10.5826/dpc.1204a140
Introduction: Vitiligo is a chronic skin disease, which its etiopathogenesis is not fully understood. Numerous studies have suggested that oxidative stress may play a role in the pathophysiology of vitiligo. There are controversial reports as to the changes of serum trace elements, copper and zinc levels in vitiligo patients.
Objective: In this study, we evaluated the alterations in the level of serum Cu and Zn among a group of Iranian vitiligo patients.
Methods: The levels of serum Cu and Zn were compared between 117 vitiligo patients and 137 healthy controls using atomic absorption spectrophotometry.
Results: The mean Cu and Zn levels in the case group (113.57 ± 59.43 and 95.01 ± 58.95 μg/dl, respectively) were significantly lower than those of the control group (138.90 ± 38.14 and 121.83 ± 33.80 μg/dl, respectively) (p= 0.00). We also observed significantly lower serum Cu and Zn concentrations in young (&lt;50 years) than the elderly (≥50 years) patients (p=0.00). The mean Cu and Zn levels in the patients with generalized vitiligo (111.63±54.18 and 93.11±59.33 μg/dl, respectively) were significantly lower than patients with localized vitiligo (120.74 ±71.64 and 98.69±58.63 μg/dl, respectively) and those in the control group (p = 0.00). The serum Cu/Zn ratio obtained in the young and male patients was higher than those in their matched control counterparts (p=0.01).
Conclusions: The current study has shown that the disturbance of serum Cu and Zn levels is associated with vitiligo, and may play an important role in the disease development of Iranian vitiligo patients.
text/xml
2160-9381
2043
en
Fakhraddin Naghibalhossaini
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
copper
Serum Copper and Zinc levels among Iranian vitiligo patients: Serum Cu and Zn in vitiligo patients  
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Original Article
2022-10-31
2021-09-14
2022-10-31
2022-11-29
e2022140
Dermatol Pract Concept
Introduction: Vitiligo is a chronic skin disease, which its etiopathogenesis is not fully understood. Numerous studies have suggested that oxidative stress may play a role in the pathophysiology of vitiligo. There are controversial reports as to the changes of serum trace elements, copper and zinc levels in vitiligo patients.
Objective: In this study, we evaluated the alterations in the level of serum Cu and Zn among a group of Iranian vitiligo patients.
Methods: The levels of serum Cu and Zn were compared between 117 vitiligo patients and 137 healthy controls using atomic absorption spectrophotometry.
Results: The mean Cu and Zn levels in the case group (113.57 ± 59.43 and 95.01 ± 58.95 μg/dl, respectively) were significantly lower than those of the control group (138.90 ± 38.14 and 121.83 ± 33.80 μg/dl, respectively) (p= 0.00). We also observed significantly lower serum Cu and Zn concentrations in young (&lt;50 years) than the elderly (≥50 years) patients (p=0.00). The mean Cu and Zn levels in the patients with generalized vitiligo (111.63±54.18 and 93.11±59.33 μg/dl, respectively) were significantly lower than patients with localized vitiligo (120.74 ±71.64 and 98.69±58.63 μg/dl, respectively) and those in the control group (p = 0.00). The serum Cu/Zn ratio obtained in the young and male patients was higher than those in their matched control counterparts (p=0.01).
Conclusions: The current study has shown that the disturbance of serum Cu and Zn levels is associated with vitiligo, and may play an important role in the disease development of Iranian vitiligo patients.
Fakhraddin Naghibalhossaini
2022/10/31
10.5826/dpc.1204a140
e2022140
Department of Biochemistry, Shiraz University of Medical Sciences, School of Medicine, Shiraz, Iran; Autoimmune Research Center, Shiraz University of Medical Sciences, School of Medicine, Shiraz, Iran
2160-9381
copper
en
e2022140
Sanna A., Firinu D., Zavattari P., Valera P. Zinc status and autoimmunity: A systematic review and meta-analysis. Nutrients. 2018; 10: 68. DOI: 10.3390/nu10010068.
Serum Copper and Zinc levels among Iranian vitiligo patients: Serum Cu and Zn in vitiligo patients  
https://dpcj.org/index.php/dpc/article/download/2043/1766
         Serum Copper and Zinc Levels Among Iranian
                      Vitiligo Patients
               Zahra Khoshdel1, Naser Gholijani2, Maryam Niknam1, Nasim Rahmani1,
                   Mohsen Hemmati-Dinarvand1, Fakhraddin Naghibalhossaini1,2


1 Department of Biochemistry, Shiraz University of Medical Sciences, School of Medicine, Shiraz, Iran
2 Autoimmune Diseases Research Center, Shiraz University of Medical Sciences, School of Medicine, Shiraz, Iran



Key words: vitiligo, trace elements, zinc, copper
Citation: Khoshdel Z, Gholijani N, Niknam M, Rahmani N, Hemmati-Dinarvand M, Naghibalhossaini F. Serum Copper and Zinc levels
among Iranian vitiligo patients. Dermatol Pract Concept. 2022;12(4):e2022140. DOI: https://doi.org/10.5826/dpc.1204a140
Accepted: January 2, 2022; Published: October 2022
Copyright: ©2022 Khoshdel et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-
NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use,
distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: This research was supported by the Vice Chancellor for Research, Shiraz University of Medical Sciences through
Grant Number 98-01-17-19678.
Competing interests: None.
Authorship: All authors have contributed significantly to this publication.
Corresponding author: Fakhraddin Naghibalhossaini (Ph. D), Department of Biochemistry, Shiraz University of Medical Sciences, School
of Medicine, Zand Street, Shiraz, 7134845794, Iran, Fax: +98-71-32303029 E-mail: fakhraddin.naghibalhossaini@mail.mcgill.ca




  ABSTRACT              Introduction: Vitiligo is a chronic skin disease, which its etiopathogenesis is not fully understood.
                        ­Numerous studies have suggested that oxidative stress may play a role in the pathophysiology of
                         ­vitiligo. There are controversial reports as to the changes of serum trace elements, copper (Cu) and
                          zinc (Zn) levels in vitiligo patients.
                        Objectives: We evaluated the alterations in the level of serum Cu and Zn among a group of Iranian
                        vitiligo patients.
                        Methods: The levels of serum Cu and Zn were compared between 117 vitiligo patients and 137
                        healthy controls using atomic absorption spectrophotometry.
                        Results: The mean Cu and Zn levels in the cases (113.57 ± 59.43 and 95.01 ± 58.95 μg/dl,
                        ­respectively) were significantly lower than those of the controls (138.90 ± 38.14 and 121.83 ± 33.80
                         μg/dl, r­ espectively) (P = 0.00). We also observed significantly lower serum Cu and Zn concentrations
                         in young (< 50 years) than the elderly (≥ 50 years) patients (P = 0.00). The mean Cu and Zn levels in
                         the patients with generalized vitiligo (111.63±54.18 and 93.11±59.33 μg/dl, respectively) were signifi-
                         cantly lower than patients with localized vitiligo (120.74 ±71.64 and 98.69±58.63 μg/dl, respectively)
                         and those in the control (P = 0.00). The serum Cu/Zn ratio obtained in the young and male patients
                         was higher than those in their matched controls (P = 0.01).
                        Conclusions: The current study has shown that the disturbance of serum Cu and Zn levels is asso-
                        ciated with vitiligo, and may play an important role in the disease development of Iranian patients.




Original Article | Dermatol Pract Concept. 2022;12(4):e2022140                                                                         1
Introduction                                                        that melanocytes degeneration and lower melanin biosynthe-
                                                                    sis in vitiligo patients may result in increased serum Cu and
Vitiligo is a multifactorial hypo-melanotic disorder charac-        Zn levels. Hence, the high serum levels of these elements in
terized by the appearance of white spots of different sizes         ­vitiligo are the result of the disease rather than its underlying
and shapes on the skin. The disease affects 0.1% to 8.8% of         cause [25]. Several other studies have reported significantly
the world’s population, with a higher prevalence among pig-         decreased serum levels of Cu and/or Zn among vitiligo
mented racial groups [1,2]. The loss of functional melanocytes      patients [21,26-29].
has been detected histochemically in the skin as well mucous
membranes, hair, and the retina of vitiligo patients [3]. Many
different factors, including genetics, oxidative stress, environ-
                                                                    Objectives
ment, metabolic abnormalities, autoimmunity mediated by             In view of this controversy, the purpose of the present study
autoreactive CD8+ T lymphocytes, and interferon-γ CXCL10            was to investigate the changes in serum Cu and Zn concen-
cytokine signaling pathway may be involved in the pathogen-         trations among Iranian vitiligo patients.
esis of the disease [4-6]. The exact mechanisms and interac-
tions of these factors in the etiology of vitiligo are unclear.
Previous studies have suggested that oxidant/antioxidant im-        Methods
balance and oxidative stress may also play important roles in
                                                                    Experiment Groups
the pathogenesis of vitiligo [7,8]. ­Antioxidant deficiency and
                                                                    One hundred and seventeen sera were obtained from the
the accumulation of reactive oxygen species in the epidermal
                                                                    previously collected serum samples of vitiligo patients
lesions of vitiligo patients have been also reported. Epidermal
                                                                    (48 men and 69 women) from the biobank of the Auto-
lesions of vitiliginous skin show decreased catalase activity
                                                                    immune Diseases ­Research Center of Shiraz University of
and increased H2O2 and nitric oxide levels [8,9]. Previous
                                                                    Medical ­Sciences (SUMS). The control group consisted of
studies have indicated that both localized and generalized
                                                                    137 healthy blood donors (62 males and 75 females) with
vitiligo were associated with low total antioxidant and high
                                                                    no signs of skin or systemic disease. According to the der-
total oxidant status, as compared with healthy controls [10].
                                                                    matology and Wood lamp examination, 84% of patients
    Oxidative stress inhibits melanin production by inter-
                                                                    had generalized/­universal and 16% of localized/segmental
fering with tyrosinase activity in the epidermis, thereby ex-
                                                                    stable vitiligo. The University ethics committee approved
erting the cytotoxicity of melanocytes [11]. Melanin, a dark
                                                                    the protocol for this study (Approval Number: IR.SUMS.
biopigment found in the skin has a high affinity for binding
                                                                    REC.1398.629), and the informed consent was obtained
and sequestering zinc, copper, and other metal ions [12]. Zn
                                                                    from all study participants.
and Cu trace elements are required as cofactors by tyrosi-
nase, and many other metalloenzymes involved in melanin
biogenesis [13,14]. They are also essential cofactors for the
                                                                    Preparation of the Samples and Analytical Methods
activity of superoxide dismutase, an antioxidant enzyme that        The methods for the preparation of samples and their anal-
protects skin against reactive oxygen species [15]. Although        ysis have been described previously [16]. Briefly, blood
these trace elements are essential for human health, the im-        ­samples were collected from participants, and allowed to
balance of the Cu/Zn ratio suggested being associated with          clot, and serum was separated and stored in plastic tubes at
many human diseases [16,17]. Zinc may play a role in the            -80 °C until analysis. The concentrations of Cu and Zn in
etiology of vitiligo through Zn-α2-Glycoprotein (ZAG), a            the samples were measured using a flame atomic absorption
major plasma protein involved in melanocyte growth and              spectrometer (PerkinElmer model analyst 300). Stock stan-
differentiation. Studies have shown that ZAG deficiency is          dard solutions of Zn and Cu were prepared by 1:1 d
                                                                                                                     ­ ilution
involved in the pathogenesis of vitiligo through the shed-          of either trace element (Merck) solutions (2 mg/ml in HCl)
ding and loss of melanocytes [18]. The relationship between         with deionized water. The stock solutions of Zn or Cu were
changes in the levels of Cu and Zn trace elements in tissues        diluted with glycerol (5% or 10%, respectively) and used
or serum and the pathogenesis of vitiligo is controversial.         as working solutions to calibrate the instrument. The absor-
Some studies have shown that oral supplementation or                bance of Cu and Zn was read at 324.7 and 213.9 nm, respec-
topical treatment of Cu and Zn may improve the clinical             tively. The concentrations of trace elements in samples were
symptoms of vitiligo [19,20]. Both increased and decreased          calculated using PerkinElmer AA WinLab software.
serum levels of these trace elements in vitiligo patients have
been reported [19,21-23]. In a study of 50 Sudanese vitiligo        Statistical Analysis
patients, a significant increase in the mean serum concen-          The statistical analyses of data were performed using the SPSS
tration of Cu level was observed [24]. It has been suggested        software package (version 16; SPSS Inc.). The ­
                                                                                                                  results were



2                                                                       Original Article | Dermatol Pract Concept. 2022;12(4):e2022140
expressed as mean ± standard deviation (SD). Differences be-             differences in serum copper and zinc levels in patients with
tween cases and controls were tested by Kruskal–Wallis test,             vitiligo (P = 0.00) (Table 1).
and the influence of sex and age on the serum levels of trace               The age of patients ranged from 19 to 66 years old
elements was evaluated using the ­Mann–Whitney U-test. The               (Mean: 37.64 ± 13.01 years) and that of control 26 to 60
Spearman rank correlation test was used to analyze the cor-              years old (Mean: 47.19 ± 8.03 years). In terms of the preva-
relation between quantitative variables. A P equal or lower              lence of disease, the highest rate was in the 25 to 28 year age
than 0.05 was considered statistically significant.                      group (17%). The median age of vitiligo patients was about
                                                                         34 years. Since the serum levels of Zn and Cu have been

Results                                                                  reported to increase by age [30], we divided the subjects
                                                                         into two groups of young (< 50 years) and old (≥ 50 years)
A total of 117 subjects with vitiligo and 137 healthy volun-             groups. We found significantly lower serum Cu and Zn
teers were included in this study. Tables 1 and 2 show the               concentration among young patients (107.12 ± 61.18 and
demographic characteristics and serum levels of Cu and Zn                82.47 ± 47.40 μg/dl, respectively) than the elderly group
in patients with vitiligo and the control group. Ninety-seven            (122.53 ±56.30 and 114.37 ± 67.27 μg/dl, respectively) (P
patients had generalized vitiligo and 20 had localized vitil-            =0.00) (Table 1). In the case-control comparison of two age
igo (Table 2). The skin phototypes were type III (70%) and               groups, we found that the serum copper concentrations of
type IV (30%). The duration of the disease ranged from 1-11              cases were lower than those in the respective control group
years, with a mean of 9.57± 9.25 years.                                  (P ≤ 0.05). The mean serum Zn levels of young cases were
    In this study, the serum Cu level in patients ranged from            also lower than the corresponding value in the respective
6.11 to 289.36 μg/dl (mean: 113.57 ± 59.43 μg/dl) and that               controls (P = 0.00) while there was no significant differ-
for the control group was 71.21 to 231 μg/dl (mean: 138.90 ±             ence between the mean serum Zn concentrations of the el-
38.14 μg/dl). Serum zinc concentrations in patients with vitil-          derly subjects and controls (P = 0.535). Although, in the
igo ranged from 6.15 to 273 μg/dl (mean: 95.01 ± 58.95 μg/dl)            case-case comparison of two age groups, a higher Cu/Zn
and that for the control group was 32.64 to 190.20 μg/dl                 ratio was found in the young cases than elderly patients
(mean: 121.83 ± 33.80 μg/dl). Statistical analysis showed                (1.96 ± 2.09 vs 1.64 ± 1.67), the difference didn’t reach
that compared with healthy controls, there were significant              the level of significance (P = 0.406). There was no signif-
                                                                         icant difference in serum copper and zinc levels between




                           Table 1. Serum copper and zinc levels among vitiligo patients
               Cu (μg/                                       Zn (μg/
                 dl)       Cu (μg/dl)                          dl)         Zn (μg/dl)
Group          Median      Mean ± SD          Pa       Pb    Median        Mean ± SD          Pa      Pb    [Cu]/[Zn]     Pa      Pb
Cases (N)   103.41 113.57 ± 59.43 0.000                          76.17     95.01 ± 58.95 0.00              1.81 ± 1.90 0.488
Total (117)
Age
<50 Y (68)   95.07 107.12 ± 61.18 0.000 0.003 72.01                        82.47 ± 47.40 0.00 0.000 1.96 ± 2.09 0.018 0.406
≥50 Y (49 ) 128.67 122.53 ± 56.30 0.050       101.06                      114.37 ± 67.27 0.535      1.64 ± 1.67 0.161
Sex
Male (48)   108.94 114.65 ± 63.88 0.015 0.992                    76.34     99.12 ± 62.10 0.000 0.429 1.67 ± 1.48 0.011 0.559
Female (69) 110.68 112.95 ± 56.32 0.00                           75.09     92.25 ± 56.83 0.000       1.90 ± 2.15 0.087
Controls,
(N)
Total (137) 138.58 138.90 ± 38.14                            118.42       121.83 ± 33.80                   1.28 ± 0.56
Age
<50 Y (71) 138.97 143.82 ± 30.73                      0.338 122.14        124.80 ± 33.05            0.321 1.24 ± 0.43           0.001
≥50 Y (66 ) 138.74 138.70 ± 31.59                           117.02        118.84 ± 34.59                  1.32 ± 0.66
Sex
Male (62)   137.08 135.46 ± 25.13                     0.044 126.10        126.87 ± 29.28            0.113 1.14 ± 0.3            0.008
Female (75) 142.38 146.22 ± 34.76                           111.40        112.53 ± 33.78                  1.39 ± 0.69
Cu = copper; SD = standard deviation; Y = years; Zn = zinc.
a
  values for case–control comparisons from Kruskal–Wallis or Mann–Whitney U test where appropriate
b
  values for case–case or control-control comparisons from Kruskal–Wallis or Mann–Whitney U test where appropriate



Original Article | Dermatol Pract Concept. 2022;12(4):e2022140                                                                         3
male and female patients. However, in male and female                 Cu level of these patients (117.04± 59.95 μg/dl) and that of
cases, the average serum copper and zinc levels were sig-             patients with type III skin (112.67±59.66 μg/dl) (P > 0.05).
nificantly lower than their matched control group (P<0.02)            The patients with a history of other autoimmune diseases
(Table 1). The patients with generalized vitiligo had sig-            had a higher serum Cu, Zn, and Cu/Zn ratio than patients
nificantly lower serum Cu levels (111.63±54.18 μg/dl)                 without a history of autoimmune disease (P < 0.01) (Ta-
than patients with localized vitiligo (120.74 ±71.64 μg/dl)           ble 2). We divided the patients into two groups of early-on-
(P ≤ 0.04) and healthy controls (138.98 ± 28.12 μg/dl) (P = 0.00).    set (the first onset before the age 50) and late-onset (the first
The mean serum Zn level of the patients with the g­ eneralized        onset after the age 50). Patients with an early-onset of vitil-
vitiligo (93.11±59.33 μg/dl) also differed significantly              igo had lower serum Cu (107.12 ± 61.17 μg/dl, P = 0.035)
with those with the localized vitiligo (98.69±58.63 μg/dl)            and Zn (83.06 ± 49.89 μg/dl, P = 0.001) than those in pa-
and the control group (P = 0.00). We found significantly              tients with late onset (122.53 ±56.30 and 112.81± 67.19
lower serum Zn, but higher Cu/Zn ratio in patients with               μg/dl, respectively) ­(Table 2). In patients with early-onset
skin type IV (86. 16±60.62 μg/dl and 2.45±2.75, respec-               vitiligo, the male subjects had significantly higher serum Zn,
tively) than in patients with skin type III (99.24± 59.91 μg/dl       but a lower Cu/Zn ratio than female subjects (P < 0.01)
and 1.48± 1.16, respectively) (P < 0.02, Table 2). However,           (Table 2). Among the patients with the late-onset vitiligo,
there was no significant difference between the mean serum            the serum copper concentration and the copper-zinc ratio




              Table 2. Selected clinical features of vitiligo patients and serum Cu and Zn levels
                         Cu (µg/                                     Zn (µg/
                           dl)         Cu (µg/dl)                      dl)        Zn (µg/dl)
        Group            Median        Mean ± SD               Pa    Median       Mean ± SD           Pa       [Cu]/[Zn]         pa
Early Onset < 50          95.07      107.12 ± 61.17       0.035       72.56       83.06 ± 49.89     0.001     1.96 ± 1.44      0.164
(59.83%)
Late Onset >50           138.37       122.53 ±56.30                  100.23     112.81± 67.19                 1.72 ± 2.13
(40.17%)
Early-Onset (<50 y)
Male (23.9%)              98.41       110.78± 62.80       0.189       76.92       89.70±45.13       0.008      1.73± 1.61       0.00
Female (35.8%)            90.04       116.54±54.15                    68.96       78.63±52.90                  1.77± 2.00
Late-Onset (>50 Y)
Male (17.1%)             131.69       119.65±57.57        0.017       88.58     113.54±78.26        0.629     1.49 ± 1.11      0.005
Female (24.7%)           128.67       124.52±56.34                   100.23     112.27± 59.25                  2.54±2.79
Clinical type
Generalized              101.96       111.63±54.18            0.04    73.01       93.11±59.33       0.006      1.88±2.02       0.078
(82.9%)
Localized (17.09%)       104.72       120.74 ±71.64                  110.50       98.69±58.63                  1.40±1.24
Skin phototype
Skin type I and II
(0%)
Skin type III            103.41       112.67±59.66        0.113       84.68       99.24± 59.91      0.015      1.48± 1.16       0.00
(69.93%)
Skin type IV             103.61       117.04± 59.95                   67.32       86. 16±60.62                 2.45±2.75
(29.97%)
History of other
auto immune
disease
Yes (6.84%)              136.36       143.99±62.61        0.001       74.48       98.29±68.92       0.008      2.08±1.33        0.00
No (93.16%)               98.15       111.34±58.89                    77.08       94.71± 58.59                 1.79± 1.96
Smoking status
Smokers (16.23%)          99.86      106.93 ± 57.08       0.023       74.03       99.67 ± 59.49      0.05      1.71± 1.63      0.273
Non-smokers              103.51      115.45 ± 60.20                   76.25       94.34± 59.50                 1.83±1.95
(83.76%)
Cu = copper; SD = standard deviation; Y = years; Zn = zinc.
Pa, case –case comparison.



4                                                                         Original Article | Dermatol Pract Concept. 2022;12(4):e2022140
  Table 3. Spearman correlation coefficient (r) and P value between serum Cu, Zn, age of onset and
                                         gender in patients
 Correlation between                                                                      r (P value)
 Serum Cu and serum Zn                                                                      0.144 (0.252)
 Serum Cu and age of onset
 Early onset                                                                                0.251 (0.039)
 Late onset                                                                                 0.042 (0.774)
 Serum Zn and age of onset
 Early onset                                                                                0.157 (0.362)
 Late onset                                                                                 0.189 (0.175)
 Serum Cu or Zn and skin type
 Type III                                                                                   0.207 (0.097)
 Type IV                                                                                    0.071(0.688)
 Serum Cu or Zn and
 clinical type of vitiligo
 Generalized                                                                                0.022 (0.844)
 Localized                                                                                  0.453 (0.105)
 Serum Cu or Zn and
 clinical type of vitiligo
 Segmental                                                                                  0.20 (0.045)
 Non-segmental                                                                              0.062 (0.666)
 Serum Zn and the duration of disease                                                      -0.018 (0.862)
 Serum Cu and the duration of disease                                                       0.256 (0.010)
 Serum Zn in male and the duration of disease                                              -0.186 (0.252)
 Serum Zn in female and the duration of disease                                             0.058 (0.662)
 Serum Cu in male and the duration of disease                                               0.112 (0.448)
 Serum Cu in female and the duration of disease                                             0.225 (0.034)
Cu = copper; Zn = zinc.


of female patients was higher than those in male patients (P      cofactors for as many as forty metallo-enzymes involved in
< 0.02). In these cases, the serum levels of Cu were signifi-     the skin pigmentation process. These two trace elements are
cantly lower (P = 0.023), but Zn levels were higher in smok-      essential cofactors of tyrosinase and superoxide dismutase,
ers than those in non-smoker patients (P = 0.05) (Table 2).       two enzymes that are widespread in the human skin and are
    We also evaluated the association between serum Cu and        specifically involved in skin pigmentation and melanocytes
Zn levels and the patients’ clinical data. The serum Cu levels    protection against free radicals, respectively [13,15,27].
showed a positive correlation with the early age of the disease   There are conflicting reports on the relationship between se-
onset (r = 0.251, P = 0.039). We found a significant positive     rum Cu and Zn concentrations and vitiligo. Some authors
correlation between serum Cu concentration and duration           have reported that compared with healthy controls, the se-
of disease (Spearman correlation test, r = 0.256, P = 0.01).      rum Zn, but not Cu levels in vitiligo patients have undergone
However, the correlation coefficient only reached statistical     significant changes [7,28,31]. A recent case-control study of
significance in females (r = 0.225, P = 0.034), but not in male   100 vitiligo patients from India reported decreased serum
patients (Table 3). We also observed a positive correlation       Zn, but increased Cu levels as compared with healthy indi-
between serum Cu and Zn levels and segmental Vitiligo             viduals [32]. Arora et al found no significant difference be-
(r = 0.20, P = 0.045). There was no correlation between the       tween serum Zn levels of vitiligo patients and the healthy
levels of two serum trace elements and other parameters in-       control group [22]. A meta-analysis of 16 studies conducted
cluding skin and clinical types of the disease (Table 3).         to compare the serum Cu and Zn concentrations among 891
                                                                  vitiligo patients and 1682 healthy controls, demonstrated
                                                                  that the serum Cu and Zn concentrations were significantly
Conclusions
                                                                  lower in the cases than controls (P < 0.0001) [27]. The con-
Numerous studies have shown a role for the oxidant–­              troversy about the changes of serum Cu and Zn levels in
antioxidant imbalance and accumulation of ROS in the skin         patients with vitiligo prompted us to carry out this study
lesion of vitiligo patients [7,10,20]. Cu and Zn are necessary    to investigate the relationship between the serum levels of



Original Article | Dermatol Pract Concept. 2022;12(4):e2022140                                                               5
these trace elements and the pathogenesis of vitiligo among a       serum Cu and Zn levels and other parameters in either pa-
group of Iranian patients.                                          tients or the control group. Some previous studies detected
    In our study, the median serum Cu and Zn levels in both         no correlation between serum Cu and Zn levels and the
the localized (104.72 and 110.50 µg/dl, respectively) and           disease subgroups [37,38]. But, others reported a negative
generalized vitiligo patients (101.96 and 73.01 µg/dl, re-          correlation between serum levels of Zn and the generalized
spectively) were significantly less than those in the control       vitiligo, age, and duration of disease [28,31].
group (138.58 and 118.42 µg/dl, respectively). Compared                 In a study of tissue copper in vitiligo patients, the mean
with the control group, the mean serum levels of Cu and             lesion (1.3 μg/g) and non-lesion (1.4 μg/g) Cu levels were
Zn in the patients group were also significantly decreased          non-significantly lower than tissue Cu levels of the control
(P = 0.00) ­(Table 1). The mean serum concentrations of both        group (1.9 μg/g) [39]. Melanin has a high affinity for the
trace ­elements were significantly lower in male and female         sequestration of metal ions, and pigmented tissues contain
vitiligo patients, as compared to their healthy counterparts        a significant amount of metal cations including Cu and
­(Table 1). Our results are consistent with the findings of         Zn [12]. By binding and sequestering metal ions, melano-
Zeng et al. who reported a significant reduction in serum           somes are protected from oxidative damage. The serum
concentrations of both Cu and Zn in Chinese vitiligo patients       concentrations of Zn and Cu have been reported to increase
[27]. Since both the increased and decreased levels of trace        with age [30,40,41]. In our study, the elderly patients (≥ 50
elements can affect the activity of antioxidant enzymes and         years) had significantly higher serum Cu and Zn concentra-
oxidative stress, a U-shaped relation between zinc and cop-         tions than young (< 50 years) patients (P = 0.00) (Table 1). In
per status and optimal health condition has been proposed           the case-control comparison, both the elderly and young pa-
[33]. Thus, the conflicting reports regarding the changes in        tients had lower serum Cu levels than their respective healthy
the level of these trace elements in vitiligo might be true find-   controls (P ≤ 0.05). The young patients also had significantly
ings. Otherwise, the discordance could be linked to the sam-        lower serum Zn levels than the respective control group, but
ple size, racial, or environmental factors such as diet variety.    no significant difference was found in terms of serum Zn
    In our study, the mean concentration of serum Cu in             concentration between elderly patients and their respective
smoker patients (106.93 ± 57.08 µg/dl) was lower, but the           elderly control group (P > 0.05). A relationship between vit-
mean Zn levels (99.67 ± 59.49 µg/dl) was higher than those          iligo and the incidence of other autoimmune disorders has
in non-smoker patients (115.45 ± 60.20 µg/dl and 94.34±             been suggested [42,43]. In our study, 6.8% of vitiligo pa-
59.50 µg/dl, respectively) (P ≤ 0.05). It has been suggested        tients had a history of other autoimmune diseases including
that there is a close relation between Cu/Zn ratio and sys-         rheumatoid arthritis, type 1 diabetes mellitus, and hypothy-
temic oxidative state and the balance between serum Cu and          roidism. Several previous studies have suggested an associa-
Zn is clinically more important than their concentrations in        tion between Zn and Cu deficiency and hypopigmentation of
serum [17,34]. Wacewicz et al found a significantly higher          the skin and hair, immune defects, and autoimmune diseases
Cu/Zn ratio in the serum of vitiligo patients as compared to        like type 1 diabetes, rheumatoid arthritis, multiple sclerosis,
healthy controls [35]. A previous study on 151 cases of three       systemic Lupus erythematosus, celiac disease, Hashimoto
groups of skin diseases including skin cancer, inflammatory,        thyroiditis, and juvenile idiopathic arthritis [44,45].
and non-inflammatory diseases reported that the serum Cu/               In the current study, the median and mean serum Cu and
Zn ratio among examined patients was higher than the con-           Zn concentrations in the generalized form of vitiligo were less
trol group and reflected the clinical severity in each disease      than those in the localized form (P ≤ 0.05). M
                                                                                                                 ­ irnezami et al
group [36]. We also found a higher Cu/Zn ratio among vit-           also reported significantly lower zinc levels in the generalized
iligo patients (1.81 ± 1.90) than healthy controls (1.28 ±          vitiligo than the localized form [28].
0.573), but the difference was not statically significant               In conclusion, our results are consistent with prior study
(P = 0.49, Table 1). We observed a higher serum Cu/Zn ratio         findings of decreased and imbalanced levels of serum Cu and
in young (1.96 ± 2.09) and male cases (1.67 ± 1.48), as com-        Zn in vitiligo patients. The main drawback of this study was
pared to their healthy counterparts (1.24 ± 0.438 and 1.11 ±        the relatively small sample size that limited the statistical power
0.358, respectively) (P = 0.01).                                    to perform analyses across all subgroups of patients. Future
    A linear regression analysis showed positive correlations       studies with a larger sample size should be conducted to un-
between serum Cu and the early age of onset (r =0.251,              derstand the etiopathogenic roles and the potential therapeutic
P = 0.039) and the segmental type of the disease (r =0.2,           benefits of Cu and Zn supplementation for ­vitiligo patients.
P = 0.045) (Table 3). A significant positive correlation was
also observed between serum Cu concentrations and the du-
ration of disease, especially in the female patients (r=0.225,
P = 0.034). No significant correlation was observed between



6                                                                       Original Article | Dermatol Pract Concept. 2022;12(4):e2022140
Acknowledgements                                                                   Med (Lausanne). 2020;7:183. DOI:10.3389/fmed.2020.00183.
                                                                                   PMID: 32478084. PMCID: PMC7235401.
This research was supported by the Vice Chancellor for Re-                   16.   Khoshdel Z, Naghibalhossaini F, Abdollahi K, Shojaei S,
                                                                                   Moradi M, Malekzadeh M. Serum Copper and Zinc Levels
search, Shiraz University of Medical Sciences through Grant
                                                                                   Among Iranian Colorectal Cancer Patients. Biol Trace Elem
Number 98-01-17-19678.                                                             Res. 2016;170(2):294-299. DOI: 10.1007/s12011-015-0483-4.
                                                                                   PMID: 26329996.17. Osredkar J, Sustar N. Copper and Zinc,
                                                                                   Biological Role and Significance of Copper/Zinc Imbalance.
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