Date: 24/06/2011



Vitiligo is a common acquired skin disorder clinically characterized by the progressive appearance of white maculae due to distruction of epidermal melanocytes in affected skin.


Vitiligo has a prevalence of approximately 0.5-1% in the world population. It affects men and women of all races equally. A female preponderance has been reported for vitiligo, but it is not statistically significant and the discrepancy has been attributed to an increase in reporting of cosmetic concerns by female patients.
Is rarely seen in infancy or old age. Nearly all cases of vitiligo are acquired relatively early in life and the onset is most commonly observed in persons aged 10-30 years. In half of sufferers, pigment loss begins before the age of 20.
In one fifth of the patients, other family members also have vitiligo.
Even though most people with vitiligo are in good general health, they face a greater risk of having other autoimmune diseases such as diabetes, thyroid disease, pernicious anaemia (B12 deficiency), Addison’s disease (adrenal gland disease) and alopecia areata (round patches of hair loss).


There are pale areas more visible in areas exposed to sunlight, including feet, hands, legs, face and lips. Other parts affected by the disease are the elbows, around the eyes, the lip and genitals. In addition to these depigmented areas, many people show a whitening in hairs grew in the depigmented areas (including hair, beard, eyelashes and eyebrows). In some cases vitiligo can lead to discoloration of the retina or eye color. the british associations of dermatologist

Clinical forms of vitiligo may be classified in two major subtypes:
General/non-segmental vitiligo (NSV): bilateral distribution of the lesions.
Segmental vitiligo (SV): unique segment of the body.

Non segmental vitiligo (NSV)

Is the most common form of the disease (85% to 90% of cases) and the lesions are usually bilateral, symmetrical and generally progressive.
May begin in childhood but a later onset is more common. Charateristic is the development of vitiligo at sites of aspecifically traumatized skin, the so called Koebner’s phenomenon, that is a valuable clinical factor to assess disease activity. Halo nevi, nevi surrounded by a ring of depigmentation, may precede the vitiligo appearance. Hair involvement may appear in later stages.
Frequently there is a familial history of vitiligo and other autoimmune disease.

Fig. 1. Non segmental vitiligo (NSV).

(a, b) NSV.
© The Koebner’s phenomenon: white areas indicate body sites where repeated traumas (local friction or pressure) most frequently cause the appearance of vitiligo.
(d). Multiple halo nevi (arrows): depigmentation around the nevus has been postulated to be a sign of autoimmune reaction against the nevus melanocytes.

Segmental Vitiligo (SV)

SV lesions have unilateral involvement and show a distribution pattern which has been considered to match one or several dermatomes [Fig. 2:a,b,c] or to correspond to areas delineated by Blaschko’s lines (lines which follow the dorso-ventral embryonic development of the cellular components of the skin) [Fig. 2: a,d,e]. However, SV does not follow either dermatomes or Blaschko’s lines in several cases, especially on the face. SV-NSV associations have been reported.

Fig. 2. Segmental vitiligo (SV).

(a)Dermatomes and Blaschko’s lines. Dermatomes (left, in blue) are segments of skin defined by sensory innervation. Blaschko’s lines (right, in red) exhibit an arc-like arrangement on the upper chest, S-like and V-like arrangements on the abdomen and back, respectively.
Isolated SV lesions with a dermatome-like (b, c) or blaschkolinear-like (d, e) arrangement.

Vitiligo: Pathogenetic Hypotheses and Targets for Current Therapies, 2010.


In patients presenting with patchy depigmentation, a thorough history and physical examination, including examination with Wood’s lamp, is done and it’s rarely necessary to perform a skin biopsy to confirm the diagnosis.
In NSV, typical macules show homogeneous depigmentation and have well-defined borders. A hyperpigmented rim at the interface of depigmented and normally pigmented skin is commonly seen after sun exposure. Pinpoint depigmentation may precede patchy depigmentation in rapidly progressing disease.
Macules in SV may have a more irregular border and less homogeneous pigment loss than those in nonsegmental vitiligo. A loss of hair pigment is usually not seen until the late stages of the disease.
Several disorders may be confused with segmental vitiligo, especially nevus depigmentosus.


The aetiology of this multifactorial disease is poorly understood. There are currently four major hypotheses for the pathogenesis of vitiligo:
1.The autoimmune hypothesis (for NSV) focuses on an immune-mediated melanocyte destruction.
2.Impaired redox status hypothesis high free radical levels and/or defective free radical defences are considered to be toxic for melanocytes.
3.The neural hypothesis (which could explain the dermatome distribution of SV), indicates that a neurochemical factor, released from the nerve endings or from skin cells, may destruct pigment cells.
4.The biochemical hypothesis, either monobenzone-like substances (exogenous) or catechols (endogenous), like noradrenaline or semiquinones of estrogens, may induce melanocyte death.
Overall, a genetic predisposition renders vitiligo melanocytes more susceptible to precipitating factors than normal healthy melanocytes. Very recently, a cross-linking between SV and genetic mosaicisms has been highlighted.

Currently, a bipolar pathogenetic approach for NSV has been proposed, which focuses on the immune-mediated damage or on the toxic-mediated injury of genetically susceptible vitiligo melanocytes.

The immune mediated damage

The autoimmune hypothesis, which mainly applies to the pathogenesis of NSV, is supported by numerous evidences. First, NSV has been reported in association with several other autoimmune disorders: endocrinopathies (thyroid diseases, diabetes mellitus, adrenal insufficiency), different skin and systemic diseases (psoriasis, lupus erythematosus, lichen planus, alopecia areata, myasthenia gravis, pernicious anemia, rheumatoid arthritis). Moreover, organ-specific circulating autoantibodies are often present, even in the absence of autoimmune disorders other than vitiligo. Non specific autoantibodies against pigment and non pigment cell antigens as well as specific melanocyte autoantibodies against tyrosinase, gp100 (melanosomal matrix glycoprotein) and the surface receptor MCHR1 (melanin-concentrating hormone receptor 1) have been described in NSV patients.
Alterations in cellular immunity participate in the pathogenesis of NSV. "T-cell"; infiltrates in vitiligo can be found in NSV patients with progressive disease. They contain CD4+ and CD8+ T-cells as well as CD68+ macrophages, but no B cells at the site of depigmentation. Infiltrating T-cells express activation molecules, such as IL-2-receptor, HLA-DR and major histocompatibility complex class II (MHC II) and the cutaneous lymphocyte antigen (CLA) typical of skin homing and produce cytokines such as IFN-gamma and TNF-alfa.
Infiltrating T-cells kill melanocytes within the skin, thereby causing the loss of pigmentation characteristic for NSV. Candidate antigens to be targeted by T-cells in NSV include tyrosinase, gp100, MART-1, TRP-2, P protein, and, to a lesser extent, TRP-1.
Under exceptional conditions, as in melanoma or vitiligo, melanocytic cells become HLA-DR+ and thus present the content of the melanosome in the context of MHC class II. These epitopes are likely excluded from peripheral tolerance, so class II-expressing melanocytes can become targets for CD4+ T-cells or they can activate in situ T-cell help for activation of adjacent cytotoxic CD8+ T-cells. Keratinocytes may contribute to this process by presenting their own antigens or melanocyte antigens in a MHC class II restricted manner. Langerhans cells act as antigen-presenting cells and T-activating cells in NSV. An increased number of Langerhans cells in varying differentiative phases has been described in the lesional skin from NSV patients.

The Cytotoxic Damage

Cellular homeostasis in the skin is guaranteed by defence mechanisms against endogenous and exogenous reactive oxygen species, such as singlet oxygen (IO2), superoxide anion (O2-), hydroxyl radicals (OH-) hydrogen peroxide (H2O2), peroxynitrite anion (OONO-), and nitric oxide. These defences include enzymes, such as superoxide dismutase, catalase, "glutathione reductase2:, glutathione peroxidase, glutathione-S-transferase, thioredoxin reductase, thioredoxin peroxidase and methionine sulfoxide reductases A and B. Moreover, small molecules such as reduced glutathione and thioredoxin (T), lipoic acid, vitamins C (ascorbic acid) and E (alpha-tocopherol), some amino acids (methionine and tryptophan), selenium and 6 and 7- tetrahydrobiopterins also act as antioxidants in the skin.
Oxidative stress [Fig. 3] occurs when the rate of ROS generation exceeds the capacity of the cell for their removal. Growth factors have been reported to induce cells to generate ROS and high levels of growth factors such as TNF-alfa, basic fibroblast growth factor (bFGF), IL-6 and IL-1alfa have been detected in vitiligo skin.
H2O2 can be generated from several enzymatic activities like epidermal monoamine oxidase A activity, NADPH oxidase activity from neutrophils and macrophages, degradation of purin bases to uric acid by xanthine oxidase, and exogenous source suche phenols, ortho- and para-quinols, UVA, UVB and X-rays. H2O2 deactivates catalase, thioredoxin reductase and methionine sulfoxide reductases and low activity of these enzymes is well documented in vitiligo skin. This affects the entire epidermal anti-oxidant defence machinery and increases in turn the H2O2 pool.
Gene expression of glutathione-S-transferase (GST) is remarkably repressed in vitiligo skin and this impairs the adaptative cellular response to various stressors, namely H2O2, 4-hydroxy-2-nonenal (a stable product of lipid peroxidation, easily reacting with proteins and DNA) and mild UV irradiation. .
Monoamine oxidase A, the degrading enzyme for noradrenaline, produces H2O2 as a reaction product from the oxidation of this catecholamine and high levels of catecholamines have been documented in plasma and urine of NSV patients, particularly in the early active phase of the disease. H2O2-mediated deactivation of acetylcholinesterase and butyrylcholinesterase induces high acetylcholine levels in vitiligo epidermis.
POMC and POMC-derived peptides such as alfa-Melanocyte Stimulating Hormone (alfa-MSH) and beta-endorphin are affected by H2O2-mediated oxidation and this may explain the reduction of alfa-MSH epidermal levels in vitiligo.
Increased ROS production in vitiligo may be due to impairment of mitochondria, that represent the major site for the generation of cellular oxidative stress.
Peripheral blood mononuclear cells (PBMCs) of patients with active vitiligo show increased ROS generation and compromised antioxidant capacity, with increased superoxide dismutase activity, reduced catalase activity, and decreased GSH and vitamin E levels.

Fig. 3.Oxidative stress.
Reactive oxygen species (ROS) are produced by cells during the course of normal metabolic processes, e.g. in the respiratory chain. Particular large amounts are produced in wounded and inflamed tissue by NADPH oxidase. Upon activation of NADPH oxidase, cells produce the highly reactive superoxide radical anion (O2). The latter is rapidly dismutated to hydrogen peroxide (H2O2) and water, and this process is enhanced by several superoxide dismutates (SODs). Both O2- and H2O may be converted to the hydroxyl radical (OH.) by iron (Fe2+) through the Haber–Weiss and Fenton reactions. Hydroxyl radicals are highly aggressive, resulting in oxidation of cellular macromolecules.
Reactive nitrogen species (RNS) are generated as a result of sequential reactions that begin with
nitric oxide synthase mediated conversion of arginine to citrulline. In this reaction, nitric oxide (NO) is generated, which reacts with O2 to produce peroxynitrite (ONOO). Numerous intracellular enzymes degrade reactive species. Some of these enzymes are specific such as SODs, whereas others have overlapping substrate affinities such as catalase and glutathione peroxidases, both of which can degrade H2O2 to water and O2. These enzymes also require GSH (reduced glutathione) during the course of peroxide degradation and convert GSH into its oxidized form (GSSG: oxidized glutathione), which is recycled by the enzyme glutathione reductase. In addition to detoxifying enzymes, ROS defense is achieved by a variety of exogenous and endogenous low molecular weight antioxidants. If the detoxification of ROS is insufficient or if ROS are produced in excessive amounts, oxidative stress occurs, resulting in severe cell
damage, premature aging or even neoplastic transformation.

Vitiligo: Pathogenetic Hypotheses and Targets for Current Therapies, 2010.




NSV is a multifactorial, polygenic disorder, resulting from a complex interaction of multiple genes. The strongest evidence for a genetic predisposition in the pathogenesis of NSV comes from studying patients’ close relatives, where the risk of NSV vitiligo is about 6-7%. An additional evidence for a genetic predisposition in NSV is its close association with other autoimmune disorders.
Numerous genes have been reported to be differentially expressed in vitiligo cells versus healthy donor cells. In particular, a reduced expression of VIT1 (a gene now renamed FBXO11, which encodes an arginine methyltransferase) in non lesional vitiligo melanocytes and a downregulation of the isoform GSTM1 of the GST gene in vitiligo keratinocytes have been confirmed recently.
Conflicting data still exist about the genetic association between NSV and AIRE (that plays a crucial role in the regulation of the immune system), CAT (catalase) and CTLA4 (cytotoxic T lymphocyte antigen 4) genes. However, genetic associations between NSV and genes such as PTPN22 (which encodes the protein lymphoid-specific phosphatase, a critical regulator of T-cell signal transduction) and GST have been demonstrated.
Genome-wide linkage analysis in multi-generation families with generalized vitiligo and associated autoimmune diseases indicated vitiligo linkage signals on chromosomes 1 (autoimmunity susceptibility locus 1- AIS1), 7 (autoimmunity susceptibility locus 2- AIS2) and 17p, whereas vitiligo unassociated with other autoimmune diseases was suggested to be linked with AIS3 (autoimmunity susceptibility locus 3- AIS3) on chromosome 8.
Very recently, the vitiligo susceptibility gene on chromosome 17p has been identified as NALP1, a gene encoding a NACHT leucine-rich-repeat protein 1, which is thought to mediate activation of the innate immune system in response to bacterial or viral triggers. NALP1 is expressed at high levels in Langerhans cells and T-cells and recruits the adapter protein ASC, caspase-1 and caspase-5 to a complex termed “NALP1-inflammasome”, which activates the proinflammatory cytokine IL-1alfa.


Acquired polygenic skin disorders such as vitiligo may present a segmental arrangement and may be associated with non segmental lesions of the same disorder. This could be better explained by an early postzygotic event in the form of “loss of heterozygosity” (LOH), involving one of the genes that predispose to the disorder, as it happens in cutaneous mosaicisms. In the mosaic disorders (among monogenic skin diseases), the surrounding skin is normal, and molecular studies have shown that the causative gene mutation is confined to the affected tissue (type 1 mosaicism), although the rest of the skin may show a milder form of the same disorder (type 2 mosaicism). Thus, the type 1 mosaicism reflects a LOH for a postzygotic mutation in an otherwise wild-type embryo. In contrast, the type 2 mosaicism reflects a postzygotic LOH in an already heterozygous individual (a second mutation with loss of the corresponding wild-type allele). In the same way, isolated segmental lesions in polygenic disorders such as SV could reflect a LOH in a somatic cell, involving one of the predisposing genes, as it happens in type 1 mosaicism . In SV-NSV associations, superimposed segmental manifestations could be caused by a LOH with the same mechanism involved in the type 2 mosaicism . This new mosaic hypothesis does not rule out the neural theory, as a local genetic defect could involve a gene encoding skin cell receptors for neuromediators or neuromediators themselves from nerve endings or from melanocytes.

Vitiligo: Pathogenetic Hypotheses and Targets for Current Therapies, 2010.
h3. Exposition to chemical agents

There is anecdotal and experimental evidence demonstrating that certain environmental chemicals are selectively toxic to melanocytes, both in culture and in vivo and are thus responsible for instigating vitiligo. The majority of these toxins are aromatic or aliphatic derivatives of phenols and catechols. Some of these compounds have been added to bleaching creams, products used to remove hyperpigmented lesions. Interestingly, these creams are not toxic to melanocytes from all individuals. Even at high dosages only a subset of humans depigment in response to application.

On the Etiology of Contact/Occupational Vitiligo, 2004.
h3. Comorbidity

People with certain autoimmune disorders appear to be more susceptible to vitiligo, but the opposite isn’t true.
Among these disorders include:
•"Hyperthyroidism": gland is too active or too little;
Adrenocortical insufficiency:the adrenal gland does not produce enough hormone corticosteroid;
Alopecia areata :patchy baldness;
Pernicious anemia:low red blood cells caused by the difficulty of the body to absorb vitamin B12.


Premature graying


Steroid creams are the first line of treatment. They are usually applied twice daily, and results require three to six months. Side effects are observed when overdosed, which include local skin damage, and glaucoma or cataracts when used around the eyes.

High-potency steroid use in children with vitiligo: a retrospective study, 2007.

For extensive vitiligo, oral medications of psoralen and phototherapy by ultra violet rays (PUVA) can be tried. It takes at least 2–3 months or about 200 treatment sessions required to have an effect. PUVA is partially successful in those treated, but complete repigmentation occurs in only 15–20%. Repigmentation occurs slowly as the cells creep back in over months to years.

Water bath PUVA
The most recent model in phototherapy is water bath PUVA, in which the patient lies in a bath tub containing psoralen water for 15 min so that the drug gets absorbed on the skin and then goes for light therapy. This kind of therapy is especially beneficial in children for whom oral medicines are not safe.
Another method of psoralen treatment, used rarely for pediatric patients with small, scattered vitiligo patches, involves the application of a very dilute solution of the drug directly to the affected skin area. This is then exposed to sunlight. Such topical treatment makes a person very liable to severe burn and blisters following too much sun exposure whereas water bath PUVA has the advantages of being done at home, and does not damage the entire skin surface.

Disseminated scleroderma of a Japanese patient successfully treated with bath PUVA photochemotherapy, 2001.

Narrow band UVB
Narrow band UVB therapy or TL-01 therapy is the latest in phototherapy for the treatment of vitiligo. The therapy is very safe and can be safely administered even to children.
Narrow band UVB light is at a wavelength of 311 nm, the faithful wavelength that vitiligo responds to best, and is safer than full spectrum UVB is.

Narrow-band UVB for the treatment of generalized vitiligo in

children, 2005.

The grafts will be implanted into perforations made at the recipient site using a biopsy punch under local anaesthesia. The grafted area will then be covered with petrolatum gauze or a transparent adhesive tape and secured with bandages to give compression and fixation for at least one week. The success rate of this technique depends upon the individual skin type. Difficult areas like lips can also be treated using this technique. Pigment spread occurs gradually after grafting within 1 month and full repigmentation can be achieved in 3–6 months.

Tissue grafts in vitiligo surgery — past, present

and future, 2009.

Split thickness skin grafts
This technique has a high success rate of 78–91%. After obtaining a split thickness skin graft using a dermatome it can be applied directly to the derma braded recipient area. Scar or keloid formation at the donor site is reported in 12% of the patients treated with split thickness grafts. As donor tissue is limited more than one split skin grafting session can be necessary.

Comparison of two surgical approaches for treating vitiligo: a preliminary study, 2002.

Suction blister grafts
Grafts are carefully removed with sharp scissors and forceps after harvesting the graft. This epidermal sheet is then grafted onto the denuded recipient site. The success rate is 73–88%. Pigment spread after epidermal blister grafting can be enhanced by pre operative radiation therapy of the donor site using PUVA. Temporary hyperpigmentation can be seen in the grafted sites in 2–65%.



Non cultured keratinocytes and melanocytes
Transplantation technique with a suspension of non cultured keratinocytes and melanocytes in the treatment of depigmented lesions is effective. Donor skin is obtained from the occipital area, the following day the epidermis of the donor skin can be separated from the dermis in vitro using fine forceps. After several procedures a cellular suspension is obtained. Liquid nitrogen is used to induce blisters in the recipient area.The cellular suspension from the donor site is injected into each blister at the recipient area after aspiration of the viscous blister fluid.
It is important not to separate keratinocytes from melanocytes before grafting because factors furnished by keratinocytes sustain melanocyte growth.


Transplantation of cultured melanocytes
Lerner et al., first described the use of cultured pure autologous human melanocytes. They explained pigment cells of a shave biopsy from normally pigmented skin in vitro with the addition of several growth factors and chemical media.

Transplantation of human melanocytes, 1987.

Stability in surgical repigmentation of vitiligo
Even after almost thirty years of implementing surgery in vitiligo, there seems to be little consensus among workers regarding the optimal required period of stability. It seems to be that even after grafting, the pigment spread from successive sessions of grafting can be unpredictable; perigraft spread of pigment may be minimal or absent and in some cases even depigmentation of grafts is noted.

Stability in vitiligo? What's that? 2009.

Autologous skin grafts
This type of skin grafting is often used for patients with small, stable patches of vitiligo (recipient sites). Normal unaffected skins from the thigh or buttocks area of a patient’s body (donor sites) were taken and fixed it to an area of vitiligo. The treated area responds almost 90% of the time, but may develop a cobblestone appearance, or a spotty pigmentation, or may fail to re-pigment at all.

Evolution and evaluation of autologous mini punch grafting in vitiligo, 2009..

Vitamin D analogues
Combination of PUVA (psoralen-sun therapy) and calcipotriol is highly effective and may be used for shortening the therapy with PUVA. Topical calcipotriol appeared to be an effective and well tolerated treatment for vitiligo and it can be safely used in conjunction with PUVA.

Combination of Puva sol and topical calcipotriol in

vitiligo, 1998.

It has been shown that patients with vitiligo have an extremely low catalase activity. Topical application of pseudocatalase (a low molecular weight inorganic complex of unknown formula with catalase activity) used in combination with short term UVB light exposure has been reported to show repigmentation. Complete repigmentation on the face and dorsum of the hands
appeared in 90% of those treated.

Topical calcipotriol as monotherapy and incombination with psoralen plus ultraviolet A in the treatment of vitiligo, 2001.

Herbal products:

Anti-vitiligo® (True Herbals, Lahore, Pakistan)
Anti-vitiligo® (True Herbals, Lahore, Pakistan) is a traditional herbal formulation which was effective both in disease of recent onset as well as long standing established cases. Formulation contains the following ingredients:

  • Psoralea corylifolia
    It is a rich source of naturally occurring psoralen. It sensitizes human skin to the tanning effect of UV and sun light. P. corylifolia has been traditionally used both orally as well as in the form of topical preparations. Oxidative stress is widely believed to be one of the likely causative factors in the initiation of white skin patches of vitiligo. Hence, the protective, anti-oxidative and anti stress properties of P. corylifolia may contribute to the improvement in the hypo-pigmented white skin patches of vitiligo.
  • Black cumin
    Seeds of Nigella sativa have an immunomodulatory as well as anti cancer effect, which is due to T cell and natural killer augmentation cell mediated immune responses.

Antivitiligo — Herbal treat for repigmentation of vitiligo.

  • Barberry root
    Barberry root or the root of Berberis vulgaris has been shown to possess antioxidant and cytoprotective properties.

Antivitiligo — Herbal treat for repigmentation of vitiligo.

  • Kalawalla® (American Life Style, New York, USA)
    Kalawalla® (American Life Style, New York, USA) is a herbal product that works as a natural immunomodulator with proven immunomodulating effect. The product contains Polypodium leucotomos standardized extracts. P. leucotomos is a fern plant extract that has been used in Europe to treat vitiligo for over 10 years with encouraging results. This extract can help to regulate the immune system bringing it to its healthiest, strongest and balanced levels. It's also be known to increase the lymphocyte levels and to regulate the CD4/CD8 ratios to their normal values. Repigmentation results can be seen within the first month of taking the product.


(Accessed on 12 June 2009).

The synthetic derivatives of piperine can stimulate pigmentation in the skin especially when combined with UVR treatment. The studies have compared the effects of piperine and its analogues tetrahydropiperine (THP), cyclohexyl analogue of piperine (CHP) and reduced CHP (rCHP) when applied to the skin of mice, either alone or followed by UV treatment. CHP did not show significant results while piperine, THP and rCHP did induce pigmentation in the skin. When used alone, the compounds stimulated pigmentation to an even, light brown color within six weeks. However, by accompanying the use of piperine or THP with UV, the skin became significantly darker, and within only seven weeks as compared to other treatments which take a year or so.

Gutierrez D, Writer S. Skin Pigment Disease Reversed with Piperine Nutrient From


vitiligo ceramide

"The hunt for natural skin whitening agents., 2009":

A glycosphingolipid-deficient melanoma culture was not pigmented and by transfection with ceramide glucosyltransferase, pigmentation could be restored.

Glycosphingolipids are required for sorting melanosomal proteins in the Golgi complex., 2001

We found that GM95 cells do not make melanin pigment because tyrosinase, the first and rate-limiting enzyme in melanin synthesis, was not targeted to melanosomes but accumulated in the Golgi complex.

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