HYPOTHESIS: ZINC CAN BE EFFECTIVE IN TREATMENT OF VITILIGO

Abstract

Vitiligo is a common depigmenting skin disorder (prevalence 0.1-2%), still represents a cause of stigmatization and quality of life impairment in a large population. Several theories on vitiligo etiopathogenesis have been suggested including in trauma, stress, and autoimmune and genetic predisposition, accumulation of toxic compounds, altered cellular environment, imbalance in the oxidant-antioxidant system, impaired melanocyte migration and/or proliferation, infection, and psychological factors. Zinc, as a trace element, has many vital functions in human. It is antiapoptotic factor and needed as a cofactor for antioxidant defense system. It plays an important role in the process of melanogenesis. It may be effective in prevention and treatment of vitiligo via some mechanism. Herein, we suggested some probable protective mechanism for zinc in association with vitiligo.

Introduction

Vitiligo is a common depigmenting skin disorder[1–3] characterized by acquired, idiopathic, progressive, circumscribed hypomelanosis of the skin, and hair.[4] It is generally agreed that there is an absence of functional melanocytes in vitiligo skin and that this loss of histochemically recognizable melanocytes is the result of destruction.[5]

Vitiligo is the most prevalent pigmentary disorder with an incidence rate between 0.1-2% showing multifactorial etiology and polygenic inheritance.[6,7] The effects of vitiligo can be cosmetically and psychologically devastating, resulting in low self-esteem, poor body image, and difficulties in sexual relationships.[8]

Because the disease is still not understood, there is a plethora of different treatments including topical corticosteroids, calcineurin inhibitors, vitamin-D derivatives, phototherapy (ultraviolet [UV] A, narrowband UVB), photochemotherapy (psoralen plus UVA [PUVA], psoralen with sunlight [PUVAsol]), surgical techniques, and combination of topical therapies and light treatment. These current treatments are largely unsatisfactory.[8]

On the other hand, there are few controlled trials assessing efficacy of natural health products (e.g., vitamins, minerals, herbal medicines, and other supplements) for vitiligo, but those that have been published generally show weakly positive outcomes with few adverse reactions.[7] For the first time, in one study, we showed that topical corticosteroid in combination with oral zinc is more effective than topical steroid alone. Although this efficacy was not statistically significant in this study, it appears that more robust long-term randomized controlled trials with more patients, maybe with high doses of oral zinc are needed to fully establish the efficacy of oral zinc in management of vitiligo.[9] Herein, we investigate the probable mechanism of zinc in treatment of vitiligo.

Etiology and Pathogenesis of Vitiligo

Vitiligo is a multifactorial disorder,[5–7,10,11] related to both genetic and nongenetic factors.[5] Due to the observed variation in clinical manifestations of the disease, it seems likely that etiology of vitiligo may differ among patients.[12] Various physiological, biochemical, histochemical, and enzymatic studies have been done to clarify the pathogenesis of vitiligo.[4]

Genes certainly play a role in all aspects of vitiligo pathogenesis, even response to environmental triggers, and so genetics really should not be separated out as a distinct phenomenon.[2,13] In the past few years, studies of the genetic epidemiology of generalized vitiligo have led to the recognition that vitiligo is part of a broader, genetically determined, autoimmune, and auto inflammatory diathesis.[2,14] Currently, there is strong support only for HLA, PTPN22, NALP1, and perhaps CTLA4, all genes associated with autoimmune susceptibility.[2,13] HLA types associated with vitiligo in more than one study include A2, DR4, DR7, and Cw6.[10] Jin et al. reported the linkage signals on chromosomes 1, 7, and 17 in Caucasian families with generalized vitiligo and associated autoimmune diseases and identified the risk loci of chromosomes 17 and 1 as NLPR1 (NALP1) and FOXD3, respectively.[3] Mutation is another theory stated in pathogenesis of vitiligo.[12]

Autoimmunity is the most popular hypothesis in pathogenesis of vitiligo.[6] The major reasons for this hypothesis are the coexistence of other autoimmune disorders,[6,7,11,14,15] detection of various autoantibodies including antithyroid and antimelanocyte antibodies in the serum of vitiligo patients and alteration of T-cell population showing decreased T-helper cells.[6,16] The pathogenic role of melanocyte-specific autoantibodies remains uncertain.[17,18] The facts that vitiligo is found more frequently in patients with metastatic melanoma and is associated with an improved prognosis, that vitiligo-like depigmentation has been observed following immunotherapy of melanoma[17,19] and that Vitiligo has also developed in recipients of bone marrow transplant or lymphocyte infusions from patients with vitiligo,[11] further support a crucial role for cell-mediated immunity in the pathogenesis of the disorder. Histological and immunohistochemical studies in prelesional skin suggest the involvement of cellular immunity in vitiligo.[15,20] T-cell analysis in peripheral blood further support this hypothesis.[14,15,20] Focal spongiosis and epidermal mononuclear cell infiltrate was found in 48% and 80% of both marginal and vitiliginous skins, respectively, in vitiligo patients. Thus, the vitiligo is an inflammatory disease and the epidermal lymphocytic infiltrate is most likely the primary immunologic event.[21]

There are some clues that point to heritable biological properties that might make the melanocyte of some people susceptible to environmental triggers or other stressors, possibly resulting in melanocyte death by necrosis, apoptosis, or pyroptosis, consequent presentation of tolerogens and loss of immune tolerance, and ultimately autoimmunity directed against melanocytes.[13,22]

As hypotheses, accumulation of toxic compounds, altered cellular environment, impaired melanocyte migration, and/or proliferation,[12] infection,[12,23] such as virus,[10] psychological (stress and personality characteristics of patients),[23] neural and autocytotoxic factors[10,11,14,16,17] can all contribute to vitiligo.

The autocytotoxic theory postulates that cytotoxic precursors to melanin synthesis accumulate in melanocytes, causing cell death[10] (self-destruct theory of Lerner).[16,24]

Segmental vitiligo frequently occurs in a dermatomal pattern, leading to a neural hypothesis.[12] There may be a relationship between stress and the development of vitiligo via increasing levels of neuroendocrine hormones.[25,26] Increases level of neuroendocrine hormones affects the immune system and alters the level of neuropeptides, which may be the initial steps in the pathogenesis of vitiligo.[24,25]

The histological and some laboratory data support apoptosis rather than cell necrosis as the mechanism of melanocyte loss.[1,27–31] Therefore, programmed melanocyte death or destruction due to inherent sensitivity to oxidative stress arising from either toxic intermediates of melanin or other factors including immune cytokines, environmental factors or other molecular mechanisms had been proposed by many authors.[1] Helmy et al. showed that highly significant increase in the percentage of apoptotic peripheral blood mononuclear cells in active vitiligo patients versus stable vitiligo patients or controls.[1]

Oxidant stress may also play an important pathogenic role in vitiligo.[10] It is suggested that the imbalance in the oxidant-antioxidant system rather than oxidative stress might play such role in vitiligo.[1] Research at the molecular level has also demonstrated deficiency of antioxidant substances in vitiliginous skin. This leads to cytotoxic action of reactive oxygen species such as superoxide anion and hydroxyl radical that are generated by the ultraviolet damaged epidermis. The free radicals are cytotoxic to melanocytes and inhibit tyrosinase.[4] A significant depletion of enzymatic and nonenzymatic antioxidants characterizes the epidermis of patients with active vitiligo, and represents a fingerprint of abnormal oxidative stress leading to impaired cofactor 6-tetrahydrobiopterin (6-BH4) levels, which inhibit melanogenesis interfering with the conversion of 1-phenylanine to tyrosine.[32]

Melanins are colloidal pigments, known to have a high affinity for metal ions; therefore, certain metal ions such as copper, zinc, and iron were found in high levels in pigmented tissues involved in melanin synthesis. As melanocyte degeneration was greater in active vitiligo, so there should be decreased zinc and copper in pigment tissues with their defective share in melanin synthesis reflecting their higher serum level. Therefore, high serum zinc and copper levels were the result rather than the cause of the disease.[1]

Zinc α-2-glycoprotein (ZAG), a plasma glycoprotein is a member of the immunoglobulin gene super family and has a three-dimensional structure that is highly homologous to major histocompatibility complex class I and II molecules.[33,34] ZAG regulates melanin production by normal and malignant melanocytes. B-16 recombinant human ZAG tumors have decreased levels of tyrosinase protein and minimal tyrosinase activity.[33] For the first time, we pointed that there may be relation between the molecule of ZAG and vitiligo.[35]

In summary, the exact etiology and pathogenesis of this disease is not clear[1] and the discovery of biological pathways of vitiligo pathogenesis will provide novel therapeutic and prophylactic targets for future approaches to the treatment and prevention of vitiligo.[2]

Significance and Function of Zinc in Human

Zinc is one of the important trace elements related to health and disease.[36] Essentiality of zinc is related mainly to its function as the metal moiety of important enzymes.[4] Historically, for more than 3000 years, zinc salts such as zinc oxide or calamine were applied topically to facilitate wound healing. In the past 50 years, progress has been made in association zinc with numerous skin pathologies.[37] Since it was first shown to be essential for Aspergillus niger by Raulin in 1869,[37] zinc has been shown to be a cofactor of over 300 metalloenzymes[37,38] and over 2000 transcription factors.[37]

In one study, we studied the efficacy of zinc in the treatment of vitiligo. In this study, we revealed that combination of zinc and topical steroid is more effective than the topical steroid alone.[9]

Zinc constitutes less than 0.005% of total body weight, and present in all cells and is indispensable for the normal functions of cells, tissues and organs of the body. Normal serum zinc level ranges from 70 to 180 μgm/100 ml with the mean value of 120 ± 22 μgm/100 ml. No statistically significant difference in the mean values of serum zinc level was observed in relation to sex, age, race, food, habits, and diurnal variation.[36]

Copper, zinc, selenium, and molybdenum are involved in many biochemical processes supporting life. The most important of these processes are cellular respiration, cellular utilization of oxygen, DNA and RNA reproduction, maintenance of cell membrane integrity, and sequestration of free radicals.[39] Zinc is found in all tissue types.[37,40] Skin contains approximately 6% of total body zinc[37,40] secondary only to muscle and bone.[37] It is presenting high concentration in pigmented tissues. Melanosomes act as reservoirs of zinc at the cellular level.[11]

Zinc takes part in virtually all body functions from spermatogenesis to growth to abstract thought processes. Zinc and vitamin A are essential for normal epithelial development.[36] Zinc is integral part of a number of metalloenzymes[36,41] necessary for normal protein, carbohydrate, lipid, and nucleic acid metabolism.[36]

Copper, zinc, and selenium are involved in destruction of free radicals through cascading enzyme systems.[42] The trace elements, copper and zinc, are linked together in cytosolic antioxidant- defense against reactive oxygen species, being constituents of copper, zinc-superoxide dismutase that catalyze the dismutation of reactive oxygen species to O₂ or H₂O₂. On the other hand, these trace elements, through this antioxidant-defense mechanism, may stimulate the protective antiapoptotic cellular stress-signaling cascades and thereby may stabilize cell proteins rendering them less prone to oxidation. Therefore, zinc is a potential antiapoptotic factor though its excess can be cytotoxic.[1]

Apoptosis related to zinc deficiency is related to another mechanism. Decline in intracellular zinc below a critical threshold level may not only trigger pathways leadings to caspase activation but may also facilitate the process by which the caspases are activated. Caspase families of enzymes are apoptotic regulators.[1]

Zinc in combination with other micronutrients such as copper, cobalt, nickel, iron, manganese, and calcium[41] plays an important role in the process of melanogenesis.[4,41] They catalyze the rearrangement of dopachrome to form 5,6-dihydroxy indole-2 carboxylic acid (DICA)[4,41] and enhancement of eumelanin polymer formation from monomers.[41] This process is at the final stage of eumelanin formation in melanogenesis.[41]

One of the importance of zinc is its involvement in gene transcription on several levels, via participation in histone deacetylation reactions[37,43] and in actual transcription by factors possessing zinc-finger motifs.[3,44]

Moreover, a high concentration of zinc is present in metallothioneins, a member of the shock proteins, expressed abundantly in the adenohypophysis. Evidence exist that, in bovine pituitary glands, metallothioneins may be involved in the synthesis and release of α-melanocyte stimulating hormone.[41,45] Hence, in a zinc-deficient state, melanogenesis may be impaired at the cellular level and the hypophyseal control mechanism on this process may be disturbed.[41]

Metabolism of Zinc in Human

Foods that are rich in zinc include beef, oysters, and liver.[37,46] Zinc is absorbed in the distal duodenum and proximal jejunum. Absorption of zinc in intestine is inhibited by phytate, among other molecules.[37,47] Zinc is excreted through the intestine and to a lesser extent in urine.[37,48]

Bioavailability of dietary zinc varies widely between different sources, but is about 20% to 30%. Zinc is distributed throughout the body with the highest concentrations found in muscle, bone, skin, eye, and prostatic fluids. It is primarily excreted in the feces, and regulation of fecal losses is important in zinc homoeostasis. Small amounts are lost in urine and perspiration.[49]

Therapeutical Values of Zinc in Dermatology

Zinc is effective in treatment of acne vulgaris,[37,50–52] diaper dermatitis, seborrheic dermatitis, dandruff, psoriasis,[37] androgenic alopecia, recalcitrant viral warts, old-world cutaneous leishmaniasis, and chronic cutaneous ulcers.[3,50–52] Success or failure of systemic treatment with zinc of acne vulgaris, or leg ulcer may be explained by understanding the metabolism of zinc in the organism interpreted as a feedback mechanism: Treatment with zinc is only successful if zinc is not available in sufficient amount for the organism, i.e., in case of primary zinc deficiency.[53]

Several groups reported oral zinc sulfate to be effective in the treatment of severe acne[37,54] and less efficient for the treatment of mild to moderate acne.[37,55] When compared with systemic tetracycline treatment, zinc salts appear to be equal to or less effective than this class of antibiotics.[37]

One study reported a cure rate of over 80% of recalcitrant viral warts with oral zinc sulfate.[37] Yaghoobi et al. also showed the effectiveness of oral zinc sulfate in treatment of viral warts.[9,56]

Contrary to popular belief, no association was found between systemic deficiency and alopecia areata. Zinc deficiency also is most probably not associated with telogen effluvium.[37]

Associations Between Serum Zinc and Vitiligo

Arora et al. found no significant alteration in serum zinc level in vitiligo. This possibly supports the autoimmune theory of vitiligo.[36]

Conversely, Helmy et al. showed that serum zinc and copper levels were significantly higher in active vitiligo patients compared to controls. While serum zinc and copper levels insignificantly higher in active vitiligo versus stable disease and in stable patients versus controls. It appears that increased apoptosis of peripheral blood mononuclear cells in active vitiligo will lead to release of zinc and copper in serum (as zinc is present maximally intracellular), resulting in increasing their serum levels significantly in active vitiligo.[1]

Inamadar et al. reported appearance of vitiligo-like depigmented cutaneous lesions in two siblings with acrodermatitis entropathica who developed decreased serum zinc level due to discontinuation of zinc supplements.[41]

Probable Therapeutic Role of Zinc in Vitiligo

To compare probable pathogenesis related to vitiligo development in various studies and functional significance of zinc in humans, it appears zinc is important in preventing and treatment of vitiligo with following mechanisms:

1. Zinc is a potential antiapoptotic factor. On the other hand, based on histological and some laboratory data, apoptosis of melanocytes has been suggested as a probable mechanism of vitiligo.[1] Hence, zinc, via preventing apoptosis of melanocytes may be able to control vitiligo.

2. Zinc and other trace elements are linked together in cytosolic antioxidant-defense system against reactive oxygen species.[1] One of the theories regarding to pathogenesis of vitiligo is oxidative stress leading to destruction of melanocytes.[1,4] Hence, zinc can control vitiligo through inhibiting production of free radicals.

3. Zinc is one of trace elements that play an important role in the process of melanogenesis.[1,4,41] Hence, zinc may be effective in melanogenesis in vitiliginous lesions.

4. Some study, revealed significant increase in the percentage of apoptotic peripheral blood mononuclear cells in vitiligo.[1] On the hand, accumulation of toxic compounds,[12,57] altered cellular environment[11] and infection[12,23] can all contribute to vitiligo. Zinc may affect in preventing vitiligo via destructing these probable environmental factors through prevention of these immunity-related cells.

5. Zinc deficiency is one of the many factors involved in the nonspecific suppression of cell-mediated immunity.[36] Hence, zinc may stimulate cell-mediated immunity against probable infective and other factors contributing in vitiligo development.

6. Zinc has a role in the synthesis and release of α-melanocyte stimulating hormone in bovine.[41,45] Hence, zinc may be effective in melanogenesis in human via release of this hormone.

7. ZAG regulates melanin production by normal and malignant melanocytes. We proposed that zinc via precipitating the ZAG in site of vitiligo patches may be effective in the treatment of vitiligo.[35]