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International Scholarly Research Network ISRN Dermatology Volume 2012, Article ID 405268, 8 pages doi:10.


Review Article The Newest Hypothesis about Vitiligo: Most of the Suggested Pathogeneses of Vitiligo Can Be Attributed to Lack of One Factor, Zinc-α2-Glycoprotein
Nooshin Bagherani
Nooshin Bagherani’s Office, 2nd Floor, Taha Physicians’ Building, 40-Meter Street, Khoramshahr, Khuzestan Province, Iran Correspondence should be addressed to Nooshin Bagherani, Received 15 March 2012; Accepted 18 April 2012 Academic Editors: E. Alpsoy, H. Takahashi, and A. Zalewska Copyright © 2012 Nooshin Bagherani. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Zinc-α2-glycoprotein (ZAG) is a recently identified adipokine, assigned to the chromosome 7q22.1. It is a multidisciplinary protein, which is secreted in various body fluids. The ZAG plays roles in lipolysis, regulation of metabolism, cell proliferation and differentiation, regulation of melanin synthesis, cell adhesion, immunoregulation, and so forth. Vitiligo is the most common depigmenting skin disorder, characterized by acquired, progressive, and circumscribed amelanosis of the skin and hair. It commonly begins in childhood or young adulthood. The pathogenesis of this disorder is uncertain, but it appears to be dependent on the interaction of genetic, immunological, and neurological factors. For the first time, we pointed the probable association between ZAG and vitiligo. Herein, I have described this association in different views. By confirming this association, a surprising progression will occur in the treatment of this prevalent debilitating disease.

1. Introduction of Zinc-α2-Glycoprotein
Zinc-α2-glycoprotein (ZAG), a recently identified adipokine [1–4], is a 41,000 Da glycoprotein, secreted by a variety of normal epithelia [5]. For the first time, this 41 kDa singlechain polypeptide [6] was reported in human serum and subsequently purified in 1961 [7]. It was named for its electrophoretic mobility and for its ability to be precipitated by zinc salts [8–10]. The gene of ZAG, assigned to the chromosome 7q22.1, comprises four exons and three introns [7]. Its first full polypeptide sequence was identified by Araki et al. [11]. The molecule of ZAG has three domains, named α1, α2, and α3 [7]. The amino acids of α1 and α2 domains are highly conserved [12], indicative of the functional importance of the groove in the biological functions. On the other hand, the α3 domain is less conserved, indicative of species specificity and evolutionary constrains [7]. The main function of ZAG gene is the decomposition of fat and reduced fat content [13]. The serum ZAG can easily be detected by tetramethylethylenediamine-enhanced photoluminescent imaging [14].

There is high degree of similarity between ZAG and antigen-presenting molecules such as class I MHC molecules both at sequence and structural levels. The ZAG is considered as a member of immunoglobulin gene superfamily [7] based on its structure so that its 2.8 angstrom crystal structure [15] has a large groove analogous to class I MHC peptide-binding grooves [7, 12, 15, 16]. Unlike other MHC molecules, ZAG is not membrane bound; so, it appears that its function is different from the peptide presentation and T-cell interaction functions of class I MHC [7, 17]. Moreover, instead of a peptide, the ZAG contains a nonpeptidic compound in the groove, which plays a role in lipid catabolism under normal and pathological conditions [15]. This structure of groove also reflects its role in immunoregulation [7]. Furthermore, it appears that ZAG is the sole soluble member of immunoglobulin gene superfamily that is implicated in cachexia [18]. The ZAG is a multidisciplinary protein, which is secreted in various body fluids [7] and is found to be ubiquitously and constitutively expressed [18]. Its presence and expression have normally been described in the following sites: normal human fluids such as serum, seminal fluid, saliva, sweat,

It appears that glucocorticoids induce β3-adrenoreceptor in adipocytes by which it amplifies the induction of ZAG expression [20]. kidney extract [7]. It has been shown that IFN-γ can strongly upregulate expression of ZAG in human epithelial cell lines [20. Regulation of ZAG Expression The gene expression of ZAG is predominately regulated by glucocorticoids [7. induction of lipolysis by corticosteroids can be attenuated by anti-ZAG antisera [7]. 19]. time-dependent decrease in body weight. The ZAG is closely related to obesity [2. 35]. they concluded that the downregulated ZAG expression in white fat depots at weaning. body mass index [2. In another study. Genetic studies have suggested that ZAG may be a candidate gene for body weight regulation [27]. In one study on mice. normal epidermal and buccal epithelia [7]. On the other hand. Tzanavari et al.2 milk. They showed that ZAG mRNA and protein levels fall significantly at weaning and thereafter. The ZAG is synthesized by adipocytes. The ZAG can stimulate energy utilization in adipose tissue and skeletal muscle by upregulation of UCP isoforms and GLUT4. At the end. 3. Interferon-γ (IFN-γ) is a potential mediator of the increased ZAG expression in cachexia. Findings have shown that ZAG can lead to phosphorylation of AMP kinase-α and ACC. ISRN Dermatology leptin. MCP-1. a major product of macrophages [25]. markers of renal function should be considered in studies on ZAG physiology [19]. 28]. 23]. The ZAG is responsible for cachexia or lipid catabolism seen in cancer patients [7. 25]. In mice it has been revealed that the action of ZAG is associated with downregulated lipogenic enzymes and upregulated lipolytic enzyme expression in adipose tissue [28]. The ZAG is known to promote lipolysis through stimulation of adenylate cyclase in a GTP-dependent process via binding through β3-adrenoreceptor [7. This body weight loss can entirely be attributed to the loss of body fat [21]. Biologic Roles of ZAG in Human 3. The ZAG is a natural adipocyte factor found in both white and brown adipose tissue [20]. It appears that renal filtration is an important route for eliminating ZAG. This effect is interestingly shown in gastrocnemius but not soleus muscle [36]. 29]. eicosapentaenoic acid can downregulate ZAG expression through interference with glucocorticoid signaling [23]. 33]. 21]. 25]. In one study. The ZAG can cause highly significant. On the 2. The findings suggest that induction of ZAG expression may play role in the action of glucocorticoids. 22. 23]. thereby activating a pathway central to the regulation of energy metabolism [34]. they showed that ZAG can decrease phosphorylation of both double-stranded RNA-dependent protein kinase in muscles of diabetic mice. and hip circumference [28]. which is the main site of ZAG synthesis postnatally. Russell and Tisdale showed that ZAG not only induces direct lipolysis. and it appears that ZAG has an autocrine/paracrine role in adipose tissue function [17]. fat mass [2.1. Although the exact role of ZAG in adipose tissue remains to be clarified. this effect appears chronic rather than acute [17]. and progestins [7]. detected ZAG mRNA from one day of birth in subcutaneous fat. It appears that the effect of TNF-α on ZAG is timedependent. IL-8. 30]. but with a rise in body temperature [31. breast. and RANTES can upregulate ZAG expression in adipocytes [25]. C reactive protein [2]. lung. It has been shown that the expression of ZAG is increased by the selective β3-adrenoreceptor agonist BRL37344. 24]. 21]. Moreover. 27–29]. 20]. Lipolysis and Lipid Mobilization. the clearance of ZAG in the circulation may be altered in obesity [17]. but also sensitizes adipose tissue to other lipolytic stimuli [31]. Serum ZAG level is inversely correlated with percentage of body fat. liver. ZAG via increasing uncoupling protein-1 (UCP-1) expression in brown adipose tissue can lead to lipolysis [21. The mechanism by which induction of β3-adrenoreceptor leads to an increase in ZAG expression is not known [20. epithelial cells of prostate. Furthermore. body weight [28. It appears that this process is due to the upregulation of ZAG secondary to increased level of circulatory glucocorticoids [7. Sanders and Tisdale have demonstrated that ZAG expression can be regulated particularly through TNF-α and the PPAR-gamma nuclear receptor [26]. . while the PPARgamma agonist rosiglitazone induces an increase in ZAG level [26]. can modulate ZAG expression and secretion by human adipocytes [17. waist circumference [28. 20]. TNF-α can decrease ZAG expression and secretion [4. Regulation of Metabolism. without any decrease in food intake. when fat mass is expanded substantially.2. 21]. cerebrospinal fluid. 32]. hence. The circulating ZAG is negatively correlated with fasting insulin. Glucocorticoid-mediated upregulation of ZAG expression in white and brown adipose tissues results in lipolysis [7. hence. The ZAG itself has been revealed to induce ZAG expression in adipocytes [20]. liver. Studies have shown that proinflammatory cytokines and chemokines such as interleukin-6 (IL-6). ZAG secretion by differentiated human adipocytes is abundant [2]. Glucocorticoids are able to enhance ZAG expression [20. androgens. suggesting that the sympathetic system can play a role in the regulation of ZAG expression [20] and that the induction of ZAG is mediated through β3-adrenoreceptor [16. Russell and Tisdale have shown that rats treated with ZAG show a progressive decrease in body weight. 29]. 28. homeostasis model assessment of insulin resistance [2. urine and amniotic fluid. 26]. and leptin [2. 19. suggests that ZAG might be involved in the postnatal development of adipose tissue mass [3]. Studies showed that tumor necrosis factor-α (TNF-α). in other words. it appears that its expression is inversely related to adiposity [27]. They showed that loss of adipose tissue accompany an increase in lean body mass [35]. 3. and prostate [17]. 30]. This ability of ZAG in inducing its own expression can explain the much greater effect of ZAG on lipolysis in vivo than its effect on lipolysis in vitro [20. thereby it can attenuate the process of skeletal muscle atrophy.

Due to high degree of structural similarities to MHC-I. 43. Collectively. As a Carrier Protein. ZAG is effective in attaining the properties of cell adhesion between cells and extracellular matrices [7]. a rate limiting step in the cell cycle. It has also been shown that ZAG is produced by normal epidermal keratinocytes. 40]. have demonstrated that ZAG and α1-antitrypsin. and antitumor activity. 12]. 7. ZAG can bind to the sperm membrane and initiate motility which is directly associated to cAMP levels in semen [7]. The common determinant with nephritogenic urinary glycoprotein and serum is ZAG. 3. The most plausible role of ZAG in immunity is through its capacity for binding and presenting lipidic ligands to T cells [7]. The capacity of macroglobulins such as ZAG for binding hydrolases makes them to prevent the enzyme-mediated tumor invasion [7. It also can influence adipocyte metabolism locally [2]. Integrins require divalent cations such as Mg2+ and Mn2+ for mediating cell adhesion. In contrast to MHC-I. the biological activity of ZAG is associated with infection. Immunoregulation. Moreover. The role of ZAG in production of melanin is different. In Jiaxian red cattle. 49]. 3. and melanin synthesis [7. and uric acid.3. it is predicted that ZAG can play a vital role in sperm motility via such process [7. Guo et al.9. 4. which are the key step for melanin synthesis. but it appears that ZAG inhibits melanin production via a TNF-independent mechanism [7]. Cell Adhesion. Z3. ZAG is considered as a member of immunoglobulin superfamily [7]. Hence. suggesting that ZAG has a different mechanism in vivo and in vitro. The role of ZAG in malignancies is different.7. 21]. 3. the presence of Mg2+ and Mn2+ is also needed for cell adhesion by ZAG. it is considered as a good marker for detecting prostate [5. ZAG indirectly plays a role in hindering tumor progression via downregulating cyclin-dependent kinase. ZAG interacts nonspecifically [39]. Serum level of ZAG is associated with the serum levels of cholesterol [37]. In detecting of doping with recombinant erythropoietins by isoelectric focusing and western double blotting. ZAG also correlates with glucose. breast. ZAG is positively correlated with adiponectin [2. 30]. 47]. Stejskal et al. 45]. It has a role in the expression of the immune response [7]. which are carriers of some cytokines and growth factors essential for proliferation [7]. 3. In vitro. so. In various organs. Growth Control. 44]. where its expression improves with cellular differentiation [7.10. played important roles during maturation of spermatozoa. 50]. 48]. and Z4. 3.5. an excess of macroglobulin/hydrolase complexes can activate apoptosis. ZAG decreases melanin production in vivo. related to the forward motility of spermatozoa in human seminal plasma. which regulates G2-M transition.ISRN Dermatology other hand. it appears that the minimal level of ZAG is required for melanin production [7]. as well as incorrectly synthesized or damaged RNA [7]. which suggests its role in fertilization [7]. Furthermore. and surprisingly. The lipid metabolism pathway is a significant mechanism for modulating sperm motility. Z2. polymorphism of four loci at the coding region of the ZAG gene has been shown including in Z1. This finding describes the role of ZAG in the integrin-mediated adhesion. Degraded RNA can be used as nutrients in cells for reproduction of RNA pool [7. RNase Activity.6. from the epididymis through fertilization in the female reproductive tract [41]. Tumor Proliferation. The members of this family present peptides to cytotoxic T cells [7. Although the role of ZAG in immunoregulation cannot be denied. the immune system does not seem to be significantly altered in the absence of ZAG [7. it is concluded that the plasma ZAG may function as a carrier protein of the nephritogenic renal glycoprotein [7]. On the other hand. Tumor necrosis factor-α (TNF-α) also inhibits melanin synthesis by human primary melanoma. 46]. The crystallographic studies of ZAG have shown that its groove can bind small hydrophobic ligands [7. It appears that ZAG via binding to lipid-like molecules in its groove can regulate lipid metabolism. showed that Z4 locus can be one of the markers of growth traits in these animals [13]. 18]. 42]. The RNase activity may be important for the physiologic function of ZAG. introduced ZAG as a marker for glucose metabolism [38]. Ding et al. Regulation of Melanin Synthesis. In one hand. 3 3. 3. The ZAG genotype appears to be associated with total cholesterol and low-density-lipoprotein cholesterol. ZAG is actively involved in inhibition of tumor growth and proliferation via its linking with immune system [7].8. Pathologic Roles of ZAG in Human The concentration of ZAG in serum has been shown to increase significantly in carcinomas [7]. On the other hand. hence. It appears that ZAG as a soluble molecule can degrade and eliminate byproduct of RNA processing reactions within cells. creatinine. the progressing tumors express many receptors to macroglobulins such as ZAG. immunoregulation. The presence of ZAG in human seminal fluid is 6 times more than that in the human serum. The ZAG plays a role in lipid metabolism [37]. This function appears to be due to the presence of ArgGly-Asp in α3 domain [7. 3. . ZAG does not require peptides and β2microglobulin for folding [7. Other mechanisms for ZAG-mediated cell adhesion have been described [7]. including melanocyte proliferation. dendricity. increased ZAG can decrease melanin production by decreasing levels of tyrosinase protein and its activity. Fertilization. Furthermore. In one study.4. It appears that ZAG as a keratinocyte-derived factor influences melanocyte behavior. It has been shown that the RNase activity of ZAG has similarities to other RNases such as human pancreatic RNase [7.

66]. characterized by acquired. Some studies have demonstrated that low levels of ZAG expression correlate with metastatic potential and a higher risk of recurrence in prostate cancer. Moreover. In cancer cachexia. Its incidence in males and females is equal [61. 7. Cancer cachexia is characterized by progressive loss of adipose tissue due to increased lipolysis. accumulation of toxic compounds [8. This suggests that the changes in ZAG expression in adipose tissue in cancer cases can be secondary to increase in serum cortisol level [20]. as another mechanism for lipolysis in cachexia. 50]. It appears that ZAG can influence the turnover of extracellular matrix components. morphological examination shows marked remodeling of adipose tissue. but not white. Irmak et al. The ZAG is one of the biomarkers in multiple sclerosis. This finding is different from other studies which have shown a hindering role for ZAG in tumor proliferation. which is directly involved in different types of tumor proliferation [7]. Rajpal et al. adipose tissue. not only ZAG is a novel regulator of cell proliferation in the aging kidneys and as a modifier of the aging phenotype but also it may be implicated in the regulation of renal interstitial homeostasis [16]. In cases of chronic hemodialysis. both LMF and ZAG can induce lipolysis directly by a cyclic AMP-mediated process. have shown that the level of ZAG in cerebrospinal fluid is downregulated in the episode of multiple sclerosis [57]. and this is initiated through binding to a β3-adrenoreceptor [20]. An Overview of Vitiligo Vitiligo is the most common depigmenting skin disorder [59]. The ZAG is involved in the pathogenesis of proliferative diabetic retinopathy [7. showed that ZAG is prominent in tumor cells at the bladder tumor invasion front [51]. immunological. and psychological. 51]. there is a higher level of ZAG in the welldifferentiated tumors than that in the moderately or poorly differentiated tumors [5. 65]. 5. but it appears to be dependent on the interaction of genetic. suggesting that ZAG can act as an inhibitor of proliferation [6. Schmitt et al. and autocytotoxic factors [8]. Furthermore. 16. Regarding these findings. neural. 7]. showed that ZAG can be of potential biomarkers for early noninvasive diagnosis of the acute rejection after renal transplantation [55]. and circumscribed amelanosis of the skin and hair [60]. The ZAG is a marker for response to thalidomidebased therapy in patients with multiple myeloma. hence. Fasting levels of serum cortisol have been revealed to be significantly higher in weight-losing patients with stage IV breast cancer than those who have no weight loss [20. 54]. it appears that upregulation of ZAG can be a promising therapeutic target for metabolic syndrome [30]. It appears that increased lipolysis is a key factor underlying fat loss in cachexia. The melanocytes in vitiligo are degenerated and seem to be replaced by Langerhans cells [8. and β2-microglobulin has significantly higher concentration in nonresponders to thalidomide-based induction therapy compared to responders. 63]. infections. It is also a biomarker for glomerular disease. resulting in the depletion of 85% of the adipose tissue mass and 30% of weight. some pathological states associated with an increase in epithelial cell proliferation. progressive. showed that aged mouse kidneys displayed a reduced epithelial proliferative reserve due to increased proximal tubular expression of ZAG. so. while inhibition of adipocyte development and lipid deposition may also contribute [54].4 oral. which can be attenuated by β3-adrenoreceptor antagonist. Some of the suggested pathogeneses include impaired melanocyte migration and/or proliferation. Sanders and Tisdale demonstrated that ZAG can induce uncoupling protein-1 (UCP-1) expression in brown. which is responsible for lipid utilization during cancer cachexia [26]. ZAG mRNA is upregulated while leptin mRNA is decreased [1]. autoimmune. serum amyloid-A protein. such as psoriasis and polycystic kidney disease. which suggests the role of ZAG in their pathogenesis [7]. It is identified that ZAG is increased in the urine samples of patients with bladder cancer [7. median ZAG serum level is elevated [19]. which is different from other previous studies that have shown the proliferative role for ZAG. It has been revealed that ZAG is among the proteins excreted in urine of microalbuminuriapositive diabetes patients [7]. It appears that results are different and inverse in the role of ZAG in cell proliferation. 33]. Tumani et al. Findings have showed that ZAG can be as a biomarker for human metabolic alterations [58]. In cachexia. 52]. ZAG can be purified from the urine of patients with cancer cachexia [17]. Their findings revealed ZAG implication in epithelial proliferative inhibition. A potential mediator of this increased lipolysis is a lipid-mobilising factor (LMF) which has been shown to be identical with the plasma ZAG [20]. showed that ZAG along with vitamin D-binding protein. and epidermal carcinomas [7]. while haptoglobin has a lower concentration [56]. Their study showed ISRN Dermatology that ZAG can directly influence UCP expression. The role of ZAG in cancer cachexia was described by Bing et al. It was expressed predominantly in tumors of apocrine and eccrine differentiations [7]. however the exact mechanism by which ZAG results in this proliferation has not been known. . and 17 in Caucasian families with generalized vitiligo and associated autoimmune diseases have been reported [64. ZAG can be considered as a marker of maturation and differentiation. [22]. The pathogenesis of this disorder is uncertain. The ZAG is decreased in liver fibrosis in hepatitis C and cirrhosis. are accompanied with decreased ZAG expression [16]. and neurological factors [8]. This inverse association between Gleason’s grade and rising serum ZAG level is similar to that seen with prostate-specific antigen [50]. The ZAG expression in prostate cancer epithelial cells is inversely associated with Gleason’s grade on pathology [6. The linkage signals on chromosomes 1. It commonly begins in childhood or young adulthood. 62]. This remodeling is characterized by shrunken adipocytes with a major reduction in cell size and increased fibrosis in the tissue matrix [53]. In cachectic cancer patients. Furthermore. It appears that ZAG is a clinically important protein. Jia et al.

75. it is expected that lack of ZAG can result in whitish patches of vitiligo. Surprisingly. If we can confirm this association. (ii) Some patients with vitiligo have serum autoantibodies and circulating autoreactive T cells against 7. depression. Therefore.ISRN Dermatology Many patients with generalized vitiligo have serum autoantibodies and circulating autoreactive T cells against melanocytes and melanocyte components [67]. Hence. Moreover. respectively [8. increased levels of soluble interleukin (IL)-2 receptor. IL6. Some of other important treatments of vitiligo include photochemotherapy. 74]. 71. 77]. 64]. 25]. which further suggest the role of T-cell activation in the vitiligo pathogenesis [68]. 5 melanocytes and melanocyte components [68]. It appears that most of the suggested pathogeneses of vitiligo can be attributed to decrease in ZAG as follows: (i) Studies have revealed that ZAG as a keratinocytederived factor influences melanocyte proliferation and dendricity [7. by precipitating circulating ZAG in the site of vitiligo. obsessive symptoms. 23]. We know that a chronic detachment of melanocytes has been suggested as a recently identified pathogenesis for vitiligo [8. This association between these findings appears to not be accidental. Moreover. oral Lphenylalanine. topical fluorouracil. 22. (vi) As a hypothesis. 72]. ZAG can be effective in prevention of vitiligo by immunoregulation. Probable Association between ZAG and Vitiligo For the first time. A new theory is emphasizing that depigmentation in vitiligo patches results from a chronic detachment of melanocytes that is proposed to be designated as melanocytorrhagy. 18. ZAG can be considered as a marker of maturation and differentiation of cells [7]. 71. 69]. Studies have shown that ZAG is effective in immunoregulation [7. It appears that there may be a relationship between stress and the development of vitiligo. . the expression of TNFα is high [8. and if we consider the Langerhans cells (placed instead of melanocytes in vitiligo sites) as poorly differentiated melanocytes. 70]. Hence. surgical producers. compared with normal skin. We can conclude that zinc. It has been demonstrated that repigmentation occurs in 10–20% of patients [8. 77]. Camouflage products and selftanning dyes can help to improve lesions cosmetically [8. 43. 72]. Conclusion Regarding mentioned subjects. (v) Topical steroids are the most effective and safest forms of treatment for vitiligo. 77]. topical minoxidil. can be effective in treatment of this disease. (viii) Some findings have shown that the minimal level of ZAG is required for melanin production [7]. Some studies revealed that TNF-α can decrease ZAG expression and secretion [4. (iii) It has been revealed that ZAG is effective in attaining the properties of cell adhesion between cells and extracellular matrices [7]. we have demonstrated that zinc also is effective in the treatment of vitiligo [61]. intralesional and oral steroids. in vitiligo. Some studies have shown that zinc can precipitate ZAG [8–10]. 44]. 76] for preventing photodamage and lessening the chance of the Koebner phenomenon [8]. it is expected the melanocyte adhesions to the other cells in epidermis to be impaired in the lack of ZAG. 67]. reveals an imbalance of epidermal cytokines at sites of lesions [8. 45. adjustment disorders. we can consider this theory for vitiligo-like diseases such as postinflammatory hypopigmentation. calcipotriol. 46]. Furthermore. the lack of ZAG is expected to inhibit melanocyte proliferation. ZAG gene is located on the chromosome 7 [7]. the association between vitiligo and ZAG must be confirmed in one robust study in vitro and in vivo. In one clinical trial. which is possibly related to increased susceptibility to mechanical and other types of stresses [8. detection of significantly higher expression of IL-6 and tumor necrosis factor (TNF)-α in vitiligo skin. increased expression of this cytokine in the site of vitiligo can result in a decrease of ZAG expression. in the process of vitiligo. 69]. Hence. this impairing in the process of maturation or differentiation of melanocytes can be attributed to the lack of ZAG. (vii) The linkage signals on chromosome 7 in patients with generalized vitiligo and associated autoimmune diseases have been reported [64. the melanocytes are impaired but not melanogenesis. 6. Regarding these findings we can conclude that steroids are effective in treating vitiligo via enhancing ZAG. and IL-8 have been found. Sun protection of the vitiliginous areas with sunblocks is important [8. Although this hypothesis is not strongly justifying vitiligo pathogenesis because. and hypochondria [8. 308 nm excimer laser. especially for the localized one [8. because vitiligo patients tend to have higher scores for anxiety. Studies have shown that steroids are able to increase ZAG expression [20. and homeopathy [8]. (iv) In whitish patches of vitiligo. 73. Studies have shown that topical steroids and narrowband UVB monotherapy are the most effective and safest forms of treatment for localized and generalized vitiligo. Bagherani et al. suggested that zinc might be effective in the treatment of vitiligo [64]. we pointed the probable association which might be present between ZAG and vitiligo [8. this discovery will result in a big progression in the field of treatment of this debilitating disease. hence.

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