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Abstract:
Background: The etiology of vitiligo is still unknown. So there
are many hypotheses to explain its pathogenesis like genetic, autoimmune,
neural, biochemical, auto-cytotoxic and oxidative stress theories. Oxidative
stress is a disorder in pro and anti-oxidants balance in which pro-oxidants
predominate; also it is a factor that initiates pathogenesis of melanocytes’
degeneration. Objective: The aim of the present work was to study the
impact of some oxidative stress markers in the pathogenesis of vitiligo.
Patients: The study was carried out on 20 vitiligo patients and 10 controls
with matched age and sex. Methods: Estimation of some markers of oxidative
stress as nitric oxide (NO), Malondialdehyde (MDA), superoxide dismutase
(SOD) and of glutathione peroxidase activity (GPx) in the blood and tissue
of vitiliginous patients compared to controls. Results: the level of
oxidative stress was more obvious in the vitiliginous lesion than that of
the systemic circulation. Conclusions: From the results of this study, we
can depend on measurement of oxidative stress in the affected skin rather
than the plasma. Introduction:
Vitiligo is an acquired cutaneous disease
characterized by pearly white patches of variable shapes and sizes that have
a tendency to increase in size centrifugally [1].
It usually begins in childhood or early adulthood but in most of the cases
it occurs before 20 years of age and the incidence decreases with increasing
age [1,2].
It affects 0.5 to 2% of the world's population [1,3]
with no sex predilection but usually women are more affected than men
because of their greater medical attention for cosmetic problems [4].
The clinical picture consists of one or more well demarcated white macules
or patches progressing in size and number and they are generally
asymptomatic [2,5].
The diagnosis of vitiligo is mainly clinical by the presence of achromatic
macules and normal skin coexisting in the same individual [1,2].
Wood’s light; which is a lamp of 35 nm causes a bluish white fluorescence in
the affected skin [5]. The etiology is
still unknown so there are several hypotheses concerning the pathogenesis of
vitiligo: genetic, autoimmune, neural, auto-cytotoxic, biochemical and
oxidative stress theories [1,2,3,4,5]
In general oxidative stress is caused by an imbalance between the production
of reactive oxygen and a biological system's ability to readily detoxify the
reactive intermediates or easily repair the resulting damage [6,7].
Reactive oxygen species (ROS) are produced as byproducts of melanogenesis in
melanocytes, and controlled in the epidermis by several antioxidant enzymes
such as catalase and glutathione peroxidase [6,8,9].Oxidative
stress is thought to be the initial pathogenic event in melanocyte
destruction [10]. In oxidative stress,
there is insufficient antioxidant activity leading to excessive accumulation
of free radicals, which damage cellular compounds such as proteins,
carbohydrates, DNA and lipids. Vitiligo is accompanied by oxidative stress
where there is overproduction of H2O2 that is cytotoxic to melanocytes by
several mechanisms [11,12,13].
Aim of the work:
The aim of the present work was to study the impact of
some oxidative stress markers in the pathogenesis of vitiligo. Patients:
The study was carried out on 20 patients with vitiligo and 10 controls with
matched age and sex. The twenty patients (Group I) with vitiligo were
attending the dermatology outpatient clinic of the main Alexandria
University Hospital and the ten control subjects (Group II) were chosen
without any clinical evidence or family history of vitiligo or history of
any autoimmune disease (attending the out patient clinic of surgical
department of the main Alexandria University Hospital to do minor surgical
procedures). Patients with the following criteria were excluded from the
study: patients with any concomitant dermatological diseases, history of the
use of any topical or systemic treatment for vitiligo at least for a
previous month, active and passive smokers, history of intake of vitamins
and anti-inflammatory drugs at least for a previous month, history of
chronic liver, kidney or cardiovascular disease, history of excessive
exercise apart from daily life activities and pregnancy. Methods:
After
obtaining consent from the participants, Blood samples as well as skin
specimens were taken from patients and control groups and it was immediately
carried in an ice box to the Department of Biochemistry, and were subjected
to the following: estimation of nitric oxide (NO) (one measure for cellular
oxidants) by colorimetric determination of nitrite [13,14],
estimation of malondialdehyde (MDA) (a measure for lipid peroxidation) by
colorimetric method [13,15],
estimation of superoxide dismutase (SOD) (antioxidant enzyme) activity by
colorimetric method [13,16]
and estimation of glutathione peroxidase activity (GPx) (antioxidant enzyme)
by spectro-photometric method [13,17].
Statistical Analysis:
The statistical analysis was performed by using
Student t test. The differences were considered significant when P < 0.05.
Results:
The study sample constituted from 20 vitiligo patients attending
the dermatology outpatient clinic of Alexandria University Hospital and 10
control subjects with no history of vitiligo or any other autoimmune
disease. Mean studied age of vitiligo patients was 44.10 ± 13.42 (range
23-67 years) and that of controls was 41.50 ± 10.56 (range 23-56 years) and
by using t-test there was no significant difference (t=0.534, p=0.598).
Nearly half of the sample were females (11 cases, 55%) and 9 were males
(45%) and also the control group consisted of 6 females (60%) and four males
(40%); so the two groups were age and sex matched. When vitiligo patients
were classified according to Fitzpatrik classification of skin types, 7
cases (35%) were skin type III and 13 cases (65%) were skin type IV, All
cases showed an insidious onset. The duration of the disease ranged from
four months to 50 years with a mean and SD of 12.80 ± 15.56. Comparison of
vitiligo patients according to the duration of lesion showed that five
patients (25%) had recent lesions ranging from one month to one year, five
patients (25%) had old lesions ranging from one year to three years and 10
patients (25%) had older lesions for more than three years. Comparison of
vitiligo patients according to stability of the disease showed that 16 cases
were progressive (70%) and four cases were stable (30%). As regards
precipitating factors, 18 cases (90%) gave history of stress in the form of
life stress as loss of money, job and death of a close relative. Five
cases (25%) complained that exposure to the sun worsens and inflames their
disease. Nineteen cases (95%) were generalized and only one case (5%) was
localized. The majority of cases (13 cases, 65%) showed a negative family
history of vitiligo and the remaining 7 cases (35%) showed a positive family
history. Nitric Oxide (NO): one measure for cellular oxidants Nitric
oxide was measured as its metabolite nitrite. Plasma concentration level in
vitiligo patients (Group I) ranged from 1.02- 9.43 µmol/L with a mean value
of 3.82 ± 2.75 µmol/L, while plasma concentration level in control group
(Group II) ranged from 1.43- 13.52 µmol/L with a mean value of 7.10 ± 3.67
µmol/L. Concentration of nitrite in skin specimen of vitiligo patients
(Group I) ranged from 1.08-7.29 µmol/mg protein with a mean value of 3.65 ±
2.13 µmol/mg protein while its concentration in skin specimen of control
group (Group II) ranged from 0.02- 5.35 µmol/mg protein with a mean value of
2.79 ± 1.78 µmol/mg protein. Comparison between the mean values of nitrite
in skin specimens of the two studied groups showed an increased value in
vitiligo patients compared to control but statistical comparison using
t-test [t=1.094,P=0.283] showed no significant difference. Malondialdehyde
(MDA): a measure for lipid peroxidation Plasma concentration level in
vitiligo patients (Group I) ranged from 1.62- 8.04 nmol/ml with a mean value
of 4.66 ± 1.82 nmol/ml, while plasma concentration level in group II ranged
from 3.30- 7.84 with a mean value of 5.45 ± 1.30 nmol/ml. Statistical
comparison between the mean values of plasma in the 2 studied groups using
t- test [t=1.213,P=0.235] showed no significant difference in MDA level.
Concentration level of MDA in skin specimen of vitiligo patients (Group I)
ranged from 2.03- 11.14 nmol/mg protein with a mean value of 5.10 ± 2.28
nmol/mg protein, while concentration level in skin specimen of control group
(Group II) ranged from 1.34- 5.50 nmol/mg protein with a mean value of 3.31
± 1.22 nmol/mg protein. Statistical comparison between the mean values of
concentration in skin specimens of the two studied groups using t-test
[t=2.319,P=0.028] showed a significant increase in vitiligo patients
compared to the control group. Superoxide dismutase (SOD): antioxidant
enzyme Plasma concentration level in vitiligo patients (Group I) ranged
from 10.14-96.28 with a mean value of 43.16 ± 28.48 U/ml, while plasma
concentration level in control group (Group II) ranged from 20.27- 81.08
U/ml with a mean value of 54.15 ± 21.72 U/ml. Statistical comparison between
the mean values of plasma of the two studied groups using t- test
[t=1.072,P=0.293] showed no significant difference. Concentration level of
SOD in skin specimen of vitiligo patients (Group I) ranged from 27.64 -
155.93 U/mg protein with a mean value of 83.98 ± 43.99 U/mg protein, while
concentration level of SOD in skin specimen of control group (Group II)
ranged from 41.93-176.08 U/mg protein and on statistical comparison between
the mean values of SOD of the two studied groups using t-test
[t=1.799,P=0.083] showed no significant difference. Glutathione peroxidase
(GPx): antioxidant enzyme Plasma concentration level of vitiligo patients
(Group I) ranged from 19.45-97.27 mU/ml with a mean value of 50.44 ± 27.14
mU/ml, while plasma concentration level in control (Group II) ranged from
19.45 – 58.36 mU/ml with a mean value of 38.42 ± 14.22 mU/ml. Comparison
between the mean values of plasma GPx of the two studied groups showed an
increase in patients compared to control group but statistical comparison
using t-test [t=1.592,P=0.123] showed no significant difference.
Concentration of GPx in skin specimen of vitiligo patients (Group I) ranged
from 15.82 - 97.27 mU/mg with a mean value of 46.33 ± 23.07 mU/mg protein,
while its concentration in skin specimen of control group (Group II) ranged
from 15.82-51.65 mU/mg protein with a mean value of 31.54 ± 14.79 m/mg
protein. Comparison between the concentration levels of GPx in skin
specimens of the two studied groups showed an increase in patients compared
to control group but statistical comparison using t-test [t=1.838,P=0.077]
showed no significant difference . Discussion:
The etiology of vitiligo
is still unknown. So there are many hypotheses to explain its pathogenesis.
One of the hypotheses to explain vitiligo is the self- destructive theory of
melanocytes, which suggests a role for oxidative stress [6,7,8,9,10].
Oxidative stress is thought to be the initial pathogenic event in melanocyte
destruction [7,18].
This is why in this study it was decided to measure the levels of two
antioxidants (SOD, GPx), an oxidant (NO), and a product of lipid
peroxidation (MDA) both in plasma and in skin specimens of vitiligo patients
to evaluate the role of oxidative stress in the pathogenesis of vitiligo.
Nitric oxide (NO) Nitric oxide (NO) is a free radical that is generated in
cells from L-arginine by nitric oxide synthetase (NOS) enzymes [19].
It was recorded that there is an increase in NOS in inflammatory conditions
and this contributes to the cytotoxic action of inflammatory cellular
infiltrates around normal human melanocytes [20,21].
The present study revealed an increase in the level of Nitrite in patients
than control when measured in skin specimen while the plasma level is more
in control than in patients. Other studies showed higher levels of NO in
patients compared to control group as Koca and Armatcu [22],
Yildirim et al [23] and Hazneci and
karabalut [24] who found higher serum NO
levels in generalized vitiligo and this was explained by the fact that NO
could lead to auto-destruction of normal human melanocytes [25]
and also due to the fact that the production of NO species reduced the
attachment of melanocytes to the extracellular matrix leading to
depigmentation [20]. Moreover, NOS requires
tetrahydrobiopterin (BH4) as a co-factor in the synthesis of NO and as in
vitiligo, there is accumulation of 6BH4 [26].
It might be responsible for the high NOS activity and therefore high levels
of NO. Also, NO is a free radical and inherently reactive and mediate
cellular toxicity by damaging critical metabolic enzymes and by reacting
with O2- to form an even more potent oxidant, peroxynitrite (ONOO-) [24].
So, NO plays a major role as a triggering agent in the patho-physiology of
vitiligo especially when elevated in the skin rather than in the plasma.
Malondialdehyde (MDA) MDA is an end-product of lipid peroxidation induced
by reactive oxygen species (ROS). It is well correlated with the degree of
lipid peroxidation and is an indicator of oxidative stress [13].
The present study revealed no significant difference in the level of MDA
when measured in plasma between vitiligo patients and control group. However
in skin specimen, there was a significant increase in vitiligo patients
compared to control group. This increase indicates high level of lipid
peroxidation due to exposure of ROS in vitiliginous lesion than that in the
systemic circulation. In agreement with this result, Picardo et al [27]
found normal serum MDA level in combined types of vitiligo. However other
studies showed higher serum MDA in patients compared to control as Yousry et
al [28] and Yildirim et al [23].
Yildirim et al [13] and Dammak et al [29]
found statistically significant high levels of MDA in tissues of vitiligo
patients compared to control group and they explained this that it is a
condition of oxidative stress. Moreover, Dammak et al added that lipid
peroxidation in the cellular membrane of melanocytes may play an important
role in the rate of depigmentation observed in the skin of patients with
active vitiligo. Superoxide dismutase (SOD) Superoxide dismutase (SOD)
is a group of metallo-enzymes that scavenges superoxide radicals and reduces
their toxicity. It is an antioxidant that dismutates the O2- anion to form
O2 and H2O2 [30]. The present study
revealed a decrease in the level of SOD in vitiligo patients than control
group both in plasma and skin specimens but this decrease was statistically
insignificant. Such decrease may be due to its utilization in detoxication
of released ROS (superoxide anion). In agreement with the present study,
Koca et al [30], found significantly lower
levels of serum SOD activity in vitiligo patients compared to healthy
control. They explained this by the fact that superoxide and hydroxyl
radicals are the most important radicals in peroxidation and decreased SOD
activity could be responsible for the increase of superoxide radicals which
may explain the increased level of MDA [30].
However, Picardo et al [27] and Passi et al
[31] reported that there were no
differences in the levels of erythrocyte SOD activity in patient with active
vitiligo versus control. On the other hand, many studies showed an increase
in SOD in erythrocytes [25], in peripheral
mononuclear cells [32], in the serum [23]
and in whole blood [33] in vitiligo
patients. They suggested that the increased SOD activity in vitiligo
patients might be an adaptation to the increased oxidative stress evident in
these individuals and their result suggested that prominent oxidative
stress, particularly in the presence of high levels of O2- levels leads to
high levels of SOD followed by high amounts of H2O2. High levels of
H2O2 and
O2- might result in destruction of defective melanocytes in vitiligo
patients. Moreover, another study was done to compare segmental and non
segmental vitiligo, they found significantly higher erythrocyte SOD activity
in both types of vitiligo patients compared with control with no significant
change in segmental compared with non-segmental vitiligo. [13,29,34,35,36]
In addition, other study showed high levels of SOD in vitiliginous and non
vitiliginous skin of vitiligo patients than the levels of normal skin of
control. They stated that these results supported the role of oxidative
stress in the pathogenesis of vitiligo and indicated that oxidative stress
is not a localized phenomenon but a more generalized process. This may be
one of the explanations for developing newer lesions in vitiligo patients in
the course of the disease [37].
Glutathione peroxidase (GPx) Glutathione peroxidase (GPx) is another
antioxidant that converts H2O2 and other peroxides into H2O. Also it
catalyzes the reduction of hydroperoxides in the presence of glutathione [38].
It protects the membranes and essential proteins from potential damaging
effect of reactive oxygen and lipid peroxide [39].
The present study revealed an increase in the level of GPx in plasma and
skin specimens of vitiligo patients compared to control group. This increase
is in order to face the increased level of ROS (hydrogen peroxide and lipid
peroxide) that has been produced in vitiligo. In agreement with this
study, another study showed statistically significant increase in the level
of plasma GPx in vitiligo patients compared to control group [40].
However some studies showed no significant difference between vitiligo
patients and control in plasma level of GPx [24,30,31,33]
and other studies showed a significant decrease in the level of plasma GPx
in vitiligo patients compared to controls [36,40,41].
Agrawal et al [42] explained that low
levels of GPx in vitiliginous patients neutralizes lipid hydroperoxides
which could lead to oxidative stress. Also, Yousry et al [28]
added that GPx has a higher affinity for H2O2. So GPx activities may be
decreased in vitiligo patients to compensate the increase in free radicals
and H2O2. Furthermore Hasse et al [43]
reported that the accumulation of millimolar concentrations of H2O2 leads to
affection of antioxidant enzymes as proved by low blood GPx activity of
vitiligo patients regardless their age group. Also Agrawal et al [29]
and Beazley et al [44] found low
erythrocytes and serum GPx activity in vitiligo patients without significant
difference among different age groups. In skin specimens, the study
revealed an increase in level of GPx in vitiligo patients compared to
control group. In agreement with results obtained in this study, Yildirim
et al [13] who found significantly higher
levels of GPx in the tissues of patients with generalized vitiligo compared
to control group. However, another study showed lower levels of GPx in the
epidermis of both lesional and non-lesional skin of vitiligo patients [24]
and during active phases of vitiligo indicating an imbalance of antioxidants
in the epidermis of vitiligo patients [45].
In this study, it was found that there was no relation between oxidant/
antioxidant parameters and skin types, stability or duration of the disease,
family history or effect of stress and sun exposure. Conclusions:
•
Oxidative stress has a role in the pathogenesis of vitiligo • From the
results of this study, the level of oxidative stress was more obvious in the
vitiliginous lesion than that of the systemic circulation so we can depend
on measurement of oxidative stress in the affected skin rather than the
plasma. • An important question may be raised, such imbalance between
oxidants and antioxidants mechanisms, is it a primary etiological factor or
secondary to other possible etiological factors for development of vitiligo?
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