doi: 10.1111/1346-8138.

12392 Journal of Dermatology 2014; 41: 245–251

ORIGINAL ARTICLE
Decreased copper and zinc in sera of Chinese vitiligo
patients: A meta-analysis
Qinghai ZENG,1 Jun YIN,2 Fan FAN,2 Jing CHEN,1 Chengxin ZUO,1 Yaping XIANG,1
Lina TAN,1 Jinhua HUANG,1 Rong XIAO3
1
Department of Dermatology, Third Xiangya Hospital, 2Xiangya Hospital, and 3Department of Dermatology, Second Xiangya Hospital,
Central South University, Changsha, China

ABSTRACT
Abnormalities of copper (Cu) and zinc (Zn) are involved in the etiology and pathogenesis of vitiligo. However, con-
troversial results exist now on Cu and Zn in serum of vitiligo patients. The purpose of this study is to compare
the serum levels of Cu and Zn between vitiligo patients and healthy controls. In the meta-analysis, 16 studies with
a total of 891 vitiligo cases and 1682 healthy controls were included. The levels of serum Cu and Zn were com-
pared between groups of case and control. The serum levels of Cu were significantly lower in vitiligo patients
than in healthy controls (Z = 4.04, P < 0.0001; standardized mean difference [SMD], 0.9; 95% confidence interval
[CI], 1.34 to 0.47). The levels of serum Zn were also significantly lower in vitiligo patients than in healthy con-
trols (Z = 4.88, P < 0.00001; SMD, 1.09; 95% CI, 1.51 to 0.64). These results demonstrate that decreased levels
of serum Cu and Zn are generally present in Chinese vitiligo patients. This may offer support for clinical adminis-
tration of oral Cu and Zn supplements.

Key words: copper, meta-analysis, vitiligo, zinc.

INTRODUCTION Copper and Zn are important trace elements related to

Vitiligo is a common pigmentary skin disorder occurring world-
wide. It is characterized by acquired, idiopathic, progressive
and circumscribed hypomelanosis on different parts of the
body.1 A recognizable absence of functional melanocytes was
observed histochemically in the skin, hair, mucous membranes
and the retina.2 Vitiligo not only leads to poor appearance but
also results in low self-esteem and difficulties in sexual rela-
tionships or social activities.3
The incidence rate is between 0.1% and 8.8% worldwide,
and people with racially pigmented skin may have a higher
incidence.4–6 Vitiligo begins in childhood or young adulthood,
but it can develop at any age. It is rarely observed/reported in
infancy or old age.4 Tonsi7 found that the incidence decreases
with increasing age. There is no obvious difference between
males and females.6
The exact etiology and pathogenesis of vitiligo is not com-
pletely understood. Autoimmunity, self-destruction of melano-
cytes, nerve-chemical factors, genes and oxidative stress are
popular hypotheses considered.8–11 It seems that dysfunction
of the immune and neuroendocrine systems are induced by
various internal and external factors in individuals or heritable
biological properties, resulting in depigmentation of skin by
destruction of melanocytes or inhibition of tyrosinase.6
health and disease. Abnormalities of Cu and Zn are involved in
the etiology and pathogenesis of vitiligo. First, Cu and Zn are
integral parts of many metalloenzymes necessary in the pro-
cess of melanogenesis. During the final stage of eumelanin for-
mation in melanogenesis, those metalloenzymes catalyze the
rearrangement of dopachrome to form 5,6-dihydroxy indole-2
carboxylic acid and the enhancement of eumelanin polymer
formation from monomers.12,13 Second, Cu and Zn are consid-
ered as antioxidants, being constituents of superoxide dismu-
tase, protecting the body against cytotoxicity of melanocytes
and inhibition of tyrosinase in oxidative stress.14 Decreased
serum Cu and Zn levels have been reported in vitiligo by some
investigators;15–17 while others have contradicted these find-
ings.18–20 Such a controversy motivated us to carry out this
study to explore the change of serum levels of Cu and Zn
among Chinese vitiligo with meta-analysis.
METHODS
Selection
Materials published in English or Chinese (from 1988 to June
2013) were extracted from the citations listed in the following
databases: (i) PubMed; (ii) Web of Science; (iii) Ovid; (iv)
EMBASE; (v) Cochrane library; (vi) the Chinese National

Correspondence: Jinhua Huang, M.D., Ph.D., Department of Dermatology, Third Xiangya Hospital, Central South University, 138 Tongzipo
Road, Changsha, Hunan 410000, China; Rong Xiao, M.D., Ph.D., Department of Dermatology, Second Xiangya Hospital, Central South Univer-
sity, 139 Renmin Road, Changsha, Hunan 410000, China. Emails: huangjinhua60@126.com and xiaorong65@aliyun.com
Received 23 September 2013; accepted 9 December 2013.

© 2014 Japanese Dermatological Association 245

Q. Zeng et al.
Knowledge Infrastructure; (vii) Wan Fang Med Online; (viii) Chi-
nese Biology Medical Literature Database; and (ix) VIP Data-
base. Key search terms included: “vitiligo/cutaneous disorder/
dermatologic disease”, “trace element/biometal”, “copper” and
“zinc”. We also reviewed the references cited in the studies
and review articles to check the missed studies.
Inclusion criteria
All the studies were limited to the following inclusion criteria: (i)
study subjects were all Chinese; (ii) vitiligo cases were diag-
nosed by typical clinical manifestations; (iii) Cu or Zn level was
detected in sera; and (iv) subjects were reported in case and
control group, or vitiligo and healthy group. Data from both
groups were calculated. The most recent publication was
selected if the identical sets of data were reported in more
than one manuscript. All identified studies were carefully
reviewed by two investigators to decide whether an individual
study met the inclusion criteria.
Data extraction
After the overlapped studies were excluded, two investigators
collected the data independently and assessed the data to
reach a consensus on all items. The basic information
extracted from the quantified article was as follows: first
author, year of publication, number of subjects, mean level of
Cu or Zn, standard deviation and journal. When it came to con-
flicting results, we sought information from the primary studies
or asked the third investigator for help.
Statistical analysis
All articles included were combined in meta-analysis using
Review Manager 5.1 developed by the Cochrane Collabora-
tion.21 The standardized mean difference (SMD) and 95% con-
fidence intervals (CI) were calculated. Heterogeneity among
studies was examined by the inconsistency index (I2) test. The
fixed effect model and the random effect model were chosen
as the result of I2-test. If there was a statistical difference in
terms of heterogeneity (I2, <50%), a fixed effect model was
adopted as the pooling method. Otherwise, a random effect
model was used. The significance of pooled SMD was deter-
mined by the Z-test, and statistical significance for all tests
and models was a two-tailed P < 0.05. Possible publication
bias was determined by using Begg test and Egger test with
STATA version 12.0 software (STATA, College Station, TX,
USA; publication bias was thought to be absent if the P-value
of Begg test or Egger test was >0.05). Influence analysis was
performed to investigate the influence of a single study on the
overall meta-analysis estimate with STATA version 12.0 soft-
ware; it showed graphically the results of an influence analysis,
in which the meta-analysis estimates were computed, omitting
one study in each turn.
RESULTS
Eligible studies
We identified 174 studies using our search strategy. In the
end, as shown in Figure 1, 16 articles were finally qualified for
246
174 articles indentified
through database search
(Article in Chinese = 152;
Article in English = 22)
Articles excluded:
Obviously irrelevance (n = 75)
Articles screened (n = 99)
Articles excluded:
Relevant articles searched Review or case report or other
from the references (n = 6) no case-control study (n = 44)
Cu or Zn was not detected in
Full-text of the articles serum of human (n = 30)
accessed for potential
eligibility (n = 31)
Articles excluded:
Not from Chinese (n = 5)
Insufficient data (n = 5)
Duplicated publication (n = 3)
Articles included in the Only subgroup analysis (n = 2)
meta-analys is (n = 16)
Figure 1. Flow diagram of article selection. A total of 16 arti-
cles were finally selected for the meta-analysis.
the meta-analysis. The characteristics of included studies are
presented in Table 1.
Levels of serum Cu
Of the 16 studies that detected the serum Cu level, six stud-
ies24,25,28,32,34,37 reported no statistically significant Cu level
change between the vitiligo group and the healthy group. The
others presented significant decrease of Cu level in the vitiligo
group. Heterogeneity among the 16 articles was examined first.
The results revealed a high statistical heterogeneity among
studies (s2 = 0.74; v2 = 271.38, d.f. = 15 [P < 0.00001];
I2 = 94%). Then, a random effect model was used for meta-
analysis. In the pooled analysis, there was a significant
decrease of Cu level in the vitiligo group (Z = 4.04; P < 0.000;
SMD = 0.9; 95% CI, 1.34 to 0.47; Figure 2).
Levels of serum Zn
Of the 14 studies that detected the serum Zn level, four
studies22,28,33,37 reported no statistical significant Zn level
change between the vitiligo group and the healthy group.
The others presented significant decrease of Zn level in the
vitiligo group. Heterogeneity among the 14 articles was also
examined first. The results revealed a high statistical hetero-
geneity among studies (s2 = 0.61; v2 = 199.83, d.f. = 13
[P < 0.00001]; I2 = 93%). Then, a random effect model was
used for meta-analysis. In the pooled analysis, there was
significant decreasing of Zn level in the vitiligo group
(Z = 4.88 [P < 0.00001]; SMD = 1.09; 95% CI, 1.51 to
0.64; Figure 3).
Publication bias
The Begg test and Egger test were used to assess the possi-
bility of publication bias with STATA version 12.0 software. No
significant publication bias was observed in both tests for main
summary estimate for serum Cu levels (Begg, P = 0.224;
Egger, P = 0.251). However, the results showed that there may
be publication bias for the main summary estimate for serum
Zn levels (Begg, P = 0.055; Egger, P = 0.05).
© 2014 Japanese Dermatological Association
 Decreased serum Cu and Zn in vitiligo

Table 1. General characteristics of the 16 selected studies for meta-analysis

Detected in serum
Sequence of First Total Vitiligo Healthy
reference author Year cases (n) group (n) group (n) Cu Zn Both
22 Wang 2012 240 120 120 Y
23 Yao 2011 140 90 50 Y
24 Wang 2011 58 28 30 Y
25 Wu 2010 140 70 70 Y
26 Wang 2007 88 68 20 Y
27 Gu 2005 66 30 36 Y N
28 Kang 2002 64 30 34 Y
29 Li 2001 126 96 30 Y N
30 Tan 1997 787 37 750 Y
31 Zhou 1996 46 26 20 Y
32 Wang 1996 189 48 141 Y
33 Wang 1993 64 30 34 Y
34 Shi 1993 270 120 150 Y
35 Tu 1991 63 27 36 Y
36 Chen 1989 90 60 30 Y
37 Li 1988 142 7 135 Y

Y, yes; N, no.

Figure 2. Meta analysis of the serum Cu level between the two groups. Compared with the control, there was a significant
decrease of Cu level in the vitiligo group (Z = 4.04, P < 0.0001; standardized mean difference, 0.9; 95% confidence interval [CI],
1.34 to 0.47). SD, standard deviation.

Influence analysis DISCUSSION

As shown in Figure 4, no individual study was found having
Copper and Zn are essential trace elements involved in
excessive influence on the pooled effect with STATA version
many biochemical processes, such as cellular respiration,
12.0 software. Each line shows the pooled effect of the remain-
DNA and RNA reproduction, maintenance of cell membrane
ing studies after deleting one single study with the correspond-
integrity and sequestration of free radicals.38 The abnormali-
ing line.

© 2014 Japanese Dermatological Association 247

Q. Zeng et al.

Figure 3. Meta analysis of the serum Zn level between the two groups. Compared with the control, there was a significant
decrease of Zn level in the vitiligo group (Z = 4.88, P < 0.00001; standardized mean difference, 1.09; 95% confidence interval [CI],
1.51 to 0.64). SD, standard deviation.

(a) (b)

Figure 4. Influence analysis of the serum Cu level among 16 articles (a), and the serum Zn level among 14 articles (b). No individual
study was found to have excessive influence on the pooled effect. CI, confidence interval.

ties of Cu and Zn participate in the pathogenesis of many dermatitis enteropathica, bullous pemphigoid, decubitus
skin diseases. Numbers of studies have suggested that ulcer, alopecia areata, psoriasis, skin cancer and viti-
alterations of Cu or Zn could be found in patients of acro- ligo.12,39–41

248 © 2014 Japanese Dermatological Association


The correlations between serum levels of Cu, Zn and vitiligo
are still controversial because apparent conflicting results have
been reported. In a study, Helmy et al.19 showed that serum
Zn and Cu levels were significantly higher in active vitiligo
patients compared to controls. The author thought that the
increased serum Zn and Cu levels came from the release of Zn
and Cu, led by increased apoptosis of peripheral blood mono-
nuclear cells in active vitiligo patients. Furthermore, melanins
are colloidal pigments and have a high affinity for metal ions;
therefore, Cu, Zn and other metal ions are found in high levels
in pigmented tissues involved in melanin synthesis. As melano-
cytes degenerate in vitiligo patients, less Cu and Zn are utilized
for the melanin synthesis, which consequently raise levels of
Cu and Zn in serum.12,19 In other studies, Arora et al.18 and
Haider et al.20 did not find significant alteration in serum Zn
level in vitiligo. This possibly supports the autoimmune theory
of vitiligo.
However, studies of Shameer et al.,15 Bru €ske and Salfeld,16
and Tsiskarishvili17 indicated that serum levels of Cu and Zn
decreased, which causes vitiligo. The roles of Cu and Zn are
mainly twofold: to promote melanogenesis and to provide a
physiological defense against oxidative stress.13 It is well
known that tyrosinase has a key role in pigmentation process.
Cu and Zn are both cofactors of this Cu/Zn-requiring enzyme.
Imbalance of the oxidant–antioxidant system plays an impor-
tant pathogenic role in vitiligo. It has been demonstrated that
deficiency of antioxidant substances could lead to high activity
of free radicals, which are cytotoxic to melanocytes and inhibit
tyrosinase.15 Cu and Zn are antioxidants involved in destruc-
tion of free radicals by constituting Cu/Zn superoxide dismu-
tase that catalyze the dismutation of reactive oxygen species
to O2 or H2O2.12 In addition, through this antioxidant-defense
mechanism, Cu and Zn could be potential anti-apoptotic
factors for protecting cell proteins from oxidation. Further-
more, Cu and Zn may play roles in stimulating cell-mediated
Table 2. Serum levels of Cu and Zn in different types of vitiligo
Indices of
Author detection Subgroups of vitiligo
Wang22 Cu and Zn Ages: ≤14 years (48) and >14 years (72)
Progressions: active vitiligo (56) and
stationary vitiligo (64)
Wu25 Cu and Zn Skin lesions: segmental vitiligo (52) and
generalized vitiligo (18)
Ages: ≤18 years (29) and >18 years (41)
Tan30 Cu and Zn Skin lesions: segmental vitiligo (11) and
vulgaris vitiligo (26)
Progressions: active vitiligo (32) and
stationary vitiligo (5)
Areas of skin lesion: ≤50% (32)
and >50% (5)
Chen36 Cu and Zn Skin lesions: segmental vitiligo (11),
distributing vitiligo (46) and generalized
vitiligo (3)
Disease courses: <1 year (15), 1–10
years (34), >10 years (11)
© 2014 Japanese Dermatological Association
Decreased serum Cu and Zn in vitiligo
immunity responses, synthesizing and releasing of melanocyte-
stimulating hormone, which are also important in melanogene-
sis.13,18
In this meta-analysis, 16 articles were included to compare
the serum levels of Cu and Zn between Chinese vitiligo
patients and healthy controls. Of the 16 articles, none pre-
sented significant increases in serum levels of Cu or Zn. It was
found that the serum levels of Cu and Zn are significantly lower
in vitiligo patients than healthy controls. Therefore, we con-
clude that decreased levels of serum Cu and Zn generally exist
in Chinese vitiligo patients. As for subgroups of vitiligo, of 16
articles, four studies22,25,30,36 investigated the serum levels of
Cu and Zn on the basis of vitiligo subgroups (Table 2). The
results of Wang et al.,22 Tan et al.,30 and Chen and Luo36 indi-
cated that the Cu and Zn serum levels had no relationship with
skin lesions, disease courses, progressions, damaged skin
areas or ages of vitiligo. Taking the results of our meta-analysis
into consideration, we proposed that deficiencies of Cu and Zn
have no relationship with subgroups of vitiligo. However, Wu
et al.’s research25 showed lower serum level of Zn in general-
ized vitiligo and younger patients, but no differences in serum
level of Cu. Therefore, more studies of large scale are needed
to confirm these findings.
It appeared that Cu and Zn supplements may be effective
in treating vitiligo. Tsiskarishvili17 found that treatment with
cuprum sulfate and vitix improved patients’ clinical condition in
56% infants with vitiligo. Jalel et al.42 reported therapeutic
success in terms of a clear repigmentation in 70% of treated
mice with supplementations of Zn and other antioxidants.
Yaghoobi et al.1 revealed that combination of Zn and topical
steroid was more effective than the topical steroid alone in the
treatment of vitiligo patients. Some researchers suggested that
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
Results
There were no differences of serum levels of Cu and Zn between
different ages and different progressions
The serum levels of Zn were significantly lower in generalized
vitiligo and younger patients, but no difference in serum levels
of Cu
There were no differences in serum levels of Cu and Zn between
different skin lesions, different progressions and different areas
of skin lesion
There were no differences in serum levels of Cu and Zn between
different skin lesions and different disease courses
249
Q. Zeng et al.
a sufficient amount in the body.43 Unfortunately, the efficacy
evaluation of supplemental Cu or Zn on the treatment of viti-
ligo was not reported whatsoever in any of the 16 articles. We
could not evaluate the effectiveness of oral Cu and Zn supple-
ments.
This meta-analysis is the first to provide pooled estimates of
the reported blood levels of Cu and Zn, focused on a Chinese
population. To our knowledge, no other such analyses have
been previously reported with regards to the Cu and Zn levels
in vitiligo patients. Our results indeed showed decreased levels
of serum Cu and Zn in vitiligo patients, but we could not con-
firm the roles played by Cu and Zn in the etiology and patho-
genesis of vitiligo. Additionally, the efficacy of Cu and Zn in the
treatment and the mechanism underlying their therapeutic
effect remain unclear. More studies are required to verify the
results and to assess the effect of oral Cu and Zn supple-
ments.
In this meta-analysis, no significant publication bias for
serum Cu level was observed. Nevertheless, possible publica-
tion bias may exist for serum Zn level. Publication bias is
derived from exclusion of results that are not published. We
specifically acknowledge the limitations and expect more stud-
ies; however, a possible publication bias does not affect the
main results. We also noticed that huge differences in the num-
ber of participants in the vitiligo and healthy groups (e.g. the
studies of Tan et al.30 and Li et al.)37 and high standard devia-
tions in Cu and Zn level (e.g. the studies of Zhou et al.31 and
Chen and Luo),36 which lead to partial inter-study variation. So,
influence analysis was performed to investigate the influence
of a single study on the overall analysis. The heterogeneities
were not changed significantly after exclusion of any single
study (data no shown). Furthermore, the corresponding pooled
SMD and 95% CI were not conspicuously altered with any sin-
gle study excluded (shown in Fig. 4). Therefore, the reliability
or stability of the results was enhanced by the influence analy-
sis in this analysis.
In conclusion, the meta-analysis demonstrates that
decreased levels of serum Cu and Zn generally exist in Chi-
nese vitiligo patients. It may support clinical administration of
oral Cu and Zn supplements. Further studies of higher quality
may lead to more solid conclusions.
ACKNOWLEDGMENTS: Thanks to the authors who made
detailed data available for this meta-analysis and our colleagues for
their hard work.
CONFLICT OF INTEREST: The authors have no conflicts
of interest.
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