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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 8  |  Issue : 1  |  Page : 42-47

Evaluation of serum levels of zinc and copper in vitiligo


1 Department of Dermatology, Maulana Azad Medical College, New Delhi, India
2 Department of Biochemistry, Maulana Azad Medical College, New Delhi, India

Date of Submission21-Dec-2019
Date of Decision03-Apr-2020
Date of Acceptance20-Jul-2020
Date of Web Publication07-Apr-2021

Correspondence Address:
MD Krishna Deb Barman
Professor, Department of Dermatology, Maulana Azad Medical College, New Delhi-110002
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/Pigmentinternational.Pigmentinternational_

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  Abstract 


Background: Vitiligo has high prevalence in India and higher socio-psychological impact due to pigmented skin. Its etiopathogenesis remains unclear and role of zinc (Zn) and copper (Cu) has been speculated in previous studies with conflicting results. Materials and Methods: This is a case-control study of 100 patients of vitiligo and 60 controls. Serum Zn and Cu were estimated by photometric analysis. Results: The mean serum levels of Zn and Cu were significantly different between the cases and controls (P < 0.001). The mean serum Zn was low whereas Cu was higher when compared to controls but the actual levels of Zn and Cu both in patients and controls were much higher than the reference range. Conclusion: Our study shows that though significant difference in levels between cases and controls does point out possibility of important role of Zn and Cu in pathogenesis of vitiligo. Various environmental and nutritional factors affect their levels and so empirical treatment with zinc-copper supplements increases cost of treatment and isn’t supported by evidence. Also, for further studies to evaluate these levels in serum, a normal reference range for that specific population has to be defined and taken into consideration.

Keywords: Anti-oxidants, copper, oxidative stress, vitiligo, zinc


How to cite this article:
Narang I, Barman KD, Sahoo B, Lali P. Evaluation of serum levels of zinc and copper in vitiligo. Pigment Int 2021;8:42-7

How to cite this URL:
Narang I, Barman KD, Sahoo B, Lali P. Evaluation of serum levels of zinc and copper in vitiligo. Pigment Int [serial online] 2021 [cited 2021 Aug 2];8:42-7. Available from: https://www.pigmentinternational.com/text.asp?2021/8/1/42/313137




  Introduction Top


Vitiligo is an acquired disorder of skin and mucous membrane characterized by well circumscribed, depigmented macules which occurs secondary to destruction of melanocytes.[1] Its prevalence ranges from 0.4% to 2% worldwide and is often reported to be higher in India.[2] The social and psychological impact of vitiligo in those with racially pigmented skin is higher.

The etiopathogenesis of vitiligo remains unclear. There are several pathophysiologic theories; the most prominent being autoimmune, neurohumoral, autocytotoxic and oxidative stress. None are mutually exclusive, and it is likely that each partially contributes.[3]

Zinc (Zn) and Copper (Cu) are necessary in the process of melanogenesis and are considered as antioxidants.[4] Zn also has a role as an antiapoptotic factor.[5] Hence, keeping these roles and the proposed theories in mind it has been often hypothesized that abnormal serum Zn and Cu levels may have a role to play in pathophysiology of vitiligo. Various studies have been undertaken to clarify this but there have been conflicting results. Therefore, we undertook a study to evaluate serum Zn and Cu levels in vitiligo


  Methods Top


A case-control study was conducted between a period of one and a half years extending from November 2014 to March 2016 where all old and new patients clinically diagnosed with vitiligo, of all age groups within the timeframe were included. Taking our annual hospital prevalence of vitiligo into account, sample size was calculated and 100 patients of vitiligo (60 males and 40 females with ratio 1:1.22) and 60 healthy age and sex-matched controls (27 males and 33 females with male to female ratio of 1:1.5) were included. These were not on any oral Zn and Cu supplements. Disease variables like disease onset, duration, type of vitiligo, diet and disease activity were noted. Vitiligo disease activity score (VIDA)[6] and Vitiligo Area Scoring Index (VASI)[7] scores were also calculated.

Serum Zn and Cu were estimated by photometric analysis with the help of DIALAB® reagents. Blood was collected from the cases and controls under aseptic precautions and serum was separated which was analysed by Stat Fax® 3300 Chemistry Analyzer (by Awareness Technology, INC) thorough photometric analysis. The reference value for these as given in kit inserts are given [Table 1].
Table 1 Zinc and copper reference ranges as per kit inserts

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Student’s ‘t’ test or Mann-Whitney ‘U’ for the quantitative variables with two independent groups and Chi-square/Fisher’s test was used for statistical significance between qualitative variables. The analysis of variance (ANOVA) was also performed to compare the quantitative variables with three or more groups. The correlations between the quantitative variables were assessed by scatter plots first and then Pearson’s or Spearman’s correlation coefficients were calculated. The 95% confidence range for Zn and Cu was calculated using the reference range [Table 1] for these variables. The two-sided P < 0.05 was considered as statistically significant. The statistical software IBM PASW (Version 22.0) was used for the entire data analysis.


  Results Top


The age of the cases ranged from 5-62 years, mean age being 26.1 years. Age of controls ranged from 8 to 64 years, mean age being 29.3 years. Age of onset of disease ranged from 6 months to 55 years, mean being 19.2 years. The disease duration varied from 1 month to 44 years. Mean duration was 6.7 years. Vegetarians constituted 27 out of 100 cases (27%), whereas 73 (73%) were non-vegetarians. Overall, generalized vitiligo was most common, in 70 out of 100 cases (70%), while rest 30 (30%) had localized vitiligo. Majority of the cases, 60 (60%) had vitiligo vulgaris, followed by focal type (22 cases, 22%), acrofacial (10, 10%), segmental (7, 7%) and mucosal vitiligo (1, 1%). Family history of vitiligo was present in 27% of patients. Stable Vitiligo was found in 32 out of 100 cases (32%) and unstable in 68 cases (68%). The VASI score of cases ranged from 0.25 to 72.60 with the mean VASI score being 9. The VIDA score ranges from −1 to +4. Majority, 32 (32%) had a score of 0, followed by a score of 2 in 25(25%) and 4 in 22 cases (22%). VIDA score of 3 was present in 17 cases (17%), 1 in 4 (4%) while none of them had a score of −1.

Out of 100 cases, as compared to the reference range, serum Zn level was increased in 58 (58%), normal in 41 (41%), and low in the remaining 1 (1%) case, whereas in the control group, it was increased in all 60. They were found to range from 2.2 µmol/L (14.3 µg/dl) to 71.0 µmol/L (464.23 µg/dl) in vitiligo cases with a mean of 24.4±10.8 µmol/L (159.4±70.8 µg/dl). On the other hand, in controls it varied from 24.2 µmol/L (157.9 µg/dl) to 67.9 µmol/L (443.7 µg/dl) with a mean of 32.2±9.1 µmol/L (210.3±59.3 µg/dl).

Out of 100 cases, serum Cu level was increased 78 cases (78%), normal in another 21 (21%) and low in none, whereas in the control group, it was normal in 21 out of 60 (35%), increased in 38 (63.33%) of them, and low in 1 subject. Serum Cu levels were found to range from 10.4 µmol/L (66.5µg/dl) to 53.5 µmol/L (340.5 µg/dl) in vitiligo cases with a mean of 32.5±10.3 µmol/L (207.2± 65.6 µg/dl). On the other hand, in controls they varied from 10.8µmol/L to 43.1µmol/L (69.0–274.6 µg/dl) with a mean of 24.2±6.7µmol/L (154.1±43.0 µg/dl).

The distribution of mean serum levels Zn and Cu was significantly different between the cases and controls (P < 0.001) [Table 2]. The mean serum Zinc was low whereas Cu was higher when compared to controls but the actual range of levels of Zn and Cu from patients and controls were much higher than the reference range. This is perhaps because the reference range used by us for comparison is from the kit inserts which is for a different population. Normal ranges for these elements for Indian population have not been defined in literature which could explain this. Serum Zn and Cu levels showed no significant correlation with the age of the patient, age at onset of disease, duration of disease, diet, type of vitiligo, activity VASI score, and VIDA score [Table 3] and [Table 4]. Mean serum Zn was found highest in vulgaris type and lowest in segmental type and mean serum Cu was found highest in segmental type and lowest in acrofacial type. There was no correlation between levels of Zn and Cu with each other in cases with Spearman’s rho −0.22 and P = 0.026 and controls with Spearman’s rho = −0.09 and P = 0.502. These values were statistically insignificant (P-value<0.05) [Figure 1].
Table 2 Comparison of Zn and copper levels in cases and controls

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Table 3 Correlation of serum Zinc and Copper levels with the patient variables

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Table 4 Correlation of serum Zinc and Copper levels with the patient variables

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Figure 1 Correlation of Zinc and Copper between cases and controls.

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  Discussion Top


Zn and Cu are essential trace elements related to health and disease due to their function as the metal moiety of important enzymes.

Cu and Zn are considered antioxidants and anti-apoptotic factors involved in destruction of free radicals through Cu-Zn superoxide dismutase and by stimulating the protective anti-apoptotic cellular stress-signalling cascades.[5] They have a role in melanogenesis in catalyzing the rearrangement of dopachrome to form5,6-dihydroxy indole-2 carboxylic acid (DICA) and enhancement of eumelanin polymer formation from monomers.[5] Also, the synthesis of melanin involves rate-limiting catalytic step the enzyme tyrosinase which requires Cu for its activity. On the basis of these functions, it has been long hypothesised that Cu and Zn have a role in pathogenesis of vitiligo and theories like oxidative stress and autocytotoxic theories have been utilised to support their role. Various studies have been conducted to elucidate their role but none of them have clearly established this.

Our study shows lower mean levels of serum Zn in cases than controls. On the contrary, Haider et al.[8] noted that Zn levels were increased in the patients than controls, but the change wasn’t statistically significant. On the similar lines, Helmy et al.[9] showed that the levels were significantly higher in active vitiligo patients compared to controls. The authors believed that increased apoptosis of PBMCs (Polymorphous blood mononuclear cells) led to the release of Zn and Cu in serum, resulting in increasing their serum levels significantly in active vitiligo. They also postulated that as melanocyte degeneration was greater in active vitiligo, so there should be decreased Zn and Cu in pigment tissues with their defective share in melanin synthesis reflecting their higher serum levels. Further, and Bruske and Salfeld[10] and Shameer et al.[11] observed significantly lower levels of Zn. Arora et al.[12] also observed lower levels in patients than in controls but this wasn’t statistically significant. Interestingly, Yaghoobhi et al.[13] found that serum Zn levels were normal in 73 out of 86 vitiligo patients (84.9%), increased in 4 (4.7%), and decreased in 9 (10.5%) of the patients. But, they had no control group for comparing the serum Zn levels. The purpose of this study was to evaluate the efficacy of supplemental Zn on the treatment of vitiligo. The patients in two equal randomized groups took TCS and combination of oral zinc sulfate-TCS and showed a mean response of 21.43% and 24.7%, respectively, which was not statistically significant. However, it is to be highlighted that, normal reference range of Zn was not mentioned in any of these studies.

In our study, mean serum levels of Cu were significantly higher in cases than in controls. The findings of higher Cu levels in cases corroborated with the study by Helmy et al.[9] where they were significantly higher in active vitiligo patients compared to controls but was in contrast to that of Bruske and Salfeld.[10] In addition, our study revealed no correlation between Zn and Cu in vitiligo patients and controls. Hence, the levels of these two elements are not interdependent on each other.

In a Chinese meta-analysis of 16 studies, by Zeng et al,[4] 14 studies evaluated serum Zn within which four studies reported no statistically significant difference in Zn levels between the vitiligo group and the healthy group, ten studies presented significant decrease and none found increased Zn levels. Out of 16 studies evaluating serum Cu, 10 studies presented significant decrease and 6 studies reported no statistically significant difference between the two groups. The metanalysis concluded that decreased levels of serum Cu and Zn generally exist in Chinese vitiligo patients. However, it is to be noted that the studies included in this meta-analysis belong to different regions in China and some of the studies themselves mention the variability in the levels due to geographical area and dietary habits. An account of this difference in determining the normal range has not been taken in this study. Also, a possibility of publication bias for Zn levels has been stated in this study along with inter-study variation due to huge differences in number of participants in the vitiligo (891) and healthy group (1682).

As for subgroups of vitiligo, four studies investigated them and indicated that their levels had no relationship with skin lesions, disease course, progression, damaged skin areas or age of vitiligo. One study showed lower serum levels of Zn in generalized vitiligo and younger patients, but no differences in serum levels of Cu[4] Also, in our study, their levels showed no significant correlation with the age of the patients at presentation, diet (Vegetarian/Non-Vegetarian), duration of disease, type of vitiligo, VASI and VIDA scores. Moreover, no significant correlation of Zn and Cu levels with the disease activity (Stable/Unstable) was observed in our study which is in contrast to the observations by Helmy et al.[9] as mentioned above. Among other studies, Haider et al.[8] showed no significant relationship between serum Zn levels and age. However, Shameer et al.[11 showed the levels of serum Zn were low in the majority of the patients with duration of disease ranging from 2 to 5 years. Also, in this study, of the 40 patients with mucosal involvement, 8 (20%) patients had reduced Zn levels and out of the 13 patients with reduced Zn levels, 6 patients had unstable vitiligo.

Driven by the oxidative stress theory and on the basis of previous studies by Yaghoobi et al.[13]and Tsiskarishvili,[14] Zn and Cu supplementation has become a common practice in the treatment of vitiligo. Some researchers suggest that the treatment with Cu and Zn in skin diseases could be successful in cases of primary Cu and Zn deficiency but the effectiveness of oral Cu and Zn supplements could be limited if they were in a sufficient amount in the body.[15]Also as mentioned before, in the study by Yaghoobi et al.[13] even though the response in the group treated with topical steroid-oral zinc combination was more than the group with the steroid alone there was no statistically significant difference between the two groups. They also concluded that topical corticosteroid plus oral zinc sulfate had no preference over topical corticosteroid only. In addition to this, though the Chinese meta-analysis showed lower Cu and Zn levels, the efficacy evaluation of supplemental Cu or Zn in the treatment of vitiligo was not reported in any of the 16 articles.[4] Despite no evidence, the supplementation with Zn has been advocated in a large way in vitiligo patients especially in India and other developing countries.


  Conclusion Top


So far our study is the largest cross-sectional study to evaluate serum zinc and copper levels in vitiligo. Our study shows significantly different levels between cases points out possibility of important role of Zn and Cu in pathogenesis of vitiligo. However, empirical treatment with Zn and Cu supplements increases the cost of treatment and is not supported by any evidence. Also, for further studies to evaluate these levels in serum of patients, a normal reference range for the specific population has to be defined and taken into consideration. More studies are required to clarify role of Zn and Cu as well as other antioxidants in pathogenesis and treatment of vitiligo considering the various nutritional and environmental factors.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Kyriakis KP, Palamaras I, Tsele E, Michailides C, Terzoudi S. Case detection rates of vitiligo by gender and age. Int J Dermatol 2009;48:328-9.  Back to cited text no. 1
    
2.
Kruger C, Schallreuter K. A review of the worldwide prevalence of vitiligo in children/adolescents and adults. Int J Dermatol 2012;51:1206-12.  Back to cited text no. 2
    
3.
Alikhan A, Felsten LM, Daly M, Petronic-Rosic V. Vitiligo: a comprehensive overview Part I. Introduction, epidemiology, quality of life, diagnosis, differential diagnosis, associations, histopathology, etiology, and work-up. J Am Acad Dermatol 2011;65:473-91.  Back to cited text no. 3
    
4.
Zeng Q, Yin J, Fan F, Chen J, Zuo C, Xiang Y et al. Decreased copper and zinc in sera of Chinese vitiligo patients: a meta-analysis. J Dermatol 2014;41:245-51.  Back to cited text no. 4
    
5.
Bagherani N, Yaghoobi R, Omidian M. Hypothesis: zinc can be effective in treatment of vitiligo. Indian J Dermatol 2011;56:480-4.  Back to cited text no. 5
[PUBMED]  [Full text]  
6.
Njoo MD, Das PK, Bos JD, Westerhof W. Association of the Kobner phenomenon with disease activity and therapeutic responsiveness in vitiligo vulgaris. Arch Dermatol 1999;135:407-13.  Back to cited text no. 6
    
7.
Hamzavi I, Jain H, McLean D, Shapiro J, Zeng H, Lui H. Parametric modeling of narrowband UV-B phototherapy for vitiligo using a novel quantitative tool: the Vitiligo Area Scoring Index. Arch Dermatol 2004;140:677-83.  Back to cited text no. 7
    
8.
Haider N, Islam M, Al Maruf A, Shohag M, Ali R, Rahman G et al. Oxidative stress and antioxidant status in vitiligo patients. Dhaka University Journal of Pharmaceutical Sciences 2010;9:103-8.  Back to cited text no. 8
    
9.
Helmy M, Gayyar E, Hawas S. Role of oxidative stress in the pathogenesis of vitiligo. J Pan-Arab League Dermatologist 2004;15:97-105.  Back to cited text no. 9
    
10.
Bruske K, Salfeld K. Zinc and its status in some dermatologic diseases − a statistical assessment. Z Hautkr 1987;62:125-31.  Back to cited text no. 10
    
11.
Shameer P, Prasad P, Kaviarasan P. Serum zinc level in vitiligo: a case-control study. Indian J Dermatol Venereol Leprol 2005;71:206-7.  Back to cited text no. 11
[PUBMED]  [Full text]  
12.
Arora PN, Dhillon KS, Rajan SR, Sayal SK, Das AL. Serum zinc levels in cutaneous disorders. Med J Armed Forces 2002;58:304-6.  Back to cited text no. 12
    
13.
Yaghoobi R, Omidian M, Bagherani N. Comparison of therapeutic efficacy of topical corticosteroid and oral zinc sulfate-topical corticosteroid combination in the treatment of vitiligo patients: a clinical trial. BMC Dermatol 2011;11:7.  Back to cited text no. 13
    
14.
Tsiskarishvili N. Cuprum sulfate and vitix in the treatment of vitiligo in children. Georgian Med News 2005;48-51.  Back to cited text no. 14
    
15.
Leyh F. Zinc − a new therapeutic principle in dermatology? Z Hautkr 1987;62:1064, 9-72, 75.  Back to cited text no. 15
    


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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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