NATURAL VITAMIN E Melanocytes can become sensitive to free radicals like peroxide when the intracellular levels of antioxidants like vitamin E get reduced (Maresca V, Roccella M, Roccella F, Camer E, Del Porto G, Passi S, Grammatico P, and Picardo M, Journal of Investigative Dermatology (1997) 109, 310�313). Free radicals like peroxide are then capable of destroying melanin. The oxidantantioxidant balance in disturbed in vitiligo melanocytes owing to the reduction in catalase activity in vitiligo melanocytes, thereby setting the state for destruction of melanin. Supplementation with Vitamin E can help to restore the antioxidant balance and thereby restore melanin synthesis.

MELON EXTRACT Melon extracts are a rich source of superoxide dismutases and catalases which are essential to restore the antioxidant levels in melanocytes. Catalases and superoxide dismutase enzymes are also involved in the final stages of melanin synthesis wherein LDOPA is spontaneously converted to DHI and DHICA (refer chapter 2), perhaps by preventing oxidative damage to the intermediates. Vitiligo patches of skin also have high levels of hydrogen peroxide which are toxic to cells. This nutrient provides the enzymes required to lower the high levels of hydrogen peroxide seen in patient melanocytes. Also, restoration of antioxidants in melanocytes will help to prevent cell death.

FOLIC ACID & VITAMIN B12 Folic acid and vitamin B12 are important for general well being of a person as well as in pathological conditions. Supplementation with vitamin B12 as well as folic acid in addition to sunlight exposure is effective in reversing the loss of skin colour. Research conducted by swedish researchers showed that exposure to sunlight and usage of UVB lamps in winter combined with oral intake of folic acid and vitamin B12 can halt the progress of vitiligo and also stimulate repigmentation (Juhlin L and Olsson MJ, Acta Derm Venereol. 1997 Nov; 77(6) 4602). The combination of these three factors can help to combat vitiligo effectively.

COPPER Copper is an important cofactor of the enzyme tyrosinase which converts tyrosine or phenylalanine into LDOPA. Copper is bound to critical histidines in the catalytic site of mammalian tyrosinase (Spritz R.A., Ho L., Furumura M and Hearing VJ Jr.; J I vest. Dermatol, 1997 Aug;109(2):20712). Loss of copper binding sites results in loss of tyrosinase activity thereby underscoring the importance of copper. Supplementing with adequate copper to maintain tyrosinase activity and therefore helps to repigment vitiligo affected skin patches. Tyrosinase being an important regulator of melanin biosynthesis, supplementation with copper can be instrumental in enhancing melanin synthesis and repigmentation in vitiligo. ZINC Divalent cations in addition to copper help to convert DOPA into the various indole intermediates that lead to the synthesis of melanin (Slominski A, Tobin D, Shibahara J and Wortsman J, Physiol Rev 84: 1155�1228, 2004). VitalGO provides adequate zinc to help stimulate melanin biosynthesis. L-PHENYLALANINE The amino acid, LPhenylalanine is an important substrate in the biosynthesis of melanin. It is a substrate for conversion into Ltyrosine and subsequently into Ldihydroxyphenylalanine (LDOPA) which is then converted through a series of enzymatic reactions into melanin. Phenylalanine therefore can promote restoration of skin colour and assist in overcoming melanin deficiency in vitiligo, however for maximum absorption, it must be taken away from other proteins, usually on an empty stomach with some form of carbohydrate like fruit juice.

1. INTRODUCTION Vitiligo, also termed as leukoderma, is an affliction that causes discolouration of skin often resulting in albinism and is caused by interplay between genetic, environmental or autoimmune factors. It is usually manifest in early adulthood with loss of skincolour seen typically in skin folds and extremities. The depigmented patches can increase in area for some time (active Vitiligo) before the condition reaches a quiescent (stable Vitiligo) stage. The reduction in pigmentation could be a result of destruction of preexisting melanin as well as melanocytes. Alternatively total shut down of melanin synthesis in skin could result in the albinism manifested in Vitiligo. Vitiligo affects nearly 4% of the world's population. Apart from its superficial manifestation as a skin discolouration, vitiligo also has debilitating effects on the nasal and mouth epithelium. Onset of Vitiligo can be seen from the early twenties in people afflicted by it. Although nonlife threatening, the visible disfigurement caused by loss of pigmentation can cause severe emotional distress to people struck by vitiligo. Since the abnormal and patchy pigmentation can last a lifetime, the mental stress and social embarrassment caused by the disease can be enormous (Parsad D, Dogra S and Kanwar A, Health and Quality of Life Outcomes, 2003, 1, 58). Small patches of Vitiligo affected skin can be concealed using makeup or skin grafting procedures but progressive vitiligo wherein the depigmentation persists over ever increasing surface of the body can only be addressed by other therapies. The treatment of vitiligo can also be protracted and lengthy depending upon the rate of progression of the depigmentation. Various treatment modalities are being practiced to alleviate the loss of skin colour in vitiliginous patches. Although a large range of surgical interventions like grafting are possible and successful, treatment of large areas of skin with surgical interventions is logistically prohibitive. Alternative therapies like VitalGO are proving themselves equally effective in the treatment of vitiligo in such cases. VitalGO is a carefully formulated dietary supplement based on various ingredients that help to stimulate remelanization of skin. It is a multipronged approach to overcome skin depigmentation manifested in vitiligo.

2. STRUCTURE OF SKIN In order to understand aberrant conditions like vitiligo and therapies to address them, an overview of the basic structure and the process of melanogenesis is essential. Skin is the most extensive organ in the human body and is the primary defense systems against invading pathogens. Skin is also a diversified organ in that areas of skin are specialized to perform specialized functions like sensory (lips), protective folds (under eye skin, eyelids) and mechanical endurance (thickened soles of hand and feet). In addition to acting as a physical barrier to pathogens, skin also performs the vital functions of thermoregulation, sensory inputs, protection of underlying tissues from photolysis, excretion and wound repair. Histological investigations show that skin can be broadly divided into two zones: a compact exterior most layer called Epidermis and a thicker underlying layer termed as Dermis (See figure 1). The epidermis consists of several layers of keratinocytes which are synthesis by a basal layer by continuous cell division. This layer consists of cells which are loaded with melanosomes and are essentially metabolically dead. The basal membrane also has specialized melanin synthesizing cells termed as melanocytes. Melanocytes are present in the epidermal layer of skin (Fig 2). These specialized cells produce melanin which is stored in special membrane bound sacs called as melanosomes. Melanosomes are then transported our of melanocytes and into the surrounding keratinocytes which results into pigmentation of skin. The dermis layer consists largely of connective tissue with specialized structures like sweat glands, hair follicles, muscles, lymphatic and blood vessels and pacinian corpuscles. Dermis is also rich in scattered free nerve endings which together with the hair follicles facilitate the sensory functions of skin. Pigmentation is a result of production of melanosomes by melanocytes which are then transported to keratinocytes and hair follicles. The biosynthesis of melanin is an interesting procedure that occurs in specialized lysosome-like compartments with melanosomes.

3. MELANIN BIOSYNTHESIS Melanin is the pigment responsible for skin, hair and eye colour in humans. Melanin synthesis, through considered as evolutionarily recent has the significant advantage ofprotecting skin from UV induced damage commonly seen in populations residing in the lower latitudes where exposure to sunlight can be very high. Skin and hair melanization is thought to confer evolutionary benefits in terms of thermoregulation, protection from the UV component of sunlight and sequestration of toxic metals. Melanins are a group of pigments derived principally from the amino acids L-phenylalanine and L-tyrosine by the action of the enzyme tyrosinase. The resultant group of melanins is a highly reactive set of compounds termed as eumelanins, pheomelanins, mixed melanins and neuromelanins. Skin pigmentation acts as in internal 'umbrella' against the harmful UV component of sunlight. (Slominski A, Tobin D, Shibahara J and Wortsman J, Physiol Rev 84: 1155� 1228, 2004). Although UVB (290nm310nm) present in sunlight is essential or the conversion of provitamin D3 to vitamin D in human, excess exposure to UV is also carcinogenic. In this context presence of melanosomes in keratinocytes is essential to facilitate synthesis of vitamin D as well as to protect underlying tissues from photo damage. Vitamins like the B group of vitamins are susceptible to photo damage. B-complex vitamins, particularly folic acid, delivered as food supplements are essential to stimulate DNA synthesis especially in skin lesions (Zhang XJ, Chinkes DL and Herndon DN, J Surg Res, 2008 Jun 1;147(1):1522). Melanins are also capable of fast ion exchange, a property that can help them to chelate heavy metals such as those found in seafood. Since bioaccumulated heavy metals like cadmium and mercury in the seafood rich diet of coastal people can cause severe abnormalities like cancer and osteoporosis, the removal or excretion of these metals via melanin sequestration is an important survival strategy. The sequestration of melanin in hair as well as dead epidermal layers of skin is also thus an effective excretion mechanism. Also, in dark skinned and dark haired individuals residing in tropical and subtropical areas, melanin can complex with salts preventing their excretion from the body (Slominski A, Tobin D, Shibahara J and Wortsman J, Physiol Rev 84: 1155�1228, 2004). Melanin thus fulfils several important physiological roles of acting as a natural sunscreen and a detoxifying agent. Melanins have ionic properties which can be useful in binding transition metals and particularly calcium. Melanin is synthesized in melanosomes present in the lower epidermal layers of skin and then is transported packaged in small intracellular organelles termed as melanosomes (melanin granules), to the keratinocytes. Melanin is synthesized primarily from the amino acids L-tyrosine and L-phenylalanine as shown in Figure 2 (adapted from Slominski A, Tobin D, Shibahara J and Wortsman J, Physiol Rev 84: 1155�1228, 2004). Phenylalanine is hydroxylated to tyrosine by the action of phenylalanine hydroxylase. Tyrosine is then converted to dihydroxyphenylalanin or LDOPA by the action of tyrosinase. LDOPA is then oxidised to dopaquinone and then subsequently converted to dihydroxyindole (DHI) and DHIcarboxylic acid (DHICA). Eumelanin is essentially a polymer of DHI and DHICA. The conversion of LDOPA to the subsequent forms is usually spontaneous but can also be aided by the presence of divalent metal cations like Mn2+, Cu2+ and Zn2+ and also by the presence of catalases and superoxidases. The dopaquinone intermediates are used in conjunction with cysteine and glutathione to yield neuromelanins as well as pheomelanins. Melansome synthesis occurs in specialized intracellular compartments called melanosomes. Although the synthetic pathway for all the melanins is similar, each melanosome is dedicated to the synthesis of only one class of melanin. Thus the manifest pigmentation of hair or skin depends upon the prevalence of each kind of melanosome.

4. ETIOLOGY OF VITILIGO Vitiligo is an acquired condition with complex origins which has generated a lot of debate in scientific and medical circles. The mechanism of the progression of the disease is also not completely understood. The apparent loss of skin pigment could be caused by two mechanisms, destruction of melanocytes or disruption of melanin biosynthesis in skin areas affected by vitiligo. Melanocytes are the pigment bearing cells which in the case of people is melanin. These cells are distributed throughout the epidermal layer of the skin (see fig 1). Additionally, melanin granules from these cells are transported to the keratinocytes in the epidermis wherein they form a natural photoprotective layer. Development of vitiligo is a complex process that is not yet fully understood. Four dominant hypotheses are being considered to understand the development and spread of vitiligo. The 'autoimmune' hypothesis suggests that melanocytes are targeted by the person's own Tcells. The Tcells then bring about targeted destruction of the melanocytes thereby causing the manifested lack of pigmentation in skin. Autoantibodies to proteins found in melanocytes have been found in patients suffering from Vitiligo (Kemp E. and Weetman A.P. Clin Exp Immunol 1998; 114:333�338). The occurrence of antibodies against enzymes proteins like tyrosinase which are central to melanogenesis, suggests that the person's own immune systems may have turned against the melanocytes. Additionally, other autoimmune diseases like thyroid disease also occur in patients suffering from vitiligo (Forschner T, BuchHoltz S, and Stockfleth E., JDDG, 2007, vol5: 467476; Ogg G, od Dunbar P, Romero P, Chen JL and Cerundolo V., J. Exp Med, 1998, Vol 188 , 6, 12031208) The 'neural' hypothesis suggests that a non-normal interaction of melanocytes and secreted neural messengers like neuropeptides and catecholamines from nerves in the dermal areas can lead to the destruction of melanocytes (Forschner T, BuchHoltz S, and Stockfleth E., JDDG, 2007, vol5: 467476). Vitiligo affected areas of skin show abnormal association between nerve endings and melanocytes which suggests that abnormal cellular communication between these cells can result in death of melanocytes. The nerve endings in these areas also show altered behaviour of growth factors like nerve growth factor (NGF). The 'selfdestruct' theory rests on metabolic errors in the synthesis of melanosomes. Melanin biosynthesis proceeds through several indole intermediates and oxidative species. Unless compartmentalized, these intermediates can cause cellular damage. Oxidative stress resulting in the altered balance between free radicals like peroxide, oxygen superanion and antioxidants like vitamin E and glutathione can result in the destruction of melanin thereby causing vitiligo. These alterations in cellular mechanisms could possibly trigger cell death in melanocytes leading to depigmentation of skin. Stress and other environmental factors are also said to trigger vitiligo (Parsad D, Dogra S and Kanwar A, Health and Quality of Life Outcomes, 2003, 1, 58) The 'biochemical' hypothesis postulates that excess synthesis of hydrobiopterin which is a cofactor of tyrosinase involved in melanin synthesis leads to the accumulation of excess indoles. The leakage of these intermediates, which are toxic, from melanosomes sets off cell death mechanisms in the pigment cells leading to loss of melanocytes and therefore the subsequent appearance of white areas on skin. It is unclear as to whether multiple mechanisms operate in all vitiligo patients or whether there is a progression of the disease whereby one mechanism sets off the development of vitiligo and then the more complex neural or autoimmune mechanisms take over. Although there are multiple theories suggested for the development of vitiligo, the autoimmune theory is the most widely accepted one (Norris S, Kissinger M, Naughton G, Bystryn JC., 1988, J. Invest. Dermatol., 90, 783789; Forschner T, BuchHoltz S, and Stockfleth E., JDDG, 2007, vol5: 467476; Ogg G, od Dunbar P, Romero P, Chen JL and Cerundolo V., J. Exp Med, 1998, Vol 188 , 6, 12031208).

5. THERAPIES FOR VITILIGO Treatment strategies for vitiligo are numerous. There are surgical options involving autologous skin grafts wherein skin from the patients' gluteus is grafted onto the leukodermal patches. Another recent development centres around isolation of melanocytes from the pigmented areas of the patient and regrafting only the melanocytes onto the depigmented areas (Gupta S, Goel A, Kanwar AJ and Kumar B, Int. J. Detrmatol, 2006, 45 (6) 74750). Dermabrasion is also another method used to stimulate generation and migration of melanocytes to the depigmented areas (Kahn A and Cohen M, J. Am Acad. Dermatol., 1995 Oct;33(4):6468; Agrawal K and Agrawal A., Dermatol Surg., 1995 Apr;21(4):295300). Surgical interventions are usually prescribed for stable vitiligo when other interventions have been unsuccessful. Although these techniques are successful, their use over large areas of skin is difficult and involve prohibitive costs of treatment. Also, their use in actively spreading vitiligo is not possible for the same reasons. Non surgical therapies for vitiligo have been successful in active vitiligo, where successful repigmentation has been seen in patients with methods like phototherapy combined with sensitisers. Phototherapy methods have been tested using narrow as well as broadband ultraviolet light as well as sunlight. Sunlight is often said to be harmful to patients whose melanin protection is lost and yet sunlight also plays a role in promoting vitamin D synthesis as well as reappearance of melanocytes in skin. It is therefore essential to have controlled exposure to sunlight in the presence of photosensitisers. Psoralens are photosensitisers that are most commonly used in conjunction with narrowband or broadband UV irradiation or sunlight. Therapeutic formulations based on plant extracts, vitamins, minerals and amino acids are emerging as a new defence against vitiligo. Given the complex nature of this debilitating skin condition, a multipronged approach is necessary to halt the spread of active vitiligo and to reverse the depigmentation seen in both static and active vitiligo. Dietary supplements along with topical treatments with sunlight or UVB exposure can help to provide relief from the progressive disfigurement resulting from vitiligo.

6. REFERENCES 1. Parsad D, Dogra S and Kanwar A, Health and Quality of Life Outcomes, 2003, 1, 58. 2. Slominski A, Tobin D, Shibahara J and Wortsman J, Physiol Rev 84: 1155�1228, 2004. 3. Zhang XJ, Chinkes DL and Herndon DN, J Surg Res, 2008 Jun 1;147(1):1522. 4. Kemp E. and Weetman A.P. Clin Exp Immunol 1998; 114:333�338. 5. Forschner T, BuchHoltz S, and Stockfleth E., JDDG, 2007, vol5: 467476. 6. Ogg G, od Dunbar P, Romero P, Chen JL and Cerundolo V., J. Exp Med, 1998, Vol 188 , 6, 12031208. 7. Forschner T, BuchHoltz S, and Stockfleth E., JDDG, 2007, vol5: 467476 8. Norris S, Kissinger M, Naughton G, Bystryn JC., 1988, J. Invest. Dermatol., 90, 783789. 9. Gupta S, Goel A, Kanwar AJ and Kumar B, Int. J. Detrmatol, 2006, 45 (6) 74750 10. Kahn A and Cohen M, J. Am Acad. Dermatol., 1995 Oct;33(4):6468. 11. Agrawal K and Agrawal A., Dermatol Surg., 1995 Apr;21(4):295300. 12. Parsad D, Pandhi R and Juneja A, Clinical and Experimental Dermatology 2003;28: 285�287. 13. Szczurko O and Boon H., BMC Dermatol. 2008 May 22;8(1):2. 14. Maresca V, Roccella M, Roccella F, Camer E, Del Porto G, Passi S, Grammatico P, and Picardo M, Journal of Investigative Dermatology (1997) 109, 310�313. 15. Juhlin L and Olsson MJ, Acta Derm Venereol. 1997 Nov; 77(6) 4602. 16. 16.Spritz R.A., Ho L., Furumura M and Hearing VJ Jr.; J Invest. Dermatol, 1997 Aug;109(2):20712.