinc sulphate had significantly higher improvement rates than those who received a therapy of vitamin preparations and steroid nasal spray. Moreover, Jiang et al. [6] determined zinc gluconate was more effective than no medicine for treating traumatic anosmia. In contrast, zinc sulphate has no significant effect on patients with non-conductive olfactory dysfunction [7], and topical administration of zinc ions has been associated with olfactory dysfunction [8]. There are various causes of zinc deficiency, such as metabolic diseases, insufficient zinc intake, and older age [9], and initial doses of zinc preparations may not normalise serum zinc levels in actual clinical practice. Therefore, it remains unclear whether normalising serum zinc levels with zinc preparations can improve olfactory function in patients with olfactory dysfunction complicated by zinc deficiency. To address this gap, we investigated the relationship between normalised serum zinc levels and the therapeutic effects on olfactory dysfunction. We specifically focused on patients with post-infectious, post-traumatic, and idiopathic olfactory dysfunction who exhibited zinc deficiency.

Study Design and Participants

This retrospective cohort study was approved by the Ethics Committee of the Jikei University (Approval No. 35-179[11808]). Adult patients (age ≥18) who visited our outpatient clinic between January 1, 2019, and December 31, 2022, and were diagnosed with post-infectious, post-traumatic, or idiopathic olfactory dysfunction and with serum zinc levels <70 μg/dL at the first visit were included in this study. The patients were treated with mecobalamin, tokishakuyakusan, and polaprezinc, which is a chelate compound consisting of zinc and l-carnosine (150 mg of polaprezinc containing 34 mg of zinc daily; Sawai Pharmaceutical Co. LTD., Osaka, Japan). Mecobalamin and tokishakuyakusan are usually prescribed for olfactory dysfunction in Japan for treating post-infectious and post-traumatic olfactory dysfunction [10, 11]. More than 3 months later, serum zinc levels and olfactory tests were checked again. They were categorised into 2 groups based on their post-treatment serum zinc levels: the zinc-normalised (≥70 μg/dL) and zinc-deficient (<70 μg/dL) groups. We excluded patients who underwent a post-treatment blood test more than 1 year after the first visit or whose blood and olfactory tests were performed more than 1 month apart. We also excluded patients with conductive olfactory dysfunction (sinonasal diseases and nasal septum deviation), neurological diseases (Parkinson’s and Alzheimer’s diseases), psychogenic olfactory dysfunction, post-operative olfactory dysfunction (classification is difficult and depends on post-operative nose condition), and congenital olfactory dysfunction (hypoplasia or absence of olfactory bulbs as diagnosed by magnetic resonance imaging).

Variables

We analysed the results of pre- and post-treatment serum zinc levels and olfactory tests. Clinical information, including age, sex, medical history, family history, smoking status, classification based on the cause of olfactory dysfunction, duration of olfactory dysfunction, and the date of blood and olfactory tests, was collected. For smoking status, patients were categorised as current or former and never smokers based on previous reports that suggest current smokers have an increased risk of developing olfactory dysfunction [12, 13].

Classification of Olfactory Dysfunction

The diagnosis and classification of olfactory dysfunction were determined by a comprehensive assessment of a patient’s medical history, blood test results, endoscopy, computed tomography scans of the sinuses, and olfactory tests. Guidelines for olfactory dysfunction [11] published in 2017 by the Journal of the Japanese Rhinologic Society and a position paper on olfactory dysfunction [14] were used as references for classification. The causes of olfactory dysfunction were classified as follows: chronic rhinosinusitis, allergic rhinitis, nasal septum deviation (with the improvement of olfactory dysfunction after nasal septum surgery), post-infectious olfactory dysfunction, post-traumatic olfactory dysfunction, olfactory dysfunction associated with exposure to drugs/toxins, olfactory dysfunction associated with neurological disease (Parkinson’s disease or Alzheimer’s disease), congenital olfactory dysfunction, psychogenic olfactory dysfunction, post-operative olfactory dysfunction (after nasal or skull base surgery), and idiopathic olfactory dysfunction (unknown cause).

Olfactory Tests

The details of the olfactory tests performed in this study are as follows.

  • Questionnaires

    • -

      Self-administered odour questionnaire (SAOQ): The participants were instructed to score 20 odours that are a part of Japanese individuals’ daily lives on a 4-point scale of “always smelled,” “sometimes smelled,” “never smelled,” and “unknown or no recent experience.” The items were assigned a score of 2 points for “always smelled,” 1 point for “sometimes smelled,” and 0 points for “never smelled.” The items rated as “unknown or no recent experience” were excluded as non-rateable items. The total score was converted to a percentage for evaluation [15].

    • -

      Visual Analogue Scale for olfactory dysfunction (VAS): The left end of a 100-mm straight line indicated “not smelling at all,” whereas the right end indicated “normally smelling.” Patients plotted their current odour status on a straight line. The score represents the distance from the left edge to the marked point (0–100 points).

  • Sensory tests

    • -

      Open Essence (OE): This is a card-type odour identification test. There were 12 types of 2-fold measurement cards, and each card had a particular odour when opened. These odourants are defined as Indian ink, wood, perfume, menthol, orange, curry, cooking gas, rose, cypress wood (Japanese cypress, “hinoki”), sweaty-smelling clothes, condensed milk, and roasted garlic. Patients were instructed to select an answer from a total of 6 choices, which included “cannot identify,” “odourless,” and names of 4 odours on the right side of the opened card (including 1 correct answer) [16]. The patient was considered normosmic if ≥ 8 of the 12 cards were correct. If ≤ 7 were correct, the patient was considered as having olfactory dysfunction [17].

    • -

      T&T olfactometer test (T&T): This is a standard olfactory threshold test in Japan, wherein 5 types of olfactory substances (β-phenyl alcohol, methyl cyclopentenolone, isovaleric acid, γ-undecalactone, and skatole) are used. Eight stages of -2–5 points with 10-fold dilutions were prepared. A point of 0 was the olfactory concentration of healthy adults. The patients sniffed each odour from the lowest (−2) concentration. The concentration at which the odour was perceived was used as the detection and recognition threshold. If the patient could not perceive the odour, a score of 6 was assigned to each threshold (a score of 5 for methyl cyclopentenolone only). The average detection and recognition threshold was obtained by dividing the total score by 5. In the average recognition threshold, <1.1 was normosmia, ≤2.5 was mild olfactory dysfunction, ≤4 was moderate olfactory dysfunction, ≤5.5 was severe olfactory dysfunction, and ≥5.6 was anosmia from guideline criteria [11].

Cut-Off for Serum Zinc Levels

Since the diagnostic criteria for zinc deficiency varied slightly in every reference [9, 18], statistical analysis was performed using 70 μg/dL as the cut-off for the serum zinc levels of the zinc-deficient group based on those in Harrison's Principles of Internal Medicine [18].

Outcomes

The outcomes were the relationships between the olfactory test results and the pre- and post-treatment in the zinc-normalised and zinc-deficient groups.

Statistical Analyses

Continuous and categorical variables are presented as medians (interquartile ranges) and counts (%), respectively. Zinc-normalised and zinc-deficient groups were compared using Fisher’s exact test {sex, age (≥65 years or not [per definition of older adults in Japan]), disease duration, follow-up duration, smoking (current or not), and causal classification} and the Mann-Whitney U test (detection and recognition threshold of T&T, OE, VAS, and SAOQ). The pre- and post-treatment olfactory tests of the 2 groups were analysed using the Wilcoxon matched-pairs signed-rank test. The changes in the olfactory test scores (calculated by subtracting the results of pre-treatment from post-treatment) were compared using the Mann-Whitney U test. A 2-sided α value <0.05 was considered statistically significant. Statistical analyses were performed using GraphPad Prism version 8.4.3 (GraphPad Software Inc., San Diego, CA, USA), unless otherwise indicated.

Patient Backgrounds

A total of 42 patients participated in this study including 21 post-infectious, 3 post-traumatic, and 18 idiopathic olfactory dysfunction cases. Their medium age was 57.0 (range, 25–82) years. The median serum zinc levels pre- and post-treatment in all the patients were 65 (range, 46–69) µg/dL and 71 (range, 32–137) µg/dL. The median follow-up duration until the secondary evaluation of zinc levels was 139 (range, 42–362) days.

Twenty-five and 17 patients were classified into the zinc-normalised (post-treatment serum zinc levels ≥70 μg/dL) and zinc-deficient (post-treatment serum zinc levels <70 μg/dL) groups. Table 1 presents the background information of the 2 groups, and there were no significant differences between the 2 groups. Moreover, there were no significant differences in medical history between the two groups, not only in diseases that can cause zinc deficiency, such as diabetes mellitus and inflammatory bowel disease, but also in diseases that may contribute to decreased olfaction, such as hypertension.

Table 1.

Demographic characteristics of zinc-normalised group and zinc-deficient group

CharacteristicsZinc-normalised group (n = 25)Zinc-deficient group (n = 17)p value
Sex, n (%) 
 Male 8 (32) 6 (35) >0.999 
 Female 17 (68) 11 (65)  
Age, median yr (IQR) 59.0 (51.0–66.0) 57.0 (41.0–68.0) 0.653 
Age, n (%) 
 65+ years 8 (32) 5 (29) >0.999 
 <65 years 17 (68) 12 (71) 
Disease duration, median month (IQR) 10.0 (3.0–36.0) 12.0 (6.0–24.0) 0.824 
Follow-up duration, median day (IQR) 140 (112–210) 138 (98–267) 0.884 
Serum zinc level, median µg/dL (IQR) 64.0 (59.0–66.0) 66.0 (62.0–68.0) 0.176 
Smoking, n (%) 
 Current 5 (20) 1 (6) 0.370 
 Former and never 17 (65) 15 (88) 
 Unknown 3 (15) 1 (6) 
Olfactory tests, median (IQR) 
 T&T olfactometer 
  Average detection threshold 3.4 (2.0–5.4) 3.0 (1.4–3.8) 0.419 
  Average recognition threshold 5.0 (3.2–5.8) 3.4 (2.8–4.2) 0.101 
 OE 3.0 (1.0–5.0) 6.0 (1.0–7.0) 0.108 
 VAS 14.0 (3.8–28.3) 30.0 (7.0–50.0) 0.077 
 SAOQ 11.7 (3.8–35.6) 16.7 (11.1–55.0) 0.257 
Classification according to cause, n (%) 
 Post-infection 10 (40) 11 (65) 0.208 
 Post-trauma 3 (12) 0 (0) 0.257 
 Idiopathic disease 12 (48) 6 (35) 0.530 
CharacteristicsZinc-normalised group (n = 25)Zinc-deficient group (n = 17)p value
Sex, n (%) 
 Male 8 (32) 6 (35) >0.999 
 Female 17 (68) 11 (65)  
Age, median yr (IQR) 59.0 (51.0–66.0) 57.0 (41.0–68.0) 0.653 
Age, n (%) 
 65+ years 8 (32) 5 (29) >0.999 
 <65 years 17 (68) 12 (71) 
Disease duration, median month (IQR) 10.0 (3.0–36.0) 12.0 (6.0–24.0) 0.824 
Follow-up duration, median day (IQR) 140 (112–210) 138 (98–267) 0.884 
Serum zinc level, median µg/dL (IQR) 64.0 (59.0–66.0) 66.0 (62.0–68.0) 0.176 
Smoking, n (%) 
 Current 5 (20) 1 (6) 0.370 
 Former and never 17 (65) 15 (88) 
 Unknown 3 (15) 1 (6) 
Olfactory tests, median (IQR) 
 T&T olfactometer 
  Average detection threshold 3.4 (2.0–5.4) 3.0 (1.4–3.8) 0.419 
  Average recognition threshold 5.0 (3.2–5.8) 3.4 (2.8–4.2) 0.101 
 OE 3.0 (1.0–5.0) 6.0 (1.0–7.0) 0.108 
 VAS 14.0 (3.8–28.3) 30.0 (7.0–50.0) 0.077 
 SAOQ 11.7 (3.8–35.6) 16.7 (11.1–55.0) 0.257 
Classification according to cause, n (%) 
 Post-infection 10 (40) 11 (65) 0.208 
 Post-trauma 3 (12) 0 (0) 0.257 
 Idiopathic disease 12 (48) 6 (35) 0.530 

OE, Open Essence; VAS, Visual Analogue Scale for olfactory dysfunction; SAOQ, self-administered odour questionnaire.

Median age, median disease duration, median follow-up duration, serum zinc level, and olfactory tests were analysed with the p value using the Mann-Whitney U test.

The other factors were analysed with p values using Fisher’s exact test. Statistical significance was set at p < 0.05.

Comparison of Olfactory Tests between Pre- and Post-treatment

Olfactory tests between pre- and post-treatment were compared in each of the 2 groups. Table 2 presents the results of the pre- and post-treatment olfactory tests in the 2 groups. All olfactory tests were significantly better in the zinc-normalised group (detection/recognition thresholds in the T&T, p = 0.002/< 0.001; OE, p = 0.001; VAS, p = 0.032; SAOQ, p = 0.002). Figure 1a shows the corresponding boxplots. In contrast, only the SAOQ was significantly better in the zinc-deficient group (p = 0.005), and there were no significant differences in the other olfactory tests. Figure 1b shows the corresponding boxplots. Furthermore, when comparing the changes in the olfactory test scores of the 2 groups, significant differences were observed in the detection/recognition thresholds of the T&T and OE (p = 0.038/0.030, 0.010). The changes in the 2 groups are presented in Table 3.

Table 2.

Comparison of pre-treatment and post-treatment data in the zinc-normalised and zinc-deficient groups

CharacteristicsZinc-normalised groupZinc-deficient group
pre-treatmentpost-treatmentp valuepre-treatmentpost-treatmentp value
Serum zinc level, median µg/dL (IQR) 
 64.0 (59.0–66.0) 83.0 (74.0–10210)  66.0 (62.0–68.0) 64.0 (58.0–66.0)  
Olfactory tests, median (IQR) 
 T&T olfactometer 
  Average detection threshold 3.4 (2.0–5.4) 2.4 (1.2–3.8) 0.0020* 3 (1.4–3.8) 3 (1.4–4.2) 0.935 
  Average recognition threshold 5 (3.2–5.8) 4.2 (2.0–5.2) <0.001* 3.4 (2.8–4.2) 3.6 (2.2–4.8) 0.985 
 OE 3.0 (1.0–5.0) 6.0 (4.0–7.0) 0.001* 6.0 (1.0–7.0) 5.0 (4.0–8.0) 0.973 
 VAS 14.0 (3.8–28.3) 22.0 (15.5–36.3) 0.032* 30.0 (7.0–50.0) 24.0 (18.0–50.0) 0.689 
 SAOQ 11.7 (3.8–35.6) 29.7 (15.1–62.1) 0.002* 16.7 (11.1–55.0) 59.4 (13.2–90.0) 0.005* 
CharacteristicsZinc-normalised groupZinc-deficient group
pre-treatmentpost-treatmentp valuepre-treatmentpost-treatmentp value
Serum zinc level, median µg/dL (IQR) 
 64.0 (59.0–66.0) 83.0 (74.0–10210)  66.0 (62.0–68.0) 64.0 (58.0–66.0)  
Olfactory tests, median (IQR) 
 T&T olfactometer 
  Average detection threshold 3.4 (2.0–5.4) 2.4 (1.2–3.8) 0.0020* 3 (1.4–3.8) 3 (1.4–4.2) 0.935 
  Average recognition threshold 5 (3.2–5.8) 4.2 (2.0–5.2) <0.001* 3.4 (2.8–4.2) 3.6 (2.2–4.8) 0.985 
 OE 3.0 (1.0–5.0) 6.0 (4.0–7.0) 0.001* 6.0 (1.0–7.0) 5.0 (4.0–8.0) 0.973 
 VAS 14.0 (3.8–28.3) 22.0 (15.5–36.3) 0.032* 30.0 (7.0–50.0) 24.0 (18.0–50.0) 0.689 
 SAOQ 11.7 (3.8–35.6) 29.7 (15.1–62.1) 0.002* 16.7 (11.1–55.0) 59.4 (13.2–90.0) 0.005* 

OE, Open Essence; VAS, Visual Analogue Scale for olfactory dysfunction; SAOQ, self-administered odour questionnaire.

Olfactory tests were analysed with the p value using the Wilcoxon matched-pairs signed-rank test.

Statistical significance was set at p < 0.05.

Fig. 1.

Boxplots of the pre- and post-treatment olfactory test results. a Zinc-normalised group. b Zinc-deficient group. Statistical significance was set at p < 0.05. OE, Open Essence; SAOQ, self-administered odour questionnaire; T&T, T&T olfactometer test; VAS, Visual Analogue Scale for olfactory dysfunction.

Fig. 1.

Boxplots of the pre- and post-treatment olfactory test results. a Zinc-normalised group. b Zinc-deficient group. Statistical significance was set at p < 0.05. OE, Open Essence; SAOQ, self-administered odour questionnaire; T&T, T&T olfactometer test; VAS, Visual Analogue Scale for olfactory dysfunction.

Close modal
Table 3.

Comparison of the changes in the olfactory test scores of the zinc-normalised and zinc-deficient groups

CharacteristicsZinc-normalised groupZinc-deficient groupp value
Serum zinc level, median µg/dL (IQR) 23.0 (13.0–34.0) −2.0 (−5.0 to 2.0)  
Olfactory tests, median (IQR) 
 T&T olfactometer 
  Average detection threshold 0.6 (0.0–1.4) −0.4 (−0.6 to 0.8) 0.038* 
  Average recognition threshold 0.6 (0.2–1.0) 0.0 (−0.6 to 0.8) 0.030* 
 OE 3.0 (0.0–4.0) 0.0 (−1.0 to 1.0) 0.010* 
 VAS 10.0 (1.0–17.0) 0.0 (−4.0 to 16.0) 0.294 
 SAOQ 10.5 (0.0–24.1) 12.5 (0.0 to 23.7) 0.864 
CharacteristicsZinc-normalised groupZinc-deficient groupp value
Serum zinc level, median µg/dL (IQR) 23.0 (13.0–34.0) −2.0 (−5.0 to 2.0)  
Olfactory tests, median (IQR) 
 T&T olfactometer 
  Average detection threshold 0.6 (0.0–1.4) −0.4 (−0.6 to 0.8) 0.038* 
  Average recognition threshold 0.6 (0.2–1.0) 0.0 (−0.6 to 0.8) 0.030* 
 OE 3.0 (0.0–4.0) 0.0 (−1.0 to 1.0) 0.010* 
 VAS 10.0 (1.0–17.0) 0.0 (−4.0 to 16.0) 0.294 
 SAOQ 10.5 (0.0–24.1) 12.5 (0.0 to 23.7) 0.864 

OE, Open Essence; VAS, Visual Analogue Scale for olfactory dysfunction; SAOQ, self-administered odour questionnaire.

Olfactory tests were analysed with the p value using the Mann-Whitney U test.

Statistical significance was set at p < 0.05.

Zinc Preparation Side Effects

There were no side effects requiring medical intervention during the observation period of our study.

Our study revealed 2 important findings. First, patients with olfactory dysfunction may have difficulty improving their olfactory function if they had zinc deficiency and it remained even after treatment. Second, the normalisation of zinc deficiency may facilitate the improvement of olfactory dysfunction.

Zinc Deficiency May Interfere with the Treatment of Olfactory Dysfunction

In a previous study, zinc deficiency exacerbated the severity of olfactory dysfunction [3]. The results of the present study suggest that it may be difficult for patients with olfactory dysfunction to improve their olfactory function if zinc deficiency remained even after treatment. In recent years, it has been reported that owing to severe zinc deficiency in rats, p53 induces apoptosis of OECs in the olfactory nerve layer of the olfactory bulb [1]. OECs can act as phagocytes responsible for cleaning apoptotic olfactory receptor neuron corpses, and the clearance of these dying cells is crucial for creating a favourable environment for olfactory nerve turnover and axon regeneration [2]. Therefore, the remaining zinc deficiency inhibits the phagocytosis of olfactory nerves damaged when various olfactory dysfunctions occur [19], resulting in a decrease in the healing rate.

Normalisation of Zinc Deficiency May Facilitate Olfactory Dysfunction Improvement

A previous report [4] showed that patients with post-infectious olfactory dysfunction and serum zinc levels ≥80 μg/dL improved significantly compared to those with <80 μg/dL. However, these patients did not take oral zinc preparations. Another study demonstrated that the administration of oral zinc preparations to patients with olfactory dysfunction improved olfactory dysfunction [20]. Since there are only a few reports that exist, whether oral administration of zinc preparations is sufficient to improve olfactory dysfunction or whether serum zinc levels need to be corrected requires further verification. We featured different approaches, and the results are the first to show that normalisation of serum zinc levels may be effective in treating olfactory dysfunction associated with zinc deficiency.

Harrison’s Principles of Internal Medicine [18] states that a serum zinc level of <70 μg/dL is considered zinc deficiency, whereas Japanese guidelines for the diagnostic criteria of zinc deficiency [9] state that a serum zinc level of <60 μg/dL is considered zinc deficiency. A previous report compared the olfactory tests between the zinc normal and deficient groups with 3 serum zinc level reference values (<70, 65, and 60 μg/dL) and suggests considering using 70 μg/dL or 65 μg/dL for zinc deficiency when olfactory dysfunction is involved [3]. In this study, we adopted 70 μg/dL as the cut-off for serum zinc levels of zinc deficiency; however, further research is warranted to determine the reference value and the degree of supplementation.

Methods for Judging Olfactory Dysfunction Therapeutic Effects

Only the results of the SAOQ showed significant improvement in the zinc-deficient group, which was inconsistent with the results of other olfactory tests. Although the recognition thresholds in T&T were unchanged or worsened, the number of cases in which SAOQ improved by 10% or more was 9 (36.0%) in the zinc-normalised group and 8 (47.1%) in the zinc-deficient group. The reassurance of being treated possibly improved the results of the subjective test. An olfactory self-assessment tends to be unreliable when assessing treatment effects; thus patient-reported outcomes should be used in conjunction with more objective forms of assessment [14]. The SAOQ is a simple and useful olfactory test for confirming the degree of olfactory dysfunction; however, it is difficult to judge therapeutic effects by only SAOQ.

Side Effects from Zinc Preparations

The zinc preparations administered in this study were polaprezinc, and the zinc content was as low as 34 mg/day; there were no side effects requiring medical intervention. Care should be taken when considering increasing the dose of zinc preparations to normalise serum zinc levels.

Limitations

First, this was a retrospective cohort study, and we were unable to recruit true controls because we did not routinely retest serum zinc levels in patients with olfactory dysfunction who had normal zinc levels. Moreover, patient compliance with medication instructions was unclear.

Second, serum zinc levels were not measured at specific times during the day. The circadian rhythm of serum zinc levels decreases in a nearly straight line from 8:00 a.m. to 4:00 p.m., and the decrease is by 1.31–2.88 μg/dL per hour [21]. Thus, it would have been more accurate if the blood test times were standardised.

Third, we prescribed not only zinc preparation with l-carnosine but also mecobalamin and tokishakuyakusan. We cannot exclude the effect of these medications.

Additionally, carnosine may act as a neurotransmitter or neuromodulator in the primary olfactory system [22] and may protect the olfactory system through its antioxidant activity [23]. These effects might promote olfactory nerve regeneration by reducing damage due to sensorineural olfactory dysfunction. Nonetheless, we believe that this study is novel because it focused on serum zinc levels as a treatment for olfactory dysfunction and demonstrated the clinical implications of using zinc supplementation for the treatment of olfactory dysfunction in the future.

Our findings suggest that patients with olfactory dysfunction may have difficulty improving olfactory function if it is complicated by zinc deficiency. Furthermore, normalisation of zinc deficiency may facilitate the improvement of olfactory dysfunction with general treatment.

We would like to thank Editage (www.editage.com) for English language editing.

This retrospective cohort study was approved by the Ethics Committee of the Jikei University (Approval No. 35-179[11808]). The information for this study was disclosed, and the participants could choose to opt out. An opt-out informed consent protocol was used for the use of participant data for research purposes. This consent procedure was reviewed and approved by the Ethics Committee of the Jikei University School of Medicine, Approval Number 35-179[11808], date of decision October 7, 2023.

The authors have no conflicts of interest to declare.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

H.T.: conceptualisation, data collection and analysis, funding acquisition, investigation, methodology, and resources. E.M.: manuscript conceptualisation, investigation, methodology, writing, review, and editing and total project administration and supervision. N.Y., R.S., and M.N.: data collection and conducted the olfactory tests. M.T.: manuscript review and editing. N.O.: supervision, and review and editing of the final manuscript.

The datasets generated and analysed during the current study are available from the corresponding author on reasonable request. The data that support the findings of this study are not publicly available due to privacy reasons but are available from the corresponding author upon reasonable request.

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